CA1116636A - Alkylthiophenoxypropanolamines - Google Patents
AlkylthiophenoxypropanolaminesInfo
- Publication number
- CA1116636A CA1116636A CA000312115A CA312115A CA1116636A CA 1116636 A CA1116636 A CA 1116636A CA 000312115 A CA000312115 A CA 000312115A CA 312115 A CA312115 A CA 312115A CA 1116636 A CA1116636 A CA 1116636A
- Authority
- CA
- Canada
- Prior art keywords
- phenoxy
- propanol
- methylethyl
- thio
- formula
- 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
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 238000000034 method Methods 0.000 claims abstract description 58
- ZAPDURRCHSKKKK-UHFFFAOYSA-N 1-(octylamino)-3-(4-propan-2-ylsulfanylphenoxy)propan-2-ol Chemical compound CCCCCCCCNCC(O)COC1=CC=C(SC(C)C)C=C1 ZAPDURRCHSKKKK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 58
- 230000008569 process Effects 0.000 claims description 35
- 125000004432 carbon atom Chemical group C* 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- -1 primary amino compound Chemical class 0.000 claims description 32
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 24
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 24
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 24
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 22
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000002947 alkylene group Chemical group 0.000 claims description 14
- 239000007795 chemical reaction product Substances 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 claims description 12
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 8
- DVDGHEZGPNPQAV-UHFFFAOYSA-N 4-propan-2-ylsulfanylphenol Chemical compound CC(C)SC1=CC=C(O)C=C1 DVDGHEZGPNPQAV-UHFFFAOYSA-N 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- NJIYJKALGDCITC-UHFFFAOYSA-N 1-(2-methyl-4-methylsulfanylphenoxy)-3-(octylamino)propan-2-ol Chemical compound CCCCCCCCNCC(O)COC1=CC=C(SC)C=C1C NJIYJKALGDCITC-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- GCYUSDHZIAFXPD-UHFFFAOYSA-N 1-(2-methylsulfanylphenoxy)-3-(octylamino)propan-2-ol Chemical compound CCCCCCCCNCC(O)COC1=CC=CC=C1SC GCYUSDHZIAFXPD-UHFFFAOYSA-N 0.000 claims description 4
- ZGRXEJDDZVCITI-UHFFFAOYSA-N 1-(dodecylamino)-3-(4-propan-2-ylsulfanylphenoxy)propan-2-ol Chemical compound CCCCCCCCCCCCNCC(O)COC1=CC=C(SC(C)C)C=C1 ZGRXEJDDZVCITI-UHFFFAOYSA-N 0.000 claims description 4
- VORNLKLJEMSFFV-UHFFFAOYSA-N 1-(2-cyclohexylethylamino)-3-(4-propan-2-ylsulfanylphenoxy)propan-2-ol Chemical compound C1=CC(SC(C)C)=CC=C1OCC(O)CNCCC1CCCCC1 VORNLKLJEMSFFV-UHFFFAOYSA-N 0.000 claims description 3
- IAGFVCWQMCZABO-UHFFFAOYSA-N 1-(4-methylsulfanylphenoxy)-3-(octylamino)propan-2-ol Chemical compound CCCCCCCCNCC(O)COC1=CC=C(SC)C=C1 IAGFVCWQMCZABO-UHFFFAOYSA-N 0.000 claims description 3
- SENNKTSISNNSHS-UHFFFAOYSA-N 1-(octylamino)-3-(3-propan-2-ylsulfanylphenoxy)propan-2-ol Chemical compound CCCCCCCCNCC(O)COC1=CC=CC(SC(C)C)=C1 SENNKTSISNNSHS-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 3
- JRBPAEWTRLWTQC-UHFFFAOYSA-N dodecylamine Chemical compound CCCCCCCCCCCCN JRBPAEWTRLWTQC-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- RZLLASOLDHULHD-UHFFFAOYSA-N 1-(2-methylsulfanylphenoxy)-3-(octylamino)propan-2-ol;hydrochloride Chemical compound Cl.CCCCCCCCNCC(O)COC1=CC=CC=C1SC RZLLASOLDHULHD-UHFFFAOYSA-N 0.000 claims description 2
- MDYVTFJMMYVONT-UHFFFAOYSA-N 1-(4-cyclohexylbutylamino)-3-(4-propan-2-ylsulfanylphenoxy)propan-2-ol;hydrochloride Chemical compound Cl.C1=CC(SC(C)C)=CC=C1OCC(O)CNCCCCC1CCCCC1 MDYVTFJMMYVONT-UHFFFAOYSA-N 0.000 claims description 2
- DXLSPFDSUIZAON-UHFFFAOYSA-N 2-methyl-4-methylsulfanylphenol Chemical compound CSC1=CC=C(O)C(C)=C1 DXLSPFDSUIZAON-UHFFFAOYSA-N 0.000 claims description 2
- QASBCTGZKABPKX-UHFFFAOYSA-N 4-(methylsulfanyl)phenol Chemical compound CSC1=CC=C(O)C=C1 QASBCTGZKABPKX-UHFFFAOYSA-N 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- AGVKXDPPPSLISR-UHFFFAOYSA-N n-ethylcyclohexanamine Chemical compound CCNC1CCCCC1 AGVKXDPPPSLISR-UHFFFAOYSA-N 0.000 claims description 2
- SOOARYARZPXNAL-UHFFFAOYSA-N 2-(Methylthio)phenol Chemical compound CSC1=CC=CC=C1O SOOARYARZPXNAL-UHFFFAOYSA-N 0.000 claims 2
- WNUPSSMAWGRQOS-UHFFFAOYSA-N 1-(2-cyclohexylethylamino)-3-(4-propan-2-ylsulfanylphenoxy)propan-2-ol;hydrochloride Chemical compound Cl.C1=CC(SC(C)C)=CC=C1OCC(O)CNCCC1CCCCC1 WNUPSSMAWGRQOS-UHFFFAOYSA-N 0.000 claims 1
- XWGFCGCMXBSIRJ-UHFFFAOYSA-N 1-(4-cyclohexylbutylamino)-3-(4-propan-2-ylsulfanylphenoxy)propan-2-ol Chemical compound C1=CC(SC(C)C)=CC=C1OCC(O)CNCCCCC1CCCCC1 XWGFCGCMXBSIRJ-UHFFFAOYSA-N 0.000 claims 1
- VTUJBLPPNLCDFB-UHFFFAOYSA-N 1-(octylamino)-3-(3-propan-2-ylsulfanylphenoxy)propan-2-ol;hydrochloride Chemical compound Cl.CCCCCCCCNCC(O)COC1=CC=CC(SC(C)C)=C1 VTUJBLPPNLCDFB-UHFFFAOYSA-N 0.000 claims 1
- QFKMDZYQWDSMPA-UHFFFAOYSA-N 1-(octylamino)-3-(4-propan-2-ylsulfanylphenoxy)propan-2-ol;hydrochloride Chemical compound Cl.CCCCCCCCNCC(O)COC1=CC=C(SC(C)C)C=C1 QFKMDZYQWDSMPA-UHFFFAOYSA-N 0.000 claims 1
- AUHGURNMOWDGBF-UHFFFAOYSA-N 3-propan-2-ylsulfanylphenol Chemical compound CC(C)SC1=CC=CC(O)=C1 AUHGURNMOWDGBF-UHFFFAOYSA-N 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 230000000903 blocking effect Effects 0.000 abstract description 13
- 238000002360 preparation method Methods 0.000 abstract description 12
- 230000002921 anti-spasmodic effect Effects 0.000 abstract description 11
- 230000000304 vasodilatating effect Effects 0.000 abstract description 10
- 210000001772 blood platelet Anatomy 0.000 abstract description 6
- 208000010110 spontaneous platelet aggregation Diseases 0.000 abstract description 6
- 230000002490 cerebral effect Effects 0.000 abstract description 2
- 230000000414 obstructive effect Effects 0.000 abstract description 2
- 230000002792 vascular Effects 0.000 abstract description 2
- 230000024883 vasodilation Effects 0.000 abstract description 2
- 208000018262 Peripheral vascular disease Diseases 0.000 abstract 1
- 230000007812 deficiency Effects 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 50
- 239000000243 solution Substances 0.000 description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- 239000003795 chemical substances by application Substances 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 230000000694 effects Effects 0.000 description 26
- 239000000203 mixture Substances 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 25
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 150000002431 hydrogen Chemical class 0.000 description 20
- 238000007792 addition Methods 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 150000003254 radicals Chemical class 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 15
- 210000001519 tissue Anatomy 0.000 description 13
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 12
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 230000004044 response Effects 0.000 description 8
- 241000282472 Canis lupus familiaris Species 0.000 description 7
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- 239000000556 agonist Substances 0.000 description 7
- CREXVNNSNOKDHW-UHFFFAOYSA-N azaniumylideneazanide Chemical group N[N] CREXVNNSNOKDHW-UHFFFAOYSA-N 0.000 description 7
- 239000000812 cholinergic antagonist Substances 0.000 description 7
- 230000036515 potency Effects 0.000 description 7
- 229940124549 vasodilator Drugs 0.000 description 7
- 239000003071 vasodilator agent Substances 0.000 description 7
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 231100000252 nontoxic Toxicity 0.000 description 6
- 230000003000 nontoxic effect Effects 0.000 description 6
- 229960001789 papaverine Drugs 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 5
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 5
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-butanol Substances CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 229940039009 isoproterenol Drugs 0.000 description 5
- 239000001103 potassium chloride Substances 0.000 description 5
- 235000011164 potassium chloride Nutrition 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 4
- SUMWYVVUFJCTQX-UHFFFAOYSA-N 2,2-dimethylhexan-1-amine Chemical compound CCCCC(C)(C)CN SUMWYVVUFJCTQX-UHFFFAOYSA-N 0.000 description 4
- GFKABXPATHSPAB-UHFFFAOYSA-N 2-(4-propan-2-ylsulfanylphenoxy)acetaldehyde Chemical compound CC(C)SC1=CC=C(OCC=O)C=C1 GFKABXPATHSPAB-UHFFFAOYSA-N 0.000 description 4
- NMPVEAUIHMEAQP-UHFFFAOYSA-N 2-Bromoacetaldehyde Chemical compound BrCC=O NMPVEAUIHMEAQP-UHFFFAOYSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 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 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 210000000709 aorta Anatomy 0.000 description 4
- 210000002376 aorta thoracic Anatomy 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
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- 238000007796 conventional method Methods 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 4
- 229960002748 norepinephrine Drugs 0.000 description 4
- NUJGJRNETVAIRJ-UHFFFAOYSA-N octanal Chemical compound CCCCCCCC=O NUJGJRNETVAIRJ-UHFFFAOYSA-N 0.000 description 4
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 4
- KJRCEJOSASVSRA-UHFFFAOYSA-N propane-2-thiol Chemical compound CC(C)S KJRCEJOSASVSRA-UHFFFAOYSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 210000003437 trachea Anatomy 0.000 description 4
- OHMXXZIUOWNPRG-UHFFFAOYSA-N 2-methyloctan-2-amine Chemical compound CCCCCCC(C)(C)N OHMXXZIUOWNPRG-UHFFFAOYSA-N 0.000 description 3
- MXFVXKGNZWGEJK-UHFFFAOYSA-N 3-amino-3-methyl-1-(4-propan-2-ylsulfanylphenoxy)butan-2-ol Chemical compound CC(C)SC1=CC=C(OCC(O)C(C)(C)N)C=C1 MXFVXKGNZWGEJK-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 208000007101 Muscle Cramp Diseases 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
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- 229910052799 carbon Inorganic materials 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
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- 238000000338 in vitro Methods 0.000 description 3
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- 230000003993 interaction Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 210000003141 lower extremity Anatomy 0.000 description 3
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- 230000010412 perfusion Effects 0.000 description 3
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- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- MRBDMNSDAVCSSF-UHFFFAOYSA-N phentolamine Chemical compound C1=CC(C)=CC=C1N(C=1C=C(O)C=CC=1)CC1=NCCN1 MRBDMNSDAVCSSF-UHFFFAOYSA-N 0.000 description 3
- 229960001999 phentolamine Drugs 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 230000002885 thrombogenetic effect Effects 0.000 description 3
- 208000019553 vascular disease Diseases 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- LXVMQKREAPQFPN-UHFFFAOYSA-N 2,2-dimethylhexanenitrile Chemical compound CCCCC(C)(C)C#N LXVMQKREAPQFPN-UHFFFAOYSA-N 0.000 description 2
- ABROBCBIIWHVNS-UHFFFAOYSA-N 2-Ethylbenzenethiol Chemical compound CCC1=CC=CC=C1S ABROBCBIIWHVNS-UHFFFAOYSA-N 0.000 description 2
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- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- 230000003247 decreasing effect Effects 0.000 description 1
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- JXSJBGJIGXNWCI-UHFFFAOYSA-N diethyl 2-[(dimethoxyphosphorothioyl)thio]succinate Chemical compound CCOC(=O)CC(SP(=S)(OC)OC)C(=O)OCC JXSJBGJIGXNWCI-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
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- 229910001873 dinitrogen Inorganic materials 0.000 description 1
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- MWEQTWJABOLLOS-UHFFFAOYSA-L disodium;[[[5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-oxidophosphoryl] hydrogen phosphate;trihydrate Chemical compound O.O.O.[Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP([O-])(=O)OP(O)([O-])=O)C(O)C1O MWEQTWJABOLLOS-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
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- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 229960003054 gallamine Drugs 0.000 description 1
- ICLWTJIMXVISSR-UHFFFAOYSA-N gallamine Chemical compound CCN(CC)CCOC1=CC=CC(OCCN(CC)CC)=C1OCCN(CC)CC ICLWTJIMXVISSR-UHFFFAOYSA-N 0.000 description 1
- 229960005271 gallamine triethiodide Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- AILKHAQXUAOOFU-UHFFFAOYSA-N hexanenitrile Chemical compound CCCCCC#N AILKHAQXUAOOFU-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000000871 hypocholesterolemic effect Effects 0.000 description 1
- JCYWCSGERIELPG-UHFFFAOYSA-N imes Chemical class CC1=CC(C)=CC(C)=C1N1C=CN(C=2C(=CC(C)=CC=2C)C)[C]1 JCYWCSGERIELPG-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 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
- 238000002955 isolation Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 210000003975 mesenteric artery Anatomy 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- VRYPROVLGPMATH-UHFFFAOYSA-N n-benzyloctan-1-amine Chemical compound CCCCCCCCNCC1=CC=CC=C1 VRYPROVLGPMATH-UHFFFAOYSA-N 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
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- FJDUDHYHRVPMJZ-UHFFFAOYSA-N nonan-1-amine Chemical compound CCCCCCCCCN FJDUDHYHRVPMJZ-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229940061319 ovide Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 208000028591 pheochromocytoma Diseases 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
- 210000002381 plasma Anatomy 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- IOVGROKTTNBUGK-SJCJKPOMSA-N ritodrine Chemical compound N([C@@H](C)[C@H](O)C=1C=CC(O)=CC=1)CCC1=CC=C(O)C=C1 IOVGROKTTNBUGK-SJCJKPOMSA-N 0.000 description 1
- 239000000050 smooth muscle relaxant Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- CSUNLSYSEQIDMO-UHFFFAOYSA-N tiprenolol Chemical compound CSC1=CC=CC=C1OCC(O)CNC(C)C CSUNLSYSEQIDMO-UHFFFAOYSA-N 0.000 description 1
- 229950004988 tiprenolol Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000005090 tracheal smooth muscle Anatomy 0.000 description 1
- QFKMMXYLAPZKIB-UHFFFAOYSA-N undecan-1-amine Chemical compound CCCCCCCCCCCN QFKMMXYLAPZKIB-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
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- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Urology & Nephrology (AREA)
- Vascular 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)
Abstract
ALKYLTHIOPHENOXYPROPANOLAMINES
Abstract of the Disclosure A new class of alkylthiophenoxypropanolamine derivatives and methods for preparation are described. The compounds have vasodilating and antispasmodic activity, inhibit blood platelet aggregation and are substantially free of beta-adrenergic blocking effects. They are particularly valuable in the treatment of disease states responsive to vasodilation such as obstructive peripheral vascular diseases and cerebral vascular deficiencies. A represent-ative and preferred embodiment of the invention consists of 1-[4-(l-methylethylthio)phenoxy]-3-(octylamino)-2-propanol.
Abstract of the Disclosure A new class of alkylthiophenoxypropanolamine derivatives and methods for preparation are described. The compounds have vasodilating and antispasmodic activity, inhibit blood platelet aggregation and are substantially free of beta-adrenergic blocking effects. They are particularly valuable in the treatment of disease states responsive to vasodilation such as obstructive peripheral vascular diseases and cerebral vascular deficiencies. A represent-ative and preferred embodiment of the invention consists of 1-[4-(l-methylethylthio)phenoxy]-3-(octylamino)-2-propanol.
Description
ALKYLTHIOPHENOXYPROPANOLAMINES
Field of the Invention _ _ This inventioll pertair.s to carbon compounds having drug and bio-affecting properties. It is particularly concerned with new and usefui al~ylthiophenoxypropanolamines use thereof in pharlna-ceutical preparations and therapeutic methods and processes for producing th~ alkylthiophenoxypropanolamines. The alkyltbio-phenoxypropanola~ines of this invention increase peripheral. b-ood flow, relax vascular smooth muscle, and inhibit p].atelet aggregatl~
and are considered to be particularly useful ln the ;reatDen~ of obstructive ~erî.pltera; vascular diseases such as interlL.tLent claudication and cerebrovasc~ r dericiencies associ.ated with arteriosclerosis.
3~i Description_of the Prior Art Various alkylthiophenoxypropanolamine modifications have been described and studied in the field of adrenergic agents primarily for the purpose of uncovering more potent and selective beta-adrenergic blocking agents free of unwanted pharmacologic effects.Such compounds are generally considered useful in treating certain forms of hypertension, angina pectoris, heart arrhythmia and pheo-chromocytoma. Representative of these efforts are compounds described in the following patents and publications.
L. Villa, et al., Il. Farmaco. Sci., Ed. 24, 349-357 (1969) specifically discloses the following alkylthiophenoxypropanol-amine compound as part of a structure-activity-relationship study.
~ OH
C~3S - ~ OcH2cHcH2NHc-~(cH3)2 Keizer, et al., U.S. 3,542,874 patented ~ovember 24, 1970 discloses 2-(alkylthio)phenoxypropanolamines of the formula 'OCH2CHCH2NH-R2 *
wherein Rl is an alkyl (Cl-C4) radical ahd R is inter alia an alkyl (Cl-C12) or a cycloalkyl (C3-C12) radical. This paten, teaches that co~pounds of this type have very effective beta-adrenerg'c bloc~ing properties. Specific compounds disclosPd by Keizer, et al. include ,hose wnerein R is methyl or ethyl and R is isopropyl; Rl is methyl, ethyl, or propyl and R is tert -butyl; R~
ls methyl and R is cyclopropyl, cyclopentyl, or cyclohexyl; R is tert.-butyl .~nd R is cyclopentyl.
Crowther, et al., U.S. 3,501,769 patented March 17, 1970 generically discloses compounds of the type ~} OCH2C-rlCH-N~-F2 Rls R3 wherein R is alkyl (up to 10 C); R is alkyl (up to 20 C), cyclo alkyi (up to 10 C), etc.~ R is hydrogen or alkyl (up to 10 C).
~lotwithstanding the scope of the generic disclosure, Cro~ther, et al.
does not des;ribe a single example of a specif~ic "alkylthio' compound.
Koppe, et al., ~.S. 3,872,147 pa,ented March 18, 1975 generically discloses alkylthiophenoxypropanolamines illustrated by tne formula ~ OC~2CUCH ~H R2 -~herein R is alkyl (1-4 C); ~ is alkyl (Cl-C5); R is alkyl ~C5-C8) containing at least one quatPrnary carbon attached directly through an alkylene chain (Cl-C4) to ths amino nitrogen atom. None of the specifically disclosed ~oppe, et al. compounds, however, constitute an example Gf an "alkylthiophenoxpropanolamine'~.
Offenlegungsschrift 2,551,141 published ~ay 18, 1977, specifically ciescribes the al'.cylthiophenoxypropanolamine .~ 63~
:., , CH35 ~ OCUzCHCH2NH
3 : ;
~, ' .
As can be seen from the above prior art, numerous alkyl- : :
thiophenoxypropanolamines have been generically disclosed but ~-relatively few alkylthiophenoxypropanolamines are specifically described. Compared to the prior art compoDnds which are reportedly beta-adrenergic blocking agents, the alkylthiophenoxypropanolami.nes of the present invention are unique in that they redlue vascular - ~', ':'`,'' resi6tance with minimal involvement of beta-adrenergic blocking :
effects.
Summary o~ the Inveotio~ :
:~
Broadly described,~the present invention is directed to .
a process for preparing an alkylthiophenoxypropanolamine compound of formula I
R ~ OH A
~ B (I) wherein A, B, and R are independently hydrogen or lower alkyl of 1 to 4 carbon a~oms lnclusive; Rl is alkyl of 1 to 8 carbon atoms inclusive;
R2 is alkyl of 6 to 12 carbon atoms inclusive or cycloalkylalkyl having 5 to 8 ring carbon atoms and from 2 to 6 carbon atoms in the alkylene chain selected from the procesæ group consisting of:
(a) reacting an alkylthiophenol deriva~ive of formula Il ~ :.
Rl-S : :
B _ 4 _ - ' ,,, . . ~ ; ~ , i3~
wherein R and Rl have meanlngs hereinab.oye described with an epihalo-hydrin of formula III
~ cu~cH2-X (III) wherein X signifies halogen, preferably chlorine or bromine, and condensing the epihalohydrin reaction product with an amine of formula IV
H2N-R2 (TV2 wherein R2 has the meaning as in formula (I);
(b) reacting a formula II phenol with a compound of formula VII in alkaline medium ~ O / 2 , 2 (YII2 to provide a compound of formula VIII
R
OH
~ OCH2CHCH2 N, R2 (VIII) wherein R, Rl and R2 have the same meaning as in formula I and R3 stands for hydrogenolysable radicals benzyl or benzhydryl; and converting said compound of formula VIII to an alkylthiophenoxy-propanolamine of formula I by catalytic hydrogenation; and (c) reducing a compound of formula IX
OH A
OCH2CH-C-N02 (IX) Rl-S
wherein A, B, R and Rl are as defined to provide the primary amino compound X
- 4a ~ ~6~36 ~ OH A
OCH2CH~ (X) Rl , and reductively alkylating a compound of formula X with an aldehyde of formula XI
O
HC-Y (XI) 5 wherein Y is straight or branched chain alkyl of 5 to 11 carbon atoms :
inclusive or cycloalkylalkyl having 5 to 8 ring carbon atoms and 1 to 5 carbon atoms in the alkylene chain; and, if desired, reacting a compound of formula I with an acid to form an acid addition salt thereof.
- 4b -This invention is also concerned with pharmaceutical compositions containing the alkylthiophenoxypropanolamines, and further contemplates methods for both producing and employing the compounds and compositions therapeutically.
Detailed Description of the Invention The alkylthiophenoxypropanolamines provided by this invention are represented by formula I
OH A
R ~
~ OCH2CH-C-NH-R2 (I) Rl-S
wherein A, B and R are independently selected from the group consisting of hydrogen and lower alkyl of 1 to 4 carbon atoms inclusive;
Rl is alkyl of 1 to 8 carbon atoms inclusive;
R2 is alkyl of 6 to 12 carbon atoms inclusive or cycloalkylalkyl having 5 to 8 ring carbon atoms inclusive and from 2 to 6 carbon atoms in the alkylene chain, and pharmaceutically acceptable acid addition salts thereof.
As used herein, the term "lower alkyl" refers to a carbon chain comprised of both straight and branched chain carbon radicals of 1 to 4 carbon atoms inclusive. Exemplary of these carbon chain radicals are methyl, ethyl, propyl, isopropyl, l-butyl, l-methyl-propyl, 2-methylpropyl, and tert.-butyl~
As used herein, the term "alkyl" refers to straight or branched chain carbon radicals with the number of carbon atoms comprising the particular alkyl radical specifically designated or referred to by standard notations such as (Cl-C4), (Cl-C8) and (C6-C12) .
As used herein, the term "cycloalkylalhyl" is intended to refer to a cycloallcyl radical containing from 5 to 8 carbon atoms inclusive (i.e., cyclopentyl, cyclohexyl~ cycloheptyl and cyclooctyl) connected to the amino nitrogen atom by an alkylene chain of 2 to 6 carbons.
It is to be understood that the "alkylene chain" connecting the cycloalkyl radical to the amino nitrogen atom may be linear or branched.
As used herein, the term "non-toxic pharmaceutically acceptable acid addition salts" refers to salts of compounds of formula I formed with a variety of inorganic and organic acids, the anions of which are relatively non-toxic. Such acid addition salts are considered pharmacologically equivalent to the bases charact~rized by structural formula I. ~xamples of useful salt forming acids are acetic, Iactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydro-chloric, hydrobromic~ hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzenesulfonic, p-toluenesulfonic, and related acids. Acid addition salts of this invention are prepared and isolated by conventional means; for insLance, by treating a solu~ion or suspension of the fr.~e base ~n a reaction inert solvent with the ~ 3 ~
desired acid and recovering the salts which form by concentration under reduced pressure or by crystallization techniques or other standard chemical manipulations. Acid addition salts which are somewhat toxic and therefore do not meet the foregoing criteria for pharmacetical acceptability are sometimes useful as intermediates for isolation and purification of the bases of formula I or fcr other chemical purposes such as separation of optical isomers. Such salts are also considered part of the invention.
As will be apparent tO those skilled in the art, the compounds characterized by general formula I have one or more assymmetric carbon atoms and can thus exist as optically active isomers, racemates and diastereoisomers all of which are considered as part of the p_esent invention. The diastereoisomeric mixtures may, depending on physical-chemical differences of the components, be separated into diastereomeric pure racemates by conventional means such as chroma,ography and/or fractional crystallizatJon.
~eso]ution of racemates of the instant invention to provide optically active isomers of formula T compounds is carried out by conventional resolution methods. For instance, reacting the bases of formula I
with optically active acids provides salts thereof from which the enantiomers may be separated by fractional crystallization. Acids suitable for resolving the compounds of formula I are the optically active forms of tartaric acid, di-o-tolyltartaric acid, diacetyl-tartaric acid, dibenzoyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, and other optically active acids known to the art. Preferably, the more bio1Ogically active optically active stereoisomer is isolated.
/
Contemplated sub-classes within the ambit of formula I
which further characterize the alkylthiophenoxypropanolamines of the invention are compounds of formula I wherein (Ia~ A, B and R are hydrogen and substituents Rl and R2 are as previously defined for formula I;
(Ib) A, B and R are hydrogen, Rl is methyl and substituent R2 is as previously defined for formula I;
(Ic) A, B and R are hydrogen, Rl is methyl and substituent R2 is (C6-C12) alkyl;
(Id) A, B and R are hydrogen, Rl is lower ~Cl-C4) alkyl and R2 is (C6-C12) alkyl;
(Ie) A, B and R are hydrogen, Rl is (Cl-C8) alkyl and R is (C -C 2) alkyl;
Field of the Invention _ _ This inventioll pertair.s to carbon compounds having drug and bio-affecting properties. It is particularly concerned with new and usefui al~ylthiophenoxypropanolamines use thereof in pharlna-ceutical preparations and therapeutic methods and processes for producing th~ alkylthiophenoxypropanolamines. The alkyltbio-phenoxypropanola~ines of this invention increase peripheral. b-ood flow, relax vascular smooth muscle, and inhibit p].atelet aggregatl~
and are considered to be particularly useful ln the ;reatDen~ of obstructive ~erî.pltera; vascular diseases such as interlL.tLent claudication and cerebrovasc~ r dericiencies associ.ated with arteriosclerosis.
3~i Description_of the Prior Art Various alkylthiophenoxypropanolamine modifications have been described and studied in the field of adrenergic agents primarily for the purpose of uncovering more potent and selective beta-adrenergic blocking agents free of unwanted pharmacologic effects.Such compounds are generally considered useful in treating certain forms of hypertension, angina pectoris, heart arrhythmia and pheo-chromocytoma. Representative of these efforts are compounds described in the following patents and publications.
L. Villa, et al., Il. Farmaco. Sci., Ed. 24, 349-357 (1969) specifically discloses the following alkylthiophenoxypropanol-amine compound as part of a structure-activity-relationship study.
~ OH
C~3S - ~ OcH2cHcH2NHc-~(cH3)2 Keizer, et al., U.S. 3,542,874 patented ~ovember 24, 1970 discloses 2-(alkylthio)phenoxypropanolamines of the formula 'OCH2CHCH2NH-R2 *
wherein Rl is an alkyl (Cl-C4) radical ahd R is inter alia an alkyl (Cl-C12) or a cycloalkyl (C3-C12) radical. This paten, teaches that co~pounds of this type have very effective beta-adrenerg'c bloc~ing properties. Specific compounds disclosPd by Keizer, et al. include ,hose wnerein R is methyl or ethyl and R is isopropyl; Rl is methyl, ethyl, or propyl and R is tert -butyl; R~
ls methyl and R is cyclopropyl, cyclopentyl, or cyclohexyl; R is tert.-butyl .~nd R is cyclopentyl.
Crowther, et al., U.S. 3,501,769 patented March 17, 1970 generically discloses compounds of the type ~} OCH2C-rlCH-N~-F2 Rls R3 wherein R is alkyl (up to 10 C); R is alkyl (up to 20 C), cyclo alkyi (up to 10 C), etc.~ R is hydrogen or alkyl (up to 10 C).
~lotwithstanding the scope of the generic disclosure, Cro~ther, et al.
does not des;ribe a single example of a specif~ic "alkylthio' compound.
Koppe, et al., ~.S. 3,872,147 pa,ented March 18, 1975 generically discloses alkylthiophenoxypropanolamines illustrated by tne formula ~ OC~2CUCH ~H R2 -~herein R is alkyl (1-4 C); ~ is alkyl (Cl-C5); R is alkyl ~C5-C8) containing at least one quatPrnary carbon attached directly through an alkylene chain (Cl-C4) to ths amino nitrogen atom. None of the specifically disclosed ~oppe, et al. compounds, however, constitute an example Gf an "alkylthiophenoxpropanolamine'~.
Offenlegungsschrift 2,551,141 published ~ay 18, 1977, specifically ciescribes the al'.cylthiophenoxypropanolamine .~ 63~
:., , CH35 ~ OCUzCHCH2NH
3 : ;
~, ' .
As can be seen from the above prior art, numerous alkyl- : :
thiophenoxypropanolamines have been generically disclosed but ~-relatively few alkylthiophenoxypropanolamines are specifically described. Compared to the prior art compoDnds which are reportedly beta-adrenergic blocking agents, the alkylthiophenoxypropanolami.nes of the present invention are unique in that they redlue vascular - ~', ':'`,'' resi6tance with minimal involvement of beta-adrenergic blocking :
effects.
Summary o~ the Inveotio~ :
:~
Broadly described,~the present invention is directed to .
a process for preparing an alkylthiophenoxypropanolamine compound of formula I
R ~ OH A
~ B (I) wherein A, B, and R are independently hydrogen or lower alkyl of 1 to 4 carbon a~oms lnclusive; Rl is alkyl of 1 to 8 carbon atoms inclusive;
R2 is alkyl of 6 to 12 carbon atoms inclusive or cycloalkylalkyl having 5 to 8 ring carbon atoms and from 2 to 6 carbon atoms in the alkylene chain selected from the procesæ group consisting of:
(a) reacting an alkylthiophenol deriva~ive of formula Il ~ :.
Rl-S : :
B _ 4 _ - ' ,,, . . ~ ; ~ , i3~
wherein R and Rl have meanlngs hereinab.oye described with an epihalo-hydrin of formula III
~ cu~cH2-X (III) wherein X signifies halogen, preferably chlorine or bromine, and condensing the epihalohydrin reaction product with an amine of formula IV
H2N-R2 (TV2 wherein R2 has the meaning as in formula (I);
(b) reacting a formula II phenol with a compound of formula VII in alkaline medium ~ O / 2 , 2 (YII2 to provide a compound of formula VIII
R
OH
~ OCH2CHCH2 N, R2 (VIII) wherein R, Rl and R2 have the same meaning as in formula I and R3 stands for hydrogenolysable radicals benzyl or benzhydryl; and converting said compound of formula VIII to an alkylthiophenoxy-propanolamine of formula I by catalytic hydrogenation; and (c) reducing a compound of formula IX
OH A
OCH2CH-C-N02 (IX) Rl-S
wherein A, B, R and Rl are as defined to provide the primary amino compound X
- 4a ~ ~6~36 ~ OH A
OCH2CH~ (X) Rl , and reductively alkylating a compound of formula X with an aldehyde of formula XI
O
HC-Y (XI) 5 wherein Y is straight or branched chain alkyl of 5 to 11 carbon atoms :
inclusive or cycloalkylalkyl having 5 to 8 ring carbon atoms and 1 to 5 carbon atoms in the alkylene chain; and, if desired, reacting a compound of formula I with an acid to form an acid addition salt thereof.
- 4b -This invention is also concerned with pharmaceutical compositions containing the alkylthiophenoxypropanolamines, and further contemplates methods for both producing and employing the compounds and compositions therapeutically.
Detailed Description of the Invention The alkylthiophenoxypropanolamines provided by this invention are represented by formula I
OH A
R ~
~ OCH2CH-C-NH-R2 (I) Rl-S
wherein A, B and R are independently selected from the group consisting of hydrogen and lower alkyl of 1 to 4 carbon atoms inclusive;
Rl is alkyl of 1 to 8 carbon atoms inclusive;
R2 is alkyl of 6 to 12 carbon atoms inclusive or cycloalkylalkyl having 5 to 8 ring carbon atoms inclusive and from 2 to 6 carbon atoms in the alkylene chain, and pharmaceutically acceptable acid addition salts thereof.
As used herein, the term "lower alkyl" refers to a carbon chain comprised of both straight and branched chain carbon radicals of 1 to 4 carbon atoms inclusive. Exemplary of these carbon chain radicals are methyl, ethyl, propyl, isopropyl, l-butyl, l-methyl-propyl, 2-methylpropyl, and tert.-butyl~
As used herein, the term "alkyl" refers to straight or branched chain carbon radicals with the number of carbon atoms comprising the particular alkyl radical specifically designated or referred to by standard notations such as (Cl-C4), (Cl-C8) and (C6-C12) .
As used herein, the term "cycloalkylalhyl" is intended to refer to a cycloallcyl radical containing from 5 to 8 carbon atoms inclusive (i.e., cyclopentyl, cyclohexyl~ cycloheptyl and cyclooctyl) connected to the amino nitrogen atom by an alkylene chain of 2 to 6 carbons.
It is to be understood that the "alkylene chain" connecting the cycloalkyl radical to the amino nitrogen atom may be linear or branched.
As used herein, the term "non-toxic pharmaceutically acceptable acid addition salts" refers to salts of compounds of formula I formed with a variety of inorganic and organic acids, the anions of which are relatively non-toxic. Such acid addition salts are considered pharmacologically equivalent to the bases charact~rized by structural formula I. ~xamples of useful salt forming acids are acetic, Iactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydro-chloric, hydrobromic~ hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzenesulfonic, p-toluenesulfonic, and related acids. Acid addition salts of this invention are prepared and isolated by conventional means; for insLance, by treating a solu~ion or suspension of the fr.~e base ~n a reaction inert solvent with the ~ 3 ~
desired acid and recovering the salts which form by concentration under reduced pressure or by crystallization techniques or other standard chemical manipulations. Acid addition salts which are somewhat toxic and therefore do not meet the foregoing criteria for pharmacetical acceptability are sometimes useful as intermediates for isolation and purification of the bases of formula I or fcr other chemical purposes such as separation of optical isomers. Such salts are also considered part of the invention.
As will be apparent tO those skilled in the art, the compounds characterized by general formula I have one or more assymmetric carbon atoms and can thus exist as optically active isomers, racemates and diastereoisomers all of which are considered as part of the p_esent invention. The diastereoisomeric mixtures may, depending on physical-chemical differences of the components, be separated into diastereomeric pure racemates by conventional means such as chroma,ography and/or fractional crystallizatJon.
~eso]ution of racemates of the instant invention to provide optically active isomers of formula T compounds is carried out by conventional resolution methods. For instance, reacting the bases of formula I
with optically active acids provides salts thereof from which the enantiomers may be separated by fractional crystallization. Acids suitable for resolving the compounds of formula I are the optically active forms of tartaric acid, di-o-tolyltartaric acid, diacetyl-tartaric acid, dibenzoyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, and other optically active acids known to the art. Preferably, the more bio1Ogically active optically active stereoisomer is isolated.
/
Contemplated sub-classes within the ambit of formula I
which further characterize the alkylthiophenoxypropanolamines of the invention are compounds of formula I wherein (Ia~ A, B and R are hydrogen and substituents Rl and R2 are as previously defined for formula I;
(Ib) A, B and R are hydrogen, Rl is methyl and substituent R2 is as previously defined for formula I;
(Ic) A, B and R are hydrogen, Rl is methyl and substituent R2 is (C6-C12) alkyl;
(Id) A, B and R are hydrogen, Rl is lower ~Cl-C4) alkyl and R2 is (C6-C12) alkyl;
(Ie) A, B and R are hydrogen, Rl is (Cl-C8) alkyl and R is (C -C 2) alkyl;
2 6 (If) A, B and R are hydrogen, Rl is isopropyl and substituent R2 is as previously defined for formula I;
(Ig) A, B and R are hydrogen, Rl is isopropyl and R2 is (C6-C12) alkyl;
(Ih) A, B and R are hydrogen, Rl is (Cl-C8) alkyl and R2 is n-octyl;
(Ii) A, B and R are hydrogen, Rl is (Cl-C4) alkyl and R2 is n-octyl;
(Ij) A, B and R are hydrogen, Rl is (Cl-C8) alkyl with the RlS radical in the para-position and R2 is (C6-C12) alkyl;
(Ik) A, B and R are hydrogen, Rl is (Cl-C4) alkyl ~-ith the RlS radical în the para-position and R2 is (C6-C12) alky ;
(Il) A, B and R are hydrogen, Rl is (Cl-C4) alkyl with the RlS radi cal in the pa a-position and R2 ls n-octyl;
, (Im) A, B and R are hydrogen, Rl is (Cl-C8) alkyl wlth the RlS radical in the ortho-position and R2 is (C6-Cl~) alkyl;
(In) A, B and R are hydrogen~ Rl is (Cl-C4) alkyl with the RlS radical in the ortho-posit:ion and R2 is n-octyl;
(Io) A and B are hydrogen, R is (Cl-C4) alkyl in the rtho-position, and R2 is n-octyl;
(Ip) A and R are hydrogen, B is (Cl-C4) alkyl, Rl is (Cl-C4) alkyl with the RlS radical in the ~ -position, and R2 is (C6-C12) alkyl;
(Iq) A and R are hydrogen, B is (Cl-C4) alkyl, Rl is (Cl-C4) alkyl with the RlS radical in the para-position, and R2 is n-octyl;
(Ir) A and R are hydrogen, B is methyl, Rl is (Cl-C8) . alkyl and R2 is (C6-C12) alkyl~
(Is) A and R are hydrogen, B is methyl, Rl is (Cl C8) alkyl and R2 is n-octyl.
(It) A, B and R are independently hydrogen or lower (Cl-C4) alkyl, Rl is (Cl-C8) alkyl with the R,S
radical in the ~ -position and R2 is (C5-C8) cycloallcyl attached through an alkylene chain of 2 to 6 carbon atoms inclusive tc the amino nitrogen atom;
~Iu) A, B and R ar~ hydrogen, Rl is (Cl-C8) alkyl with the RlS radical in the para-position and R2 is (C5-C8) cycloalkyl attached through an alkylene chain of 2 to 6 carbon atoms inclusive to the amino nitrogen atom, (Iv) A, B and R are hydrogen, Rl is (Cl-C8) alkyl with the RlS radical in the meto-position and R2 is (C6-C12) alkyl, (Iw) A, B and R are hydrogen, Rl is (Cl-C4) alkyl with the RlS radical in the meta-position and R2 is n-octyl.
According to a feature of the present invention, there i~
provided a process for preparing those alkylthiophenoxypropanol-amines of formula I wherein A and B are limited to hydrogen which comprises reacting an alkylthiophenol derivative of formula II
R ~
~ /~ OH (II) T
Rl-S
wherein R and Rl have meanings hereinabove described with an epihalohydrin of for~ula III
CH ~ CH-CH2-X (III~
wherein X signifies halogen, preferably chlorine or bromine, and condensing the epihalohydrin reaction product with an amine of formula IV
82N-R2 . ~IV) wherein R2 has the meaning hereinabove described; whereafter, if desired, the formula I product in free base form is reacted with an acid to form an acid addition salt thereof.
The required formula Il alkylthiophenols are ob~ained by coupling a diazotized aminophenol with an alkyl mercaptan to form a diazosulfide wilich is then decomposed providing the corresponding alkylthiophenol. This is a conventional method and adaptations thereof are described in R. B. Wagner, and H. D. Zook, ~y~ ic Organic Chemistry, page 739 (1953 Wiley); E. Miller, et al., J. Am.
Chem. Soc., 55, 1224 ~1933); S. Asak3, et al., Chem. Abrs. 61, 13243a.
Suitable Alkylthiophenol reactants of formula II which may be employed in the present process include:
4-methylthiophenol, 4-ethylthiophenol, 4-n-propylthiopheno~, 4-n-butylthiophenol, 4-n-pentylthiophenol, 4-n-hexylthiophenol, 4-n-heptylthiophenol, 4-n-octylthiophenol, 4-isopropylthiop'nenol, 4-(3-methylbutyltilio)phenol, 2-n-butylthiophenol,
(Ig) A, B and R are hydrogen, Rl is isopropyl and R2 is (C6-C12) alkyl;
(Ih) A, B and R are hydrogen, Rl is (Cl-C8) alkyl and R2 is n-octyl;
(Ii) A, B and R are hydrogen, Rl is (Cl-C4) alkyl and R2 is n-octyl;
(Ij) A, B and R are hydrogen, Rl is (Cl-C8) alkyl with the RlS radical in the para-position and R2 is (C6-C12) alkyl;
(Ik) A, B and R are hydrogen, Rl is (Cl-C4) alkyl ~-ith the RlS radical în the para-position and R2 is (C6-C12) alky ;
(Il) A, B and R are hydrogen, Rl is (Cl-C4) alkyl with the RlS radi cal in the pa a-position and R2 ls n-octyl;
, (Im) A, B and R are hydrogen, Rl is (Cl-C8) alkyl wlth the RlS radical in the ortho-position and R2 is (C6-Cl~) alkyl;
(In) A, B and R are hydrogen~ Rl is (Cl-C4) alkyl with the RlS radical in the ortho-posit:ion and R2 is n-octyl;
(Io) A and B are hydrogen, R is (Cl-C4) alkyl in the rtho-position, and R2 is n-octyl;
(Ip) A and R are hydrogen, B is (Cl-C4) alkyl, Rl is (Cl-C4) alkyl with the RlS radical in the ~ -position, and R2 is (C6-C12) alkyl;
(Iq) A and R are hydrogen, B is (Cl-C4) alkyl, Rl is (Cl-C4) alkyl with the RlS radical in the para-position, and R2 is n-octyl;
(Ir) A and R are hydrogen, B is methyl, Rl is (Cl-C8) . alkyl and R2 is (C6-C12) alkyl~
(Is) A and R are hydrogen, B is methyl, Rl is (Cl C8) alkyl and R2 is n-octyl.
(It) A, B and R are independently hydrogen or lower (Cl-C4) alkyl, Rl is (Cl-C8) alkyl with the R,S
radical in the ~ -position and R2 is (C5-C8) cycloallcyl attached through an alkylene chain of 2 to 6 carbon atoms inclusive tc the amino nitrogen atom;
~Iu) A, B and R ar~ hydrogen, Rl is (Cl-C8) alkyl with the RlS radical in the para-position and R2 is (C5-C8) cycloalkyl attached through an alkylene chain of 2 to 6 carbon atoms inclusive to the amino nitrogen atom, (Iv) A, B and R are hydrogen, Rl is (Cl-C8) alkyl with the RlS radical in the meto-position and R2 is (C6-C12) alkyl, (Iw) A, B and R are hydrogen, Rl is (Cl-C4) alkyl with the RlS radical in the meta-position and R2 is n-octyl.
According to a feature of the present invention, there i~
provided a process for preparing those alkylthiophenoxypropanol-amines of formula I wherein A and B are limited to hydrogen which comprises reacting an alkylthiophenol derivative of formula II
R ~
~ /~ OH (II) T
Rl-S
wherein R and Rl have meanings hereinabove described with an epihalohydrin of for~ula III
CH ~ CH-CH2-X (III~
wherein X signifies halogen, preferably chlorine or bromine, and condensing the epihalohydrin reaction product with an amine of formula IV
82N-R2 . ~IV) wherein R2 has the meaning hereinabove described; whereafter, if desired, the formula I product in free base form is reacted with an acid to form an acid addition salt thereof.
The required formula Il alkylthiophenols are ob~ained by coupling a diazotized aminophenol with an alkyl mercaptan to form a diazosulfide wilich is then decomposed providing the corresponding alkylthiophenol. This is a conventional method and adaptations thereof are described in R. B. Wagner, and H. D. Zook, ~y~ ic Organic Chemistry, page 739 (1953 Wiley); E. Miller, et al., J. Am.
Chem. Soc., 55, 1224 ~1933); S. Asak3, et al., Chem. Abrs. 61, 13243a.
Suitable Alkylthiophenol reactants of formula II which may be employed in the present process include:
4-methylthiophenol, 4-ethylthiophenol, 4-n-propylthiopheno~, 4-n-butylthiophenol, 4-n-pentylthiophenol, 4-n-hexylthiophenol, 4-n-heptylthiophenol, 4-n-octylthiophenol, 4-isopropylthiop'nenol, 4-(3-methylbutyltilio)phenol, 2-n-butylthiophenol,
3-n-butylthiophenol, 2-ethylthiophenol, 2-n-propylthiophenol, 2-isopropylthiophenol, 3-ethylthiophenol, 3-n-propylthiophenvl, 3-isopropylthiophenol, 2-methyl-4-(methylthio)phenol, 3-methyl-4-(methylthio)phenol.
Suitable amines of formula IV which may be employed in the present process include:
n-hexylamine, n-heptylamine, n-octylamine, n-nonylamine, n-decylamine, _ n-undecylamine, n-dodecylamine, n-isoactylamine, 2,2-dimethylhexylamine, l,l-dimethylheptylamine.
Inasmuch as an epiha].ohydrin molecule of formula III has two reactive positions, reaction with an alkylthiophenol of formula II may yield a mixture of formulas V and VI reaction products wherein R, P~l and X are as defined above.
OH R ~
OCH2CHCH2-x ~ CH2CH - CH
Rl-S ~l-S
(V) ~VI) During the furtller course of the process, however, the two possible intermediat~s of formula V and formula VI on. condensation - .2 -i3~.o with a formula IV amlne yield the same final alkylthiophenoxypropanol-amine product. Consequently, it i3 not necessary to effect a separation of any mixtures of intermediates of formulas V and VI
which may result from interaction of a formula II phenol with a formula III epihalohydrin. Under the reaction conditions employed in the instant process, the epoxides of formula VI are preferentially formed.
If desired, the epihalohydrin reaction product may be taken up in an inert solvent such as chloroform and shaken with excess concentrated hydrochloric acid to convert epoxides of formula VI into the corresponding formula V alkylthiophenoxy-halohydrin.
Conversely, if desired, the halGhydrins of formula V may be converted to the corresponding formula VI by a conventional methods, e.g., by treatment with base according to the procedure of 0. Ste?henson, J.
15 Chem. Soc., 1574 (1954).
The interaction of formula II phenols with fGrmula III
epihalohydrins is carried out in the presence of a sufficient amount of a dilute aqueous alkaline metal hydroxide such as sodium hydroxide to neutralize the acidic p~enolic group at temper tures in the range 20 of 0-100 and preferably at 25-35 according to the procedure of Y. M. Beasley, et al., J. Pharm. Pharmacol., 10, 47-59 (195$).
Alternatively, the interaction of formula II phenols with fornula III epihalohydrins can also be effected with catalysts such as N-benzylisopropylamine hydrochloride, pyrrolidine, pyridine, piperidine, piperidine acetate, piperidine hydrochloride, and the like with an excess of epihalohydrin.
The condens~tion of the epillalohydrin reaction product of formula V or VI with a formula IV amine is carried out ?referably in organic solvent inert under the reaction conditions. Suitable solvents include methanol, ethanol, butanol, hexanol, toluene,.
dioxane, tetrahydrofuran, dibutylether, dimethoxyethane, ethylene glycol. The condensation can also be effected in the ab~ence of a reaction solvent with equimolar amounts of the react&nts.
Another feature of the present invention involves an alternate method for producing compounds of formula I wherein A
and B are limited to hydrogen which comprises reacting a formula II
phenol with a compound of formu.a VII in alkaline medium , C ~ ~-CH2-N-R (~II) to provide a compound of f ormula VIII
R ~ OH
OcH2cHcH2-N-R2 (VIII) Rl-S
wherein R, R~ and R~ have the same meaning as in formula I and R3 stands for hydrog~nolysabl.e radical such as ben~yl or benzhydryl;
and converting said compound of formula VIII to an alkylthiopheno~y-propanolamine of formula 1. Removal of ,he hydrogenol-J~able blockirg group may be effected by catalytic hydrogenation, for e~amp].e by hydrogenation in the presence of palladium-on-charcoal catalyst, in an inert solvent, e.g., ethanol or aqueous ethanol.
The compounds of formula ~II may be obtained according to known methods. ~or example, l-[(N-ben~yl)-n-octylamino]-2,3-epo~y-propane is obtainea by reaction of N-benzyl-n-octylamine and epichloro-hydrin in alkaline medium (e.g., aqueous potassium hydroxide) accordingto the method described by L. Villa, et al., Farmaco., Ed. Sci., 24(3), 349-357 (196g).
A further feature of the invention is directed to a method for producing compounds of formula I wherein A, B, and R are independently selected from the group consisting of hydrogen and lower (Cl-C4) alkyl, Rl is (Cl-C8) alkyl, and R2 is (C6-C12) straight or branched chain alkyl with the carbon atom thereof attached through a divalent methylene (i.e. -CH2-) radical to the amino nitrogen atom or (C5-C8) cycloalkyl attached through an alkylene chain of 2 to 6 car~on atoms inclusive wherein said alkylene chain is attached through a divalent methylene (i.e. -CH2-) radical to the amino nitrogen atom which comprises sequenti~l steps of reducing a compound of ~ormula IX
R OH A
OCH CH-C-NO2 (IX) Rl-S
wherein A, B, R and Rl are as defined to provide the primary amino compound X
OH A
'Q+s~ OC~12CH-C-~H~ (X~
Rl-S
&3~
wherein A, B, R and Rl are as defined, and reductively alkylating compound of formula X with an aldehyde of formula XI
o HC-Y (XI) wherein Y is straight or branched chain alkyl of 5 to 11 carbon atoms inclusive or cycloalkylalkyl having 5 to 8 ring carbon atoms and 1 to 5 carbon atoms in the alkylene chain.
The nitro alcohols of formula IX are obtained by an aldol-type condensation of a?propriate nitroalkanes and aldehydes in the presence of base or by condensation oE the Rodium salt of the nitro alkane with sodium bisulfite addition products of the aldehyde in the presence of a trace of alkali or weak acid. Alkylthiophenoxy aldehyde starting materials are obtained by reac~ng the appropriate alkylthiophenol with the diethylacetal of bromo-acetaldehyde followed by acid catalyzed hydrolysis of the acetal g~oups .
As stated hereinabove, the alkylthiophenoxypropanolamines of the present invention increase peripheral blood flow, relax vascular smooth muscle, and inhibit platelet aggregation. The compounds are substantially fr~e of beta-adrenergic blocking effects which inhibit peripheral vasodilating activity of beta-adrenergic stimulatory endogenous amines. Standard in vivo and in vitro pharmacological test methods can be employed in assessing the activity of compounds characterized by formula I. Among such tes.s consider~d useful are the perfused dog hind limb preparation (vaso-dilator action~, the spasmogen-challanged rabbit ~ortic strip (antispasmodic activity) and nhibition of adenosine diphosphate and -- 1 o collagen-induced platelet aggregation in human platelet-rich plasma (antithrombogenic action~. The isoproterenol chal'enged gulnea pig trachea test, which is standard in the art, is suitable for mezsuring beta-adrenergic blocking action.
In addition to having vasodilating, antispasmodic and inhibition of blood platelet aggregation properties, some of the compounds of Formula I inhibit lipoly3is (as shown in the rat epidimal fat pad lipolysis model) and cholesterol biosynthesis.
Compounds of this type are of value as hypocholesterolemic agentC.
Another aspect of the in~tant invention concerns a thera-peutic process for treating a mammal requiring vasodilation which comprises systemically administerïng to the mammal an effective vasodilating amount of a compound selected from the group charac-terized by formula I and pharmaceutically acceptable non-toxic acid addition salt thereof.
As used herein, the term "effective vasodilating amOuDt"
is construed to mean a dose which exerts a vasodilator effect in the effected mammal without untoward side effects.
By systemic administration, it is intended to include both oral and parenteral routes. ~xamples of parenteral administration are intramuscular~ intravenous, intraperitoneal, rectal, and sub-cutaneous administration. In rec,al adminlstration, both ointments and suppositories may be employed. While the dosage will vary to some extent with the mode of administration and the particular compound chosen, from about 0.5 Dlg. per kg. body weight ~o 25 mg.
per ~g. body weight of a co~pound characterized by formula I or non-toxic pnarmaceutlcaliy accepLable salts thereof administered i-.l 3~
effective single or multiple dosage units generally provides the desired vasodilating e~fect.
In carrying out the therapeutic process of the instant invention, the formula I compounds are generally administered for vasodilating purposes in the form of a pharmaceutical preparation containing either a formula I free base or a pharmaceutically acceptable non-toxic acid addition salt thereof as the active component in combination with a pharmaceutically acceptable carrier.
The carrier may be solid, semi-solid, liquid diluent or a capsule.
Accordingly, a further feature of the instant invention is directed to pharmaceutical compositions containing the compounds of formula I
or non-toxic pharmaceutically acceptable acid addition salts thereof in combinaticn with a pharm2ceutically acceptable carrier.
For the preparation of pharmaceutical compositions con-taining the compounds of formula I in the form of dosage units fororal administration, the compound is mixed with a solid, pulverulent carrier, (e.g. lactose, sucrose, sorbitol, manni,ol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin) as well as with an anti-friction agent (e.g. magnesium stearate, calcium stearate, polyethylene glycol waxes or the like) and pressed into tablets. The tablets m~y be used uncoated or coated by conventional techniques to delay disintegration and absorption in the gastro-intestinal tract thereby providing a sustained actior. over a longer time period. If co~ted tablets are wanted, the above prepared core may be coated with concentrated solution of sugar, which solution may contain e.g. gum, arabic, gelatin, talc, ~itanium dioxide, or the like. Furthermore, tablets may be coated with a lacquer clissolved 3~
in an easily volatile organic solvent or mixture of solv~nts. If desired, dye may be added to this coating.
In the preparation of soft gelatin capsules or in the preparation of similar closed capsules, the active compound is mixed with a vegetable oil. Hard gelatin capsules may contain granules of the active ingredient in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, starch, (e.g., potato starch, corn starcn, or amylopectin), cellulose derivatives or gelatin.
Dose units for rectal administration may be prepared in the form of suppositories containing the active substance oE formula I
in mixture with a neucral fat base, or they may be prepared in form Gf gelatin-rectal capsules conta~ning the active substance in a mixture with a vegetable oil or paraffin oil.
Liquid preparations for oral administration may be present in the form of elixirs, syrups or suspensions containing from about 0.2% by weight to about 20% by weight of the ac~ive ingre~ient.
Such liquid preparations may contain coloring agents, flavoring agents, sweetening agents, and carboxymethylcellulose as a thickening agent.
Suitable solutions for parenteral administration by injection may be prepared as an aqueous solution of a water-soluhle pharmaceutically acceptab]e salt of the comT)ounds of formula I
adiusted to a physiologically acceptable p~. These solutions may also contain stabilizing agents.
Pharmaceutical tab~ets for ora] use are prepar~d by conventional methods involvil~g mixing the ~herapeutic compound of formula I and necessary axillarv agents.
_ 19 _ Specific alkylthiophenoxypropanolamines of the invention are those hereinafter described in the examples. Of these9 compo~mds particularly preferred for their vasodilating properties and absence of significant beta-adrenergic blocking activity are:
1-[4-(methylthio)phenoxy]-3-(octylamino)-2-propanol, 1-[4-[(1-methylethyl)thio]phenoxy]-3-(octylamino)-2-propanol, 1-[3-[(1-methylethyl)thio]phenoxy]-3-(octylamino)-2-propanol, 1-[4-[(1-methylethyl)thio]phenoxy]-3-(dodecylamino)-2-propanol, 1-[(2-cyclohexylethyl)amino]-3-[4-[(1-methylethyl)thio]-phenoxy]-2-propanol, 1-[(4-cyclohexylbutyl)amino]-3-[4-~(1-methylethyl~thio]-phenoxy]-2-propanol, 1-[2-methyl-4-(methylthio)phenoxy]-3-(octylamino)-2-propanol, 1-[2-(methylthio)phenoxy]-3-(octylamino)-2-propanol.
The following examples illustrate but do not limit the scope of the invention. All temperatures expressed herein are in degrees centigrade.
l-[4-(Methylthio)phenoxy]-3-(octylamino)-2-propanol ~ OH
3 ~ OCH2CHCH2~H-(CH2)7CH3 A solution of 4-(methylthio)phenol (5,6 g., 0.04 moles) 25 and soclium hydroxide ~2.4 g., 0.06 moles) in 50 ml. of water is treated ~ith epichiorohydrin (7.4 g., 0.08 moles). The resulting mixture is first stirred at 30-35 for 24 hr. and then extracted with chloroform. After washing the chloroform extract with water and drying over magnesium sulfate, distilla~les are removed under reduced pressure to provide the epichlorohydrin derivative 1-(4-methylthlo)phenoxy-2,3-epoxypropane which is taken up in 30 ml. of ethanol, treated with n-octylamine (7.5 g., 0.06 mole) and refluxed for a period of 4 hr. Concentration of the reaction mixture under reduced pressure to about one-half volume provides a white solid which is collected and crystallized from ethanol to afford a 21%
yield of analytically pure 1-[4-(methylthio)phenoxy]-3-'octylamino)-2-propanol, m.p. 79.5-80.5 (corr.).
Anal. Calcd. for C18H31NO2S: C, 66.42; H, 9.60; N, 4.30;
S, 9.85. Found: C, 66.30; H, 9.69; N, 4.13; S, 9.58.
EXAMPL~ 2 1-[4-~(1-Methylethyl)thio]phenoxy]-3-(octylamino)-2-propanol Hydrochloride ~ OH
(Cl~3)2cH-s ~ OcH2cHcH2~-(cH2)7c~3 (a) 4-(Isopropylthio)phenol.- A solution of sodiun nitrite (113.8 ~., 1.65 mole) in 210 ml. of water is added to a stirred solutiGn of p-aminophenol (163.7 g., 1.5 mGle) in 825 ml.
of 4 N hydrochloric acid at -5 . After stirring for an additional 2 hr. period at -5, the solution of the diazotized phenol is added over a 45 min. period to a previously prepared cold (-5) solution of sodium hydroxide (270.6 g., 6.77 moles) and 2-propanethiol (126.4 g., 1.66 moles) in 525 ml. of water with the reaction maintained under a nitrogen atmosphere. I~hen addition is complete, the mixture is permitted to warm to 27 and is kapt at that temperature for a period of 16 hr. Then, the mixture is cooled to Oc and acidified with 570 ml. of 12 N hydrochloric acid. Excess 2-propanethiol is removed by bubbling nitrogen gas through the acidified solution into a permanganate trap for a 2 hr. period. The resulting solution is extracted with several portions of dichloromethane and the combined extracts washed with water, dried over magnesium sulfate containing charcoal and filtered. Concentration of the filtrate under reduced pressure provides a residual oil which is distilled affordirg 81 g.
(32% yield) of 4-(isopropylthio)phenoi, b.p. 114-123 (1.2 mm Hg).
(b) A solution of 4-(isopropylthio)phenol, ($.6 g., 0.04 mole) and sodium hydroxide (2.6 g., 0.065 mole) in 50 ml. of water 15 is treated with epichlorohydrin (7.4 g., 0.08 moles). T-ne resulting mixture is first stirred at 30-35 for 24 hr. &nd then extracted with chloroform. After washing the chloroform extract with water and drying over magnesium sulfate, distillables are removed under reduced pressure to provide the epichlorohydrin intermediate 1-(4-isopropylthiophenoxy)-2,3-epoxypropane. The epichlorohydrin inter-mediate is taken up in 30 ml. of ethanol, treated with n-octylamine (7.5 g., 0.06 mole) and refluxed for a period of 4 hr. Concen-tration of the reaction mixture under reduced pressure affords a residue which is taken Up in ethanol and treatet with 5 ml. of 12 N
hydrochloric acid. Concentration of the asidified solution under reduced pressure and crystalli~ation of residual material from ethanol provid~s an analytically pure (20~ yielt) 1-[4-i(l-methyl-ethyl)thio]pheno~y]-3-(octylamino)-2-propanol hydrochloride, m.p. 171-173-186.5 (corr.) (double melting point).
Anal. Calcd. for C2 H ~O2S.HCl: C, 61.59; H, 9.30; N, 3.59;
S9 8.22; Cl, 9.09. Found: C, 61.68, H, 9.29; N, 3.47; S, 8.15; Cl, 9.15.
1-[3-[(1-Methylethyl)thiolphenoxy]-3-(octylamino)-2-propanol Hydrochloride OH
~ OCH2CHCH2NH-(CH2)7CH3 (Ca3) 2CH-S
Reaction of the epichlorohydrin derivative of 3-(isopropyl-thio)phenol (4.85 g., 0.029 mole) with n-octylamine (4 g., 0.031 mole) according to the procedure of Example 2~b) and crystalliæation of the crude product from ethanol-ether affords a 13% yield of analytically pure 1-[3-[(1-methylethyl)thio]phenoxy]-3-(c.tylamino)-2-propanol hydrochloride, m.p. 12;-127 (corr.).
Anal. Calcd. for C20H35N02S.HCl: C, 61.59; H, 9.30; N, 3.59. Found: C, 61.22; H, 9.09; N, 3.53.
1-[4-[(1-Methylethyl)thio]phenoxy]-3-(dodecylamino)-2-Propanol Hydrochloride OH
(CH3?2CH-S - ~ OCH2CHCH2~H-(cH2)l1c 3 Reaction of the epichlorohydrin derivative of 4-(isopropyl-thio)phenoi ~15.7 g., 0.07 mole) with n-dodecylamine (13.9 g., 0.075 mole) according to the procedure of Example 2(b) and crystallization of the crude product lrom n;ethanol affords a 13~ yield of analytically pure 1-[4-[(1-methylethyl)thio]phenoxy]-3-dodecylamino)-2-propanol hydrochloride, m.p. 153.5-156.6-190.5 (corr.) (double melting pOillt).
Anal. Calcd. for C24H43N02S.HCl: C, 64.61; H, 9.94, ~, 3.14. Found: C, 64.38; H, 10.07; N, 2.97.
1-[(2-Cyclohexylethyl)amino]-3-~4-[(1-methylethyl)thio]phenoxy3-2-propanol Hydrochloride OH
(CH3)2CH-S ~ OcH2cHcH2~H-(cH2)2 3 Reaction of the epichlorohydrin derivative of 4-(isopropyl-thio)phenol (5.0 g., 0.022 mole) with cyclohexylethylamine (3.3 g., 0.026 mole) according to the procedure of Example 2(b) and crystal-lization of the crude product from isopropyl alcohol affords an 18 yield of analytically pure 1-[(2-cyclohexylethyl)amino]-3-[4-[(l-methylethyl)thio]phenoxy]-2-propanol hy~rochloride, m.p. 180-182 (corr.).
Anal. Calcd. for C20H33N02S.HCl: C, 61.91; H, 8.83;
N, 3.61. Found: C, 61.73; H, 8.71; N, 3.88.
1-[~4-Cyclohexylbutyl)amino]-3-[4-[(1-methylethyl)thio]phenoxy]-2-propanol Hydrochloride ( 3j2 S ~ OCH2C~cH2NH~(c~2)4 3~`.i Reaction of the epichlorohydrin derivative of 4-(iso-propylthio)phenol ~9.0 g., 0.04 mole) with cyclohexylbutylamine (6.7 g., 0.043 mole) according to procedure of Example 2 (D) and crystallization of the crude product from ethanol affords an 11.4%
yield of analytically pure 1-[(4-cyclohexylbutyl)amino]-3-[4-[(l-methylethyl)thio]phenoxy]-2-propanol hydrochloride, m.p. 179 with prior softening from 118.
Anal. Calcd. for C22H37N02S-HCl: C, 63-51; H~ 9-20;
N, 3.37. Found: C, 63.46; H, 9.35; N, 3.29.
E~AMPLE 7 1-[2-Methyl-4-(methylthio)phenoxy]-3-(octylamino)-2-propanol OH
3 ~ OCH2CHCH2NH-(CH2)7CH3 The epichlorohydrin derivative of 2-methyl-4-(methylthio)-phenol (3.14 g., O.OlS mole) is reacted with n-octylamine (1.93 g.
0.015 mole) according to the procedure of Example 1. Concentrating the reaction mixture and crystallization of residual material from ethylacetate-hexane affords a 19% yield of analytically pure 1-[2-methyl-4-(methylthio)phenoxy]-3-(octylamino)-2-propanol, m.p. 59-60 (corr.).
Anal. Calcd. for ClgH33N02S: C, 67-21; H, 9-80; N~ 4-13-Found: C, 66.80; E, 9.92; N, 3.81.
- ~5 -1-[2-(Methyithio)phenoxy]-3-(octylamino)-2-propanol Hydrochloride OH
CH2CHCH2N~-(cll2)7cH3 Reactior. of the epichlorhydrin derivative of 2-(methyl-5 thio)phenol (14 g., 0.071 mole) with n-octylamine (9.04 g., 0.07 mole) according to the procedure of Example 2(b) and crystalli~ation of the crude product from methanol-ether affords an 18~ yield of analytically pure 1-[2-(methylthio)phenoxy]-3-(octylamino)-2-propanol hydrochloride, m.p. 105.5-107.5 (corr.).
10Anal. Calcd. for C18H31N02S.HCl: C, 59.73; H, 8-91 N, 3.87. Found: C, 59.86; H, 9.07; N, 3.71.
1-[4-[(1-Methylethyl)thio]phenoxy]-3-[(2,2-dimethyl-1-hexyl)amino]-2-propanol ~ OH ,CH3 ( 3)2 ~ OCH2CHCH2NH-CH2,C-(CH2)3CH3 (a~ 2,2-Dimethylhex-l-ylamine.- A solution of capro-nitrile (25 g., 0.26 mole) and methyl iodide (75 g., 0.53 mole) in 80 ml. of dry toluene is warmed to 80 and treated gradually ~ith a suspension of sodium amide (25.4 g., 0.65 mole~ in 100 ml.
of toluene at 2 rate sufficient to maintain general reflux. After addition is compl~te, the mixture is stirred and refl1lxed for an additional 2 hr. per~od, cooled and treated with 150 ml. of water.
The organic layer is separated, washed with water and dried over magnesium sulfate. Concentral-ion of the dried solution under reduced pressure and distillation of residual material affords an 8l% yield of 2,2-dimethylcapronitrile.
A solution of 2,2-dimethylcapronitrile (10.0 g., 0.078 mole) in 100 ml. of ether is added slowly to a suspension of lithium aluminum hydride (6.0 g., 0.158 mole) in 200 m~. of ether while maintaining the reaction at 0-5 . After stirring the reaction mixture for an additional 2 hr. at 0.5 , the mixture is hydrolyzed by sequentially adding 6.0 ml. of water, 6.0 ml. of 15% sodium hydroxide solution, and finally 18 ml. of water. The hydrolyzed mixture i5 stirred for an additional hour, filtered and the ether pha~e concentrated under reduced pressure. Distillation of residual material provides 2,2-dimethylhex-1-ylamine.
(b) Reaction of the epichlorhydrin derivative of 4-(isopropylthio)phenol with 2,2-dimethylhex-1-ylamine according to the procedure of Example 2(b) and conversion of the free base to the hydrochloride provides 1-[4-[(1-methylethyl)thio]phenoxy]-3-[(2,2dimethyl-1-hexylamino]-2-propanol hydrochloride.
1-[4-[(1-Methylethyl)thio]phenoxy]-3-[(2-methyl-2-octyl)amino]-2-propanol ~ 0,Y. CH3 (CH3)2CH-S--~ OCH2CT~CH2NH-C, (Cff2)5 3 (a) 2-Ketnyl-2-octanol.- A solution of ~ethyl-heptanoate (14.5 g., Q.l mole) in 200 ml. of ether is added to .. . .
3~
200 ml. of 3~1 solutioll (0.6 mole) of methyl magnesium bromide in ether at a rate sufficient to maintain refluxing. After addition is complete, the resulting mixture is refluxed for l hr. and then stirred at 26 for a 16 hour period. The mixture is hydrolyzed by the addition of d lute ammonium chloride solution, filtered and the filter cake dissolved in 2N hydrochloric acid and extracted with ether. The ethereal extract and filtrate are combined, sequen~ially washed with water, dilute sodium bicarbonate solution and brine and dried over magnesium sulfate. Concentration of the dried solution and distillation of residual material under reduced pressure provides 13.1 g. (91% yield) of 2-methyl-2-octanol, b.p. 130 (100 mm Hg).
(b) N-(2-~lethyl-2-octyl)acetamide.- A solution of con-centrated sulfuric acid (5.55 g., 0.055 mole) in 32 ml. of glacial acetic acid is treated with acetonitrile (2.5 g., 0.016 mole) and 2-15 methyl-2-octanol (8.0 g., 0.055 mole) ~nd the resulting mixture stirred at 26 for a 17 hr. period. After diluting with 125 ml. o water, the mixture is extracted with ether and the ethereal extract sequentially ~ashed with water, dilute sodium bicarbonate solution and brine and dried over magnesium sulfate. Concentration of the 20 dried solution provides 8.7 g. (85% yield) of N-(2-methyl-2-octyl)-acetan~ide which is used in the next step without further purification.
(c) 2-Methyl-2-octylamine.- A solution of potassium hydroxide (10.0 g., 0.18 mole) in lO0 ml. of ethylene glycol is treated with N-(2-metnyl-2-octyl)acetamide (13.0 g., 0.07 mole) and 25 the mixture heated at 200 for a 64 hr. period. The reaction m xture is diluted with 400 ml. of water and extracted with ether.
The ethereal extract is washed with water and brine and then dried - 2~ -.. . .
~ ~4fi3~
over sodium sulfate. Concentration of the dried solution under reduced pressure affords 10.4 g. (62% yield) of 2-methyl-2-octyl-amine which is used in the next step without further purification.
(d) 1-[4-[(1-Methylethyl)thio]phenoxy]-3-[(2-methyl-2-S octyl)amino]-2-propanol Preparation.- A solution of the epichlo-hydrin derivative of 4-(isopropylthio)phenol (7.8 g., 0.035 mole) and 2-methyl-2-octylamine (5.0 g., 0.035 mole) in 100 ml. of ethanol is refluxed for a 17 hr. period. The reaction mixture is concen-trated under reduced pressure and residual material heated at 80 (0.5 mm Hg) to remove residual excess reagents. The crude free base is treated with 6N hydrochloric acid to provide the hydrochloride salt which crystallized from ether-hexane ~ffords 3.0 g. (21% yield) of l-[4-[(1-methylethyl)thio]phenoxy]-3-[(2-methyl-2-octyl)a~ino]-2-propanol hydrochloride, m.p. 165.
3-Methyl-1-[4-[(1-methylethyl)thio]-phenoxy]-3-(octylamino)-2-butanol -- OH CH
( 3)2C~ S ~ OcH2cH-c-NH-(cH2)7CH3 (a) Diethylacetyl of 4-[(1-methylethy])thio]phenoxy~
acetaldehyde.- A solution of 4-[(1-methylethyl)thio]phenol (24.2 g., 0.144 mole) in 180 ml. of 2-ethoxyethanol is treated with 7.2 g.
of a 50% dispersion of sodium hydride in mineral oil and the mixture stirred until hydrogen evolution ceases. The diethylacetal of bromoacetaldehyde (30.0 g., 0.152 mole) is added to the reaction mixture which is ~hen stirred and refluxed for a 19 hr. period, -- 2g --cooled, diluted with water and extracted with ether. Ether extracts are combined, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to an oil. Distillation of residual oil under reduced pressure provides 28.1 g., (69% yield) of the diethylacetal of 4-[(1-methylethyl),hio]phenoxyacetaldehyde, b.p. 142-146 (0.07 mm Hg).
(b) 4-[(1-Methylethyl)thio]phenoxyacetaldehyde.-solution of the diethylacetal of 4-[(1-methylethyl)thio]phenoxy-acetaldehyde (10 g., 0.035 mole) in 100 ml. of aqueous ethanol (60:40) is treated with 5 ml. of 6N hydrochlor~c acid and the resulting mixture refluxed for a period of 2 hr. The cooled mixture is partitioned between ether and water and the ethereal phase washed with water and brine and then dried over magnesium sulfate. Concentration of the dried ethereal solution under reduced pressure and distillation of .esidual materia] affords
Suitable amines of formula IV which may be employed in the present process include:
n-hexylamine, n-heptylamine, n-octylamine, n-nonylamine, n-decylamine, _ n-undecylamine, n-dodecylamine, n-isoactylamine, 2,2-dimethylhexylamine, l,l-dimethylheptylamine.
Inasmuch as an epiha].ohydrin molecule of formula III has two reactive positions, reaction with an alkylthiophenol of formula II may yield a mixture of formulas V and VI reaction products wherein R, P~l and X are as defined above.
OH R ~
OCH2CHCH2-x ~ CH2CH - CH
Rl-S ~l-S
(V) ~VI) During the furtller course of the process, however, the two possible intermediat~s of formula V and formula VI on. condensation - .2 -i3~.o with a formula IV amlne yield the same final alkylthiophenoxypropanol-amine product. Consequently, it i3 not necessary to effect a separation of any mixtures of intermediates of formulas V and VI
which may result from interaction of a formula II phenol with a formula III epihalohydrin. Under the reaction conditions employed in the instant process, the epoxides of formula VI are preferentially formed.
If desired, the epihalohydrin reaction product may be taken up in an inert solvent such as chloroform and shaken with excess concentrated hydrochloric acid to convert epoxides of formula VI into the corresponding formula V alkylthiophenoxy-halohydrin.
Conversely, if desired, the halGhydrins of formula V may be converted to the corresponding formula VI by a conventional methods, e.g., by treatment with base according to the procedure of 0. Ste?henson, J.
15 Chem. Soc., 1574 (1954).
The interaction of formula II phenols with fGrmula III
epihalohydrins is carried out in the presence of a sufficient amount of a dilute aqueous alkaline metal hydroxide such as sodium hydroxide to neutralize the acidic p~enolic group at temper tures in the range 20 of 0-100 and preferably at 25-35 according to the procedure of Y. M. Beasley, et al., J. Pharm. Pharmacol., 10, 47-59 (195$).
Alternatively, the interaction of formula II phenols with fornula III epihalohydrins can also be effected with catalysts such as N-benzylisopropylamine hydrochloride, pyrrolidine, pyridine, piperidine, piperidine acetate, piperidine hydrochloride, and the like with an excess of epihalohydrin.
The condens~tion of the epillalohydrin reaction product of formula V or VI with a formula IV amine is carried out ?referably in organic solvent inert under the reaction conditions. Suitable solvents include methanol, ethanol, butanol, hexanol, toluene,.
dioxane, tetrahydrofuran, dibutylether, dimethoxyethane, ethylene glycol. The condensation can also be effected in the ab~ence of a reaction solvent with equimolar amounts of the react&nts.
Another feature of the present invention involves an alternate method for producing compounds of formula I wherein A
and B are limited to hydrogen which comprises reacting a formula II
phenol with a compound of formu.a VII in alkaline medium , C ~ ~-CH2-N-R (~II) to provide a compound of f ormula VIII
R ~ OH
OcH2cHcH2-N-R2 (VIII) Rl-S
wherein R, R~ and R~ have the same meaning as in formula I and R3 stands for hydrog~nolysabl.e radical such as ben~yl or benzhydryl;
and converting said compound of formula VIII to an alkylthiopheno~y-propanolamine of formula 1. Removal of ,he hydrogenol-J~able blockirg group may be effected by catalytic hydrogenation, for e~amp].e by hydrogenation in the presence of palladium-on-charcoal catalyst, in an inert solvent, e.g., ethanol or aqueous ethanol.
The compounds of formula ~II may be obtained according to known methods. ~or example, l-[(N-ben~yl)-n-octylamino]-2,3-epo~y-propane is obtainea by reaction of N-benzyl-n-octylamine and epichloro-hydrin in alkaline medium (e.g., aqueous potassium hydroxide) accordingto the method described by L. Villa, et al., Farmaco., Ed. Sci., 24(3), 349-357 (196g).
A further feature of the invention is directed to a method for producing compounds of formula I wherein A, B, and R are independently selected from the group consisting of hydrogen and lower (Cl-C4) alkyl, Rl is (Cl-C8) alkyl, and R2 is (C6-C12) straight or branched chain alkyl with the carbon atom thereof attached through a divalent methylene (i.e. -CH2-) radical to the amino nitrogen atom or (C5-C8) cycloalkyl attached through an alkylene chain of 2 to 6 car~on atoms inclusive wherein said alkylene chain is attached through a divalent methylene (i.e. -CH2-) radical to the amino nitrogen atom which comprises sequenti~l steps of reducing a compound of ~ormula IX
R OH A
OCH CH-C-NO2 (IX) Rl-S
wherein A, B, R and Rl are as defined to provide the primary amino compound X
OH A
'Q+s~ OC~12CH-C-~H~ (X~
Rl-S
&3~
wherein A, B, R and Rl are as defined, and reductively alkylating compound of formula X with an aldehyde of formula XI
o HC-Y (XI) wherein Y is straight or branched chain alkyl of 5 to 11 carbon atoms inclusive or cycloalkylalkyl having 5 to 8 ring carbon atoms and 1 to 5 carbon atoms in the alkylene chain.
The nitro alcohols of formula IX are obtained by an aldol-type condensation of a?propriate nitroalkanes and aldehydes in the presence of base or by condensation oE the Rodium salt of the nitro alkane with sodium bisulfite addition products of the aldehyde in the presence of a trace of alkali or weak acid. Alkylthiophenoxy aldehyde starting materials are obtained by reac~ng the appropriate alkylthiophenol with the diethylacetal of bromo-acetaldehyde followed by acid catalyzed hydrolysis of the acetal g~oups .
As stated hereinabove, the alkylthiophenoxypropanolamines of the present invention increase peripheral blood flow, relax vascular smooth muscle, and inhibit platelet aggregation. The compounds are substantially fr~e of beta-adrenergic blocking effects which inhibit peripheral vasodilating activity of beta-adrenergic stimulatory endogenous amines. Standard in vivo and in vitro pharmacological test methods can be employed in assessing the activity of compounds characterized by formula I. Among such tes.s consider~d useful are the perfused dog hind limb preparation (vaso-dilator action~, the spasmogen-challanged rabbit ~ortic strip (antispasmodic activity) and nhibition of adenosine diphosphate and -- 1 o collagen-induced platelet aggregation in human platelet-rich plasma (antithrombogenic action~. The isoproterenol chal'enged gulnea pig trachea test, which is standard in the art, is suitable for mezsuring beta-adrenergic blocking action.
In addition to having vasodilating, antispasmodic and inhibition of blood platelet aggregation properties, some of the compounds of Formula I inhibit lipoly3is (as shown in the rat epidimal fat pad lipolysis model) and cholesterol biosynthesis.
Compounds of this type are of value as hypocholesterolemic agentC.
Another aspect of the in~tant invention concerns a thera-peutic process for treating a mammal requiring vasodilation which comprises systemically administerïng to the mammal an effective vasodilating amount of a compound selected from the group charac-terized by formula I and pharmaceutically acceptable non-toxic acid addition salt thereof.
As used herein, the term "effective vasodilating amOuDt"
is construed to mean a dose which exerts a vasodilator effect in the effected mammal without untoward side effects.
By systemic administration, it is intended to include both oral and parenteral routes. ~xamples of parenteral administration are intramuscular~ intravenous, intraperitoneal, rectal, and sub-cutaneous administration. In rec,al adminlstration, both ointments and suppositories may be employed. While the dosage will vary to some extent with the mode of administration and the particular compound chosen, from about 0.5 Dlg. per kg. body weight ~o 25 mg.
per ~g. body weight of a co~pound characterized by formula I or non-toxic pnarmaceutlcaliy accepLable salts thereof administered i-.l 3~
effective single or multiple dosage units generally provides the desired vasodilating e~fect.
In carrying out the therapeutic process of the instant invention, the formula I compounds are generally administered for vasodilating purposes in the form of a pharmaceutical preparation containing either a formula I free base or a pharmaceutically acceptable non-toxic acid addition salt thereof as the active component in combination with a pharmaceutically acceptable carrier.
The carrier may be solid, semi-solid, liquid diluent or a capsule.
Accordingly, a further feature of the instant invention is directed to pharmaceutical compositions containing the compounds of formula I
or non-toxic pharmaceutically acceptable acid addition salts thereof in combinaticn with a pharm2ceutically acceptable carrier.
For the preparation of pharmaceutical compositions con-taining the compounds of formula I in the form of dosage units fororal administration, the compound is mixed with a solid, pulverulent carrier, (e.g. lactose, sucrose, sorbitol, manni,ol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin) as well as with an anti-friction agent (e.g. magnesium stearate, calcium stearate, polyethylene glycol waxes or the like) and pressed into tablets. The tablets m~y be used uncoated or coated by conventional techniques to delay disintegration and absorption in the gastro-intestinal tract thereby providing a sustained actior. over a longer time period. If co~ted tablets are wanted, the above prepared core may be coated with concentrated solution of sugar, which solution may contain e.g. gum, arabic, gelatin, talc, ~itanium dioxide, or the like. Furthermore, tablets may be coated with a lacquer clissolved 3~
in an easily volatile organic solvent or mixture of solv~nts. If desired, dye may be added to this coating.
In the preparation of soft gelatin capsules or in the preparation of similar closed capsules, the active compound is mixed with a vegetable oil. Hard gelatin capsules may contain granules of the active ingredient in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, starch, (e.g., potato starch, corn starcn, or amylopectin), cellulose derivatives or gelatin.
Dose units for rectal administration may be prepared in the form of suppositories containing the active substance oE formula I
in mixture with a neucral fat base, or they may be prepared in form Gf gelatin-rectal capsules conta~ning the active substance in a mixture with a vegetable oil or paraffin oil.
Liquid preparations for oral administration may be present in the form of elixirs, syrups or suspensions containing from about 0.2% by weight to about 20% by weight of the ac~ive ingre~ient.
Such liquid preparations may contain coloring agents, flavoring agents, sweetening agents, and carboxymethylcellulose as a thickening agent.
Suitable solutions for parenteral administration by injection may be prepared as an aqueous solution of a water-soluhle pharmaceutically acceptab]e salt of the comT)ounds of formula I
adiusted to a physiologically acceptable p~. These solutions may also contain stabilizing agents.
Pharmaceutical tab~ets for ora] use are prepar~d by conventional methods involvil~g mixing the ~herapeutic compound of formula I and necessary axillarv agents.
_ 19 _ Specific alkylthiophenoxypropanolamines of the invention are those hereinafter described in the examples. Of these9 compo~mds particularly preferred for their vasodilating properties and absence of significant beta-adrenergic blocking activity are:
1-[4-(methylthio)phenoxy]-3-(octylamino)-2-propanol, 1-[4-[(1-methylethyl)thio]phenoxy]-3-(octylamino)-2-propanol, 1-[3-[(1-methylethyl)thio]phenoxy]-3-(octylamino)-2-propanol, 1-[4-[(1-methylethyl)thio]phenoxy]-3-(dodecylamino)-2-propanol, 1-[(2-cyclohexylethyl)amino]-3-[4-[(1-methylethyl)thio]-phenoxy]-2-propanol, 1-[(4-cyclohexylbutyl)amino]-3-[4-~(1-methylethyl~thio]-phenoxy]-2-propanol, 1-[2-methyl-4-(methylthio)phenoxy]-3-(octylamino)-2-propanol, 1-[2-(methylthio)phenoxy]-3-(octylamino)-2-propanol.
The following examples illustrate but do not limit the scope of the invention. All temperatures expressed herein are in degrees centigrade.
l-[4-(Methylthio)phenoxy]-3-(octylamino)-2-propanol ~ OH
3 ~ OCH2CHCH2~H-(CH2)7CH3 A solution of 4-(methylthio)phenol (5,6 g., 0.04 moles) 25 and soclium hydroxide ~2.4 g., 0.06 moles) in 50 ml. of water is treated ~ith epichiorohydrin (7.4 g., 0.08 moles). The resulting mixture is first stirred at 30-35 for 24 hr. and then extracted with chloroform. After washing the chloroform extract with water and drying over magnesium sulfate, distilla~les are removed under reduced pressure to provide the epichlorohydrin derivative 1-(4-methylthlo)phenoxy-2,3-epoxypropane which is taken up in 30 ml. of ethanol, treated with n-octylamine (7.5 g., 0.06 mole) and refluxed for a period of 4 hr. Concentration of the reaction mixture under reduced pressure to about one-half volume provides a white solid which is collected and crystallized from ethanol to afford a 21%
yield of analytically pure 1-[4-(methylthio)phenoxy]-3-'octylamino)-2-propanol, m.p. 79.5-80.5 (corr.).
Anal. Calcd. for C18H31NO2S: C, 66.42; H, 9.60; N, 4.30;
S, 9.85. Found: C, 66.30; H, 9.69; N, 4.13; S, 9.58.
EXAMPL~ 2 1-[4-~(1-Methylethyl)thio]phenoxy]-3-(octylamino)-2-propanol Hydrochloride ~ OH
(Cl~3)2cH-s ~ OcH2cHcH2~-(cH2)7c~3 (a) 4-(Isopropylthio)phenol.- A solution of sodiun nitrite (113.8 ~., 1.65 mole) in 210 ml. of water is added to a stirred solutiGn of p-aminophenol (163.7 g., 1.5 mGle) in 825 ml.
of 4 N hydrochloric acid at -5 . After stirring for an additional 2 hr. period at -5, the solution of the diazotized phenol is added over a 45 min. period to a previously prepared cold (-5) solution of sodium hydroxide (270.6 g., 6.77 moles) and 2-propanethiol (126.4 g., 1.66 moles) in 525 ml. of water with the reaction maintained under a nitrogen atmosphere. I~hen addition is complete, the mixture is permitted to warm to 27 and is kapt at that temperature for a period of 16 hr. Then, the mixture is cooled to Oc and acidified with 570 ml. of 12 N hydrochloric acid. Excess 2-propanethiol is removed by bubbling nitrogen gas through the acidified solution into a permanganate trap for a 2 hr. period. The resulting solution is extracted with several portions of dichloromethane and the combined extracts washed with water, dried over magnesium sulfate containing charcoal and filtered. Concentration of the filtrate under reduced pressure provides a residual oil which is distilled affordirg 81 g.
(32% yield) of 4-(isopropylthio)phenoi, b.p. 114-123 (1.2 mm Hg).
(b) A solution of 4-(isopropylthio)phenol, ($.6 g., 0.04 mole) and sodium hydroxide (2.6 g., 0.065 mole) in 50 ml. of water 15 is treated with epichlorohydrin (7.4 g., 0.08 moles). T-ne resulting mixture is first stirred at 30-35 for 24 hr. &nd then extracted with chloroform. After washing the chloroform extract with water and drying over magnesium sulfate, distillables are removed under reduced pressure to provide the epichlorohydrin intermediate 1-(4-isopropylthiophenoxy)-2,3-epoxypropane. The epichlorohydrin inter-mediate is taken up in 30 ml. of ethanol, treated with n-octylamine (7.5 g., 0.06 mole) and refluxed for a period of 4 hr. Concen-tration of the reaction mixture under reduced pressure affords a residue which is taken Up in ethanol and treatet with 5 ml. of 12 N
hydrochloric acid. Concentration of the asidified solution under reduced pressure and crystalli~ation of residual material from ethanol provid~s an analytically pure (20~ yielt) 1-[4-i(l-methyl-ethyl)thio]pheno~y]-3-(octylamino)-2-propanol hydrochloride, m.p. 171-173-186.5 (corr.) (double melting point).
Anal. Calcd. for C2 H ~O2S.HCl: C, 61.59; H, 9.30; N, 3.59;
S9 8.22; Cl, 9.09. Found: C, 61.68, H, 9.29; N, 3.47; S, 8.15; Cl, 9.15.
1-[3-[(1-Methylethyl)thiolphenoxy]-3-(octylamino)-2-propanol Hydrochloride OH
~ OCH2CHCH2NH-(CH2)7CH3 (Ca3) 2CH-S
Reaction of the epichlorohydrin derivative of 3-(isopropyl-thio)phenol (4.85 g., 0.029 mole) with n-octylamine (4 g., 0.031 mole) according to the procedure of Example 2~b) and crystalliæation of the crude product from ethanol-ether affords a 13% yield of analytically pure 1-[3-[(1-methylethyl)thio]phenoxy]-3-(c.tylamino)-2-propanol hydrochloride, m.p. 12;-127 (corr.).
Anal. Calcd. for C20H35N02S.HCl: C, 61.59; H, 9.30; N, 3.59. Found: C, 61.22; H, 9.09; N, 3.53.
1-[4-[(1-Methylethyl)thio]phenoxy]-3-(dodecylamino)-2-Propanol Hydrochloride OH
(CH3?2CH-S - ~ OCH2CHCH2~H-(cH2)l1c 3 Reaction of the epichlorohydrin derivative of 4-(isopropyl-thio)phenoi ~15.7 g., 0.07 mole) with n-dodecylamine (13.9 g., 0.075 mole) according to the procedure of Example 2(b) and crystallization of the crude product lrom n;ethanol affords a 13~ yield of analytically pure 1-[4-[(1-methylethyl)thio]phenoxy]-3-dodecylamino)-2-propanol hydrochloride, m.p. 153.5-156.6-190.5 (corr.) (double melting pOillt).
Anal. Calcd. for C24H43N02S.HCl: C, 64.61; H, 9.94, ~, 3.14. Found: C, 64.38; H, 10.07; N, 2.97.
1-[(2-Cyclohexylethyl)amino]-3-~4-[(1-methylethyl)thio]phenoxy3-2-propanol Hydrochloride OH
(CH3)2CH-S ~ OcH2cHcH2~H-(cH2)2 3 Reaction of the epichlorohydrin derivative of 4-(isopropyl-thio)phenol (5.0 g., 0.022 mole) with cyclohexylethylamine (3.3 g., 0.026 mole) according to the procedure of Example 2(b) and crystal-lization of the crude product from isopropyl alcohol affords an 18 yield of analytically pure 1-[(2-cyclohexylethyl)amino]-3-[4-[(l-methylethyl)thio]phenoxy]-2-propanol hy~rochloride, m.p. 180-182 (corr.).
Anal. Calcd. for C20H33N02S.HCl: C, 61.91; H, 8.83;
N, 3.61. Found: C, 61.73; H, 8.71; N, 3.88.
1-[~4-Cyclohexylbutyl)amino]-3-[4-[(1-methylethyl)thio]phenoxy]-2-propanol Hydrochloride ( 3j2 S ~ OCH2C~cH2NH~(c~2)4 3~`.i Reaction of the epichlorohydrin derivative of 4-(iso-propylthio)phenol ~9.0 g., 0.04 mole) with cyclohexylbutylamine (6.7 g., 0.043 mole) according to procedure of Example 2 (D) and crystallization of the crude product from ethanol affords an 11.4%
yield of analytically pure 1-[(4-cyclohexylbutyl)amino]-3-[4-[(l-methylethyl)thio]phenoxy]-2-propanol hydrochloride, m.p. 179 with prior softening from 118.
Anal. Calcd. for C22H37N02S-HCl: C, 63-51; H~ 9-20;
N, 3.37. Found: C, 63.46; H, 9.35; N, 3.29.
E~AMPLE 7 1-[2-Methyl-4-(methylthio)phenoxy]-3-(octylamino)-2-propanol OH
3 ~ OCH2CHCH2NH-(CH2)7CH3 The epichlorohydrin derivative of 2-methyl-4-(methylthio)-phenol (3.14 g., O.OlS mole) is reacted with n-octylamine (1.93 g.
0.015 mole) according to the procedure of Example 1. Concentrating the reaction mixture and crystallization of residual material from ethylacetate-hexane affords a 19% yield of analytically pure 1-[2-methyl-4-(methylthio)phenoxy]-3-(octylamino)-2-propanol, m.p. 59-60 (corr.).
Anal. Calcd. for ClgH33N02S: C, 67-21; H, 9-80; N~ 4-13-Found: C, 66.80; E, 9.92; N, 3.81.
- ~5 -1-[2-(Methyithio)phenoxy]-3-(octylamino)-2-propanol Hydrochloride OH
CH2CHCH2N~-(cll2)7cH3 Reactior. of the epichlorhydrin derivative of 2-(methyl-5 thio)phenol (14 g., 0.071 mole) with n-octylamine (9.04 g., 0.07 mole) according to the procedure of Example 2(b) and crystalli~ation of the crude product from methanol-ether affords an 18~ yield of analytically pure 1-[2-(methylthio)phenoxy]-3-(octylamino)-2-propanol hydrochloride, m.p. 105.5-107.5 (corr.).
10Anal. Calcd. for C18H31N02S.HCl: C, 59.73; H, 8-91 N, 3.87. Found: C, 59.86; H, 9.07; N, 3.71.
1-[4-[(1-Methylethyl)thio]phenoxy]-3-[(2,2-dimethyl-1-hexyl)amino]-2-propanol ~ OH ,CH3 ( 3)2 ~ OCH2CHCH2NH-CH2,C-(CH2)3CH3 (a~ 2,2-Dimethylhex-l-ylamine.- A solution of capro-nitrile (25 g., 0.26 mole) and methyl iodide (75 g., 0.53 mole) in 80 ml. of dry toluene is warmed to 80 and treated gradually ~ith a suspension of sodium amide (25.4 g., 0.65 mole~ in 100 ml.
of toluene at 2 rate sufficient to maintain general reflux. After addition is compl~te, the mixture is stirred and refl1lxed for an additional 2 hr. per~od, cooled and treated with 150 ml. of water.
The organic layer is separated, washed with water and dried over magnesium sulfate. Concentral-ion of the dried solution under reduced pressure and distillation of residual material affords an 8l% yield of 2,2-dimethylcapronitrile.
A solution of 2,2-dimethylcapronitrile (10.0 g., 0.078 mole) in 100 ml. of ether is added slowly to a suspension of lithium aluminum hydride (6.0 g., 0.158 mole) in 200 m~. of ether while maintaining the reaction at 0-5 . After stirring the reaction mixture for an additional 2 hr. at 0.5 , the mixture is hydrolyzed by sequentially adding 6.0 ml. of water, 6.0 ml. of 15% sodium hydroxide solution, and finally 18 ml. of water. The hydrolyzed mixture i5 stirred for an additional hour, filtered and the ether pha~e concentrated under reduced pressure. Distillation of residual material provides 2,2-dimethylhex-1-ylamine.
(b) Reaction of the epichlorhydrin derivative of 4-(isopropylthio)phenol with 2,2-dimethylhex-1-ylamine according to the procedure of Example 2(b) and conversion of the free base to the hydrochloride provides 1-[4-[(1-methylethyl)thio]phenoxy]-3-[(2,2dimethyl-1-hexylamino]-2-propanol hydrochloride.
1-[4-[(1-Methylethyl)thio]phenoxy]-3-[(2-methyl-2-octyl)amino]-2-propanol ~ 0,Y. CH3 (CH3)2CH-S--~ OCH2CT~CH2NH-C, (Cff2)5 3 (a) 2-Ketnyl-2-octanol.- A solution of ~ethyl-heptanoate (14.5 g., Q.l mole) in 200 ml. of ether is added to .. . .
3~
200 ml. of 3~1 solutioll (0.6 mole) of methyl magnesium bromide in ether at a rate sufficient to maintain refluxing. After addition is complete, the resulting mixture is refluxed for l hr. and then stirred at 26 for a 16 hour period. The mixture is hydrolyzed by the addition of d lute ammonium chloride solution, filtered and the filter cake dissolved in 2N hydrochloric acid and extracted with ether. The ethereal extract and filtrate are combined, sequen~ially washed with water, dilute sodium bicarbonate solution and brine and dried over magnesium sulfate. Concentration of the dried solution and distillation of residual material under reduced pressure provides 13.1 g. (91% yield) of 2-methyl-2-octanol, b.p. 130 (100 mm Hg).
(b) N-(2-~lethyl-2-octyl)acetamide.- A solution of con-centrated sulfuric acid (5.55 g., 0.055 mole) in 32 ml. of glacial acetic acid is treated with acetonitrile (2.5 g., 0.016 mole) and 2-15 methyl-2-octanol (8.0 g., 0.055 mole) ~nd the resulting mixture stirred at 26 for a 17 hr. period. After diluting with 125 ml. o water, the mixture is extracted with ether and the ethereal extract sequentially ~ashed with water, dilute sodium bicarbonate solution and brine and dried over magnesium sulfate. Concentration of the 20 dried solution provides 8.7 g. (85% yield) of N-(2-methyl-2-octyl)-acetan~ide which is used in the next step without further purification.
(c) 2-Methyl-2-octylamine.- A solution of potassium hydroxide (10.0 g., 0.18 mole) in lO0 ml. of ethylene glycol is treated with N-(2-metnyl-2-octyl)acetamide (13.0 g., 0.07 mole) and 25 the mixture heated at 200 for a 64 hr. period. The reaction m xture is diluted with 400 ml. of water and extracted with ether.
The ethereal extract is washed with water and brine and then dried - 2~ -.. . .
~ ~4fi3~
over sodium sulfate. Concentration of the dried solution under reduced pressure affords 10.4 g. (62% yield) of 2-methyl-2-octyl-amine which is used in the next step without further purification.
(d) 1-[4-[(1-Methylethyl)thio]phenoxy]-3-[(2-methyl-2-S octyl)amino]-2-propanol Preparation.- A solution of the epichlo-hydrin derivative of 4-(isopropylthio)phenol (7.8 g., 0.035 mole) and 2-methyl-2-octylamine (5.0 g., 0.035 mole) in 100 ml. of ethanol is refluxed for a 17 hr. period. The reaction mixture is concen-trated under reduced pressure and residual material heated at 80 (0.5 mm Hg) to remove residual excess reagents. The crude free base is treated with 6N hydrochloric acid to provide the hydrochloride salt which crystallized from ether-hexane ~ffords 3.0 g. (21% yield) of l-[4-[(1-methylethyl)thio]phenoxy]-3-[(2-methyl-2-octyl)a~ino]-2-propanol hydrochloride, m.p. 165.
3-Methyl-1-[4-[(1-methylethyl)thio]-phenoxy]-3-(octylamino)-2-butanol -- OH CH
( 3)2C~ S ~ OcH2cH-c-NH-(cH2)7CH3 (a) Diethylacetyl of 4-[(1-methylethy])thio]phenoxy~
acetaldehyde.- A solution of 4-[(1-methylethyl)thio]phenol (24.2 g., 0.144 mole) in 180 ml. of 2-ethoxyethanol is treated with 7.2 g.
of a 50% dispersion of sodium hydride in mineral oil and the mixture stirred until hydrogen evolution ceases. The diethylacetal of bromoacetaldehyde (30.0 g., 0.152 mole) is added to the reaction mixture which is ~hen stirred and refluxed for a 19 hr. period, -- 2g --cooled, diluted with water and extracted with ether. Ether extracts are combined, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to an oil. Distillation of residual oil under reduced pressure provides 28.1 g., (69% yield) of the diethylacetal of 4-[(1-methylethyl),hio]phenoxyacetaldehyde, b.p. 142-146 (0.07 mm Hg).
(b) 4-[(1-Methylethyl)thio]phenoxyacetaldehyde.-solution of the diethylacetal of 4-[(1-methylethyl)thio]phenoxy-acetaldehyde (10 g., 0.035 mole) in 100 ml. of aqueous ethanol (60:40) is treated with 5 ml. of 6N hydrochlor~c acid and the resulting mixture refluxed for a period of 2 hr. The cooled mixture is partitioned between ether and water and the ethereal phase washed with water and brine and then dried over magnesium sulfate. Concentration of the dried ethereal solution under reduced pressure and distillation of .esidual materia] affords
4-[(1-methylethyl)thio]phenoxyacetaldehyde.
(c) 3-Methyl-1-[4-[(1-methylethyl)thio]phenoxy]-3-nitro-2-butano].- A solution of 2-nitropropane (1.8 g., 0.02 mole) and 1.0 g. of sodium hydroxide in 10 ml. of water is added to a stirred suspensior. of 4-[(1-methylethyl)thio]phenoxyacetaldehyde (4.2 g., 0.02 mole) in a solution of sodium bisulfate (2.1 g., 0.02 mole) in 10 ml. of water. The mixture is warmed on a steam bath for 8 hr., cooled and acidified with glacial acetic acid.
The acidified mixture is extracted with ether, and the combined ether extracts sequentially washed with watPr, dilute sodiurl bicarbonate solution and brine and dried over magnesium sulfate.
Concentration of the dried etherea] solution under reduced ?ressure - 3û --6~
provides 3-methyl-1-[4-[(1-methylethyl)thio]phenoxy]-3-nitro-2-butanol.
(d) 3-Amino-3-methyl-1-[4-[(1-methylethyl)thio]phenoxy]-2-butanol.- A solution of 3-methyl-1-[4-[(1-methylethyl)thio]phenoxy]-3-nitro-2-butanol (2.5 g., 0.008 mole) in 100 ml. of ether is treated with lithium aluminum hydride (0.5 g., 0.013 mole). The mixture is stirred at 25 for a 4 hr. period, cooled and then hydrolyzed by the sequential addition of 0.5 ml. of water, 0.5 ml. of 15% sodium hydroxide solution, and 1.5 ml. of water. After stirring at room temperature for 1 hr., the solution is filtered and concentrated under reduced pressure to p.ovide 3-amino-3-methyl-1-[4-[(1-methyl-ethyl)thio]phenoxy]-2-butanol.
(e) 3-Methyl-1-[4-[(1-me.hylethyl)thio]phenoxy]-3-(octylamino)-2-butanol Preparation.- A solution of 3-amino-3-methyl-1-[4-[(1-methylethyl)thio]phenoxy]-2-butanol (2.0 g., 0.007 mole) in 60 ml. of isopropyl alcohol is treated with n-octanal (1.0 g., 0.008 mole) and sodium cyanoborohydride (1.0 g., 0.017 mole). After stirrin~ at room temperature for a period of 16 hr., it is poured into water and the product extracted with ether. The ethereal extract is washed with water and brine and dried over magnesium sulfate. Concentration of the dried ethereal solution and conversion of the residual free base to the hydrochloride salt provides 3-methyl-1-i4-[(1-methylethyl)thio]phenoxy]-3--(octyl-amino)-2-butanol hydrochloride.
- 3] -;
3~;
E~LE 12 1-[4-[(l-Methylethyl)thic]-phenoxy]-3-(octylamino)-2-butanol ~ OH
(CH3)~cH-S ~ ocb2cHcH~ -(cH2)7 3 (a) 3-Amino-1-[4-~(1-methylethyl?tnio]phenoxy]-Z-butanol.-This amine precursor is obtair.ed by reducing 1-[4-[(l-methylethyl)-thio]phenoxy]-3-nitro-2-butanol with lithium aluminum hydride according to the procedure of Example ll(d). The nitro starting material (l-[4-[~l-methylethyl)thio]phenoxy]-3-nitro-2-butanol~
is obtained by using an equivalent quantity of nitroethane ir. place of the 2-nitropropane Jn the procedure of Example ll(c).
(b) 1-[4-[(l-Methylethyl)thio~phenoxy~-3-octylamino-2-butanol Preparation.- Treatment of 3-ami.no-1-[4-[(l-methylethyl)-thio]phenoxy~-2-butanol with n-octanal and sodium cyanoborohydride according to the procedure of Example ll(e) affords the product :
1-[4-[(1-methyl.ethyl)thio]phenoxy]-3-octylamino-2-butanol.
The follo~ing compounds of Table A are prepared according to the procedure of Example 1 by reacting the epichlorohydrin derivative of the starting phenol with n-octylamine.
- 32 ~
TA~LE A
~ OH
Rl-S ~ ~---- OC~12CHCH2~H-(CH2)7CH3 `Product _xample Star;ing Thiophenol RlS
13 4-ethylthiophenol 4 C2H5
(c) 3-Methyl-1-[4-[(1-methylethyl)thio]phenoxy]-3-nitro-2-butano].- A solution of 2-nitropropane (1.8 g., 0.02 mole) and 1.0 g. of sodium hydroxide in 10 ml. of water is added to a stirred suspensior. of 4-[(1-methylethyl)thio]phenoxyacetaldehyde (4.2 g., 0.02 mole) in a solution of sodium bisulfate (2.1 g., 0.02 mole) in 10 ml. of water. The mixture is warmed on a steam bath for 8 hr., cooled and acidified with glacial acetic acid.
The acidified mixture is extracted with ether, and the combined ether extracts sequentially washed with watPr, dilute sodiurl bicarbonate solution and brine and dried over magnesium sulfate.
Concentration of the dried etherea] solution under reduced ?ressure - 3û --6~
provides 3-methyl-1-[4-[(1-methylethyl)thio]phenoxy]-3-nitro-2-butanol.
(d) 3-Amino-3-methyl-1-[4-[(1-methylethyl)thio]phenoxy]-2-butanol.- A solution of 3-methyl-1-[4-[(1-methylethyl)thio]phenoxy]-3-nitro-2-butanol (2.5 g., 0.008 mole) in 100 ml. of ether is treated with lithium aluminum hydride (0.5 g., 0.013 mole). The mixture is stirred at 25 for a 4 hr. period, cooled and then hydrolyzed by the sequential addition of 0.5 ml. of water, 0.5 ml. of 15% sodium hydroxide solution, and 1.5 ml. of water. After stirring at room temperature for 1 hr., the solution is filtered and concentrated under reduced pressure to p.ovide 3-amino-3-methyl-1-[4-[(1-methyl-ethyl)thio]phenoxy]-2-butanol.
(e) 3-Methyl-1-[4-[(1-me.hylethyl)thio]phenoxy]-3-(octylamino)-2-butanol Preparation.- A solution of 3-amino-3-methyl-1-[4-[(1-methylethyl)thio]phenoxy]-2-butanol (2.0 g., 0.007 mole) in 60 ml. of isopropyl alcohol is treated with n-octanal (1.0 g., 0.008 mole) and sodium cyanoborohydride (1.0 g., 0.017 mole). After stirrin~ at room temperature for a period of 16 hr., it is poured into water and the product extracted with ether. The ethereal extract is washed with water and brine and dried over magnesium sulfate. Concentration of the dried ethereal solution and conversion of the residual free base to the hydrochloride salt provides 3-methyl-1-i4-[(1-methylethyl)thio]phenoxy]-3--(octyl-amino)-2-butanol hydrochloride.
- 3] -;
3~;
E~LE 12 1-[4-[(l-Methylethyl)thic]-phenoxy]-3-(octylamino)-2-butanol ~ OH
(CH3)~cH-S ~ ocb2cHcH~ -(cH2)7 3 (a) 3-Amino-1-[4-~(1-methylethyl?tnio]phenoxy]-Z-butanol.-This amine precursor is obtair.ed by reducing 1-[4-[(l-methylethyl)-thio]phenoxy]-3-nitro-2-butanol with lithium aluminum hydride according to the procedure of Example ll(d). The nitro starting material (l-[4-[~l-methylethyl)thio]phenoxy]-3-nitro-2-butanol~
is obtained by using an equivalent quantity of nitroethane ir. place of the 2-nitropropane Jn the procedure of Example ll(c).
(b) 1-[4-[(l-Methylethyl)thio~phenoxy~-3-octylamino-2-butanol Preparation.- Treatment of 3-ami.no-1-[4-[(l-methylethyl)-thio]phenoxy~-2-butanol with n-octanal and sodium cyanoborohydride according to the procedure of Example ll(e) affords the product :
1-[4-[(1-methyl.ethyl)thio]phenoxy]-3-octylamino-2-butanol.
The follo~ing compounds of Table A are prepared according to the procedure of Example 1 by reacting the epichlorohydrin derivative of the starting phenol with n-octylamine.
- 32 ~
TA~LE A
~ OH
Rl-S ~ ~---- OC~12CHCH2~H-(CH2)7CH3 `Product _xample Star;ing Thiophenol RlS
13 4-ethylthiophenol 4 C2H5
5 14 4--n-propylthiophenol 4-n-C3H7S
4-n-butvlthiophenol 4-n-C4HgS
16 4-n-pentylthiophenol 4-n-C5HllS
17 4-n-hexylthiophenol 4-n-C6H13S
18 4-n-heptylthiop'lenol 4-n-C7Hl5s 1019 4-n-octylthiophenol 4-n-C8~17S
4-(3-methyl.butylthio)phenol 4-(CH3)2CXCH2CH2S
21 2-n-butylthiophenol 2-n-C4HgS
22 3-n-butylthiophenol 3-n-C4H9S
23 2-ethylthiophenol C2H5~
1524 2-n-propylthiophenol 2-n-C3H7S
2-isopropylthiophenol 2-i-C H7S
26 3-ethylthiophenol 3 C2 5S
27 3-n-propylthiophenol 3-n-C3H7S
28 3-isopropylthiophenol 3-i-C3H7S
EXA~LE 29 Tablets The following ingredients are blended into proportion by weight indicated according to conventional pharmaceutical tec'.miques to provide a tabl.et base.
Amount Lactose 79 Corn starch 10 Talcum 6 Tragancanth 4 Magnesium steara,e This tablet base is blended with sufficîent 1-[4-[(l-methyl~
ethyl)thio]phenoxy]-3-(octylar,lino)-2-propanol hydrochloride to provide tablets containing 10, 20, 40, 80, 160 and 320 mg. of active ingredient and compressed into conventional tablet press.
Dry-Filled Capsules The following ingredients are blended in a conventional manner in the proportion by weight indicated.
Ingredient Amount Lactose, U.S.P. 50 Starch 5 Magnesium stearate 2 Sufficient 1-~4-[(l-methylethyl)thio]phenoxy]-3-(octylamino)-2-propanol hydrochloride is added to the blend to provide capsules containing 10, 20, 40, 80, 160 and 320 mg. of active ingredient which is filled into hard gelatin capsules of a suitable size.
Comparison of Peripherai Vasodilator Activity In The ~nesthetized Dog Test Method.- Mongrol dogs of either sex weighing between 11 and 16 kg., each, were anesthetized with pentobarbital (30 mg./kg.) administered intravenously. The left brachia] vein was cannulated and pentobarbital infused continuously throughout the experiment at a rate of 5 mg./kg./hr. A tracheotomy was performed and dogs venti-lated mechanically with room air at a rate of 18 strokes/min. and a volume equivalent to 20 ml./kg. The vagi were sectiGned bilaterally in the mid-cervical region of the neck. The right brachial vein and artery were cannulated to inject drugs and to monitor blood pressure via a Statham pressure transducer, respectively. All measurements were recorded on a Beckman-Offner dynograph. The abdominal aorta was exposed through midline incision and a loose ligature placed around the aorta distal to the left renal artery. The right (donor) and left (recipient) femoral arteries were exposed for cannulati,on and subsequent hind-limb perfursion. Following intravenous administration of heparin (5 mg./kg.) and gallamine triethiodide (2 mg./kg.), the right femorel artery was cannulated and the tip of the catheter advanced into the abdominal aorta to the level of the renal arteries.
The left femoral artery was cannulated and the hind-limb perfused using a Harvard Perfusion pump. The ligature previously placed around the aorta was subsequently tied to minimize collateral circu-lation. Heparin and gallamine trietniodide were infused intravenouslyat rates of 2.5 and 1 mg./kg./hr. 5 respectively. Perfusion pressure, measured at a point distal to the perfusion pump was set equal to 150 mm Hg. by adjusting pump speed. Blood flow to the limb was determined volumetrically at the conclusion of the experiment. The test agent was administered by infusion at a rate of from 0.1-1.0 m8./min. for a six-minute period and maximum reduction in pressure determined. One to three animals were employed per test agent.
Results.- Table I below gives results obtained according to the above test for representative alkylthiophenoxypropanolamines of the instant invention. Data is also shown for the alkylthio-phenoxypropanolamine prior art compounds of Keizer, et al., U.S.
3,542,874 "1-(isopropylamino)-3-[2-(methylthio)phenoxy]-2-propanol (tiprenolol)" and Villa, et al., Il. Farmaco. Sci., Ed. 24, 349-357 (1969) "1-(isopropylamino)-3-[~l-(methylthio)phenoxy]-2-propanol"
identified herein as test agents "A" and "B", respectively, and the reference standard papaverine.
With respect to prior art compounds "A" and "B" and ~he compound of Example 2 (test agent 2), comparative testing was repeated essentially as described above with the modification that the three compounds were tested in the same dog preparation (blood pressure was allowed to return to control values between infusion cf test agents). This protocol precludes effects resulting from anima1 variation thus permitting a direct side-by-side comparison of vaso-dilating activity. The results of this comparison are also set forth in Table I.
- 3~ -TABLE I
Vasodilator Activity - PerEused Dog Hlnd Limb R ~ OH
R -S
Pressure Decreaseb Test Dose (mg./m1n.) 5 ~ R _ Rl R2 --~ - 0 3 1.0 2 H 4-i-Pr n C8H17 -63 3 H 3-i-Pr _ 8H17 -20 -87 10 5 H 4-i-Pr ( 2~2 ~ -63 -87
4-n-butvlthiophenol 4-n-C4HgS
16 4-n-pentylthiophenol 4-n-C5HllS
17 4-n-hexylthiophenol 4-n-C6H13S
18 4-n-heptylthiop'lenol 4-n-C7Hl5s 1019 4-n-octylthiophenol 4-n-C8~17S
4-(3-methyl.butylthio)phenol 4-(CH3)2CXCH2CH2S
21 2-n-butylthiophenol 2-n-C4HgS
22 3-n-butylthiophenol 3-n-C4H9S
23 2-ethylthiophenol C2H5~
1524 2-n-propylthiophenol 2-n-C3H7S
2-isopropylthiophenol 2-i-C H7S
26 3-ethylthiophenol 3 C2 5S
27 3-n-propylthiophenol 3-n-C3H7S
28 3-isopropylthiophenol 3-i-C3H7S
EXA~LE 29 Tablets The following ingredients are blended into proportion by weight indicated according to conventional pharmaceutical tec'.miques to provide a tabl.et base.
Amount Lactose 79 Corn starch 10 Talcum 6 Tragancanth 4 Magnesium steara,e This tablet base is blended with sufficîent 1-[4-[(l-methyl~
ethyl)thio]phenoxy]-3-(octylar,lino)-2-propanol hydrochloride to provide tablets containing 10, 20, 40, 80, 160 and 320 mg. of active ingredient and compressed into conventional tablet press.
Dry-Filled Capsules The following ingredients are blended in a conventional manner in the proportion by weight indicated.
Ingredient Amount Lactose, U.S.P. 50 Starch 5 Magnesium stearate 2 Sufficient 1-~4-[(l-methylethyl)thio]phenoxy]-3-(octylamino)-2-propanol hydrochloride is added to the blend to provide capsules containing 10, 20, 40, 80, 160 and 320 mg. of active ingredient which is filled into hard gelatin capsules of a suitable size.
Comparison of Peripherai Vasodilator Activity In The ~nesthetized Dog Test Method.- Mongrol dogs of either sex weighing between 11 and 16 kg., each, were anesthetized with pentobarbital (30 mg./kg.) administered intravenously. The left brachia] vein was cannulated and pentobarbital infused continuously throughout the experiment at a rate of 5 mg./kg./hr. A tracheotomy was performed and dogs venti-lated mechanically with room air at a rate of 18 strokes/min. and a volume equivalent to 20 ml./kg. The vagi were sectiGned bilaterally in the mid-cervical region of the neck. The right brachial vein and artery were cannulated to inject drugs and to monitor blood pressure via a Statham pressure transducer, respectively. All measurements were recorded on a Beckman-Offner dynograph. The abdominal aorta was exposed through midline incision and a loose ligature placed around the aorta distal to the left renal artery. The right (donor) and left (recipient) femoral arteries were exposed for cannulati,on and subsequent hind-limb perfursion. Following intravenous administration of heparin (5 mg./kg.) and gallamine triethiodide (2 mg./kg.), the right femorel artery was cannulated and the tip of the catheter advanced into the abdominal aorta to the level of the renal arteries.
The left femoral artery was cannulated and the hind-limb perfused using a Harvard Perfusion pump. The ligature previously placed around the aorta was subsequently tied to minimize collateral circu-lation. Heparin and gallamine trietniodide were infused intravenouslyat rates of 2.5 and 1 mg./kg./hr. 5 respectively. Perfusion pressure, measured at a point distal to the perfusion pump was set equal to 150 mm Hg. by adjusting pump speed. Blood flow to the limb was determined volumetrically at the conclusion of the experiment. The test agent was administered by infusion at a rate of from 0.1-1.0 m8./min. for a six-minute period and maximum reduction in pressure determined. One to three animals were employed per test agent.
Results.- Table I below gives results obtained according to the above test for representative alkylthiophenoxypropanolamines of the instant invention. Data is also shown for the alkylthio-phenoxypropanolamine prior art compounds of Keizer, et al., U.S.
3,542,874 "1-(isopropylamino)-3-[2-(methylthio)phenoxy]-2-propanol (tiprenolol)" and Villa, et al., Il. Farmaco. Sci., Ed. 24, 349-357 (1969) "1-(isopropylamino)-3-[~l-(methylthio)phenoxy]-2-propanol"
identified herein as test agents "A" and "B", respectively, and the reference standard papaverine.
With respect to prior art compounds "A" and "B" and ~he compound of Example 2 (test agent 2), comparative testing was repeated essentially as described above with the modification that the three compounds were tested in the same dog preparation (blood pressure was allowed to return to control values between infusion cf test agents). This protocol precludes effects resulting from anima1 variation thus permitting a direct side-by-side comparison of vaso-dilating activity. The results of this comparison are also set forth in Table I.
- 3~ -TABLE I
Vasodilator Activity - PerEused Dog Hlnd Limb R ~ OH
R -S
Pressure Decreaseb Test Dose (mg./m1n.) 5 ~ R _ Rl R2 --~ - 0 3 1.0 2 H 4-i-Pr n C8H17 -63 3 H 3-i-Pr _ 8H17 -20 -87 10 5 H 4-i-Pr ( 2~2 ~ -63 -87
6 H 4-i-Pr ( 2)4 ~ -47 _74
7 2-CH3 4-CH3 - 8 17 -56 -80
8 H 2-CH3 - 8 17 -15 -64 A H 2-CH3 i-Pr _20d _27d 15 B H 4-CH3 i-Pr - 3d -29 Papaverine -31 -55 a. Test agent numbers correspond to example numbers.
b. Millimeters of mercury.
c. Infusion rate.
20 d. Side-by-side comparison in same animals.
~ 3~
Findings.- Compared to prior art compuounds "A and B", all of the instant alkylthiophenoxypropanolamines tested (i.e. test agents 1-3 and 5-8) provided substalltially greater vasodilating effects in that at an infusion dose of 1.0 mg./min. they produced a pressure reduction of from 59-99 mm Hg. whereas "A and B" at an identical dose provide a reduction in pressure of some 27-'9 mm Hg.
In comparison to prior art compounds "A and B" at a dose of 0.3 mg./min. the compounds tested were, respectively, from 0.~ to 3.2 and 5 to 21 .imes more acti-~e. All of the compounds tested are of interest with respect to vasodilator activity in that at an infusion rate of l.0 mg./min. they produced a decrease in pressure substan-tially greater than or approximately equivalent to papaverine.
According to the side-by-side comparison of test agent 2 and prior art alkylthiophenoxyproparlolamines "A and B" at identical 0.3 mg./min.
dose levels~ test agent 2 has a vasodilator effect approximately 3.2 and 21 times greater than that of test agents "A" and l'B", respectively.
This i.llustrate~ that test agent 2 is a substantially superior vaso-dilator compared to the prior art alkylthiophenoxypropanolamine "A
and B".
Inhibition of Platelet Aggregation (Antithrombogenic Activity) est Method.- A method similar to that descr bed in Born, Nature 194, 927 (1962~ and O'~rien, J. Clinical Pathology lS, 446 (1962). This test compri~es ~ nephelometric method in which the change in turbidity of a specimen of human platelet-rich plasma is measured on causation of plate]et aggregation by addition of adenosine diphosphate ~ADP) or collagen as the thrombogenic inducing agent. An - 3g -increase in transMittance light occurs when the thrombogenic agent is added to the specimen or platelet-rich plasm due to clumping of platelets. Ef.icacy of the test compound is determined by abili~y to prevent the clumping and concommitant increase in transmittance.
Various concentrations of the test agent are tested and that con-centration causing a 50% reduction in the thrombogenic response is determined from a concentration-response curve.
Results.- Table II below provides results obtained according to the above test for representative compounds of the instant ~nvention and prior art compounds "A" and "B" of Example 31.
TABLE II
Inhibition of Platelet Agg~ation In Vitro ED50b Test Agenta ADP Coll a. Test agent numbers correspond to exampl~ numbers.
b. Microgram/0.5 ml. platelet--rich human plasma when l mcg. of adenosine-5'-diphospahte (ADP) or the minimal amollnt of collagen (coll~ producing maximal degree nf aggregation are used to induce aggregation.
c. Refer to Example 31.
Findings.- The abo~e data demonstrates that all of the compounds tested are significantly more active in inhibiting ADP-induced platelet aggregation than the prior art alkylthiophenoxq-propanolamines "A" and "B".
Isolated Guinea Pig Trachea (beta-Adrenergic Blo_king Activity) Test Method.- Tracheas excised from adult guinea pigs (body weight greater than 400 g.) are cut spirally and suspended vertically in 20 ml. of modified Tyrode's bath solution maintained at 37.5C. and aerated continuously with oxygen. The lower end of a tracheal segment is fixed to a stationary glass rod and the upper end is threaded to an isometric tension transducer. Changes in the spontaneous tonus of the tracheal smooth muscle are monitored via the transducer and recorded continuously on an electronic recorder.
Adrenergic beta-receptor blocking activity is determined by the ability of a test agent to inhibit the response of the isolated tissue to the adrenergic beta-stimulant "isoproterenol" at a concen-tration of 0.1 mcg./ml. bath fluid. The tissues are exposed to the test agent solution for a 15-min. interval prior to the addition of isoproterenol to the bath fluid. Beta-receptor blocking potencq of a test drug is ascertained from concentration-response relationships wherein the response is expressed as a percent inhibition of isoproterenol-induced tissue response. The IC50 value, which is the concentration of the test drug providing a 50% inhibition of the effect of the relaxant dose of isoprGterenol, is determined by interpolation. Each drug solution is added to the tissue bathing medium at a constant volume of 0.2 m1./ml. of bath fluid and only one test drug concentration 3~ 3..~
is employed for an individual tissue segment. Potency of the test agent relative to tbat of the beta-adrenergic blocking agent "propanolol"
as a reference standard is assessed by comparing the IC50 values.
Results.- Table III below provides results obtained according to the above tèst for representative alkylthiophenoxy-propanolamines of the instant invention identified by test number (example No.) compared to the alkylthiophenoxypropanolamine prior art compounds of Xeizer, et al. supra. and Villa, et al. supra. referred to as test agents "A" and "B", re~pectively (consult ~xample 31 for chemical name).
" .
TABLE III
Beta-Adrenergic Blocking ~ctivity in the Isolated Guinea Pi~ Trachea R ~ OH
~O-CH2CHCH2NH-R2 Rl-S
Test Beta-Adrenergic 5 Agenta R Rl R2 Blocking Potency 1 H 4-CH3 n-C8H17 < ~
2 H 4-i-Pr - 8 17 <0.001 3 H 3-i-Pr - 8 17 <0.001 4 }I 4-1-Pr - 12 25 <0.001 H 4-i-Pr ( 2)2 ~ <0.0006 H 4-i-Pr ( 2)4 ~ <0.002 7 2-CH3 4-CH3 - 8 17 <0.0006 8 H 2-CH3 n-C8H17 0-004 AC H 2-CH3 i-Pr 1.0 Bc H 4-CH3 i-Pr 0.2 a. Test agent numbers correspond to example nu~bers.
b. Potency relative to Dropanol (equals one) estimated from determinations of test drug concentrations causing 50% bloc~ade of isoproterenol-induced tissue response (propanol EC50 = 0.028 mcg./ml. ~ath fluid).
c. Refer to Example 31.
q~
_indings.- The date of Table III clearly establishes tha~, with respect to beta-adrenergic bloc~ing activity, a marked distinc-tion exists between the compounds of test agents 1 through 8 and the prior art alkylthiophenoxypropanolamlnes. It is apparent that test agents 1 through 8 are comparatively devoid of beta-adrenergic blocking activity in contrast to the coresponding prior art alkyl-thiophenoxypropanolamines "A" and "B" which have substantial activity.
Consequently, the instant compounds when used for purposes described herein, would be relatively free of side effects associated with beta-adrenergic blocking activity.
Isolated Rabbit Thoracic Aorta (Antispasmctic Activity vs. Po~assium Chloride) Test Methcd. Antispasmodic activi,y was assessed in vitro lS by determining the effect OI the test subst2nce on induced contraction of arterial smooth muscle as follows. Adult, ~ale, ~ew Zealand White rabbits (body weight 2.5-~ kg.j were used. Each rabbit ~as killed by i.v. air injection. The thorax was opened and the descending thoracic aorta removed and placed in Kreb's-bicarbonate solution. Extraneous tissue was r~moved and the aorta was cut spirally along its entire length. Four spiral segments, each approximately 2 cm. in length (unstretched), were obtained from each thoracic aorta. A spiral segment was placed in a 10 ml. volume bath chamber, fixed at the lower end to a glass rod tissue holder, and the upper, freP end threaded to a tension transducer which exerted a constant baseline tension of 3 gm on the tissue. The bath medium surrounding the aortic spiral (Kreb's-bic~rbonate soiution) was maintained at 37.5C. and constantly aerated with ~5% 2 5% C0,. Activity of the aortic smooth muscle was recorded on an electornic polygraph via its connection to the tenslon transducer. After an equiiibration period of 60 min., a cumulative dose-response curve was obtained to an agonist (e.g. potassium chloride or norepinephrine) and the tissue then washed. Seventy-five min. later, a second cumulative dose~
response curve to the agonist was obtained ~tld the tissue washed again. Sixty min. later, a test drug solution was added to the tissue bath fluid and, after 15 min., drug exposure and, without washing, a third and final agonist-response curve W2S obtained. All additions to the bath fluid were 0.1 ml. volumes of aqueous solutions.
Results.- Table IV below provides a comparison of potencies relative to papaverine in the above test employing potassium chloride as agonist for the instant alkylthiophenoxypropanolamines of Example 33 and prior art compounds of Keizer, et al., supra. ("A") and Villa, et al., supra. ("B") (consult Example 31 for chemical name). Papaverine is considered a direct-acting antispasmodic agent and is a standard in the art.
;3~
TABLE I~
Antispasmodic Activity (Rabbit Thcracic Aorta) Antispasmgdic Test Agent Potency 2 0.6 3 0.7 4 0.08 2.4 6 0.02 7 0.8 8 2.6 Ac 0.04 Bc 0.04 a. Test agent numbers correspond to example numbers.
b. Potency relaeive to papaverine (equals one) estimated from PA2 values determined versus potassium chloride-induced contractions. The PA2 value represents the negative log of the molar concentration of the aDtagonist which reduces the effect of a double dose of the agonist to that of a single dose of the agonist without the antagonist present.
c. Refer to Example 31.
Findin~~. Antagonist activity against potassium chloride-induced spasms is indicative of non-adrenergic direct-acting anti-spasmodic action. Accordingly, the results set forth Ln Table IV
illustrate that most of the in~stant co~.pounds tested have a sub-3Q stantial level of antispasmodic activity whereas the prior art _ ~5 _ compounds "A" and "B" have relatively weak acLivity. The datafurther establishes that relative to potassium chloride-induced spasms, test agents 2, 3, 5, 7, and 8 are from about 15 to 65 times more potent as non-adrenergic antispasmodic agents than the corres-ponding prior art alkylthlophenoxypropanolamines "A" and "B". Theantispasmodic potencies of test agents 4 and 6 are approximately the same as prior art compounds "A" and "B" with test agent 4 being twice as potent and test agent 6 being about 1/2 as potent.
Isolated Rabbit Thoracic Aorta ~Antispasmodic Activity vs. Norepinephrine) Test agents 1-8 and prior art compounds "~" and "B" of Example 34 were further tested for anti-alpha-adrenergic activity according to the method of Example 34 but employing the alpha-adrenergic stimulant agent norepinephrine as the agonist rather thanpotassium chloride. Selective activity against norepinephrine-induced spasms is indicative of alpha-adrenergic blocking ~i.e.
antispasmodic) activity. This modification of the antispasmodic test established that all o the instant alkylthiophenoxypropanolamines with exception of test agent 8, were essentially devoid of anti-alpha-adrenergic action having 0.3% or less of the activity exhibited by phentolamine. Phentolamine is an alpha-adrenergic blocking agent and a standard reference in the art. While prior art compound "~" is essentially inactive as an anti-alpha-adrenergic agent, test agent 8 and prior art compound "A" have some~Jhat more activity than compounds 1-7 in that they are 1--2% as potent as phentolamine. This experi-ment illustrates that the instant compounds are non-anti-alpha-adrenergic antispasmodic a~2nts in that they have a substantial direct smooth muscle relaxant effect (as shown in Example 3~) relatively uncom-plicated by any significant selective alpha-adrenergic blocking effect.
EXA~LE 36 Additional Biological Testing of 1-[4-[(1-Methyl-ethyl)thi_ phenox~J]-3-(octy:lamino)-2-prcpanol The vasoactivity of tne above compound of Example 2 was further evaluated according to various pharmacological tests employed for that purposc. Thus:
(a~ Rats with intra-arterial catheters have periods of shortened platelet survival time. This shortened survival time is normalized w~th the compound of Example 2.
(b) The compound of Example 2 elevated basal tone of mesenteric arteries of dogs and rabbits. This effect is considered valuable i~l the treatment of peripheral and cerebral vascular diseases.
(c) The compound of Example 2 decreased red 'olood cell rigidity determined via a chromium labeling technique and accordingly the cells are better able to pass through sclerosed narrowed capillaries of tissues af f ected by vascular disease.
b. Millimeters of mercury.
c. Infusion rate.
20 d. Side-by-side comparison in same animals.
~ 3~
Findings.- Compared to prior art compuounds "A and B", all of the instant alkylthiophenoxypropanolamines tested (i.e. test agents 1-3 and 5-8) provided substalltially greater vasodilating effects in that at an infusion dose of 1.0 mg./min. they produced a pressure reduction of from 59-99 mm Hg. whereas "A and B" at an identical dose provide a reduction in pressure of some 27-'9 mm Hg.
In comparison to prior art compounds "A and B" at a dose of 0.3 mg./min. the compounds tested were, respectively, from 0.~ to 3.2 and 5 to 21 .imes more acti-~e. All of the compounds tested are of interest with respect to vasodilator activity in that at an infusion rate of l.0 mg./min. they produced a decrease in pressure substan-tially greater than or approximately equivalent to papaverine.
According to the side-by-side comparison of test agent 2 and prior art alkylthiophenoxyproparlolamines "A and B" at identical 0.3 mg./min.
dose levels~ test agent 2 has a vasodilator effect approximately 3.2 and 21 times greater than that of test agents "A" and l'B", respectively.
This i.llustrate~ that test agent 2 is a substantially superior vaso-dilator compared to the prior art alkylthiophenoxypropanolamine "A
and B".
Inhibition of Platelet Aggregation (Antithrombogenic Activity) est Method.- A method similar to that descr bed in Born, Nature 194, 927 (1962~ and O'~rien, J. Clinical Pathology lS, 446 (1962). This test compri~es ~ nephelometric method in which the change in turbidity of a specimen of human platelet-rich plasma is measured on causation of plate]et aggregation by addition of adenosine diphosphate ~ADP) or collagen as the thrombogenic inducing agent. An - 3g -increase in transMittance light occurs when the thrombogenic agent is added to the specimen or platelet-rich plasm due to clumping of platelets. Ef.icacy of the test compound is determined by abili~y to prevent the clumping and concommitant increase in transmittance.
Various concentrations of the test agent are tested and that con-centration causing a 50% reduction in the thrombogenic response is determined from a concentration-response curve.
Results.- Table II below provides results obtained according to the above test for representative compounds of the instant ~nvention and prior art compounds "A" and "B" of Example 31.
TABLE II
Inhibition of Platelet Agg~ation In Vitro ED50b Test Agenta ADP Coll a. Test agent numbers correspond to exampl~ numbers.
b. Microgram/0.5 ml. platelet--rich human plasma when l mcg. of adenosine-5'-diphospahte (ADP) or the minimal amollnt of collagen (coll~ producing maximal degree nf aggregation are used to induce aggregation.
c. Refer to Example 31.
Findings.- The abo~e data demonstrates that all of the compounds tested are significantly more active in inhibiting ADP-induced platelet aggregation than the prior art alkylthiophenoxq-propanolamines "A" and "B".
Isolated Guinea Pig Trachea (beta-Adrenergic Blo_king Activity) Test Method.- Tracheas excised from adult guinea pigs (body weight greater than 400 g.) are cut spirally and suspended vertically in 20 ml. of modified Tyrode's bath solution maintained at 37.5C. and aerated continuously with oxygen. The lower end of a tracheal segment is fixed to a stationary glass rod and the upper end is threaded to an isometric tension transducer. Changes in the spontaneous tonus of the tracheal smooth muscle are monitored via the transducer and recorded continuously on an electronic recorder.
Adrenergic beta-receptor blocking activity is determined by the ability of a test agent to inhibit the response of the isolated tissue to the adrenergic beta-stimulant "isoproterenol" at a concen-tration of 0.1 mcg./ml. bath fluid. The tissues are exposed to the test agent solution for a 15-min. interval prior to the addition of isoproterenol to the bath fluid. Beta-receptor blocking potencq of a test drug is ascertained from concentration-response relationships wherein the response is expressed as a percent inhibition of isoproterenol-induced tissue response. The IC50 value, which is the concentration of the test drug providing a 50% inhibition of the effect of the relaxant dose of isoprGterenol, is determined by interpolation. Each drug solution is added to the tissue bathing medium at a constant volume of 0.2 m1./ml. of bath fluid and only one test drug concentration 3~ 3..~
is employed for an individual tissue segment. Potency of the test agent relative to tbat of the beta-adrenergic blocking agent "propanolol"
as a reference standard is assessed by comparing the IC50 values.
Results.- Table III below provides results obtained according to the above tèst for representative alkylthiophenoxy-propanolamines of the instant invention identified by test number (example No.) compared to the alkylthiophenoxypropanolamine prior art compounds of Xeizer, et al. supra. and Villa, et al. supra. referred to as test agents "A" and "B", re~pectively (consult ~xample 31 for chemical name).
" .
TABLE III
Beta-Adrenergic Blocking ~ctivity in the Isolated Guinea Pi~ Trachea R ~ OH
~O-CH2CHCH2NH-R2 Rl-S
Test Beta-Adrenergic 5 Agenta R Rl R2 Blocking Potency 1 H 4-CH3 n-C8H17 < ~
2 H 4-i-Pr - 8 17 <0.001 3 H 3-i-Pr - 8 17 <0.001 4 }I 4-1-Pr - 12 25 <0.001 H 4-i-Pr ( 2)2 ~ <0.0006 H 4-i-Pr ( 2)4 ~ <0.002 7 2-CH3 4-CH3 - 8 17 <0.0006 8 H 2-CH3 n-C8H17 0-004 AC H 2-CH3 i-Pr 1.0 Bc H 4-CH3 i-Pr 0.2 a. Test agent numbers correspond to example nu~bers.
b. Potency relative to Dropanol (equals one) estimated from determinations of test drug concentrations causing 50% bloc~ade of isoproterenol-induced tissue response (propanol EC50 = 0.028 mcg./ml. ~ath fluid).
c. Refer to Example 31.
q~
_indings.- The date of Table III clearly establishes tha~, with respect to beta-adrenergic bloc~ing activity, a marked distinc-tion exists between the compounds of test agents 1 through 8 and the prior art alkylthiophenoxypropanolamlnes. It is apparent that test agents 1 through 8 are comparatively devoid of beta-adrenergic blocking activity in contrast to the coresponding prior art alkyl-thiophenoxypropanolamines "A" and "B" which have substantial activity.
Consequently, the instant compounds when used for purposes described herein, would be relatively free of side effects associated with beta-adrenergic blocking activity.
Isolated Rabbit Thoracic Aorta (Antispasmctic Activity vs. Po~assium Chloride) Test Methcd. Antispasmodic activi,y was assessed in vitro lS by determining the effect OI the test subst2nce on induced contraction of arterial smooth muscle as follows. Adult, ~ale, ~ew Zealand White rabbits (body weight 2.5-~ kg.j were used. Each rabbit ~as killed by i.v. air injection. The thorax was opened and the descending thoracic aorta removed and placed in Kreb's-bicarbonate solution. Extraneous tissue was r~moved and the aorta was cut spirally along its entire length. Four spiral segments, each approximately 2 cm. in length (unstretched), were obtained from each thoracic aorta. A spiral segment was placed in a 10 ml. volume bath chamber, fixed at the lower end to a glass rod tissue holder, and the upper, freP end threaded to a tension transducer which exerted a constant baseline tension of 3 gm on the tissue. The bath medium surrounding the aortic spiral (Kreb's-bic~rbonate soiution) was maintained at 37.5C. and constantly aerated with ~5% 2 5% C0,. Activity of the aortic smooth muscle was recorded on an electornic polygraph via its connection to the tenslon transducer. After an equiiibration period of 60 min., a cumulative dose-response curve was obtained to an agonist (e.g. potassium chloride or norepinephrine) and the tissue then washed. Seventy-five min. later, a second cumulative dose~
response curve to the agonist was obtained ~tld the tissue washed again. Sixty min. later, a test drug solution was added to the tissue bath fluid and, after 15 min., drug exposure and, without washing, a third and final agonist-response curve W2S obtained. All additions to the bath fluid were 0.1 ml. volumes of aqueous solutions.
Results.- Table IV below provides a comparison of potencies relative to papaverine in the above test employing potassium chloride as agonist for the instant alkylthiophenoxypropanolamines of Example 33 and prior art compounds of Keizer, et al., supra. ("A") and Villa, et al., supra. ("B") (consult Example 31 for chemical name). Papaverine is considered a direct-acting antispasmodic agent and is a standard in the art.
;3~
TABLE I~
Antispasmodic Activity (Rabbit Thcracic Aorta) Antispasmgdic Test Agent Potency 2 0.6 3 0.7 4 0.08 2.4 6 0.02 7 0.8 8 2.6 Ac 0.04 Bc 0.04 a. Test agent numbers correspond to example numbers.
b. Potency relaeive to papaverine (equals one) estimated from PA2 values determined versus potassium chloride-induced contractions. The PA2 value represents the negative log of the molar concentration of the aDtagonist which reduces the effect of a double dose of the agonist to that of a single dose of the agonist without the antagonist present.
c. Refer to Example 31.
Findin~~. Antagonist activity against potassium chloride-induced spasms is indicative of non-adrenergic direct-acting anti-spasmodic action. Accordingly, the results set forth Ln Table IV
illustrate that most of the in~stant co~.pounds tested have a sub-3Q stantial level of antispasmodic activity whereas the prior art _ ~5 _ compounds "A" and "B" have relatively weak acLivity. The datafurther establishes that relative to potassium chloride-induced spasms, test agents 2, 3, 5, 7, and 8 are from about 15 to 65 times more potent as non-adrenergic antispasmodic agents than the corres-ponding prior art alkylthlophenoxypropanolamines "A" and "B". Theantispasmodic potencies of test agents 4 and 6 are approximately the same as prior art compounds "A" and "B" with test agent 4 being twice as potent and test agent 6 being about 1/2 as potent.
Isolated Rabbit Thoracic Aorta ~Antispasmodic Activity vs. Norepinephrine) Test agents 1-8 and prior art compounds "~" and "B" of Example 34 were further tested for anti-alpha-adrenergic activity according to the method of Example 34 but employing the alpha-adrenergic stimulant agent norepinephrine as the agonist rather thanpotassium chloride. Selective activity against norepinephrine-induced spasms is indicative of alpha-adrenergic blocking ~i.e.
antispasmodic) activity. This modification of the antispasmodic test established that all o the instant alkylthiophenoxypropanolamines with exception of test agent 8, were essentially devoid of anti-alpha-adrenergic action having 0.3% or less of the activity exhibited by phentolamine. Phentolamine is an alpha-adrenergic blocking agent and a standard reference in the art. While prior art compound "~" is essentially inactive as an anti-alpha-adrenergic agent, test agent 8 and prior art compound "A" have some~Jhat more activity than compounds 1-7 in that they are 1--2% as potent as phentolamine. This experi-ment illustrates that the instant compounds are non-anti-alpha-adrenergic antispasmodic a~2nts in that they have a substantial direct smooth muscle relaxant effect (as shown in Example 3~) relatively uncom-plicated by any significant selective alpha-adrenergic blocking effect.
EXA~LE 36 Additional Biological Testing of 1-[4-[(1-Methyl-ethyl)thi_ phenox~J]-3-(octy:lamino)-2-prcpanol The vasoactivity of tne above compound of Example 2 was further evaluated according to various pharmacological tests employed for that purposc. Thus:
(a~ Rats with intra-arterial catheters have periods of shortened platelet survival time. This shortened survival time is normalized w~th the compound of Example 2.
(b) The compound of Example 2 elevated basal tone of mesenteric arteries of dogs and rabbits. This effect is considered valuable i~l the treatment of peripheral and cerebral vascular diseases.
(c) The compound of Example 2 decreased red 'olood cell rigidity determined via a chromium labeling technique and accordingly the cells are better able to pass through sclerosed narrowed capillaries of tissues af f ected by vascular disease.
Claims (29)
1. A process for preparing an alkylthiophenoxypropanol-amine compound of formula I
(I) wherein A, B and R are independently hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive;
R1 is alkyl of 1 to 8 carbon atoms inclusive;
R2 is alkyl of 6 to 12 carbon atoms inclusive or cyclo-alkylalkyl having 5 to 8 ring carbon atoms and from 2 to 6 carbon atoms in the alkylene chain selected from the process group consisting of:
(a) reacting an alkylthiophenol derivative of formula II
(II) wherein R and R1 have meanings hereinabove described with an epihalo-hydrin of formula III
(III) wherein X signifies halogen, preferably chlorine or bromine, and condensing the epihalohydrin reaction product with an amine of formula IV
H2N-R2 (IV) wherein R2 has the meaning as in formula (I);
(b) reacting a formula II phenol with a compound of formula VII in alkaline medium (VII) to provide a compound of formula VIII
(VIII) wherein R, R1 and R2 have the same meaning as in formula I and R3 stands for hydrogenolysable radicals benzyl or benzhydryl; and converting said compound of formula VIII to an alkylthiophenoxy-propanolamine of formula I by catalytic hydrogenation; and (c) reducing a compound of formula IX
(IX) wherein A, B, R and R1 are as defined to provide the primary amino compound X
(X) and reductively alkylating a compound of formula X with an aldehyde of formula XI
(XI) wherein Y is straight or branched chain alkyl of 5 to 11 carbon atoms inclusive or cycloalkylalkyl having 5 to 8 ring carbon atoms and 1 to 5 carbon atoms in the alkylene chain; and, if desired, reacting a compound of formula I with an acid to form an acid addition salt thereof.
(I) wherein A, B and R are independently hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive;
R1 is alkyl of 1 to 8 carbon atoms inclusive;
R2 is alkyl of 6 to 12 carbon atoms inclusive or cyclo-alkylalkyl having 5 to 8 ring carbon atoms and from 2 to 6 carbon atoms in the alkylene chain selected from the process group consisting of:
(a) reacting an alkylthiophenol derivative of formula II
(II) wherein R and R1 have meanings hereinabove described with an epihalo-hydrin of formula III
(III) wherein X signifies halogen, preferably chlorine or bromine, and condensing the epihalohydrin reaction product with an amine of formula IV
H2N-R2 (IV) wherein R2 has the meaning as in formula (I);
(b) reacting a formula II phenol with a compound of formula VII in alkaline medium (VII) to provide a compound of formula VIII
(VIII) wherein R, R1 and R2 have the same meaning as in formula I and R3 stands for hydrogenolysable radicals benzyl or benzhydryl; and converting said compound of formula VIII to an alkylthiophenoxy-propanolamine of formula I by catalytic hydrogenation; and (c) reducing a compound of formula IX
(IX) wherein A, B, R and R1 are as defined to provide the primary amino compound X
(X) and reductively alkylating a compound of formula X with an aldehyde of formula XI
(XI) wherein Y is straight or branched chain alkyl of 5 to 11 carbon atoms inclusive or cycloalkylalkyl having 5 to 8 ring carbon atoms and 1 to 5 carbon atoms in the alkylene chain; and, if desired, reacting a compound of formula I with an acid to form an acid addition salt thereof.
2. The alkylthiophenoxypropanolamine product of formula I
(I) wherein A, B and R are independently selected from the group consisting of hydrogen and lower alkyl of 1 to 4 carbon atoms inclusive;
R1 is alkyl of 1 to 8 carbon atoms inclusive;
R2 is alkyl of 6 to 12 carbon atoms inclusive or cyclo-alkylalkyl having 5 to 8 ring carbon atoms and from 2 to 6 carbon atoms in the alkylene chain;
and, if desired, an acid addition salt thereof whenever prepared according to the process of Claim 1.
(I) wherein A, B and R are independently selected from the group consisting of hydrogen and lower alkyl of 1 to 4 carbon atoms inclusive;
R1 is alkyl of 1 to 8 carbon atoms inclusive;
R2 is alkyl of 6 to 12 carbon atoms inclusive or cyclo-alkylalkyl having 5 to 8 ring carbon atoms and from 2 to 6 carbon atoms in the alkylene chain;
and, if desired, an acid addition salt thereof whenever prepared according to the process of Claim 1.
3. The process of claim 1 wherein the reaction product of 4-(methylthio)phenol and epichlorohydrin is condensed with n-octyl-amine to provide 1-[4-(methylthio)phenoxy]-3-(octylamino)-2-propanol.
4. The product 1-[4-(methylthio)phenoxy]-3-(octylamino) 2-propanol whenever prepared according to the process of claim 3.
5. The process of claim 1 wherein the reaction product of 4-(isopropylthio)phenol and epichlorohydrin is condensed with n-octyl-amine to provide 1-[4-[(1-methylethyl)thio]phenoxy]-3-(octylamino)-2-propanol.
6. The product 1-[4-[(1-methylethyl)thio]phenoxy]-3-(octylamino)-2-propanol whenever prepared according to the process of claim 5.
7. The process of claim 1 wherein 1-[4-[(1-methylethyl)-thio]phenoxy]-3-(octylamino)-2-propanol is reacted with hydrochloric acid to provide the hydrochloride salt thereof.
8. The product 1-[4-[(1-methylethyl)thio]phenoxy]-3-(octylamino)-2-propanol hydrochloride whenever prepared according to the process of claim 7.
9. The process of claim 1 wherein the reaction product of 3-(isopropylthio)phenol and epichlorohydrin is condensed with n-octyl-amine to provide l-[3-[(1-methylethyl)thio]phenoxy]-3-(octylamino)-2-propanol.
10. The product 1-[3-[(1-methylethyl)thio]phenoxy]-3-(octylamino)-2-propanol whenever prepared according to the process of claim 9.
11. The process of claim 1 wherein 1-[3-[(1-methylethyl)-thio]phenoxy]-3-(octylamino)-2-propanol is reacted with hydrochloric acid to provide the hydrochloride salt thereof.
12. The product 1-[3-[(1-methylethyl)thio]phenoxy]-3-(octyl-amino)-2-propanol hydrochloride whenever prepared according to the process of claim 11.
13. The process of claim 1 wherein the reaction product of 4-(isopropylthio)phenol and epichlorohydrin is condensed with n-dodecylamine to provide 1-[4-[(1-methylethyl)thio]phenoxy]-3-(dodecylamino)-2-propanol.
14. The product 1-[4-[(1-methylethyl)thio]phenoxy]-3-(dodecylamino)-2-propanol whenever prepared according to the process of claim 13.
15. The process of claim 1 wherein 1-[4-[(1-methylethyl)-thio]phenoxy]-3-(dodecylamino)-2-propanol is reacted with hydrochloric acid to provide the hydrochloride salt thereof.
16. The product 1-[4-[(1-methylethyl)thio]phenoxy]-3-(dodocylamino)-2-propanol hydrochloride whenever prepared according to the process of claim 15.
17. The process of claim 1 wherein the reaction product of 4-(isopropylthio)phenol and epichlorohydrin is condensed with cyclo-hexylethylamine to provide 1-[(2-cyclohexylethyl)amino]-3-[4-(1-methylethyl)thio]phenoxy]-2-propanol.
18. The product 1-[(2-cyclohexylethyl)amino]-3-[4-(1-methylethyl)thiolphenoxyl-2-propanol whenever prepared according to the process of claim 17.
19. The process of claim 1 wherein 1-[(2-cyclohexylethyl)-amino]-3-[4-[(1-methylethyl)thio]phenoxy]-2-propanol is reacted with hydrochloric acid to provide the hydrochloride salt thereof.
20. The product 1-[(2-cyclohexylethyl)amino]-3-[4-[(1-methylethyl)thio]phenoxy]-2-propanol hydrochloride whenever prepared according to the process of claim 19.
21. The process of claim 1 wherein reaction product of 4-(isopropylthio)phenol and epichlorohydrin is condensed with eyclo-hexylbutylamine to provide 1-[(4-cyclohexylbutyl)amino]-3-[4-(1-methylethyl)thio]phenoxy]-2-propanol.
22. The product 1-[(4-cyclohexylbutyl)amino]-3-[4-[(1-methylethyl)thio]phenoxy]-2-propanol whenever prepared according to the process of claim 21.
23. The process of claim 1 wherein 1-[(4-cyclohexylbutyl)-amino]-3-[4-(1-methylethyl)thio]phenoxy]-2-propanol is reacted with hydroehloric acid to provide the hydrochloride salt thereof.
24. The product 1-[(4-cyclohexylbutyl)amino]-3-[4-[(1-methylethyl)thio]phenoxy]-2-propanol hydrochloride whenever prepared according to the process of claim 23.
25. The process of claim 1 wherein the reaction product of 2-methyl-4-(methylthio)phenol and epichlorohydrin is reacted with n-octylamine to provide 1-[2-methyl-4-(methylthio)phenoxy]-3-(octyl-amino)-2-propanol.
26. The product 1-[2-methyl-4-(methylthio)phenoxy]-3-(octylamino)-2-propanol whenever prepared according to the process of claim 25.
27. The process of claim 1 wherein the reaction product of 2-(methylthio)phenol and epichlorohydrin is condensed with n-octyl-amine to provide 1-[2-(methylthio)phenoxy]-3-(octylamino)-2-propanol.
28. The product 1-[2-(methylthio)phenoxy]-3-(octylamino)-2-propanol whenever prepared according to the process of claim 27.
29. The process of claim 1 wherein 1-[2-(methylthio)phenoxy]-3-(octylamino)-2-propanol is reacted with hydrochloric acid to provide the hydrochloride salt thereof.
30. The product 1-[2-(methylthio)phenoxy]-3-(octylamino)-2-propanol hydrochloride whenever prepared according to the process of
29. The process of claim 1 wherein 1-[2-(methylthio)phenoxy]-3-(octylamino)-2-propanol is reacted with hydrochloric acid to provide the hydrochloride salt thereof.
30. The product 1-[2-(methylthio)phenoxy]-3-(octylamino)-2-propanol hydrochloride whenever prepared according to the process of
claim 29.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US84116877A | 1977-10-11 | 1977-10-11 | |
US841,168 | 1977-10-11 | ||
US94222278A | 1978-09-14 | 1978-09-14 | |
US942,222 | 1978-09-14 |
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CA1116636A true CA1116636A (en) | 1982-01-19 |
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ID=27126241
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CA000312115A Expired CA1116636A (en) | 1977-10-11 | 1978-09-26 | Alkylthiophenoxypropanolamines |
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JP (1) | JPS6049188B2 (en) |
AR (2) | AR224239A1 (en) |
AU (1) | AU520181B2 (en) |
CA (1) | CA1116636A (en) |
CH (1) | CH642349A5 (en) |
DE (1) | DE2844353C2 (en) |
DK (1) | DK146005C (en) |
ES (1) | ES474156A1 (en) |
FI (1) | FI70883C (en) |
FR (1) | FR2405932A1 (en) |
GB (1) | GB2006197B (en) |
GR (1) | GR73919B (en) |
IE (1) | IE47449B1 (en) |
IL (1) | IL55695A (en) |
IT (1) | IT1109310B (en) |
LU (1) | LU80345A1 (en) |
NL (1) | NL7810156A (en) |
NO (1) | NO146161C (en) |
PH (1) | PH15824A (en) |
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YU (1) | YU41602B (en) |
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US4396629A (en) | 1980-12-29 | 1983-08-02 | Sterling Drug Inc. | Compositions, processes and method |
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NL6504268A (en) * | 1965-04-03 | 1966-10-04 | ||
DE2551141A1 (en) * | 1975-11-14 | 1977-05-18 | Dolorgiet Arzneimittelfabrik | (1)-Cyclododecylamino'(2)-hydroxy-propane derivs. - selective beta-receptor blockers |
DE2552266A1 (en) * | 1975-11-21 | 1977-05-26 | Dolorgiet Arzneimittelfabrik | (1)-Aryloxy or arylthio-(3)-cyclohexylamino-(2)-propanol derivs. - prepd. e.g. by reacting epoxy propane cpds. with (3,3,5)-trimethyl-cyclohexylamine |
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1978
- 1978-09-26 CA CA000312115A patent/CA1116636A/en not_active Expired
- 1978-09-26 GR GR57313A patent/GR73919B/el unknown
- 1978-10-02 GB GB7838985A patent/GB2006197B/en not_active Expired
- 1978-10-04 AR AR273952A patent/AR224239A1/en active
- 1978-10-04 AU AU40393/78A patent/AU520181B2/en not_active Expired
- 1978-10-06 YU YU2352/78A patent/YU41602B/en unknown
- 1978-10-09 FI FI783068A patent/FI70883C/en not_active IP Right Cessation
- 1978-10-09 NL NL7810156A patent/NL7810156A/en not_active Application Discontinuation
- 1978-10-09 IL IL55695A patent/IL55695A/en unknown
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- 1978-10-10 LU LU80345A patent/LU80345A1/en unknown
- 1978-10-10 DK DK450978A patent/DK146005C/en not_active IP Right Cessation
- 1978-10-10 PH PH21691A patent/PH15824A/en unknown
- 1978-10-10 SE SE7810574A patent/SE443782B/en not_active IP Right Cessation
- 1978-10-10 IT IT51437/78A patent/IT1109310B/en active
- 1978-10-10 NO NO783416A patent/NO146161C/en unknown
- 1978-10-10 FR FR7828916A patent/FR2405932A1/en active Granted
- 1978-10-11 CH CH1056478A patent/CH642349A5/en not_active IP Right Cessation
- 1978-10-11 ES ES474156A patent/ES474156A1/en not_active Expired
- 1978-10-11 DE DE2844353A patent/DE2844353C2/en not_active Expired
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