CA1055528A - Alkylsulfonylphenoxypropanolamines - Google Patents
AlkylsulfonylphenoxypropanolaminesInfo
- Publication number
- CA1055528A CA1055528A CA221,803A CA221803A CA1055528A CA 1055528 A CA1055528 A CA 1055528A CA 221803 A CA221803 A CA 221803A CA 1055528 A CA1055528 A CA 1055528A
- Authority
- CA
- Canada
- Prior art keywords
- methylsulfonyl
- propanol
- acid addition
- pharmaceutically acceptable
- addition salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 claims abstract description 48
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 239000002253 acid Substances 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 28
- 231100000252 nontoxic Toxicity 0.000 claims description 24
- 230000003000 nontoxic effect Effects 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 13
- 239000007795 chemical reaction product Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 10
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 10
- -1 phenoxyisopropyl Chemical group 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- KGPGKOSHODHUSR-UHFFFAOYSA-N 3-methyl-4-methylsulfonylphenol Chemical compound CC1=CC(O)=CC=C1S(C)(=O)=O KGPGKOSHODHUSR-UHFFFAOYSA-N 0.000 claims description 6
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- 150000002989 phenols Chemical class 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- IKYFHRVPKIFGMH-UHFFFAOYSA-N 1-phenoxypropan-2-amine Chemical compound CC(N)COC1=CC=CC=C1 IKYFHRVPKIFGMH-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 4
- YDEYSUHFFPVVEU-UHFFFAOYSA-N 1-(5-methyl-2-methylsulfonylphenoxy)-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NCC(O)COC1=CC(C)=CC=C1S(C)(=O)=O YDEYSUHFFPVVEU-UHFFFAOYSA-N 0.000 claims 2
- KECCFSZFXLAGJS-UHFFFAOYSA-N 4-methylsulfonylphenol Chemical compound CS(=O)(=O)C1=CC=C(O)C=C1 KECCFSZFXLAGJS-UHFFFAOYSA-N 0.000 claims 2
- ZWPDLYUJFRYTKN-UHFFFAOYSA-N 1-(2-methyl-5-methylsulfonylphenoxy)-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NCC(O)COC1=CC(S(C)(=O)=O)=CC=C1C ZWPDLYUJFRYTKN-UHFFFAOYSA-N 0.000 claims 1
- ACPNTKLYQRFQJN-UHFFFAOYSA-N 1-(4-methylsulfonylphenoxy)-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NCC(O)COC1=CC=C(S(C)(=O)=O)C=C1 ACPNTKLYQRFQJN-UHFFFAOYSA-N 0.000 claims 1
- JVHYYNCSPAFJMI-UHFFFAOYSA-N 2-methyl-4-methylsulfonylphenol Chemical compound CC1=CC(S(C)(=O)=O)=CC=C1O JVHYYNCSPAFJMI-UHFFFAOYSA-N 0.000 claims 1
- ZWTZHHHSRDUVRT-UHFFFAOYSA-N 2-methylsulfonylphenol Chemical compound CS(=O)(=O)C1=CC=CC=C1O ZWTZHHHSRDUVRT-UHFFFAOYSA-N 0.000 claims 1
- 230000000903 blocking effect Effects 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 5
- 238000011282 treatment Methods 0.000 abstract description 4
- 208000019622 heart disease Diseases 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 14
- 150000003945 chlorohydrins Chemical class 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 230000036515 potency Effects 0.000 description 4
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000000674 adrenergic antagonist Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 230000002057 chronotropic effect Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000000297 inotrophic effect Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 150000002924 oxiranes Chemical class 0.000 description 2
- KHUXNRRPPZOJPT-UHFFFAOYSA-N phenoxy radical Chemical compound O=C1C=C[CH]C=C1 KHUXNRRPPZOJPT-UHFFFAOYSA-N 0.000 description 2
- 229960003712 propranolol Drugs 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BNIITVMZJJEYHV-UHFFFAOYSA-N 1-(2-methylsulfonylphenoxy)-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1S(C)(=O)=O BNIITVMZJJEYHV-UHFFFAOYSA-N 0.000 description 1
- SVRSFQXERGLUFF-UHFFFAOYSA-N 1-(5-methyl-2-methylsulfonylphenoxy)-3-[phenoxy(propan-2-yl)amino]propan-2-ol Chemical compound C=1C=CC=CC=1ON(C(C)C)CC(O)COC1=CC(C)=CC=C1S(C)(=O)=O SVRSFQXERGLUFF-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- JPPFLCUUYBYBGZ-UHFFFAOYSA-N 3-methyl-4-methylsulfonylphenol;sodium Chemical compound [Na].CC1=CC(O)=CC=C1S(C)(=O)=O JPPFLCUUYBYBGZ-UHFFFAOYSA-N 0.000 description 1
- ROLMZTIHUMKEAI-UHFFFAOYSA-N 4,5-difluoro-2-hydroxybenzonitrile Chemical compound OC1=CC(F)=C(F)C=C1C#N ROLMZTIHUMKEAI-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 240000001546 Byrsonima crassifolia Species 0.000 description 1
- 235000003197 Byrsonima crassifolia Nutrition 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- PXTOZBMKFACODY-UHFFFAOYSA-N Cl.C1(CCCC1)NCC(COC=1C=C(C=CC1S(=O)(=O)C)C)O Chemical compound Cl.C1(CCCC1)NCC(COC=1C=C(C=CC1S(=O)(=O)C)C)O PXTOZBMKFACODY-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000007443 Neurasthenia Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003182 bronchodilatating effect Effects 0.000 description 1
- UVZGOOXAARJPHD-UHFFFAOYSA-N butan-2-one;methanol Chemical compound OC.CCC(C)=O UVZGOOXAARJPHD-UHFFFAOYSA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000003944 halohydrins Chemical class 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001990 intravenous administration Methods 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
- LYBKPDDZTNUNNM-UHFFFAOYSA-N isopropylbenzylamine Chemical compound CC(C)NCC1=CC=CC=C1 LYBKPDDZTNUNNM-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- PEIJPMBOGRPKQJ-UHFFFAOYSA-N n-benzylpropan-2-amine;hydrochloride Chemical compound Cl.CC(C)NCC1=CC=CC=C1 PEIJPMBOGRPKQJ-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
- 239000000312 peanut oil Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- RAIYODFGMLZUDF-UHFFFAOYSA-N piperidin-1-ium;acetate Chemical compound CC([O-])=O.C1CC[NH2+]CC1 RAIYODFGMLZUDF-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (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)
Abstract
ALKYLSULFONYLPHENOXYPROPANOLAMINES
Abstract of the Disclosure A new class of phenoxypropanolamine alkylsulfonyl derivatives and methods for their preparation are described. The new compounds possess cardioselective .beta.-adrenergic blocking properties and are useful in the treatment of heart diseases. l-(Isopropylamino)-3-[4-(methyl-sulfonyl)-m-tolyloxy]-2-propanol is representative of the compounds disclosed.
Abstract of the Disclosure A new class of phenoxypropanolamine alkylsulfonyl derivatives and methods for their preparation are described. The new compounds possess cardioselective .beta.-adrenergic blocking properties and are useful in the treatment of heart diseases. l-(Isopropylamino)-3-[4-(methyl-sulfonyl)-m-tolyloxy]-2-propanol is representative of the compounds disclosed.
Description
1SSsz8 ALKYLSULFONYLPHENOXYPROPANOLAMINES
Background of the Invention ; This invention pertains to carbon compounds having drug and blo-affecting properties and in particular to alkylsulfonylphenoxypropyl-amine B-adrenergic blocking agents.
According to present belief, there are at least two sub-groups of ~-adrenergic receptors. Bl-Receptors are thought to mediate cardiac ; ~timulation and ~2-recePtors sre supposed to mediate relaxa~ion of smooth muscle responsible for vasodilating and bronchodilating effects;
refer to C. G. Dollery, et al., Clinical Pharmacology and Therapeu~icc, 10(6), 765-799 (1969); D. Jack, The Pharmaceutical Journal, 237-240 (August 29, 1970). Various derivatives of phenoxypropanolamines reportedly ~tl have ~-adrenergic blocking properties and there can be mentioned as representative of the state of the art, Netherlands Patent 69,0770C
(Derwent Basic No. 41,107) and Belgium Patent 762629 (Derwent Basic No.
55533S-B). The Netherlands patent, while generically disclosing pharmaceutical prepara~ions containing a variety of substituted (including alkylsulfonyl) phenoxypropanolamines, does not specifically disclose the lass of alkylsulfonylphenoxypropanolamines of the present invention. The Belgium patent 762629 describes a group of alkylsulfollylalkylplle-loxyprop.lno-lamine derivatives.
Summar~ of the Invention This invention relates generally to novel alkylsulfonylphenoxy-propylamines which possess cardioselective ~l-adrenergic blocking properties.
More particularly, the present invention provides a process for preparing a compound selected from the group consisting of alkylsulfonylphenoxyprop~nol-amines characterized by general structural Formula I and non-toxic pharmaceutically acceptable acid addition salts thereof.
~ O-CH2CHCHlNH-Rl R~ ~ R2 OH Formula I
R~
In Formula I, Rl represents a branched chain alkyl radical of 3 or 4 carbon atoms inclusive; phenoxyisopropyl or cycloalkyl of 3 to 6 carbon atoms inclusive; R2 represents hydrogen, lower alkyl of 1 to 4 carbon atoms inclusive; or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive; R3 represents hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive; and R4 represents hydrogen or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive.
The compounds of Formula I are further defined in tllat one and only one of R2 or R4 is lower alkylsulfonyl.
Formulas Ia and Ib below and non-toxic pharmaceutically acceptable acid addition salts thereof further characterize the compounds of the invention.
~ O-CH C}3CH,~3-R~ ~ O-CH2CHCH,~3-R, R, Formula Ia Formula Ib _; ~ - 2 -105SS~
In Formulas Ia and Ib, R i8 lower alkyl, R, and R, are as defined above and only one of R, ls lower alkyl.
By the term "lower alkyl" as used herein, lt i8 meant that the carbon chain comprising thls group lnclute both straight and branched chsln carbon radlcals of 1 to 4 carbon atoms inclusive. Exemplary of these carbon chain radicals are methyl, ethyl, propyl, isopropyl, l-butyl, l-methylpropyl, 2-methylpropyl, and tert.-butyl. As used herein, the term "cycloalkyl" of 3 to 6 carbon atoms inclusive is intended to refer to any of the cycloalkyl radicals of 3 to 6 carbon atoms inclusive such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term "non-toxic pharmaceutically acceptable acid addition 6alts" as used herein refers to salts of compounds of Formula I formed with a variety of relatively non-toxic inorganic or organic acids such as acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzenesulfonic, p-toluenesulfonic, ant related acids. The acid addition salts of this lnvention are prepared in conventional manner by treating a solution or suspension of the free base in a reaction inert organic solvent with the desired acid and then recovering the salts which form by concentration under reduced pressure or by crystallization techniques.
Inasmuch as the compounds of general Formula I possess at least one asymmetric carbon atom, the present invention also includes all possible optically active forms and racemic mixture of the compounds. Resolution of the racemlc mixtures to provlde the optically active isomers of the compounds of Formula I i8 carried out by conventional methods relating to resolution of phenethanolamines, for example, by salt formation with an optically ~iiSS5~8 active acit such 88 d-tartaric, tibenzoyl-d-tart~ric, d-camphorsulfonic, d-mantelic, etc., followed by fractional crystallization.
According to the present inventlon, the alkylsulfonylphenoxyamines of Formula I are preparet by a process which comprises reactlng a phenol derivative of Formula II
R4 ~ R~ Formula II
wherein R2, R~ ant R4 have meanings hereinabove described with an epihalohytrin of Formula III
\ ~ Formula III
wherein X signifies halogen, prsferably chlorine or bromine, and condenslng the eplhalohytrln reaction product wlth an amine of Formula IV
H~N-Rl Formula IV
wherein Rl has the meanlng hereinabove tescribet; whereafter, if tesiret, the Formula I protuct in free base form is reactet with an acid in order to form an acit addition salt.
The Formula II alkylsulfonylphenols are obtainet by oxitizing the corresponding alkylthlophenols with hytrogen peroxide in accordance with standard procedures, refer to R. B. Wagner and H. D. Zook, Synthetlc Organlc Chemlstry, page 801 (1953 Wlley).
Slnce an epihalohydrin molecule of Formula III has two reactive positions, reaction with a phenol of Formula II may yield a mixture of Formulas V and VI reaction products wherein R2, R3, R4, and X are as 1~555;28 defined above.
~ OC~IlCHCH~-X , , ~ OCH2CH-CH2 R4 ~ R~ OH R~ ~ d R, R, Formula V Formula VI
During the further course of the process, however, the two possible intermediates of Formula V and Formula VI on condensation with a Formula IV amine yield the same flnal product of the present invention.
Consequently, it is not necessary to effect a separation of any mixtures of lntermediates of Formulas V and VI which may result from interaction of a Formula II phenol with a Formula III apihalohydrin.
If desired, the epihalohydrin reaction product may be taken up ln an inert solvent such as chloroform and shaken with excess concentrated hydrochloric acld to convert epoxides of Formula VI into the corresponding Formula V sulfonylphenoxyhalohydrin. Conversely, if desired, the halohydrins of Formula V may be converted to the corresponding Formula VI
epoxide ln conventional manner, e.g., by treatment with base according to the procedure of O. Stephenson, J. Chem. Soc., 1574 (1954).
~he interaction of Formula II phenols with Formula III epihalo-hydrins i9 carried out employing an excess of the epihalohydrin and a catalytic amount of a base catalyst such as N-benzylisopropylamine hydrochloride or pyrrolidine base. Other catalysts such as pyridine, piperidine, piperidine acetate, or piperidine hydrochloride are about equally effective.
Interaction of Formula II phenols with Formula III epihalohydrins can also be effected in basic med~um, e.g., sodium hydroxide, at ambient 1(3 SS528 temperatures aceording to the procedure of Y. M. Beasley, et al., J. Pharm.
Pharmacol., 10, 47-59 (1958).
Contensatlon of the epihalohydrin reaction produet with a Formula IV amine is carried out preferably in an organic solvent lnert under the reaction conditions, e.g., ethanol, toluene, dioxane.
The eondensation can also be effected in the absence of a reaction solvent by using exeess amine such as isopropylamine or tert.-butylamine.
Aecording to a further feature of the present invention, an alternate method for producing compounds of Formula I comprises reacting a Formula II phenol wlth a compound of Formula VII in alkaline medium CH,-/CH-CH,-N-R, Formula VII
~ R, to provide a compound of Formula VIII
OH
~ O-CH,CHCH,N-R, R ~ R~ R, Formula VIII
R, wherein R" R" R, and R4 have the same meaning as in Formula I and R~ stands for a hydrogenolysable radical such as benzyl or benzhydryl;
and converting said compound of Formula VIII to an alkylsulfonylphenoxy-amine of Formula I. Removal of the hydrogenolysable blocking group maybe effected by catalytic hydrogenation, for example by hydroger.ation in the presence of palladium-on-charcoal catalyst, in an inert solvent, e.g., ethanol or aqueou~ ethanol.
The co~pounds of Formula VII may be obtained according to known methods. For example, l-C(N-benzyl)isopropylamino]-2,3-epoxypropane is obtained by reactlon of N-benzylisopropylamine and epichlorohydrin in alkaline medium (e.g., aqueous potassium hydroxide) as described by L. Vllla, et al., Farmaco., Ed. Sci., 24(3), 349-357 (1969).
A preferred group of alkylsulfonylphenoxyamines of the preeent invention comprises compounds of Formula IX
~O-CH2CHCH~NH-Rl ~ OH Formula IX
R"
R, wherein specific values for Rl, R~ and R4 are those defined above.
Speclflc alkylsulfonylphenoxyamlnes whlch fall wlthln the scope of the preferred group are, for example, l-(lsopropylamlno-3-C4-(methylsulfonyl)-m-tolyloxy]-2-propanol, 1-(tert.-butylamlno)-3-C4-(methylsulfonyl)-m-tolyloxy]-2-propanol, l-(lsopropylamino)-3-[4-(methylsulfonyl)phenoxy]-2-propanol, 1- ~ ,--butylamino)-3-C4-(methylsulfonyl)phenoxy]-2-propanol.
A stlll further preferred group of compound~ of Formula rx are those whereln R, i9 limited to isopropyl and tert.-butyl radicals and R4 is limited to the methylsulfonyl radical.
Cardioselective ~l-adrenergic blocking activity of the
Background of the Invention ; This invention pertains to carbon compounds having drug and blo-affecting properties and in particular to alkylsulfonylphenoxypropyl-amine B-adrenergic blocking agents.
According to present belief, there are at least two sub-groups of ~-adrenergic receptors. Bl-Receptors are thought to mediate cardiac ; ~timulation and ~2-recePtors sre supposed to mediate relaxa~ion of smooth muscle responsible for vasodilating and bronchodilating effects;
refer to C. G. Dollery, et al., Clinical Pharmacology and Therapeu~icc, 10(6), 765-799 (1969); D. Jack, The Pharmaceutical Journal, 237-240 (August 29, 1970). Various derivatives of phenoxypropanolamines reportedly ~tl have ~-adrenergic blocking properties and there can be mentioned as representative of the state of the art, Netherlands Patent 69,0770C
(Derwent Basic No. 41,107) and Belgium Patent 762629 (Derwent Basic No.
55533S-B). The Netherlands patent, while generically disclosing pharmaceutical prepara~ions containing a variety of substituted (including alkylsulfonyl) phenoxypropanolamines, does not specifically disclose the lass of alkylsulfonylphenoxypropanolamines of the present invention. The Belgium patent 762629 describes a group of alkylsulfollylalkylplle-loxyprop.lno-lamine derivatives.
Summar~ of the Invention This invention relates generally to novel alkylsulfonylphenoxy-propylamines which possess cardioselective ~l-adrenergic blocking properties.
More particularly, the present invention provides a process for preparing a compound selected from the group consisting of alkylsulfonylphenoxyprop~nol-amines characterized by general structural Formula I and non-toxic pharmaceutically acceptable acid addition salts thereof.
~ O-CH2CHCHlNH-Rl R~ ~ R2 OH Formula I
R~
In Formula I, Rl represents a branched chain alkyl radical of 3 or 4 carbon atoms inclusive; phenoxyisopropyl or cycloalkyl of 3 to 6 carbon atoms inclusive; R2 represents hydrogen, lower alkyl of 1 to 4 carbon atoms inclusive; or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive; R3 represents hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive; and R4 represents hydrogen or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive.
The compounds of Formula I are further defined in tllat one and only one of R2 or R4 is lower alkylsulfonyl.
Formulas Ia and Ib below and non-toxic pharmaceutically acceptable acid addition salts thereof further characterize the compounds of the invention.
~ O-CH C}3CH,~3-R~ ~ O-CH2CHCH,~3-R, R, Formula Ia Formula Ib _; ~ - 2 -105SS~
In Formulas Ia and Ib, R i8 lower alkyl, R, and R, are as defined above and only one of R, ls lower alkyl.
By the term "lower alkyl" as used herein, lt i8 meant that the carbon chain comprising thls group lnclute both straight and branched chsln carbon radlcals of 1 to 4 carbon atoms inclusive. Exemplary of these carbon chain radicals are methyl, ethyl, propyl, isopropyl, l-butyl, l-methylpropyl, 2-methylpropyl, and tert.-butyl. As used herein, the term "cycloalkyl" of 3 to 6 carbon atoms inclusive is intended to refer to any of the cycloalkyl radicals of 3 to 6 carbon atoms inclusive such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term "non-toxic pharmaceutically acceptable acid addition 6alts" as used herein refers to salts of compounds of Formula I formed with a variety of relatively non-toxic inorganic or organic acids such as acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzenesulfonic, p-toluenesulfonic, ant related acids. The acid addition salts of this lnvention are prepared in conventional manner by treating a solution or suspension of the free base in a reaction inert organic solvent with the desired acid and then recovering the salts which form by concentration under reduced pressure or by crystallization techniques.
Inasmuch as the compounds of general Formula I possess at least one asymmetric carbon atom, the present invention also includes all possible optically active forms and racemic mixture of the compounds. Resolution of the racemlc mixtures to provlde the optically active isomers of the compounds of Formula I i8 carried out by conventional methods relating to resolution of phenethanolamines, for example, by salt formation with an optically ~iiSS5~8 active acit such 88 d-tartaric, tibenzoyl-d-tart~ric, d-camphorsulfonic, d-mantelic, etc., followed by fractional crystallization.
According to the present inventlon, the alkylsulfonylphenoxyamines of Formula I are preparet by a process which comprises reactlng a phenol derivative of Formula II
R4 ~ R~ Formula II
wherein R2, R~ ant R4 have meanings hereinabove described with an epihalohytrin of Formula III
\ ~ Formula III
wherein X signifies halogen, prsferably chlorine or bromine, and condenslng the eplhalohytrln reaction product wlth an amine of Formula IV
H~N-Rl Formula IV
wherein Rl has the meanlng hereinabove tescribet; whereafter, if tesiret, the Formula I protuct in free base form is reactet with an acid in order to form an acit addition salt.
The Formula II alkylsulfonylphenols are obtainet by oxitizing the corresponding alkylthlophenols with hytrogen peroxide in accordance with standard procedures, refer to R. B. Wagner and H. D. Zook, Synthetlc Organlc Chemlstry, page 801 (1953 Wlley).
Slnce an epihalohydrin molecule of Formula III has two reactive positions, reaction with a phenol of Formula II may yield a mixture of Formulas V and VI reaction products wherein R2, R3, R4, and X are as 1~555;28 defined above.
~ OC~IlCHCH~-X , , ~ OCH2CH-CH2 R4 ~ R~ OH R~ ~ d R, R, Formula V Formula VI
During the further course of the process, however, the two possible intermediates of Formula V and Formula VI on condensation with a Formula IV amine yield the same flnal product of the present invention.
Consequently, it is not necessary to effect a separation of any mixtures of lntermediates of Formulas V and VI which may result from interaction of a Formula II phenol with a Formula III apihalohydrin.
If desired, the epihalohydrin reaction product may be taken up ln an inert solvent such as chloroform and shaken with excess concentrated hydrochloric acld to convert epoxides of Formula VI into the corresponding Formula V sulfonylphenoxyhalohydrin. Conversely, if desired, the halohydrins of Formula V may be converted to the corresponding Formula VI
epoxide ln conventional manner, e.g., by treatment with base according to the procedure of O. Stephenson, J. Chem. Soc., 1574 (1954).
~he interaction of Formula II phenols with Formula III epihalo-hydrins i9 carried out employing an excess of the epihalohydrin and a catalytic amount of a base catalyst such as N-benzylisopropylamine hydrochloride or pyrrolidine base. Other catalysts such as pyridine, piperidine, piperidine acetate, or piperidine hydrochloride are about equally effective.
Interaction of Formula II phenols with Formula III epihalohydrins can also be effected in basic med~um, e.g., sodium hydroxide, at ambient 1(3 SS528 temperatures aceording to the procedure of Y. M. Beasley, et al., J. Pharm.
Pharmacol., 10, 47-59 (1958).
Contensatlon of the epihalohydrin reaction produet with a Formula IV amine is carried out preferably in an organic solvent lnert under the reaction conditions, e.g., ethanol, toluene, dioxane.
The eondensation can also be effected in the absence of a reaction solvent by using exeess amine such as isopropylamine or tert.-butylamine.
Aecording to a further feature of the present invention, an alternate method for producing compounds of Formula I comprises reacting a Formula II phenol wlth a compound of Formula VII in alkaline medium CH,-/CH-CH,-N-R, Formula VII
~ R, to provide a compound of Formula VIII
OH
~ O-CH,CHCH,N-R, R ~ R~ R, Formula VIII
R, wherein R" R" R, and R4 have the same meaning as in Formula I and R~ stands for a hydrogenolysable radical such as benzyl or benzhydryl;
and converting said compound of Formula VIII to an alkylsulfonylphenoxy-amine of Formula I. Removal of the hydrogenolysable blocking group maybe effected by catalytic hydrogenation, for example by hydroger.ation in the presence of palladium-on-charcoal catalyst, in an inert solvent, e.g., ethanol or aqueou~ ethanol.
The co~pounds of Formula VII may be obtained according to known methods. For example, l-C(N-benzyl)isopropylamino]-2,3-epoxypropane is obtained by reactlon of N-benzylisopropylamine and epichlorohydrin in alkaline medium (e.g., aqueous potassium hydroxide) as described by L. Vllla, et al., Farmaco., Ed. Sci., 24(3), 349-357 (1969).
A preferred group of alkylsulfonylphenoxyamines of the preeent invention comprises compounds of Formula IX
~O-CH2CHCH~NH-Rl ~ OH Formula IX
R"
R, wherein specific values for Rl, R~ and R4 are those defined above.
Speclflc alkylsulfonylphenoxyamlnes whlch fall wlthln the scope of the preferred group are, for example, l-(lsopropylamlno-3-C4-(methylsulfonyl)-m-tolyloxy]-2-propanol, 1-(tert.-butylamlno)-3-C4-(methylsulfonyl)-m-tolyloxy]-2-propanol, l-(lsopropylamino)-3-[4-(methylsulfonyl)phenoxy]-2-propanol, 1- ~ ,--butylamino)-3-C4-(methylsulfonyl)phenoxy]-2-propanol.
A stlll further preferred group of compound~ of Formula rx are those whereln R, i9 limited to isopropyl and tert.-butyl radicals and R4 is limited to the methylsulfonyl radical.
Cardioselective ~l-adrenergic blocking activity of the
2~ compounds of the present lnvention can be assessed ln standsrd in vitro pharmacologlcal tests systems such as the spontaneously beating rabbit atrlal preparation and the guinea pig tracheal preparation. The following Table 1, which compares potency ratios of 1-(isopropylamino)-3-C4-(methyl-sulfonyl)-3-tolyloxy]-2-propanol hydrochloride and the clinically useful B-adrenergic receptor antagonist propranolol, is illustrative of the cartlac selectivlty of the compounds of the present invention.
Table 1.
A Comparison of ~-Adrenergic Receptor Antagonlst Molar Potencies Determined in Rabbit Atrial and Guinea Pi~ Tracheal Preparations Cardio-selectivity Potency Ratio Potency Ratio Ratio:
ComPound Atria Trachea Atria/Trachea 10 Propranolol l-(Isopropylamino)-3-C4-(methylsulfonyl)-3-tolyloxy]-2-propanol hydrochloride 0~37 0.01 37 A preferred compound of this invention, l-(isopropylamino)-3-[4-(methylsulfonyl)-3-tolyloxy]-2-propanol hydrochloride, inhibits lncreased contractile force and heart rate in the anesthetized dog $ntuced by a standard challenge dose of 0.2 mcg./kg. (intravenous) of lsoproterenol when intravenously administered at an ED,o of 0.71 mg./kg.
body weight and 2.02 mg./kg. body weight respectively.
Another important property of the compounds of the inventlon is that they have llttle toxicity in mammals. With l-(isopropylamino)-3-C4-(methylsulfonyl)-m-tolyloxy]-2-propanol hydrochloride, for lnstance, oral LD,o values in the mouse and rat are 1504 and 1792 mg./kg. body weight respectively; the intraper~toneal LD,o value ~n the mouse is 339 mg./kg. body weight.
Substances of the present invention represented by Formula I
are novel compositions useful in the prophylaxis and treatment of heart diseases such as angina pectoris, cardiac arrhythmia~, cardiovascular anxiety (neurasthenia) and hypertension. The Formula I alkylsulfonyl-phenoxyamines are partlcularly of value in the treatment of heart dlseases 1055S2~3 because they possess selective ~-adrenergic blocking activlty. Compounds exhiblting thls selective action preferentially block cardiac inotropic and chronotropic actlon of catecholamines such as epinephrine and ~soproterenol without greatly affecting the ~l-adrenergic receptors in bronchial and vascular muscle.
For the purpose of exerting a cardioselective ~l-adrenergic blocking effect, the alkylsulfonylphenoxypropanolamines of Formula I
may be administered orally or parenterally to a mammal in doses ranging from 0.05 mg. per kilogram body weight to 20 mg. per kilogram body weight.
Preferably, the compoundQ of the inventlon are administered to a mammal ln an effective amount sufficient to reduce the inotropic, chronotropic effect of ~-adrenergic agonists withouth appreciably affecting the ~-adrenergic receptors in the mammalian smooth muscle tissue.
The alkylsulfonylphenoxypropanolamines of Formula I may be compoundet and formulated with organic or inorganic solid materials or liqulds which are pharmaceutically acceptable carriers to provide pharmaceutical compositlons of unit dosage form suitable for administration to mammals. Phsrmaceutlcal compositions may take the form of tablets, capsules, powder, granules,~suspensions, solutions and the like. Suitable pharmaceutical carriers comprise both solids and liquids such as corn starch, lactose, calcium phosphate, stearic acid, polyethyleneglycol, water, sesame seed oil, peanut oil, propyleneglycol, and so for.h.
Standard formulating procedures are employed to prepare the pharmaceutical compositions.
The following examples illustrate the preparation of specific compounds having ~-adrenergic cardioselective blocking activlty and should not be construed as a limitation of the invention.
The nuclear magnetic spectral data reported herein includes the chemical shift6 (~) In parts per million, the multiplicity for that shift ~ncludlng the coupling constant (Hz = J value) when appropriate, and the relative area under the curve for each chemical shift which corresponds to the number of protons. Multiplicity symbols are: s, single;; bs, broad slnglet; d, doublet; and m, multiplet. Tetramethylsilane was used as the internal reference.
Example 1 (a) A mixture of 4-(methylsulfonyl)-m-cresol (18.6 g., 0.1 mole), epichlorohydrin (60 g., 0.65 mole) and 0.6 g. of pyrrolidine iB heated on a steam bath for 12 hr. Excess epichlorohydrin is removed under reduced pressure, the resulting chlorohydrin derivative taken up in 50 ml. of absolute ethanol and filtered through diatomaceous earth.
Isopropylamine (50 g., 0.85 mole) and 0.1 g. of potassium iodide are added to the ethanol filtrat~ of the epichlorohydrin derivative and the mixture iB refluxed for 18 hr. and filtered. Concentration of the filtrate under reduced pressure affords a residue which is taken up in 70 ml. of lN
hydrochloric acid and 300 ml. of absolute ethanol. Distillables are removed under reduced pressure and the resulting residue stirred with ether to provide solid crude product. Crystallization of the crude product from butanone-methanol and again from 95% ethanol-ether, affords l-(ISOPROPYIA~IINO)-3{ 4-(~THYLSUnFONYL)-m-TOLYLOXY]-2-PROP~NOL HYDROCHLORIDE, m.p. 177.0-179.0C. (corr.) i3 a 62~ overall yield. A sample, m.p.
176.0-178.0C. (corr), analyzed as follows.
Analysis. Calcd. for C,4H~,NO4-HCl: C, 49.77; H, 7.16;
N, 4.15. Found: C, 49.72; H, 7.16; N, 4.08.
Nuclear Magnetic Res~nance, DMSO-d 6, ~ (ppm): 1.28 Cd, 6.5 Hz, 6H~; 2.58 [s, 3H]; 3.11 [s, 3H]; 3.13 [m, 3H]; 4.11 ~m, 3H]; 7.01 Cm, 2H];
7-77 Cd, 9.2 Hz, lH~; 8.9 [bs, 2H].
(b) A modificatlon of the procedure for preparing l-(isopropyl-amino)-3-C4-(methyl3ulfonyl)-m-tolyloxy~-2-propanol employing aqueous sodlum hydroxlde as the reaction medium follows. Epichlorohydrin (37 g., 0.4 mole) is atded portionwise in 5 min. to a solution of 4-(methylsulfonyl)-m-cresol (0.2 mole) and sodium hydroxide (13 g., 0.32 mole) in 250 ml. of water at 30C. Stirring is continued for 24 hr. and the final pH of the solution is 8-8.5. The reaction mixture extracted with two 250 ml. portions of chloroform, the chloroform extract dried over sodium carbonate, filtered and the filtrate concentrated under reduced pressure provides the crude epichlorohydrin terivative. The epichlorohydrin derivative is taken up ln 150 ml. of ethanol and trested with lsopropylamlne (17 g., 0.286 mole) ln 20 ml. of water. After stirring for 10 min., the mixture i8 refluxed for 4 hr. and distillables removed under reduced pressure. The residue taken up in ethanol and acidified with ethanolic hydrogen chloride affords 1-(ISOPROPYI~IINO)-3-L4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL HYDROCHLORIDE.
(c) A further modi~icatlon of the procedure for preparing l-(lsopropylamlno)-3-C4-(methylsulfonyl)-m-tolyloxy]-2-propanol employing an eplhalohydrin derivatlve of Formula VII containing a hydrogenolyæiable blocking group f ollows; l-C (N-Benzyl)isopropylamino]-2,3-epoxypropane 18 reacted wlth 4-(methylsulfonyl)-m-cresol sodium salt in ethanol to provlde l-C(N-benzyl)isopropylamino]-3- 4-(methylsulfonyl)-m-tolyloxy -2-propanol.
The reaction mixture is filtered, acidified with ethanolic hydrogen chloride and the benzyl bloc~ing group removed by catalytic hydrogenation employing palladium-on-charcoal catalyst. The catalyst ls collected and the filtrate concentrated to provide l-(ISOPROPYL-AMINO)-3-C4-(METHYLSULFONYL)-m-TOLYLOXY~-2-PROPANOL HYDROCHLORIDE.
1~5552~
Example 2.- Reac~ion of the chlorohydrin derivative of 4-(methylsulfonyl)-m-cresol with tert.-butylamine according to the procedure of Example 1 ta) affords l-(tert.-BU m ~YINO)-3-C4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL HYDROCHLORIDE, m.p. 175.0-176.0C. (resolidifying and remelting at 197.0C.)(corr.)., from acetonitrile.
Analysis. Calcd. for C,5H~NO4S-HCl: C, 51.20; H, 7.45; N, 3.98.
Found: C, 50.99; H, 7.72; N, 4.20.
Nuclear Magnetic Resonance, DMSO-d6, ~(ppm): 1.31 Cs, 9H];
2.59 [8, 3H]; 3.02 [m, 2H]; 3.11 C8, 3H]; 4.10 Cm, 3H]; 6.97 Cm, 2H];
7-75 Cd, 9.5 Hz, lH]; 8.7 Cbs, 2H].
Example 3.- Reaction of the chlorohydrin derivative of 4-(metnylsulfonyl)phenol with isopropylamine according to the procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-C4-(METHYLSULFONYL)PHENOXY]-2-PROPANOL HYDROCHLORIDE, m.p. 193.0-195.0C., from ethanol.
Analysis. Calcd. for Cl,H2,NO4S-HCl: C, 48.22; H, 6.85;
N, 4.32. Found: C, 48.00; H, 7.02; N, 4.25.
Nuclear Magnetic Resonance, DMSO-d6, ~(ppm): 1.28 Cd, 6.5 Hz, 6H]; 3.12 Cm, 3H]; 3.14 Cs, 3H]; 4.13 Cm, 3H]; 5.91 Cd, 4.2 Hz, lH];
7.13 Cm, 2H]; 7.80 Cm, 2H]; 8.9 Cbs, 2H].
~ -- Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)-o-cresol with isopropylamine sccording to the proc~dure of Example 1 (a) affords 1-(ISOPROPYLAMINO~-3-C4-(METHYLSULFONYL)-o-TOLYLOXY]-2-PRQPANOL as the free base, m.p. 118.0-120.0C., from butanone.
Analysis. Calcd. for Cl4H~9NO4S: C, 55.79; H, 7.69; N, 4.65.
Found: C, 56.00; H, 7.68; N, 4.42.
~uclear Magnetic Resonance, CDCl" ~(ppm): 1.10 Cd, 6.4 Hz, 6H]; 2.27 Cs, 3H~; 2.50 [bs, 2H]; 2.85 [m, 3H]; 2.99 [s, 3H]; 4.11 Cm, 3H];
6.86 Cd, 9.3 Hz, lH~; 7.65 Cm, 2P.].
Example 5.- Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)phenol with tert.-butylamine according to the procedure of Example 1 (a) affords 1-(tert.-BUTYLAMINO)-3-[4-(METHYLSULFONYL)PHENOXY]-2-PROPANOL, m.p. 221.0 - 223.0C. (corr.) Analysis. Calcd. for C H NO S.HCl: C, 49.77; H, 7.16; N, 4.15.
Found: C, 50.10; H, 7.33; N, 4.00.
Example 6.- Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)-m-cresol with cyclopropylamine according to the procedure of Example l (a) affords l-(CYCLOPROPYLAMINO)-3-[4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL, m.p. 144.5 - 147.5C. (corr.) Analysis- Calcd. for C14H21NO4S.HCl: C, 50.07; H, 6.60; N, 4.17.
Found: C, 50.23; H, 6.76; N, 4.02.
Example 7.- Reaction of chlorohydrin derivative of 4-(methylsulfonyl)-m-cresol with phenoxyisopropylamine according to the procedure of Example 1 (a) affords 1-(PHENOXYISOPROPYLAMINO)-3-[4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL, m.p. 143.5 - 147.5C. (corr.) Analysis- Calcd- for C20H27NO5S: C, 61.05; H, 6.92; N, 3.56.
Found: C, 61.12; H, 7.14; N. 3.32.
Example 8.- Reaction of the chlorohydrin derivative of 2-(methylsulfonyl)phenol with isopropylamine according to the procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-[2-(METHYLSULFONYL)PHENOXY]-2-PROPANOL, m.p. 187.5 - 189.5C. (corr.) Analysis- Calcd- for C13H21NO4S.HCl: C, 48.22; H, 6.85; N, 4.32.
Found: C, 48.19; H, 7.05; N, 4.37.
Example 9.- Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)-m-cresol with cyclopentylamine according to the procedure of Example 1 (a) affords 1-(CYCLOPENTYLAMINO)-3-[4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL HYDROCHLORIDE, m.p. 183.0 - 185.0C. (corr.) Analysis. Calcd. for Cl6H25NO4S HCl: C, 52.81; H, 7.20; N, 3.85-Found: C, 53.04; H, 7.37; N, 3.69.
Nuclear Magnetic Resonance, DMSO-d6, ~(ppm); 1.70 [m, 9H]; 2.58 [s, 3H]; 3,12 [s, 3H]; 3.15 [m, 3H]; 4.10 Lm, 3H]; 5.84 [bs, lH]; 6.94 [m, 2H]; 7.76 [d, 9.5 Hz, lH]; 9.0 [bs, 2H].
Example 10.- Reaction of the chlorohydrin derivative of 4-(sec.-butylsulfonyl)phenol with isopropylamine according to the ..~
procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-[4-(sec.-BUTYLSULFONYL)P}IENOXY]-2-PROPANOL.
Example 11.- Reaction of the chlorohydrin derivative of 4-(lsopropylsulfonyl)-m-cresol with tert.-butylamine according to the procedure of Example 1 (a) affords 1-(tert.-BUTYLAMINO)-3-C4-(ISOPROPYLSULFONYL)-m-TOLYLOXY~-2-PROPANOL.
Example 12.- Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)-3-isopropylphenol with isopropylamine according to the procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-C4-(METHYLSULFONYL)-3-ISOPROPYLPHENOXY]-2-PROPANOL.
Table 1.
A Comparison of ~-Adrenergic Receptor Antagonlst Molar Potencies Determined in Rabbit Atrial and Guinea Pi~ Tracheal Preparations Cardio-selectivity Potency Ratio Potency Ratio Ratio:
ComPound Atria Trachea Atria/Trachea 10 Propranolol l-(Isopropylamino)-3-C4-(methylsulfonyl)-3-tolyloxy]-2-propanol hydrochloride 0~37 0.01 37 A preferred compound of this invention, l-(isopropylamino)-3-[4-(methylsulfonyl)-3-tolyloxy]-2-propanol hydrochloride, inhibits lncreased contractile force and heart rate in the anesthetized dog $ntuced by a standard challenge dose of 0.2 mcg./kg. (intravenous) of lsoproterenol when intravenously administered at an ED,o of 0.71 mg./kg.
body weight and 2.02 mg./kg. body weight respectively.
Another important property of the compounds of the inventlon is that they have llttle toxicity in mammals. With l-(isopropylamino)-3-C4-(methylsulfonyl)-m-tolyloxy]-2-propanol hydrochloride, for lnstance, oral LD,o values in the mouse and rat are 1504 and 1792 mg./kg. body weight respectively; the intraper~toneal LD,o value ~n the mouse is 339 mg./kg. body weight.
Substances of the present invention represented by Formula I
are novel compositions useful in the prophylaxis and treatment of heart diseases such as angina pectoris, cardiac arrhythmia~, cardiovascular anxiety (neurasthenia) and hypertension. The Formula I alkylsulfonyl-phenoxyamines are partlcularly of value in the treatment of heart dlseases 1055S2~3 because they possess selective ~-adrenergic blocking activlty. Compounds exhiblting thls selective action preferentially block cardiac inotropic and chronotropic actlon of catecholamines such as epinephrine and ~soproterenol without greatly affecting the ~l-adrenergic receptors in bronchial and vascular muscle.
For the purpose of exerting a cardioselective ~l-adrenergic blocking effect, the alkylsulfonylphenoxypropanolamines of Formula I
may be administered orally or parenterally to a mammal in doses ranging from 0.05 mg. per kilogram body weight to 20 mg. per kilogram body weight.
Preferably, the compoundQ of the inventlon are administered to a mammal ln an effective amount sufficient to reduce the inotropic, chronotropic effect of ~-adrenergic agonists withouth appreciably affecting the ~-adrenergic receptors in the mammalian smooth muscle tissue.
The alkylsulfonylphenoxypropanolamines of Formula I may be compoundet and formulated with organic or inorganic solid materials or liqulds which are pharmaceutically acceptable carriers to provide pharmaceutical compositlons of unit dosage form suitable for administration to mammals. Phsrmaceutlcal compositions may take the form of tablets, capsules, powder, granules,~suspensions, solutions and the like. Suitable pharmaceutical carriers comprise both solids and liquids such as corn starch, lactose, calcium phosphate, stearic acid, polyethyleneglycol, water, sesame seed oil, peanut oil, propyleneglycol, and so for.h.
Standard formulating procedures are employed to prepare the pharmaceutical compositions.
The following examples illustrate the preparation of specific compounds having ~-adrenergic cardioselective blocking activlty and should not be construed as a limitation of the invention.
The nuclear magnetic spectral data reported herein includes the chemical shift6 (~) In parts per million, the multiplicity for that shift ~ncludlng the coupling constant (Hz = J value) when appropriate, and the relative area under the curve for each chemical shift which corresponds to the number of protons. Multiplicity symbols are: s, single;; bs, broad slnglet; d, doublet; and m, multiplet. Tetramethylsilane was used as the internal reference.
Example 1 (a) A mixture of 4-(methylsulfonyl)-m-cresol (18.6 g., 0.1 mole), epichlorohydrin (60 g., 0.65 mole) and 0.6 g. of pyrrolidine iB heated on a steam bath for 12 hr. Excess epichlorohydrin is removed under reduced pressure, the resulting chlorohydrin derivative taken up in 50 ml. of absolute ethanol and filtered through diatomaceous earth.
Isopropylamine (50 g., 0.85 mole) and 0.1 g. of potassium iodide are added to the ethanol filtrat~ of the epichlorohydrin derivative and the mixture iB refluxed for 18 hr. and filtered. Concentration of the filtrate under reduced pressure affords a residue which is taken up in 70 ml. of lN
hydrochloric acid and 300 ml. of absolute ethanol. Distillables are removed under reduced pressure and the resulting residue stirred with ether to provide solid crude product. Crystallization of the crude product from butanone-methanol and again from 95% ethanol-ether, affords l-(ISOPROPYIA~IINO)-3{ 4-(~THYLSUnFONYL)-m-TOLYLOXY]-2-PROP~NOL HYDROCHLORIDE, m.p. 177.0-179.0C. (corr.) i3 a 62~ overall yield. A sample, m.p.
176.0-178.0C. (corr), analyzed as follows.
Analysis. Calcd. for C,4H~,NO4-HCl: C, 49.77; H, 7.16;
N, 4.15. Found: C, 49.72; H, 7.16; N, 4.08.
Nuclear Magnetic Res~nance, DMSO-d 6, ~ (ppm): 1.28 Cd, 6.5 Hz, 6H~; 2.58 [s, 3H]; 3.11 [s, 3H]; 3.13 [m, 3H]; 4.11 ~m, 3H]; 7.01 Cm, 2H];
7-77 Cd, 9.2 Hz, lH~; 8.9 [bs, 2H].
(b) A modificatlon of the procedure for preparing l-(isopropyl-amino)-3-C4-(methyl3ulfonyl)-m-tolyloxy~-2-propanol employing aqueous sodlum hydroxlde as the reaction medium follows. Epichlorohydrin (37 g., 0.4 mole) is atded portionwise in 5 min. to a solution of 4-(methylsulfonyl)-m-cresol (0.2 mole) and sodium hydroxide (13 g., 0.32 mole) in 250 ml. of water at 30C. Stirring is continued for 24 hr. and the final pH of the solution is 8-8.5. The reaction mixture extracted with two 250 ml. portions of chloroform, the chloroform extract dried over sodium carbonate, filtered and the filtrate concentrated under reduced pressure provides the crude epichlorohydrin terivative. The epichlorohydrin derivative is taken up ln 150 ml. of ethanol and trested with lsopropylamlne (17 g., 0.286 mole) ln 20 ml. of water. After stirring for 10 min., the mixture i8 refluxed for 4 hr. and distillables removed under reduced pressure. The residue taken up in ethanol and acidified with ethanolic hydrogen chloride affords 1-(ISOPROPYI~IINO)-3-L4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL HYDROCHLORIDE.
(c) A further modi~icatlon of the procedure for preparing l-(lsopropylamlno)-3-C4-(methylsulfonyl)-m-tolyloxy]-2-propanol employing an eplhalohydrin derivatlve of Formula VII containing a hydrogenolyæiable blocking group f ollows; l-C (N-Benzyl)isopropylamino]-2,3-epoxypropane 18 reacted wlth 4-(methylsulfonyl)-m-cresol sodium salt in ethanol to provlde l-C(N-benzyl)isopropylamino]-3- 4-(methylsulfonyl)-m-tolyloxy -2-propanol.
The reaction mixture is filtered, acidified with ethanolic hydrogen chloride and the benzyl bloc~ing group removed by catalytic hydrogenation employing palladium-on-charcoal catalyst. The catalyst ls collected and the filtrate concentrated to provide l-(ISOPROPYL-AMINO)-3-C4-(METHYLSULFONYL)-m-TOLYLOXY~-2-PROPANOL HYDROCHLORIDE.
1~5552~
Example 2.- Reac~ion of the chlorohydrin derivative of 4-(methylsulfonyl)-m-cresol with tert.-butylamine according to the procedure of Example 1 ta) affords l-(tert.-BU m ~YINO)-3-C4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL HYDROCHLORIDE, m.p. 175.0-176.0C. (resolidifying and remelting at 197.0C.)(corr.)., from acetonitrile.
Analysis. Calcd. for C,5H~NO4S-HCl: C, 51.20; H, 7.45; N, 3.98.
Found: C, 50.99; H, 7.72; N, 4.20.
Nuclear Magnetic Resonance, DMSO-d6, ~(ppm): 1.31 Cs, 9H];
2.59 [8, 3H]; 3.02 [m, 2H]; 3.11 C8, 3H]; 4.10 Cm, 3H]; 6.97 Cm, 2H];
7-75 Cd, 9.5 Hz, lH]; 8.7 Cbs, 2H].
Example 3.- Reaction of the chlorohydrin derivative of 4-(metnylsulfonyl)phenol with isopropylamine according to the procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-C4-(METHYLSULFONYL)PHENOXY]-2-PROPANOL HYDROCHLORIDE, m.p. 193.0-195.0C., from ethanol.
Analysis. Calcd. for Cl,H2,NO4S-HCl: C, 48.22; H, 6.85;
N, 4.32. Found: C, 48.00; H, 7.02; N, 4.25.
Nuclear Magnetic Resonance, DMSO-d6, ~(ppm): 1.28 Cd, 6.5 Hz, 6H]; 3.12 Cm, 3H]; 3.14 Cs, 3H]; 4.13 Cm, 3H]; 5.91 Cd, 4.2 Hz, lH];
7.13 Cm, 2H]; 7.80 Cm, 2H]; 8.9 Cbs, 2H].
~ -- Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)-o-cresol with isopropylamine sccording to the proc~dure of Example 1 (a) affords 1-(ISOPROPYLAMINO~-3-C4-(METHYLSULFONYL)-o-TOLYLOXY]-2-PRQPANOL as the free base, m.p. 118.0-120.0C., from butanone.
Analysis. Calcd. for Cl4H~9NO4S: C, 55.79; H, 7.69; N, 4.65.
Found: C, 56.00; H, 7.68; N, 4.42.
~uclear Magnetic Resonance, CDCl" ~(ppm): 1.10 Cd, 6.4 Hz, 6H]; 2.27 Cs, 3H~; 2.50 [bs, 2H]; 2.85 [m, 3H]; 2.99 [s, 3H]; 4.11 Cm, 3H];
6.86 Cd, 9.3 Hz, lH~; 7.65 Cm, 2P.].
Example 5.- Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)phenol with tert.-butylamine according to the procedure of Example 1 (a) affords 1-(tert.-BUTYLAMINO)-3-[4-(METHYLSULFONYL)PHENOXY]-2-PROPANOL, m.p. 221.0 - 223.0C. (corr.) Analysis. Calcd. for C H NO S.HCl: C, 49.77; H, 7.16; N, 4.15.
Found: C, 50.10; H, 7.33; N, 4.00.
Example 6.- Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)-m-cresol with cyclopropylamine according to the procedure of Example l (a) affords l-(CYCLOPROPYLAMINO)-3-[4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL, m.p. 144.5 - 147.5C. (corr.) Analysis- Calcd. for C14H21NO4S.HCl: C, 50.07; H, 6.60; N, 4.17.
Found: C, 50.23; H, 6.76; N, 4.02.
Example 7.- Reaction of chlorohydrin derivative of 4-(methylsulfonyl)-m-cresol with phenoxyisopropylamine according to the procedure of Example 1 (a) affords 1-(PHENOXYISOPROPYLAMINO)-3-[4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL, m.p. 143.5 - 147.5C. (corr.) Analysis- Calcd- for C20H27NO5S: C, 61.05; H, 6.92; N, 3.56.
Found: C, 61.12; H, 7.14; N. 3.32.
Example 8.- Reaction of the chlorohydrin derivative of 2-(methylsulfonyl)phenol with isopropylamine according to the procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-[2-(METHYLSULFONYL)PHENOXY]-2-PROPANOL, m.p. 187.5 - 189.5C. (corr.) Analysis- Calcd- for C13H21NO4S.HCl: C, 48.22; H, 6.85; N, 4.32.
Found: C, 48.19; H, 7.05; N, 4.37.
Example 9.- Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)-m-cresol with cyclopentylamine according to the procedure of Example 1 (a) affords 1-(CYCLOPENTYLAMINO)-3-[4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL HYDROCHLORIDE, m.p. 183.0 - 185.0C. (corr.) Analysis. Calcd. for Cl6H25NO4S HCl: C, 52.81; H, 7.20; N, 3.85-Found: C, 53.04; H, 7.37; N, 3.69.
Nuclear Magnetic Resonance, DMSO-d6, ~(ppm); 1.70 [m, 9H]; 2.58 [s, 3H]; 3,12 [s, 3H]; 3.15 [m, 3H]; 4.10 Lm, 3H]; 5.84 [bs, lH]; 6.94 [m, 2H]; 7.76 [d, 9.5 Hz, lH]; 9.0 [bs, 2H].
Example 10.- Reaction of the chlorohydrin derivative of 4-(sec.-butylsulfonyl)phenol with isopropylamine according to the ..~
procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-[4-(sec.-BUTYLSULFONYL)P}IENOXY]-2-PROPANOL.
Example 11.- Reaction of the chlorohydrin derivative of 4-(lsopropylsulfonyl)-m-cresol with tert.-butylamine according to the procedure of Example 1 (a) affords 1-(tert.-BUTYLAMINO)-3-C4-(ISOPROPYLSULFONYL)-m-TOLYLOXY~-2-PROPANOL.
Example 12.- Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)-3-isopropylphenol with isopropylamine according to the procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-C4-(METHYLSULFONYL)-3-ISOPROPYLPHENOXY]-2-PROPANOL.
Claims (20)
1. A process for preparing a compound selected from the group consisting of an alkylsulfonylphenoxypropanolamine of the formula Formula I
and a non-toxic pharmaceutically acceptable acid addition salt thereof wherein R1 is a branched chain alkyl group of 3 or 4 carbon atoms inclusive, phenoxyisopropyl or cycloalkyl of 3 to 6 carbon atoms inclusive;
R2 is hydrogen, lower alkyl of 1 to 4 carbon atoms inclusive or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive;
R3 is hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive; and R4 is hydrogen or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive;
wherein one and only one of R2 and R4 is lower alkylsulfonyl which comprises reacting a phenol derivative of Formula II
Formula II
wherein R2, R3, and R4 have meanings hereinabove described with an epihalohydrin of Formula III
Formula III
wherein X signififies halogen, preferably chlorine or bromine, and con-densing the epihalohydrin reaction product with an amine of Formula IV
H2N-R1 Formula IV
wherein R1 has the meaning hereinabove described; whereafter, if desired, the Formula I product in free base form is reacted with an acid in order to form an acid addition salt.
and a non-toxic pharmaceutically acceptable acid addition salt thereof wherein R1 is a branched chain alkyl group of 3 or 4 carbon atoms inclusive, phenoxyisopropyl or cycloalkyl of 3 to 6 carbon atoms inclusive;
R2 is hydrogen, lower alkyl of 1 to 4 carbon atoms inclusive or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive;
R3 is hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive; and R4 is hydrogen or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive;
wherein one and only one of R2 and R4 is lower alkylsulfonyl which comprises reacting a phenol derivative of Formula II
Formula II
wherein R2, R3, and R4 have meanings hereinabove described with an epihalohydrin of Formula III
Formula III
wherein X signififies halogen, preferably chlorine or bromine, and con-densing the epihalohydrin reaction product with an amine of Formula IV
H2N-R1 Formula IV
wherein R1 has the meaning hereinabove described; whereafter, if desired, the Formula I product in free base form is reacted with an acid in order to form an acid addition salt.
2. The compound selected from the group consisting of an alkylsulfonylphenoxypropanolamine of the formula Formula I
and a non-toxic pharmaceutically acceptable acid addition salt thereof wherein R1 is a branched chain alkyl group of 3 or 4 carbon atoms inclusive, phenoxyisopropyl or cycloalkyl of 3 to 6 carbon atoms inclusive;
R2 is hydrogen, lower alkyl of 1 to 4 carbon atoms inclusive or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive;
R3 is hydrogen or lower alkvl of 1 to 4 carbon atoms inclusive; and R4 is hydrogen or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive;
wherein one and only one of R2 and R4 is lower alkylsulfonyl, whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.
and a non-toxic pharmaceutically acceptable acid addition salt thereof wherein R1 is a branched chain alkyl group of 3 or 4 carbon atoms inclusive, phenoxyisopropyl or cycloalkyl of 3 to 6 carbon atoms inclusive;
R2 is hydrogen, lower alkyl of 1 to 4 carbon atoms inclusive or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive;
R3 is hydrogen or lower alkvl of 1 to 4 carbon atoms inclusive; and R4 is hydrogen or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive;
wherein one and only one of R2 and R4 is lower alkylsulfonyl, whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.
3. The process of preparing 1-(isopropylamino)-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the reaction product of 9-(methylsulfonyl)-m-cresol and epichlorohydrin is reacted with isopropylamine.
4. The compound 1-(isopropylamino)-3-[4-(methyl-sulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 3 or an obvious chemical equivalent thereof.
5. The process of preparing l-(tert.-butylamino)-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the reaction product of 4-(methylsulfonyl)-m-cresol and epichlorohydrin is reacted with tert.-butylamine.
6. The compound l-(tert.-butylamino)-3-[4-(methylsulfonyl)-m-tolyloxyl-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 5 or an obvious chemical equivalent thereof.
7. The process of preparing l-(isopropylamino)-3-[4-(methylsulfonyl)phenoxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the reaction product of 4-(methylsulfonyl)phenol and epichlorohydrin is reacted with isopropylamine.
8. The compound 1-(isopropylamino)-3-[4-(methylsulfonyl)-phenoxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 7 or an obvious chemical equivalent thereof.
9. The process of preparing 1-(isopropylamino)-3-[4-(methylsulfonyl)-o-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the reaction product of 4-(methylsulfonyl)-o-cresol and epichlorohydrin is reacted with isopropylamine.
10. The compound l-(isopropylamino)-3-L4-(methylsulfonyl)-o-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 9 or an obvious chemical equivalent thereof.
11. The process of preparing l-(tert.-butylamino)-3-[4-(methylsulfonyl)phenoxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the reaction product of 4-(methylsulfonyl)phenol and epichlorohydrin is reacted with tert.-butylamine.
12. The compound l-(tert.-butylamino)-3-[4-(methylsulfonyl)-phenoxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 11 or an obvious chemical equivalent thereof.
13. The process of preparing l-(cyclopropylamino)-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the reaction product of 4-(methylsulfonyl)-m-cresol and epichlorohydrin is reacted with cyclopropylamine.
14. The compound l-(cyclopropylamino)-3-[4-methylsulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 13 or an obvious chemical equivalent thereof.
15. The process of preparing l-(phenoxyisopropyl-amino)-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the reaction product of 4-(methylsulfonyl)-m-cresol and epichlorohydrin is reacted with phenoxyisopropylamine.
16. The compound l-(phenoxyisopropylamino)-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 15 or an obvious chemical equivalent thereof.
17. The process of preparing l-(isopropylamino)-3-[2-(methylsulfonyl)phenoxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the product of 2-(methylsulfonyl)phenol and epichlorohydrin is reacted withisopropylamine.
18. The compound l-(isopropylamino)-3-[2-(methylsulfonyl)-phenoxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 17 or an obvious chemical equivalent thereof.
19. The process of preparing l-(cyclopentylamino)-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the product of 4-(methylsulfonyl)-m-cresol and epichlorohydrin is reacted with cyclopentylamine.
20. The compound l-(cyclopentylamino)-3-[4-(methylsulfonyl-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 19 or an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
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US45509974A | 1974-03-27 | 1974-03-27 |
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CA1055528A true CA1055528A (en) | 1979-05-29 |
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CA221,803A Expired CA1055528A (en) | 1974-03-27 | 1975-03-11 | Alkylsulfonylphenoxypropanolamines |
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JP (1) | JPS5822478B2 (en) |
BE (1) | BE826873A (en) |
CA (1) | CA1055528A (en) |
CH (1) | CH612932A5 (en) |
DE (1) | DE2513806A1 (en) |
DK (1) | DK144246C (en) |
FI (1) | FI62065C (en) |
FR (2) | FR2265358B1 (en) |
GB (1) | GB1451180A (en) |
IE (1) | IE40887B1 (en) |
LU (1) | LU72100A1 (en) |
NL (1) | NL7503489A (en) |
NO (1) | NO140856C (en) |
SE (1) | SE424548B (en) |
YU (2) | YU59175A (en) |
ZA (1) | ZA751853B (en) |
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US4117128A (en) | 1976-08-03 | 1978-09-26 | Smithkline Corporation | Sulfonyl benzofurans and benzothiophenes having coronary vasodilator activity |
ATE161145T1 (en) * | 1993-12-07 | 1998-01-15 | S & R Maschbau Gmbh | METHOD AND DEVICE FOR BAKING CAKES |
EP0972766A4 (en) | 1997-01-30 | 2000-05-03 | Senju Pharma Co | Hydroquinone derivatives |
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1975
- 1975-03-11 CA CA221,803A patent/CA1055528A/en not_active Expired
- 1975-03-12 YU YU00591/75A patent/YU59175A/en unknown
- 1975-03-19 BE BE154495A patent/BE826873A/en unknown
- 1975-03-20 LU LU72100A patent/LU72100A1/xx unknown
- 1975-03-20 JP JP50033124A patent/JPS5822478B2/en not_active Expired
- 1975-03-24 DK DK123875A patent/DK144246C/en active
- 1975-03-24 NO NO750993A patent/NO140856C/en unknown
- 1975-03-24 FR FR7509047A patent/FR2265358B1/fr not_active Expired
- 1975-03-24 ZA ZA00751853A patent/ZA751853B/en unknown
- 1975-03-24 NL NL7503489A patent/NL7503489A/en not_active Application Discontinuation
- 1975-03-24 FI FI750875A patent/FI62065C/en not_active IP Right Cessation
- 1975-03-26 IE IE670/75A patent/IE40887B1/en unknown
- 1975-03-26 SE SE7503582A patent/SE424548B/en unknown
- 1975-03-26 GB GB1265275A patent/GB1451180A/en not_active Expired
- 1975-03-27 DE DE19752513806 patent/DE2513806A1/en not_active Ceased
- 1975-03-27 CH CH399675A patent/CH612932A5/en not_active IP Right Cessation
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1978
- 1978-08-31 FR FR7825229A patent/FR2391725A1/en active Granted
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1982
- 1982-06-03 YU YU01171/82A patent/YU117182A/en unknown
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FR2265358A1 (en) | 1975-10-24 |
NL7503489A (en) | 1975-09-30 |
LU72100A1 (en) | 1976-02-04 |
NO140856B (en) | 1979-08-20 |
NO140856C (en) | 1979-11-28 |
FR2391725B1 (en) | 1981-07-17 |
BE826873A (en) | 1975-09-19 |
FR2265358B1 (en) | 1980-02-08 |
DK123875A (en) | 1975-09-28 |
SE7503582L (en) | 1975-09-29 |
FI750875A (en) | 1975-09-28 |
FR2391725A1 (en) | 1978-12-22 |
CH612932A5 (en) | 1979-08-31 |
FI62065B (en) | 1982-07-30 |
FI62065C (en) | 1982-11-10 |
DE2513806A1 (en) | 1975-10-09 |
NO750993L (en) | 1975-09-30 |
YU117182A (en) | 1982-10-31 |
ZA751853B (en) | 1976-02-25 |
IE40887B1 (en) | 1979-09-12 |
DK144246C (en) | 1982-06-28 |
DK144246B (en) | 1982-01-25 |
GB1451180A (en) | 1976-09-29 |
AU7839175A (en) | 1976-08-26 |
JPS5822478B2 (en) | 1983-05-09 |
JPS50130736A (en) | 1975-10-16 |
SE424548B (en) | 1982-07-26 |
YU59175A (en) | 1982-10-31 |
IE40887L (en) | 1975-09-27 |
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