EP0463119A1 - use of SUBSTITUTED 2-AMINOTETRALINS for the preparation of a medicament for inducing anorexia or weight loss. - Google Patents
use of SUBSTITUTED 2-AMINOTETRALINS for the preparation of a medicament for inducing anorexia or weight loss.Info
- Publication number
- EP0463119A1 EP0463119A1 EP90911220A EP90911220A EP0463119A1 EP 0463119 A1 EP0463119 A1 EP 0463119A1 EP 90911220 A EP90911220 A EP 90911220A EP 90911220 A EP90911220 A EP 90911220A EP 0463119 A1 EP0463119 A1 EP 0463119A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- oxygen
- compound
- propyl
- carbon atoms
- 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.)
- Ceased
Links
- 230000001939 inductive effect Effects 0.000 title claims description 4
- 208000022531 anorexia Diseases 0.000 title abstract description 4
- 206010061428 decreased appetite Diseases 0.000 title abstract description 4
- 230000004580 weight loss Effects 0.000 title abstract description 4
- 238000002360 preparation method Methods 0.000 title description 28
- 239000003814 drug Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- -1 hydrocarbyl radicals Chemical class 0.000 claims description 42
- 229910052760 oxygen Inorganic materials 0.000 claims description 40
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 39
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 39
- 239000001301 oxygen Substances 0.000 claims description 39
- 125000004432 carbon atom Chemical group C* 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 26
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 25
- 239000011593 sulfur Substances 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 230000003291 dopaminomimetic effect Effects 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 150000003254 radicals Chemical group 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 6
- 125000004442 acylamino group Chemical group 0.000 claims description 6
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- GYLJIEHSOUHIBS-UHFFFAOYSA-N 6-[2-phenoxyethyl(propyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CCOC1=CC=CC=C1 GYLJIEHSOUHIBS-UHFFFAOYSA-N 0.000 claims description 5
- 150000005840 aryl radicals Chemical group 0.000 claims description 5
- BGQDEMJKJJIKQW-UHFFFAOYSA-N 3-[2-[(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-propylamino]ethyl]-3h-2-benzofuran-1-one Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CCC1C2=CC=CC=C2C(=O)O1 BGQDEMJKJJIKQW-UHFFFAOYSA-N 0.000 claims description 4
- NSJIYVYWYACLEA-UHFFFAOYSA-N 6-[2,2-diphenylethyl(propyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CC(C=1C=CC=CC=1)C1=CC=CC=C1 NSJIYVYWYACLEA-UHFFFAOYSA-N 0.000 claims description 4
- ZFOQMDTYYGTMQJ-UHFFFAOYSA-N 6-[3,3-diphenylpropyl(propyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CCC(C=1C=CC=CC=1)C1=CC=CC=C1 ZFOQMDTYYGTMQJ-UHFFFAOYSA-N 0.000 claims description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 239000011574 phosphorus Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 3
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 6
- 241000124008 Mammalia Species 0.000 abstract description 3
- 208000027089 Parkinsonian disease Diseases 0.000 abstract description 3
- 206010034010 Parkinsonism Diseases 0.000 abstract description 3
- 230000002526 effect on cardiovascular system Effects 0.000 abstract description 3
- 201000000980 schizophrenia Diseases 0.000 abstract description 3
- 230000004406 elevated intraocular pressure Effects 0.000 abstract description 2
- 102000004980 Dopamine D2 Receptors Human genes 0.000 abstract 1
- 108090001111 Dopamine D2 Receptors Proteins 0.000 abstract 1
- 208000012902 Nervous system disease Diseases 0.000 abstract 1
- 230000002124 endocrine Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 27
- 239000000047 product Substances 0.000 description 27
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 22
- 102000005962 receptors Human genes 0.000 description 17
- 108020003175 receptors Proteins 0.000 description 17
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical class NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 14
- 230000027455 binding Effects 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 229960003638 dopamine Drugs 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 102000015554 Dopamine receptor Human genes 0.000 description 6
- 108050004812 Dopamine receptor Proteins 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 125000005297 thienyloxy group Chemical group S1C(=CC=C1)O* 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000006308 propyl amino group Chemical group 0.000 description 4
- 239000012264 purified product Substances 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000005556 structure-activity relationship Methods 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- LCGFVWKNXLRFIF-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-2-amine Chemical class C1=CC=C2CC(N)CCC2=C1 LCGFVWKNXLRFIF-UHFFFAOYSA-N 0.000 description 2
- SEMCIDRMWWMJAG-UHFFFAOYSA-N 3-[2-[(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-propylamino]ethyl]-3h-2-benzofuran-1-one Chemical compound C1CC(C(=CC=C2)OC)=C2CC1N(CCC)CCC1C2=CC=CC=C2C(=O)O1 SEMCIDRMWWMJAG-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- YONZHWNMIUCOLK-UHFFFAOYSA-N 5-methoxy-n-(2-phenoxyethyl)-n-propyl-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1CC(C(=CC=C2)OC)=C2CC1N(CCC)CCOC1=CC=CC=C1 YONZHWNMIUCOLK-UHFFFAOYSA-N 0.000 description 2
- QPDZUKXRRNRZTC-UHFFFAOYSA-N 6-[propyl(2,2,2-triphenylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 QPDZUKXRRNRZTC-UHFFFAOYSA-N 0.000 description 2
- VQTOHRBBKFVQEA-UHFFFAOYSA-N 6-[propyl(3,3,3-triphenylpropyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CCC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 VQTOHRBBKFVQEA-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 210000000748 cardiovascular system Anatomy 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 210000003710 cerebral cortex Anatomy 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 210000000750 endocrine system Anatomy 0.000 description 2
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 239000002287 radioligand Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- MHPQCGZBAVXCGA-GFCCVEGCSA-N (6ar)-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinoline-10,11-diol Chemical compound N1CCC2=CC=CC3=C2[C@H]1CC1=CC=C(O)C(O)=C13 MHPQCGZBAVXCGA-GFCCVEGCSA-N 0.000 description 1
- FGHVSEXHEAUJBT-HFNHQGOYSA-N (z)-but-2-enedioic acid;(5r)-8-chloro-3-methyl-5-phenyl-1,2,4,5-tetrahydro-3-benzazepin-7-ol Chemical compound OC(=O)\C=C/C(O)=O.C1([C@@H]2C3=CC(O)=C(Cl)C=C3CCN(C2)C)=CC=CC=C1 FGHVSEXHEAUJBT-HFNHQGOYSA-N 0.000 description 1
- NTAGXJQHJQUOOA-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid Chemical compound C1=CC=C2CC(C(=O)O)CCC2=C1 NTAGXJQHJQUOOA-UHFFFAOYSA-N 0.000 description 1
- 150000005206 1,2-dihydroxybenzenes Chemical class 0.000 description 1
- GHRYSOFWKRRLMI-UHFFFAOYSA-N 1-naphthyloxyacetic acid Chemical compound C1=CC=C2C(OCC(=O)O)=CC=CC2=C1 GHRYSOFWKRRLMI-UHFFFAOYSA-N 0.000 description 1
- DCYGAPKNVCQNOE-UHFFFAOYSA-N 2,2,2-triphenylacetic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)O)C1=CC=CC=C1 DCYGAPKNVCQNOE-UHFFFAOYSA-N 0.000 description 1
- JBQMFBWTKWOSQX-UHFFFAOYSA-N 2,3-dihydro-1h-indene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)CCC2=C1 JBQMFBWTKWOSQX-UHFFFAOYSA-N 0.000 description 1
- NIPZZANLNKBKIS-UHFFFAOYSA-N 2-(3,5-dimethylphenoxy)acetic acid Chemical compound CC1=CC(C)=CC(OCC(O)=O)=C1 NIPZZANLNKBKIS-UHFFFAOYSA-N 0.000 description 1
- FJWKEFBYCZSVNZ-UHFFFAOYSA-N 2-(3-oxo-1h-2-benzofuran-1-yl)acetic acid Chemical compound C1=CC=C2C(CC(=O)O)OC(=O)C2=C1 FJWKEFBYCZSVNZ-UHFFFAOYSA-N 0.000 description 1
- GMAAOECEUNSKCO-UHFFFAOYSA-N 2-N-(2,6-dichlorophenyl)-4,5-dihydroimidazole-1,2-diamine Chemical compound NN1C(=NCC1)NC1=C(C=CC=C1Cl)Cl GMAAOECEUNSKCO-UHFFFAOYSA-N 0.000 description 1
- SXERGJJQSKIUIC-UHFFFAOYSA-N 2-Phenoxypropionic acid Chemical compound OC(=O)C(C)OC1=CC=CC=C1 SXERGJJQSKIUIC-UHFFFAOYSA-N 0.000 description 1
- BZQGAPWJKAYCHR-UHFFFAOYSA-N 3,3-diphenylpropanoic acid Chemical compound C=1C=CC=CC=1C(CC(=O)O)C1=CC=CC=C1 BZQGAPWJKAYCHR-UHFFFAOYSA-N 0.000 description 1
- BUSOTUQRURCMCM-UHFFFAOYSA-N 3-Phenoxypropionic acid Chemical compound OC(=O)CCOC1=CC=CC=C1 BUSOTUQRURCMCM-UHFFFAOYSA-N 0.000 description 1
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 1
- UMKXSOXZAXIOPJ-UHFFFAOYSA-N 5,6,7,8-tetrahydro-2-naphthol Chemical compound C1CCCC2=CC(O)=CC=C21 UMKXSOXZAXIOPJ-UHFFFAOYSA-N 0.000 description 1
- TWSPRZGDUCMKEF-UHFFFAOYSA-N 5-methoxy-N-(2-phenylpropyl)-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine 6-[2-phenylpropyl(propyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C(CC)N(CC(C)C1=CC=CC=C1)C1CC2=CC=CC(=C2CC1)OC.C(CC)N(CC(C)C1=CC=CC=C1)C1CC2=CC=CC(=C2CC1)O TWSPRZGDUCMKEF-UHFFFAOYSA-N 0.000 description 1
- IXDPNNDSXFDGLG-UHFFFAOYSA-N 5-methoxy-n-(2-naphthalen-1-yloxyethyl)-n-propyl-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1CC(C(=CC=C2)OC)=C2CC1N(CCC)CCOC1=CC=CC2=CC=CC=C12 IXDPNNDSXFDGLG-UHFFFAOYSA-N 0.000 description 1
- LQLMWVNRSYIQOH-UHFFFAOYSA-N 5-methoxy-n-(3-phenoxypropyl)-n-propyl-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1CC(C(=CC=C2)OC)=C2CC1N(CCC)CCCOC1=CC=CC=C1 LQLMWVNRSYIQOH-UHFFFAOYSA-N 0.000 description 1
- ICJPCRXVYMMSJY-UHFFFAOYSA-N 5-methoxy-n-propyl-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1=CC=C(OC)C2=C1CC(NCCC)CC2 ICJPCRXVYMMSJY-UHFFFAOYSA-N 0.000 description 1
- GNNDCHQSERDVJB-UHFFFAOYSA-N 5-methoxy-n-propyl-n-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1CC(C(=CC=C2)OC)=C2CC1N(CCC)CC1CC2=CC=CC=C2CC1 GNNDCHQSERDVJB-UHFFFAOYSA-N 0.000 description 1
- HTJUCMSULCSBJM-UHFFFAOYSA-N 5-methoxy-n-propyl-n-(2,2,2-triphenylethyl)-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1CC(C(=CC=C2)OC)=C2CC1N(CCC)CC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 HTJUCMSULCSBJM-UHFFFAOYSA-N 0.000 description 1
- FXPWJGGVGZDIRL-UHFFFAOYSA-N 5-methoxy-n-propyl-n-(3,3,3-triphenylpropyl)-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1CC(C(=CC=C2)OC)=C2CC1N(CCC)CCC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 FXPWJGGVGZDIRL-UHFFFAOYSA-N 0.000 description 1
- OHVAUXYLMANDHY-UHFFFAOYSA-N 6-[2,3-dihydro-1h-inden-1-ylmethyl(propyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CC1C2=CC=CC=C2CC1 OHVAUXYLMANDHY-UHFFFAOYSA-N 0.000 description 1
- FTZHFZBPPUXVKY-UHFFFAOYSA-N 6-[2-(1,3-dihydro-2-benzofuran-1-yl)ethyl-propylamino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CCC1C2=CC=CC=C2CO1 FTZHFZBPPUXVKY-UHFFFAOYSA-N 0.000 description 1
- AVTBTTNVKCYRGQ-UHFFFAOYSA-N 6-[2-(1-benzothiophen-2-yloxy)ethyl-propylamino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CCOC1=CC2=CC=CC=C2S1 AVTBTTNVKCYRGQ-UHFFFAOYSA-N 0.000 description 1
- WVKXJXXRUZKDCM-UHFFFAOYSA-N 6-[2-(1-benzothiophen-3-yloxy)ethyl-propylamino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CCOC1=CSC2=CC=CC=C12 WVKXJXXRUZKDCM-UHFFFAOYSA-N 0.000 description 1
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- PJSGZXZANRFHFH-UHFFFAOYSA-N 6-[2-(2,6-dimethylphenoxy)ethyl-propylamino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CCOC1=C(C)C=CC=C1C PJSGZXZANRFHFH-UHFFFAOYSA-N 0.000 description 1
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- AWUAIGQMLPXFSS-UHFFFAOYSA-N 6-[2-anilinoethyl(propyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CCNC1=CC=CC=C1 AWUAIGQMLPXFSS-UHFFFAOYSA-N 0.000 description 1
- DQTLSEOWPVOKER-UHFFFAOYSA-N 6-[2-naphthalen-2-yloxyethyl(propyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CCOC1=CC=C(C=CC=C2)C2=C1 DQTLSEOWPVOKER-UHFFFAOYSA-N 0.000 description 1
- QFMPMWVQUFASNB-UHFFFAOYSA-N 6-[3-naphthalen-1-yloxypropyl(propyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CCCOC1=CC=CC2=CC=CC=C12 QFMPMWVQUFASNB-UHFFFAOYSA-N 0.000 description 1
- XSWBBRVPDWPBGE-UHFFFAOYSA-N 6-[3-phenoxypropyl(propyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CCCOC1=CC=CC=C1 XSWBBRVPDWPBGE-UHFFFAOYSA-N 0.000 description 1
- HJAWRTABSSXZHN-UHFFFAOYSA-N 6-[propyl(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CC1CC2=CC=CC=C2CC1 HJAWRTABSSXZHN-UHFFFAOYSA-N 0.000 description 1
- WFFUKDVNPRRWFV-UHFFFAOYSA-N 6-[propyl(2-thiophen-2-yloxyethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CCOC1=CC=CS1 WFFUKDVNPRRWFV-UHFFFAOYSA-N 0.000 description 1
- AUBNLLGXUCCYFZ-UHFFFAOYSA-N 6-amino-5,6,7,8-tetrahydronaphthalen-1-ol Chemical class C1=CC=C2CC(N)CCC2=C1O AUBNLLGXUCCYFZ-UHFFFAOYSA-N 0.000 description 1
- FSMRTTIHBZCVJG-UHFFFAOYSA-N 6-amino-5,6,7,8-tetrahydronaphthalene-1,2-diol Chemical class C1=CC(O)=C(O)C2=C1CC(N)CC2 FSMRTTIHBZCVJG-UHFFFAOYSA-N 0.000 description 1
- ASXGAOFCKGHGMF-UHFFFAOYSA-N 6-amino-5,6,7,8-tetrahydronaphthalene-2,3-diol Chemical compound OC1=C(O)C=C2CC(N)CCC2=C1 ASXGAOFCKGHGMF-UHFFFAOYSA-N 0.000 description 1
- 102000055025 Adenosine deaminases Human genes 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
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- ZZJYIKPMDIWRSN-HWBMXIPRSA-N LSM-20934 Chemical compound C12=CC=CC=C2CCC2=CC=CC3=C2[C@H]1CN1CC[C@](C(C)(C)C)(O)C[C@H]13 ZZJYIKPMDIWRSN-HWBMXIPRSA-N 0.000 description 1
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- GOTMKOSCLKVOGG-UHFFFAOYSA-N SCH 23390 Chemical compound C1N(C)CCC2=CC(Cl)=C(O)C=C2C1C1=CC=CC=C1 GOTMKOSCLKVOGG-UHFFFAOYSA-N 0.000 description 1
- BLGXFZZNTVWLAY-CCZXDCJGSA-N Yohimbine Natural products C1=CC=C2C(CCN3C[C@@H]4CC[C@@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-CCZXDCJGSA-N 0.000 description 1
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- 229960004046 apomorphine Drugs 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- BLGXFZZNTVWLAY-UHFFFAOYSA-N beta-Yohimbin Natural products C1=CC=C2C(CCN3CC4CCC(O)C(C4CC33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-UHFFFAOYSA-N 0.000 description 1
- LRJRPHROCLHMHK-UHFFFAOYSA-N boron;n,n-dimethylmethanamine Chemical compound [B].CN(C)C LRJRPHROCLHMHK-UHFFFAOYSA-N 0.000 description 1
- 229950006479 butaclamol Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
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- 238000001727 in vivo Methods 0.000 description 1
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- QVAPGEAAVQZBGK-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-1-ylmethyl)-5-methoxy-n-propyl-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1CC(C(=CC=C2)OC)=C2CC1N(CCC)CC1C2=CC=CC=C2CC1 QVAPGEAAVQZBGK-UHFFFAOYSA-N 0.000 description 1
- FTGBNHJNZRVYDT-UHFFFAOYSA-N n-(3,3-diphenylpropyl)-5-methoxy-n-propyl-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1CC(C(=CC=C2)OC)=C2CC1N(CCC)CCC(C=1C=CC=CC=1)C1=CC=CC=C1 FTGBNHJNZRVYDT-UHFFFAOYSA-N 0.000 description 1
- QCERTVHZQMVLAF-UHFFFAOYSA-N n-[2-(3,5-dimethylphenoxy)ethyl]-5-methoxy-n-propyl-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1CC(C(=CC=C2)OC)=C2CC1N(CCC)CCOC1=CC(C)=CC(C)=C1 QCERTVHZQMVLAF-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical group [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
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- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- DKGZKTPJOSAWFA-UHFFFAOYSA-N spiperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 DKGZKTPJOSAWFA-UHFFFAOYSA-N 0.000 description 1
- 229950001675 spiperone Drugs 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
- GQDDNDAYOVNZPG-SCYLSFHTSA-N yohimbine Chemical compound C1=CC=C[C]2C(CCN3C[C@@H]4CC[C@H](O)[C@@H]([C@H]4C[C@H]33)C(=O)OC)=C3N=C21 GQDDNDAYOVNZPG-SCYLSFHTSA-N 0.000 description 1
- 229960000317 yohimbine Drugs 0.000 description 1
- AADVZSXPNRLYLV-UHFFFAOYSA-N yohimbine carboxylic acid Natural products C1=CC=C2C(CCN3CC4CCC(C(C4CC33)C(O)=O)O)=C3NC2=C1 AADVZSXPNRLYLV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/16—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring not being further substituted
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Definitions
- the invention relates generally to substituted 2-aminotetralins and to processes for preparing such compounds. More particularly, the invention relates to compounds for therapeutic use, in particular in treating disorders of the central nervous, cardiovascular and endocrine systems. The compounds of this invention are also useful for alleviating glaucoma, parkinsonism, and schizophrenia, and for inducing anorexia and weight loss in mammals.
- R 1 and R 2 are saturated alkyl groups and n is 1 or 2 , are dopamine receptor agonists (McDermed et al., J. Med. Chem. 18 , 362 (1975); Feenstra et al., Arch. Pharmacol. 313, 213 (1980). Many structure-activity relationship studies have been conducted to find compounds with high dopamine-receptor stimulating activity. A survey is contained in Katerinopoulos, H. E., et al., "Structure-Activity Relationships for Dopamine Analogues," Drugs of the Future. Vol. 12, No. 3, 1987, 223-253.
- D 2 receptor potency of dopamine agonists is at a maximum when one of the two N-substituents fits into a receptor niche which, because of size constraints maximally accommodates an n-propyl group Conversely, activity drops off when the propyl group is replaced by the smaller groups ethyl or methyl. When the compound contains no N-substituent at least as small as n-propyl, activity is small or non-existent.
- R 2 , R 3 and R 4 are each selected from the group consisting of H and OA with the provision that at least one of R 2 , R 3 and R 4 is H, that R 2 and R 4 are not both OA;
- A is H or is selected from the group consisting of hydrocarbyl radicals, for example lower alkyl radicals optionally substituted with aromatic residues (i.e. methyl, ethyl, propyl, benzyl, etc.), as well as and
- R 5 is selected from the group consisting of alkyl and aromatic residues having between 1 and 12, preferably between 1 and 6, carbon atoms, for example alkyl, optionally sub ⁇ titued with aromatic residues, and aromatic residues optionally substituted with alkyl radicals; n is an integer between 1 and 4; R 6 is an alkyl chain comprising between 1 and 4 carbon atoms, X is selected from the group consisting of -CH 2 -, oxygen, sulfur, and nitrogen, with the provision that when X is not -CH 2 -, R 1 is selected from the group consisting of
- Z is oxygen, nitrogen or sulfur
- Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carbpxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl, and hetero atom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, and a is an integer of from zero to 3; and with the further provision that when X is -CH 2 -, R 1 is either or
- R 8 is hydrogen, aryl, or R 6 ; and further wherein R 9 is aryl, R 6' -OH, -NH 2 , -OR 6 , or -N(R 6 ) 2 ; or R 1 is
- B is oxygen, sulfur or two hydrogen atoms, and pharmaceutically acceptable salts thereof.
- R 2 is OA and A is H.
- the compounds in the present invention be an optically active compound or racemic mixture thereof having substantial affinity and selectivity for binding to dopamine D 2 receptors, e.g., in a human.
- 2-(N-n-propyl,N-2-[phenyloxy]ethylamino)-5-hydroxytetralin is especially preferred for its high affinity and selectivity for binding to dopamine D 2 receptors.
- R 2 , R 3 and R 4 are each selected from the group consisting of H and OA with the provision that at least one of R 2 R 3 and R 4 is H, that R 2 and R 4 are not both OA;
- A is H or is selected from the group consisting of hydrocarbyl radicals, for example lower alkyl radicals, optionally substituted with aromatic residues (i.e. methyl, ethyl, propyl, benzyl, etc.),
- R 5 is selected from the group consisting of alkyl and a tic residues having between 1 and 12, preferably between 1 and 6, carbon atoms, for example alkyl residues optionally substituted with aromatic residues and aromatic residues optionally substituted with alkyl radicals; n is an integer between 1 or 4; R 6 is an alkyl chain comprising between 1 and 4 carbon atoms; X is selected from the group consisting of -CH 2 -, oxygen, sulfur, and nitrogen, with the provision that when X is not -CH 2 -, R is selected from the group consisting of
- Z is oxygen, nitrogen or sulfur
- Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and hetero atom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12, preferably 1 to 6, carbon atoms, and a is an integer of from zero to 3, for instance zero to 2; and with the further provision that when X is -CH 2 -, R 1 is either
- R 8 is hydrogen, aryl, or R 6 ; and further wherein R 9 is aryl, R 6 , -OH, -NH 2, -OR 6 , or -N(R 6 ) 2 ;
- B is oxygen, sulfur or two hydrogen atoms, and pharmaceutically acceptable salts thereof.
- R 2 is OA and A is H.
- A is preferably H or is selected from the group consisting of phenyl and alkyl radicals having from 1 to 12 carbon atoms, and more preferably R 5 is an alkyl or aryl radical that would serve to extend the activity of the compound in the body, for example phenyl, methyl, t-butyl, o-methylphenyl, o-, m- or p-methoxyphenyl, p-isopropylphenyl or nonyl.
- R The more preferred groups represented by R are thienyl, phenyl, hydroxyphenyl, furanyl and naphthalenyl, e.g., 2-thienyl, 3-thienyl, 3 -hydroxyphenyl, 4-hydroxyphenyl, etc.
- n 2
- X oxygen or -CH 2 - and R 2 is OA; and most preferably A is H and R 6 is propyl.
- the compounds herein be an optically active or racemic mixtures capable of binding selectively to one or more dopamine D 2 receptors, e.g., in a human.
- 2-(N-n-propyl,N-2-[phenyloxy] ethylamino)-5-hydroxytetralin is an especially preferred compound because of its high affinity and selectivity for binding to D 2 dopamine receptors.
- the compounds herein will be useful in the treatment of disorders of the central nervous, cardiovascular, and endocrine systems. In particular it is believed that the compounds herein are useful in the treatment of such conditions in humans as elevated intraocular pressure, schizophrenia and parkinsonism, and for inducing anorexia and weight loss in humans and other mammals.
- Y comprises no more than 5 carbon atoms and a is an integer from 0 to 2.
- Specific preferred compounds of this group include:
- R 1 is phenyl and/or substituted phenyl and is selected from the group of radicals represented by the formula:
- Example 2 The product of Example 2 was also obtained by dissolving the product of Example 1 in dry dichloromethane and adding a solution of boron tribromide in dichloromethane dropwise at room temperture under nitrogen. After completion, the reaction was poured into a beaker containing NH 4 OH and ice and stirred for 0.5 h. The organic layer was separated, and the product was purified as in Example 2.
- Example 1 phenoxyacetic acid can be replaced by 3-phenoxy-propionic acid.
- Example 1 phenoxyacetic acid was replaced by (1-naphthoxy)-acetic acid.
- the resulting oil was sujbected to flash chromatography (silica; pet ether) and the product was isolated; characteristic peak of NMR (300 MHz, CDCl 3 ); ⁇ 8.3-6.7 (m,10H), 4.2(m, 2H), 3.85(s, 3H), 1.0(t, 3H).
- Example 6 The product of Example 6 was used as the starting material in Example 2. The resulting oil was subjected to flash chromatography and the isolated product showed characteristic peaks at : NMR (CDCl 3 ) ⁇ 8.3-6.6 (m, 10H), 4.2(m, 2H), 0.9(t,3H).
- Example 1 phenoxyacetic acid was replaced by phthalide-3-acetic acid. The resulting oil was subjected to flash chromatography and the isolated product showed distinct peaks at: NMR (CDCl 3 ) ⁇ 8.0-6.7(m, 7H) , 5.7(m, 1H), 3.8(s, 3H), 0.9 (t, 3H).
- NMR CDCl 3
- Example 8 The product of Example 8 was used as the starting material for Example 3.
- the resulting oil after purification showed distinct peaks at: NMR(CDC1 3 ) ⁇ 7.9-6.6(m, 7H), 5.7(m, 1H), 0.95(t, 3H).
- Example 1 phenoxyacetic acid was replaced by diphenylactic acid.
- the purified product showed characteristic peaks at: NMR(CDCl 3 ) ⁇ 7.8-6.65(m, 13H), 4.1(t, 1H), 3.8(s, 3H), 3.2(d, 2H), 0.7(t, 3H).
- Example 1 phenoxyacetic acid was replaced by 3,3-diphenylpropionic acid.
- the purified product showed distinct peaks at: NMR(CDCl 3 ) ⁇ 7.4-7.2 (m, 11H), 6.65(m, 2H), 4.05(t,lH), 3.8(s, 3H), 0.9(s, 3H).
- Example 13 The product of Example 13 was used as starting material for Example 3.
- the isolated product showed distinct peaks at: NMR(CDCl 3 ) ⁇ 7.4-7.0(m, 1H) , 6.7-6.5(m, 2H), 4.0(t, 1H), 0.9(t, 3H).
- Example 1 phenoxyacetic acid was replaced by DL-2-phenoxypropionic acid.
- the purified product showed distinct peaks at: NMR(CDCl 3 ) ⁇ 7.3-6.65 (m, 8H) , 4.45(m, 1H), 3.8(S, 3H) , 0.9(t, 3H) .
- Example 15 The product of Example 15 was used as starting material for Example 2. The isolated product showed characteristic peaks at: NMR(CDCl 3 ) ⁇ 7.3-6.65(m, 8H) , 4.45(m, 1H), 0.9 (t, 3H). EXAMPLE 17
- Example 1 phenoxyacetic acid was replaced by 3,3,3-lriphenylpropionic acid.
- the purified product showed characteristic peaks at : NMR(CDCl 3 ) ⁇ 7.4-6.65(m, 18H), 3.8(s, 3H), 0.9(t, 3H).
- Example 17 The product of Example 17 was used as starting material in Example 3. After purification the product showed distinct peaks at: NMR(CDCl 3 ) ⁇ 7.4-6.65(m, 18H), 0.9(t, 3H).
- pehnoxyacetic acid can be replaced by triphenylacetic acid.
- Example 19 The product of Example 19 can be used as the starting material for Example 3.
- Example 2 phenoxyacetic acid can be replaced by ⁇ -methoxyphenlyacetic acid.
- Example 21 The product of Example 21 can be used as the starting material for Example 2.
- Example 1 phenoxyactic acid can be replaced by 1-indancarboxylic acid.
- Example 23 The product of Example 23 can be used as the starting material for Example 3.
- Example 1 phenoxyacetic acid can be replaced by 1,2,3,4-tetrahydro-2-naphthoic acid.
- EXAMPLE 26
- Example 25 The product of Example 25 can be used as the starting material for Example 3.
- phenoxyacetic acid can be replaced by 3,5-dimethylphenoxyacetic acid.
- Example 27 The product of Example 27 can be used as the starting material for Example 3.
- the bovine caudate nuclei assay was employed. Bovine brains were obtained fresh from a local slaughterhouse. The caudate nuclei were dissected out and homogenized in Buffer A (50 mM Tris; 1 mM Na 2 -EDTA; 5 mM KCl; 1 mM MgCl 2 ; 2 mM CaCl 2 ; pH 7.4) using a Brinkman Polytron. The homogenate was centrifuged at 40,000 ⁇ g for 20 minutes and washed once. The pellett was resuspended in Buffer A, incubated at 37°C for 15 minutes, then centrifuged. The pellet was washed once more, resuspended to a protein concentration of 5-10 mg/ml in Buffer A and frozen at -70°C until used.
- Buffer A 50 mM Tris; 1 mM Na 2 -EDTA; 5 mM KCl; 1 mM MgCl 2 ; 2 mM Ca
- the rat cerebral cortex assay was employed. Male Sprague Dawley rats were killed by decapitation and the brains removed. The cerebral cortices were homogenized in 50 mM Tris; 2mM MgCl 2 (pH 7.4), and centrifuged at 40,000 ⁇ g for 10 minutes. The pellet was washed once, resuspended in Tris/MgCl 2 and incubated with 8 units/ml adenosine deaminase at 37 °C for 30 minutes. The homogenate was centrifuged, washed once, resuspended to a protein concentration of 5-10 mg/ml and frozen at -70°C until use.
- radioligands were used as radioligands for each of the receptors tested: [ 3 H]-Spiperone 21-24 Ci/mmol for D 2 receptors, [ 3 H]-SCH23390 75-85 Ci/mmol for D 1 receptors, and [ 3 H]-Para aminoclonidine 48-52 Ci/mmol for ⁇ 2 -adrenergic receptors.
- the radioligands were incubated with various concentrations of competing drug and the appropriate membrane source for periods of ' time as follows: 75 minutes at room temperature for D 2 receptors, 15 minutes at 37°C for D 1 receptors, or 30 minutes at room temperature for ⁇ 2 receptors.
- D 2 1 ⁇ M butaclamol
- D 1 1 ⁇ M SCH23390
- ⁇ 2 1 ⁇ M yohimbine
- the D 2 assays contained 30 nM Kotaserin in order to block the binding of 3 H-spiperone to 5HT 2 receptors.
- the assays were terminated by filtration using a 24-port Brandell cell harvester over filters that had been previously soaked in 0.1% polyethyleneimine, and the filters were washed three times by filtration of cold buffer.
- the filters were then placed in 5 ml scintillation vials to which 4 ml of Beckman Ready-Protein was then added, and each vial was counted for 2 minutes in a Beckman 3801 scintillation counter calibrated for conversion of cpm to dpm. Binding data were analyzed using the Ligand program of Munson and Rodbard (1980). The results are presented as K i values if the data were best fitted to a one-site model, or as K H and K L values if a two-site model produced the better fit.
Abstract
Composés optiquement actifs ou des racémates dont la formule est (I), où les radicaux R1, R2, R3, R4, R6, X et N ont la notation donnée dans la description. Ces composés sont des mélanges optiquement actifs ou racémiques pouvant sélectivement lier un ou plusieurs récepteurs de dopamine D2, par exemple chez l'être humain. Ils sont utiles dans le traitement des troubles des systèmes nerveux central, cardio-vasculaire, et endocrinien tels que la pression intraoculaire élevée, les schizophrénies et le parkinsonisme, et pour provoquer l'anorexie et l'amaigrissement chez les êtres humains et d'autres mammifères.Optically active compounds or racemates whose formula is (I), where the radicals R1, R2, R3, R4, R6, X and N have the notation given in the description. These compounds are optically active or racemic mixtures which can selectively bind one or more dopamine D2 receptors, for example in humans. They are useful in the treatment of central, cardiovascular, and endocrine nervous system disorders such as elevated intraocular pressure, schizophrenia and parkinsonism, and to cause anorexia and weight loss in humans and others mammals.
Description
SUBSTITUTED 2-AMINOTETRALINS
Background of the Invention
Field of the Invention
The invention relates generally to substituted 2-aminotetralins and to processes for preparing such compounds. More particularly, the invention relates to compounds for therapeutic use, in particular in treating disorders of the central nervous, cardiovascular and endocrine systems. The compounds of this invention are also useful for alleviating glaucoma, parkinsonism, and schizophrenia, and for inducing anorexia and weight loss in mammals.
Background of the Prior Art
It is known that various hydroxylated 2-aminotetralins of the general formula
where R1 and R2 are saturated alkyl groups and n is 1 or 2 , are dopamine receptor agonists (McDermed et al., J. Med. Chem. 18 , 362 (1975); Feenstra et al., Arch. Pharmacol. 313, 213 (1980).
Many structure-activity relationship studies have been conducted to find compounds with high dopamine-receptor stimulating activity. A survey is contained in Katerinopoulos, H. E., et al., "Structure-Activity Relationships for Dopamine Analogues," Drugs of the Future. Vol. 12, No. 3, 1987, 223-253. Based upon the high activity of apomorphine, many derivatives and simplified structural analogues have been tested and found to have dopaminergic activity. For instance, some of the bicyclic analogues of dopamine, 2-amino-5,6- and 2-amino-6,7-dihydroxytetralin, and their N-alkylated derivatives were tested and showed activity.
In addition, studies have shown that the 5-hydroxy derivatives of 2-aminotetralins possess high potency almost equivalent to that of the 5,6 catechols, with the additional advantage of increased stability, selectivity and duration of biochemical action. These studies have also shown that in bicyclic compounds the size of the- two nitrogen substituents controls activity. For instance, the N-butyl and N,N-dibutyl derivatives of 2-amino-5,6-dihydroxytetralin, dopamine and norapomorphine have little or no dopaminergic activity, while analogues having at least one N-ethyl or N-n-propyl group possess high activity.
Further studies have shown that the D2 receptor potency of dopamine agonists is at a maximum when one of the two N-substituents fits into a receptor niche which, because of size constraints maximally accommodates an n-propyl group Conversely, activity drops off when the propyl group is replaced by the smaller groups ethyl or methyl. When the
compound contains no N-substituent at least as small as n-propyl, activity is small or non-existent.
However, the structural requirements for the second N-substituent in such compounds have not been established-Consequently, the search continues for new and better N-substituents to enhance both dopamine receptor binding and activity, especially as shown by in vivo studies designed to test the dopaminergic activity of compounds, such as contralateral turning studies in 6-OH-DA-lesioned rats. See Seiler, Max P., et al., "Structure-Activity Relationships of Dopaminergic 5-Hydroxy-2-aminotetralin Derivatives with Functionalized N-Alkyl Substituents." J. Med. Chem. 1986, 29, 912-917.
The receptor site into which this second N-substituent is thought to interact appears to accommodate a wide variety of large, bulky groups having different functionalities without loss of activity. See McDermed, J. D., et al., J. Med. Chem. 1975, 18, 362; Cannon, J. G., et al., J. Med. Chem. 1977, 20, 1111; and Wikstroem, H., et al., J. Med. Chem. 1982, 25, 925. However, the dopaminergic activity and potency conferred upon the compound by the choice of the second N-substituent is at present, unpredictable so that the search continues for new and better dopamine receptor agonists, especially for compounds showing a high degree of selectivity and specificity as either D1 or D2 receptor agonists.
Summary of the Invention
There has now been discovered certain novel compounds having dopaminergic activity and having the structural formula
where R2, R3 and R4 are each selected from the group consisting of H and OA with the provision that at least one of R2, R3 and R4 is H, that R2 and R4 are not both OA; A is H or is selected from the group consisting of hydrocarbyl radicals, for example lower alkyl radicals optionally substituted with aromatic residues (i.e. methyl, ethyl, propyl, benzyl, etc.), as well as and
R5 is selected from the group consisting of alkyl and aromatic residues having between 1 and 12, preferably between 1 and 6, carbon atoms, for example alkyl, optionally subεtitued with aromatic residues, and aromatic residues optionally substituted with alkyl radicals; n is an integer between 1 and 4; R6 is an alkyl chain comprising between 1 and 4 carbon atoms, X is selected from the group consisting of -CH2-, oxygen, sulfur, and nitrogen, with the provision that when X is not -CH2-, R1 is selected from the group consisting of
wherein Z is oxygen, nitrogen or sulfur, wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carbpxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl, and hetero atom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, and a is an integer of from zero to 3; and with the further provision that when X is -CH2-, R1 is either or
wherein R8 is hydrogen, aryl, or R 6; and further wherein R9 is aryl, R6' -OH, -NH2, -OR6, or -N(R6)2; or R1 is
wherein B is oxygen, sulfur or two hydrogen atoms, and pharmaceutically acceptable salts thereof.
Preferably, R2 is OA and A is H.
It is essential that the compounds in the present invention be an optically active compound or racemic mixture thereof having substantial affinity and selectivity for binding to dopamine D2 receptors, e.g., in a human. In particular, it is found that 2-(N-n-propyl,N-2-[phenyloxy]ethylamino)-5-hydroxytetralin is especially preferred for its high affinity and selectivity for binding to dopamine D2 receptors.
Detailed Description of the Invention The compounds used in the present invention are selected from the group of steroisomers or mixtures thereof of compounds having dopaminergic activity represented by the formula:
where R2, R3 and R4 are each selected from the group consisting of H and OA with the provision that at least one of R2 R3 and R4 is H, that R2 and R4 are not both OA; A is H or is selected from the group consisting of hydrocarbyl radicals, for example lower alkyl radicals, optionally
substituted with aromatic residues (i.e. methyl, ethyl, propyl, benzyl, etc.),
R 5 is selected from the group consisting of alkyl and a tic residues having between 1 and 12, preferably between 1 and 6, carbon atoms, for example alkyl residues optionally substituted with aromatic residues and aromatic residues optionally substituted with alkyl radicals; n is an integer between 1 or 4; R6 is an alkyl chain comprising between 1 and 4 carbon atoms; X is selected from the group consisting of -CH2-, oxygen, sulfur, and nitrogen, with the provision that when X is not -CH2-, R is selected from the group consisting of
wherein Z is oxygen, nitrogen or sulfur, wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and hetero atom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12, preferably 1 to 6, carbon atoms, and a is an integer of from zero to 3, for
instance zero to 2; and with the further provision that when X is -CH2-, R1 is either
wherein R8 is hydrogen, aryl, or R6;; and further wherein R9 is aryl, R6, -OH, -NH2, -OR6, or -N(R6)2;
or R1 is
wherein B is oxygen, sulfur or two hydrogen atoms, and pharmaceutically acceptable salts thereof.
Preferably, R2 is OA and A is H.
A is preferably H or is selected from the group consisting of phenyl and alkyl radicals having from 1 to 12 carbon atoms, and more preferably R5 is an alkyl or aryl radical that would serve to extend the activity of the compound in the body, for example phenyl, methyl, t-butyl, o-methylphenyl, o-, m- or p-methoxyphenyl, p-isopropylphenyl or nonyl.
The more preferred groups represented by R are thienyl, phenyl, hydroxyphenyl, furanyl and naphthalenyl, e.g., 2-thienyl, 3-thienyl, 3 -hydroxyphenyl, 4-hydroxyphenyl, etc.
In the more preferred compounds for use in the present invention n is 2, X is oxygen or -CH2- and R2 is OA; and most preferably A is H and R6 is propyl.
It is essential that the compounds herein be an optically active or racemic mixtures capable of binding selectively to one or more dopamine D2 receptors, e.g., in a human. In particular, 2-(N-n-propyl,N-2-[phenyloxy] ethylamino)-5-hydroxytetralin is an especially preferred compound because of its high affinity and selectivity for binding to D2 dopamine receptors. Due to their high affinity for binding to D2 dopamine receptors, it is believed that the compounds herein will be useful in the treatment of disorders of the central nervous, cardiovascular, and endocrine systems. In particular it is believed that the compounds herein are useful in the treatment of such conditions in humans as elevated intraocular pressure, schizophrenia and parkinsonism, and for inducing anorexia and weight loss in humans and other mammals.
Particularly preferred compounds are as follows:
Compounds wherein X is oxygen, nitrogen or sulfur and R1 is selected from the group consisting of radicals represented by the general formula:
wherein specific preferred compounds of this group include:
2-(N-n-propyl-N-2-[2-thienyloxy]ethylamino)-5-hydroxytetralin,
2-(N-n-propyl-N-2-[3-thienyloxy]ethylamino)-5-hydroxtetralin,
2-(N-n-propyl-N-2-[2-furanyloxy]ethylamino)-5-hydroxytetralin,
2-(N-n-propyl-N-2-[3-furanyloxy]ethylamino)-5-hydroxytetralin,
2-(N-n-propyl-N-2-[2-(4-methyl)thienyloxy]ethylamino-5-hydroxytetralin,
2-(N-n-propyl-N-2-[2-(3,4,5-trimethy1)thienyloxy]ethylamino)-5-hydroxytetralin,
2-(N-n-propyl-N-2-[2-(5-chloro)thienyloxy]ethylamino)-5-hydroxytetralin,
2-(N-n-propyl-N-2-[2-(4-bromo-5-methyl)thienyloxy]ethylamino)-5-hydroxytetralin,
2-(N-n-propyl-N-2-[2-(4-methyl-5-ethyl)thienyloxy]ethylamino)-5-hydroxytetralin,
Compounds wherein X is oxygen, nitrogen or sulfur and wherein R1 is selected from the group of radicals represented by the formulae:
More preferably, in these compounds Y comprises no more than 5 carbon atoms and a is an integer from 0 to 2. Specific preferred compounds of this group include:
2-(N-n-propyl-N-2-[2-naphthalenyloxy]ethylamino)-5-hydroxytetralin,
2-(N-n-propyl-N-2-[4-indolyloxy]ethylamino)-5-hydroxytetralin,
2-(N-n-propyl-N-2-[2-benzothienyloxy]ethylamino)-5-hydroxytetralin, and
2-(N-n-propyl-N-2-[3-benzothienyloxy]ethylamino)-5-hydroxytetralin;
Compounds wherein R1 is phenyl and/or substituted phenyl and is selected from the group of radicals represented by the formula:
and wherein X is oxygen, nitrogen or sulfur. Specific preferred compounds of this group include:
2-(N-n-propyl-N-2-[phenyloxy]ethylamino)-5-hydroxytetralin,
2-(N-n-propyl-N-2-[4-hydroxyphenyloxy]ethylamino)-5-hydroxytetralin, and
2-(N-n-propyl-N-2-[3-hydroxyphenyloxy]ethylamino)-5-hydroxytetralin,
2-(N-n-propyl-N-2-[phenyloxy]ethylamino)-5-methoxytetralin
2-(N-n-propyl-N-2-[phenylamino]ethylamino)-5-hydroxytetralin
2-(N-n-propyl-N-2-[4-hydroxyphenylamino]ethylamino)-5-hydroxytetralin
2-(N-n-propyl-N-3-[phenyloxy]propylamino)-5-hydroxytetra1in
2-(N-n-propyl-N-2-[2,6-dimethylphenyloxy]ethylamino)-5-hydroxytetralin
2-(N-n-propyl-N-2-[3,5-dimethylphenyloxy)ethylamino)-5-hydroxytetralin
Compounds wherein X is -CH2- and R1 is selected from the group consisting of radicals represented by the following formulae:
and wherein B is O, S, or H2. Specific preferred compounds in this group include:
3-[2-[propyl(1,2,3,4-tetrahydro-5-methoxy-2-naphthalenyl)amino]ethyl]-1(3H)-isobenzofuranone
3-[2-[propyl(1,2,3,4-tetrahydro-5-hydroxy-2-naphthalenyl)amino]ethyl]-1(3H)-isobenzofuranone
6- [2-(1,3-dihydro-1-isobenzofuranyl)ethyl]propylamino]-5,6,7,8-tetrahydro-1-naphthalenol
2-(N-n-propyl-N-3,3,3-triphenylpropylamino)-5-hydroxytetralin
2-(N-n-propyl-N-2,2,2-triphenylethylamino)-5-hydroxytetralin
2-(N-n-propyl-N-3,3-diphenylpropylamino)-5-hydroxytetralin
2-(N-n-propyl-N-2,2-diphenylethylamino)-5-hydroxytetralin
2-(N-n-propyl-N-2-phenylpropylamino)-5-hydroxytetralin 2-(N-n-propyl-N-2-phenylpropylamino)-5-methoxytetralin 2-(N-n-propyl-N-2-(-2-methoxy)phenethylamino)-5-hydrσxytetralin
2-[N-n-propyl-N-2-(2-phenyloxy)propylamino]-5-hydroxytetralin
The invention is further illustrated by the following examples which are illustrative of various aspects of the invention, and are not intended as limiting the scope of the inventions defined by the appended claims.
EXAMPLE 1
Preparation of 2-[N-n-propyl,N-2-(phenyloxy)ethylamino]-5-methoxytetralin.
A mixture of 2- (N-n-propylamino)-5-methoxytetralin (7.0 g, 0.0319 mol; prepared according to J. Chem. Soc., 1965, pp 26-36), phenoxyacetic acid (4.86 g, 0.0319 mol), and borane trimethylamine complex (2.33 g, 0.0319 mol) was refluxed in xylenes overnight. The cooled reaction mixture was extracted with NaHCO3 and the organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The resulting oil was subjected to flash chromatography (silica; 9:1 pet ether/EtOAc) and product was isolated: NMR of the free base (300 MHz, CDCl3): S 7.3-6.6 (m, 8H), 4.0(t, 2H), 3.7(s, 3H), 3.1-2.5 (m, 9H) , 2.1(m, 1H), 1.7-1.4 (m, 3H), 0.9(t, 3H). The free base thus isolated was converted to a hydrochloride salt by the addition of dry ether-HCl.
EXAMPLE 2
Preparation of 2-[N-n-propyl,N-2-(phenyloxy)ethylamino]-5-hydroxytetralin.
A mixture of pyridine hydrochloride and the product of Example 1 was heated in an oil bath at 200°C. When the reaction was complete (TLC), it was cooled, diluted with H2O, made basic with NH4OH and extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to flash chromatography (silico: C.E. pet ether/EtOAc). The product was dissolved in ether and converted to a hydrochloride salt by the addtition of dry
ether-HCl. Anal. Calcd. for C21H27NO2.HCl: C, 69.69; H, 7.80; N, 3.87. Found: C, 69.54; H, 7.90; N, 3.87. NMR of the free base (300 MHz, CDCl3) : δ 7.3-6.6(m, 8H), 4.0(t, 2H), 3.1-2.5 (m, 9H), 2.1(m, 1H), 1.7-1.4 (in, 3H) , 0.9(t, 3H).
EXAMPLE 3
The product of Example 2 was also obtained by dissolving the product of Example 1 in dry dichloromethane and adding a solution of boron tribromide in dichloromethane dropwise at room temperture under nitrogen. After completion, the reaction was poured into a beaker containing NH4OH and ice and stirred for 0.5 h. The organic layer was separated, and the product was purified as in Example 2.
EXAMPLE 4
Preparation of 2-[N-n-propyl,N-3-(phenyloxy)propylamino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid can be replaced by 3-phenoxy-propionic acid.
EXAMPLE 5
Preparation of 2-[N-n-propyl,N-3-(phenyloxy)propylamino]-5-hydroxytetralin.
The product of Example 4 can be used as the starting material for Example 2.
EXAMPLE 6
Preparation of 2-[N-n-propyl,N-2-(1-naphthalenyloxy) ethylamino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid was replaced by (1-naphthoxy)-acetic acid. The resulting oil was sujbected to flash chromatography (silica; pet ether) and the product was isolated; characteristic peak of NMR (300 MHz, CDCl3); δ 8.3-6.7 (m,10H), 4.2(m, 2H), 3.85(s, 3H), 1.0(t, 3H).
EXAMPLE 7
Preparation of 2-[N-n-propyl,N-3-(1-naphthalenyloxy) propylamino]-5-hydroxytetralin.
The product of Example 6 was used as the starting material in Example 2. The resulting oil was subjected to flash chromatography and the isolated product showed characteristic peaks at : NMR (CDCl3) δ 8.3-6.6 (m, 10H), 4.2(m, 2H), 0.9(t,3H).
EXAMPLE 8
Preparation of 3-[2-[propyl(1,2,3,4-tetrahydro-5-methoxy-2- naphthalenyl)amino]ethyl]-1(3H)-isobenzofuranone.
In Example 1, phenoxyacetic acid was replaced by phthalide-3-acetic acid. The resulting oil was subjected to flash chromatography and the isolated product showed distinct peaks at: NMR (CDCl3) δ 8.0-6.7(m, 7H) , 5.7(m, 1H), 3.8(s, 3H), 0.9 (t, 3H). Anal. Calc. for C24H29NO3 HCl: C, 69.00, N, 7.27, N, 3.37. Found: C, 69. OS; H, 7.23; N, 3.28.
EXAMPLE 9
Preparation of 3-[2-[propyl(1,2,3,4-tetrahydro-5-hydroxy-2-naphthalenyl)amino]ethyl]-1(3H)-isobenzofuranone.
The product of Example 8 was used as the starting material for Example 3. The resulting oil after purification showed distinct peaks at: NMR(CDC13) δ 7.9-6.6(m, 7H), 5.7(m, 1H), 0.95(t, 3H). Anal. Calc. for C23H27NO3 . HCl: C, 68.73; H, 7.02; N, 3.48. Found: C, 68.62; H, 7.09; N, 3.35.
EXAMPLE 10
Preparation of 6-[[2-(1,3-dihydro-1-isobenzofuranyl) ethyl]propylamino]-5,6,7,8-tetrahydro-1-naphthalenol.
The reduction of the product of Example 9 will result in the desired product.
EXAMPLE 11
Preparation of 2-[N-n-propyl,N-2,2-diphenylethylamino)-5-methoxytetralin.
In Example 1, phenoxyacetic acid was replaced by diphenylactic acid. The purified product showed characteristic peaks at: NMR(CDCl3) δ 7.8-6.65(m, 13H), 4.1(t, 1H), 3.8(s, 3H), 3.2(d, 2H), 0.7(t, 3H).
EXAMPLE 12
Preparation of 2-[N-n-propyl,N-2,2-diphenylethylamino]-5-hydroxytetralin.
The product of Example 11 was used as starting material in Example 3. After purification the product showed distinct peaks at: NMR(CDCl3) δ 7.8-6.65(m, 13H), 4.1(t, 1H), 3.2 (d, 2H), 0.7(t, 3H). Anal. calc. for C27H31NO . HCl: C, 76.84; H, 7.64; N, 3.32. Observed: C, 77.00; H, 7.69; N, 3.21.
EXAMPLE 13
Preparation of 2-[N-n-propyl,N-3,3-diphenylpropylamino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid was replaced by 3,3-diphenylpropionic acid. The purified product showed distinct peaks at: NMR(CDCl3) δ 7.4-7.2 (m, 11H), 6.65(m, 2H), 4.05(t,lH), 3.8(s, 3H), 0.9(s, 3H).
EXAMPLE 14
Preparation of 2-[N-n-propyl,N-3,3-diphenylpropylamino]-5-hydroxytetralin.
The product of Example 13 was used as starting material for Example 3. The isolated product showed distinct peaks at: NMR(CDCl3) δ 7.4-7.0(m, 1H) , 6.7-6.5(m, 2H), 4.0(t, 1H), 0.9(t, 3H).
EXAMPLE 15
Preparation of 2-[N-n-propyl,N-2-(2-phenyloxy)propylamino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid was replaced by DL-2-phenoxypropionic acid. The purified product showed distinct peaks at: NMR(CDCl3) δ 7.3-6.65 (m, 8H) , 4.45(m, 1H), 3.8(S, 3H) , 0.9(t, 3H) .
EXAMPLE 16
Preparation of 2-[N-n-propyl,N-2-(2-phenyloxy)propylamino]-5-hydroxytetralin.
The product of Example 15 was used as starting material for Example 2. The isolated product showed characteristic peaks at: NMR(CDCl3) δ 7.3-6.65(m, 8H) , 4.45(m, 1H), 0.9 (t, 3H). EXAMPLE 17
Preparation of 2-[N-n-propyl,N-3,3,3-triphenylpropylamino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid was replaced by 3,3,3-lriphenylpropionic acid. The purified product showed characteristic peaks at : NMR(CDCl3) δ 7.4-6.65(m, 18H), 3.8(s, 3H), 0.9(t, 3H).
EXAMPLE 18
Preparation of 2-[N-n-propyl,N-3,3,3-triphenylpropylamino]-5-hydroxytetralin.
The product of Example 17 was used as starting material in Example 3. After purification the product showed distinct peaks at: NMR(CDCl3) δ 7.4-6.65(m, 18H), 0.9(t, 3H).
EXAMPLE 19
Preparation of 2-[N-n-propyl,N-2,2,2-triphenylethylamino]-5-methoxytetralin.
In Example 1, pehnoxyacetic acid can be replaced by triphenylacetic acid.
EXAMPLE 20-Preparation of 2-[N-n-propyl,N-2,2,2-triphenylethylamino]5-hydroxytetralin.
The product of Example 19 can be used as the starting material for Example 3.
EXAMPLE 21
Preparation of 2-[N-n-propyl,N-2-[2-methoxy]phenethyl-amino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid can be replaced by α-methoxyphenlyacetic acid.
EXAMPLE 22
Preparation of 2-[N-n-propyl,N-2-(2-methoxy)phenethyl-amino]-5-hyroxytetralin.
The product of Example 21 can be used as the starting material for Example 2.
EXAMPLE 23
Preparation of 2-[N-n-propyl,N-(2,3-dihydro-1H-inden-1-yl)methylamino]-5-methoxytetralin.
In Example 1, phenoxyactic acid can be replaced by 1-indancarboxylic acid.
EXAMPLE 24
Preparation of 2-[N-n-propyl,N-(2,3-dihydro-1H-inden-1- yl)methylamino]-5-hydroxytetralin.
The product of Example 23 can be used as the starting material for Example 3.
EXAMPLE 25
Preparation of 2-[N-n-propyl,N-(tetrahydro-2-naphthyl) methylamino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid can be replaced by 1,2,3,4-tetrahydro-2-naphthoic acid.
EXAMPLE 26
Preparation of 2-[N-n-propyl,N-(tetrahydro-2-naphthyl) methylamino]-5-hydroxytetralin.
The product of Example 25 can be used as the starting material for Example 3.
EXAMPLE 27
Preparation of 2-[N-n-propyl,N-2-(3,5-dimethylphenyloxy) ethylamino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid can be replaced by 3,5-dimethylphenoxyacetic acid.
EXAMPLE 28
Preparation of 2-[N-n-propyl,N-2-(3,5-dimethylphenyloxy) ethylamino]-5-hydroxytetralin.
The product of Example 27 can be used as the starting material for Example 3.
EXAMPLE 29
To test the selectivity and specificity of the present compounds for binding to dopamine receptors tests were conducted using the following standard procedures.
To test binding to dopamine receptors, the bovine caudate nuclei assay was employed. Bovine brains were obtained fresh from a local slaughterhouse. The caudate nuclei were dissected out and homogenized in Buffer A (50 mM Tris; 1 mM Na2-EDTA; 5 mM KCl; 1 mM MgCl2 ; 2 mM CaCl2; pH 7.4) using a Brinkman Polytron. The homogenate was
centrifuged at 40,000 × g for 20 minutes and washed once. The pellett was resuspended in Buffer A, incubated at 37°C for 15 minutes, then centrifuged. The pellet was washed once more, resuspended to a protein concentration of 5-10 mg/ml in Buffer A and frozen at -70°C until used.
To test binding of the compounds to α2-adrenergic receptors, the rat cerebral cortex assay was employed. Male Sprague Dawley rats were killed by decapitation and the brains removed. The cerebral cortices were homogenized in 50 mM Tris; 2mM MgCl2 (pH 7.4), and centrifuged at 40,000 × g for 10 minutes. The pellet was washed once, resuspended in Tris/MgCl2 and incubated with 8 units/ml adenosine deaminase at 37 °C for 30 minutes. The homogenate was centrifuged, washed once, resuspended to a protein concentration of 5-10 mg/ml and frozen at -70°C until use.
The following tritiated drugs were used as radioligands for each of the receptors tested: [3H]-Spiperone 21-24 Ci/mmol for D2 receptors, [3H]-SCH23390 75-85 Ci/mmol for D1 receptors, and [3H]-Para aminoclonidine 48-52 Ci/mmol for α2-adrenergic receptors. The radioligands were incubated with various concentrations of competing drug and the appropriate membrane source for periods of ' time as follows: 75 minutes at room temperature for D2 receptors, 15 minutes at 37°C for D1 receptors, or 30 minutes at room temperature for α2 receptors. Specific binding was defined using 1μM butaclamol (D2), 1 μM SCH23390 (D1), or 1 μM yohimbine (α2). In addition the D2 assays contained 30 nM Kotaserin in order to block the binding of 3H-spiperone to 5HT2 receptors.
The assays were terminated by filtration using a 24-port Brandell cell harvester over filters that had been previously soaked in 0.1% polyethyleneimine, and the filters were washed three times by filtration of cold buffer. The filters were then placed in 5 ml scintillation vials to which 4 ml of Beckman Ready-Protein was then added, and each vial was counted for 2 minutes in a Beckman 3801 scintillation counter calibrated for conversion of cpm to dpm. Binding data were analyzed using the Ligand program of Munson and Rodbard (1980). The results are presented as Ki values if the data were best fitted to a one-site model, or as KH and KL values if a two-site model produced the better fit.
Results of the binding tests are summarized in Table 1 below:
Table 1
RECEPTOR AFFINITIES (Ki, nM)
Example D2 (KL) D1(KL) α2
Compound
14 340 1,350 2,600
2 125 12,000 500
12 47 8,964 11,000
9 66 2,130 100
N-0437 110 1,000 190
This table shows high dopamine D2 receptor affinities of compounds chosen from the examples above, with unexpectedly high degrees of selectivity and specificity. The compound N-0437, a potent dopamine D2 a ganist is included as a reference compound for comparative purposes.
While particular embodiments of the invention have been described it will be understood of course that the invention is not limited thereto since many obvious modifications can be made and it is intended to include within this invention any such modifications as will fall within the scope of the appended claims.
Claims
1. Optically active or racemic compounds having the formula
where R2, R3 and R4 are each selected from the group consisting of H and OA with the provision that at least one of R2, R3 and R4 is H, that R2 and R4 are not both OA; A is
H or is selected from the group consisting of hydrocarbyl radicals said hydrocarbyl radicals being further optionally substituted with radicals selected from the group consisting of aromatic residues and
-
R5 is selected from the group consisting of alkyl and aromatic residues, having between 1 and 12 carbon atoms; n is an integer between 1 and 4; R6 is an alkyl chain comprising between 1 and 4 carbon atoms, X is selected from the group consisting of -CH2-, oxygen, sulfur, and nitrogen, with the provision that when X is not -CH2-, R1 is selected from the group consisting of
wherein Z is oxygen, nitrogen or sulfur, wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and heteroatom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, and a is an integer of from zero to 3; and with the further provision that when X is -CH2-, R1 is selected from a group consisting of -C-Aryl and -C-Z-Aryl wherein R8 is hydrogen,
aryl, or R6; and further wherein R9 is aryl, R6, -OH, NH , or -N(R
6..) 2„; or R1. is
wherein B is oxygen, sulfur or two hydrogen atoms, and a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein A is hydrogen or a hydrocarbyl radical having between 1 and 12 carbon atoms selected from a group consisting of phenyl, alkyl and alkyl substituted with aromatic residues.
3. The compound of claim 2 wherein A is selected from the group consisting of and R5 is
selected from the group of alkyl, alkyl substituted with aryl radicals, and aryl radicals having between 1 and 12 carbon atoms.
4. The compound of claim 1 wherein R5 is selected from the group consisting of phenyl, methyl, t-butyl, o-methylphenyl, o-, m- and p-methoxyphenyl, p-isopropylphenyl, and nonyl.
5. The compound of claim 1 wherein X is selected from the group consisting of nitrogen, oxygen and sulfur, and R2 is OA and A is H.
6. The compound of claim 5 wherein R1 is selected from the group consisting of thienyl, phenyl, hydroxyphenyl, dimethylphenyl , furanyl and napthalenyl .
7. The compound of claim 6 wherein the R1 is selected from the group consisting of 2-thienyl, 3-thienyl, 3-hydroxyphenyl, 2,6-dimethylphenyl, and 4-hydroxyphenyl.
8. The compound of claim 1 where n is 2, X is selected from oxygen or -CH2-, and R2 is OA.
9. The compound of claim 5 wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, ammo, acylamino , and cαrboxyamido.
10. The compound of claim 5 wherein Y is selected from the group consisting of trifluoromethyl, sulfate, halogen, hydrocarbyl and heteroatom-substituted hydrocarbyl radicals having between 1 and 12 carbon atoms.
11. The compound of claim 10 wherein the heteroatoms are oxygen, nitrogen or sulfur.
12. The compound of claim 1 wherein R1 is selected from the group consisting of
13. The compound of claim 12 wherein R9 is selected from the group consisting of or -N(R6)2.
14. The compound of claim 12 wherein Rg is selected from the group consisting of aryl, -R6, -NH2, -OH and -OR6.
15. The compound of claim 1 wherein R1 is
and B is selected from the group consisting of oxygen and two hydrogen atoms.
16. The compound of claim 15 wherein B is two hydrogen atoms.
17. The compound of claim 1 wherein R1 is
X is oxygen, and Z is oxygen, nitrogen or sulfur.
18. The compound of claim 1 wherein R1 is selected from the group consising of
wherein X is oxygen, Y comprises 1 to 5 carbon atoms, and a is an integer from 0 to 2.
19. The compound of claim 1 wherein R1 is
X is oxygen and Y is a hydrocarbyl radical comprising 1 to 12 carbon atoms.
20. The compounds of claim 17, 18, or 19 wherein Y comprises no more than 6 carbon atoms, and a is 0 to 2.
21. The compound of claim 19 where Y is methyl and a is
2.
22. The compound of claim 19 wherein a is zero.
23. The compound of claim 20 wherein A is H and R6 is propyl.
24- The compound of claim 1 selected from the group consisting of 2-[N-n-propyl,N-3,3-diphenylpropylamino]-5-hydroxytetralin; 2-[N-n-propyl,N-(2-phenoxy) ethylamino]-5-hydroxytetralin; 2-[N-n-propyl,N-2,2-diphenylethylamino]-5-hydroxytetralin; and 3-[2-[propyl(l,2,3,4-tetrahydro-5-hydroxy-2-naphthalenyl)amino] ethyl]-1(3H)-isobenzofuranone.
25. A method comprising inducing a dopaminergic response in a patient by administering a pharmacologically-effective amount of a compound represented by the formula
where R2, R3 and R4 are each selected from the group consisting of H and OA with the provision that at least one of R2, R3 and R4 is H, that R2 and R4 are not both OA; A is
H or is selected from the group consisting of hydrocarbyl radicals, said radicals being further optionally substituted with radicals selected from the group consisting of aromatic residues and
R5 is selected from the group consisting of alkyl and aromatic residues having between 1 and 12 carbon atoms; n is an integer between 1 and 4; R6 is an alkyl chain comprising between 1 and 4 carbon atoms, X is selected from the group consisting of -CH2-, oxygen, sulfur, and
nitrogen, with the provision that when X is not -CH2-, R1 is selected from the group consisting of
wherein Z is oxygen, nitrogen or sulfur, wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and heteroatom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, and a is an integer of from zero to 3; and with the further provision that when X is -CH2-, R1 is selected from a group consisting of
wherein R8 is hydrogen, aryl, or R6; and further wherein R9 is aryl, R6' -OH, -NH2, -OR6, or -N(R6)2; or R1 is
wherein B is oxygen, sulfur or two hydrogen atoms, and a pharmaceutically acceptable salt thereof.
26. The method of claim 23 wherein A is hydrogen, or a hydrocarbyl radical having between 1 and 12 carbon atoms selected from a group consisting of phenyl, alkyl and alkyl substituted with aryl radicals.
27. The method claim 24 wherein A is selected from the group consisting of
and R5 is selected from the group of alkyl and aryl radicals having between 1 and 12 carbon atoms.
28. The method of claim 23 wherein R5 is selected from the group consisting of phenyl, methyl, t-butyl, o-methylphenyl, o-, m- and p-methoxyphenyl, p-isopropylphenyl and nonyl.
29. The method of claim 23 wherein X is selected from the group consisting of oxygen, nitrogen and sulfur, and R2 is OA and A is hydrogen.
30. The method of claim 29 wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, and carboxyamido.
31. The method of claim 29 wherein Y is selected from the group consisting of trifluoromethyl, sulfate, halogen, and hydrocarbyl and heteroatom-subs tituted hydrocarbyl radicals having between 1 and 12 carbon atoms.
32. The method of claim 31 wherein the heteroatoms are oxygen or sulfur.
33. The method of claim 28 wherein R1 is selected from wherein X is -CH2-.
.
34. The method of claim 33 wnerein R9 is selected from the group consisting of and -N(R6)2.
35. The method of claim 34 wherein R9 is selected from the group consisting of aryl, R6, -NH , -OH, and -OR6.
36. The method of claim 23 wherein R1 is
and X is oxygen, and B is selected from the group consisting of oxygen and two hydrogen atoms.
37. The method of claim 36 wherein B is two hydrogen atoms.
38. The method of claim 36 wherein B is oxygen.
39. The method of claim 23 wherein R1 is
X is oxygen , and Z is oxygen or sulfur .
40. The method of claim 23 wherein R1 is selected from the group consisting of
and X is oxygen, Y comprises 1 to 5 carbon atoms, and a is 0 or .1.
41. The method of claim 23 wherein R1 is
X is oxygen, and Y is a hydrocarbyl radical comprising 1 to 12 carbon atoms.
42. The method of claim 23 wherein R1 is
Y is methyl and a is 2,
43. The method of claim 23 wherein R1 is and a is zero.
44. The method of claim 39, 40 or 41 wherein X is oxygen, Y comprises no more than 5 carbon atoms, and a is 0 to 2.
45. The method of claim 29 wherein R1 is selected from the group consisting of thienyl, phenyl, hydroxyphenyl, furanyl and napthalenyl.
46. The method of claim 45 wherein the napthalenyl is selected from the group consisting of 2-thienyl, 3-thienyl, 3-hydroxyphenyl, and 4-hydroxyphenyl.
47. The method of claim 23 wherein n is 2, X is selected from oxygen or -CH2-, and R2 is OA.
48. The method of claim 47 wherein A is H and R6 is propyl.
49. The method of claim 23 selected from the group consisting of 2-[N-n-propyl,N-3,3-diphenylpropylamino]-5-hydroxytetralin; 2-[N-n-propyl, N-2-(2-phenoxy) ethylamino]-5-hydroxytetralin; 2-[N-n-propyl,N-2,2-diphenylethylamino]-5-hydroxytetralin; and 3-[2 -[propyl (1,2,3,4-tetrahydro-5-hydroxy-2-naphthalenyl) amino]ethyl]-1(3H)-isobenzofuranone.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US37558389A | 1989-07-05 | 1989-07-05 | |
| US375583 | 1989-07-05 |
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| Publication Number | Publication Date |
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| EP0463119A1 true EP0463119A1 (en) | 1992-01-02 |
| EP0463119A4 EP0463119A4 (en) | 1992-01-22 |
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| EP (1) | EP0463119A4 (en) |
| AU (1) | AU6072090A (en) |
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| WO (1) | WO1991000727A1 (en) |
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|---|---|---|---|---|
| US5382596A (en) * | 1993-08-05 | 1995-01-17 | Whitby Research, Inc. | Substituted 2-aminotetralins |
| IT1271411B (en) * | 1993-09-14 | 1997-05-28 | Zambon Spa | 2-AMINO-1,2,3,4-TETRAIDRO-NAFTALENE DERIVATIVES ACTIVE IN THE CARDIOVASCULAR SYSTEM |
| SV2001000202A (en) * | 1999-10-20 | 2001-10-16 | Warner Lambert Co | USE OF (-) - 5-CETO-2-N, N-D1-N-PROPYLAMINE-TETRAHYDROTETHRALINE FOR THE TREATMENT OF PARKINSON'S EVIL |
| SE0001438D0 (en) | 2000-04-18 | 2000-04-18 | Axon Chemicals Bv | New chemical compounds and their use in therapy |
| US7829587B2 (en) | 2008-01-09 | 2010-11-09 | Allergan, Inc. | Substituted 2-aminotetralin derivatives as selective alpha 2B agonist |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4267373A (en) * | 1972-07-03 | 1981-05-12 | E. R. Squibb & Sons, Inc. | 5,6,7,8-Tetrahydronaphthalene hypotensive agents |
| CA1017359A (en) * | 1972-07-03 | 1977-09-13 | Frederic P. Hauck | Substituted cyclic polymethylene phenols |
| US3930022A (en) * | 1972-07-03 | 1975-12-30 | Squibb & Sons Inc | Certain tetrahydronaphthalenes used in the treatment of cardiac arrhythmia |
| US4314082A (en) * | 1978-07-14 | 1982-02-02 | American Hospital Supply Corporation | Derivatives of 2-amino-6,7-dihydroxytetrahydro naphthalene (ADTN) |
| EP0026848B1 (en) * | 1979-09-14 | 1983-05-04 | Sandoz Ag | Derivatives of tetraline, their preparation and medicaments containing these compounds |
| US4743618A (en) * | 1983-01-03 | 1988-05-10 | Nelson Research & Development Co. | Substituted 2-aminotetralins |
| US4882352A (en) * | 1986-07-28 | 1989-11-21 | Nelson Research & Development Co. | Method for treating schizophrenia |
| US4657925A (en) * | 1984-08-13 | 1987-04-14 | Nelson Research & Development Co. | Method and compositions for reducing the intraocular pressure of mammals |
| US4885308A (en) * | 1984-08-13 | 1989-12-05 | Nelson Research & Development Co. | Method and compositions for treatment of parkinsonism syndrome in mammals |
-
1990
- 1990-07-02 EP EP19900911220 patent/EP0463119A4/en not_active Ceased
- 1990-07-02 WO PCT/US1990/003761 patent/WO1991000727A1/en not_active Application Discontinuation
- 1990-07-02 AU AU60720/90A patent/AU6072090A/en not_active Withdrawn
- 1990-07-02 CA CA002065450A patent/CA2065450A1/en not_active Abandoned
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| See also references of WO9100727A1 * |
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| Publication number | Publication date |
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| WO1991000727A1 (en) | 1991-01-24 |
| CA2065450A1 (en) | 1991-01-06 |
| AU6072090A (en) | 1991-02-06 |
| EP0463119A4 (en) | 1992-01-22 |
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