WO1991000727A1 - Substituted 2-aminotetralins - Google Patents
Substituted 2-aminotetralins Download PDFInfo
- Publication number
- WO1991000727A1 WO1991000727A1 PCT/US1990/003761 US9003761W WO9100727A1 WO 1991000727 A1 WO1991000727 A1 WO 1991000727A1 US 9003761 W US9003761 W US 9003761W WO 9100727 A1 WO9100727 A1 WO 9100727A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- oxygen
- compound
- propyl
- carbon atoms
- Prior art date
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- LCGFVWKNXLRFIF-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-2-amine Chemical class C1=CC=C2CC(N)CCC2=C1 LCGFVWKNXLRFIF-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 230000001939 inductive effect Effects 0.000 claims abstract description 4
- -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
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- 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
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- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 1
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
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- 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
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- 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
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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
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- 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
- FCEHBMOGCRZNNI-UHFFFAOYSA-N c1c[s]c2ccccc12 Chemical compound c1c[s]c2ccccc12 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 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
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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
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- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
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- 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.
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US37558389A | 1989-07-05 | 1989-07-05 | |
US375,583 | 1989-07-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1991000727A1 true WO1991000727A1 (en) | 1991-01-24 |
Family
ID=23481446
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1990/003761 WO1991000727A1 (en) | 1989-07-05 | 1990-07-02 | Substituted 2-aminotetralins |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0463119A4 (en) |
AU (1) | AU6072090A (en) |
CA (1) | CA2065450A1 (en) |
WO (1) | WO1991000727A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995007885A1 (en) * | 1993-09-14 | 1995-03-23 | Zambon Group S.P.A. | Derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene active on the cardiovascular system |
EP0717620A1 (en) * | 1993-08-05 | 1996-06-26 | Discovery Therapeutics, Inc. | Substituted 2-aminotetralins |
WO2001028977A1 (en) * | 1999-10-20 | 2001-04-26 | Warner-Lambert Company | Method for treating parkinson's disease by administering (-)-5-keto-2-n,n-di-n-propylamino-tetrahydrotetralin |
WO2001078713A1 (en) * | 2000-04-18 | 2001-10-25 | Axon Biochemicals B.V. | Phenylethylamines and condensed rings variants as prodrugs of catecholamines, and their use |
US7829587B2 (en) | 2008-01-09 | 2010-11-09 | Allergan, Inc. | Substituted 2-aminotetralin derivatives as selective alpha 2B agonist |
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-
1990
- 1990-07-02 EP EP19900911220 patent/EP0463119A4/en not_active Ceased
- 1990-07-02 AU AU60720/90A patent/AU6072090A/en not_active Withdrawn
- 1990-07-02 CA CA002065450A patent/CA2065450A1/en not_active Abandoned
- 1990-07-02 WO PCT/US1990/003761 patent/WO1991000727A1/en not_active Application Discontinuation
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Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0717620A1 (en) * | 1993-08-05 | 1996-06-26 | Discovery Therapeutics, Inc. | Substituted 2-aminotetralins |
EP0717620A4 (en) * | 1993-08-05 | 1997-05-28 | Discovery Therapeutics Inc | Substituted 2-aminotetralins |
WO1995007885A1 (en) * | 1993-09-14 | 1995-03-23 | Zambon Group S.P.A. | Derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene active on the cardiovascular system |
US5747513A (en) * | 1993-09-14 | 1998-05-05 | Zambon Group, S.P.A. | Derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene active on the cardiovascular system |
WO2001028977A1 (en) * | 1999-10-20 | 2001-04-26 | Warner-Lambert Company | Method for treating parkinson's disease by administering (-)-5-keto-2-n,n-di-n-propylamino-tetrahydrotetralin |
US6683087B2 (en) | 2000-04-18 | 2004-01-27 | Axon Biochemicals B.V. | Phenylethylamines and condensed rings variants as prodrugs of catecholamines, and their use |
WO2001078713A1 (en) * | 2000-04-18 | 2001-10-25 | Axon Biochemicals B.V. | Phenylethylamines and condensed rings variants as prodrugs of catecholamines, and their use |
US6998405B2 (en) | 2000-04-18 | 2006-02-14 | H. Lundbeck A/S | Phenylethylamines and condensed rings variants as prodrugs of catecholamines, and their use |
CN100383126C (en) * | 2000-04-18 | 2008-04-23 | H.伦德贝克公司 | Phenylethylamines and condensed rings variants as prodrugs of catecholamines, and their use |
USRE42802E1 (en) | 2000-04-18 | 2011-10-04 | H. Lundbeck A/S | Phenylethylamines and condensed rings variants as prodrugs of catecholamines, and their use |
JP4819280B2 (en) * | 2000-04-18 | 2011-11-24 | ハー.ルンドベック アー/エス | Phenylethylamine and fused ring variant as catecholamine prodrug and use thereof |
USRE43244E1 (en) | 2000-04-18 | 2012-03-13 | H. Lundbeck A/S | Phenylethylamines and condensed rings variants as prodrugs of catecholamines, and their use |
US7829587B2 (en) | 2008-01-09 | 2010-11-09 | Allergan, Inc. | Substituted 2-aminotetralin derivatives as selective alpha 2B agonist |
Also Published As
Publication number | Publication date |
---|---|
EP0463119A4 (en) | 1992-01-22 |
CA2065450A1 (en) | 1991-01-06 |
EP0463119A1 (en) | 1992-01-02 |
AU6072090A (en) | 1991-02-06 |
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