WO1996020930A1 - Acetylenes disubstituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity - Google Patents
Acetylenes disubstituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity Download PDFInfo
- Publication number
- WO1996020930A1 WO1996020930A1 PCT/US1995/016367 US9516367W WO9620930A1 WO 1996020930 A1 WO1996020930 A1 WO 1996020930A1 US 9516367 W US9516367 W US 9516367W WO 9620930 A1 WO9620930 A1 WO 9620930A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carbons
- compound
- alkyl
- group
- phenyl
- Prior art date
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- 125000002534 ethynyl group Chemical class [H]C#C* 0.000 title claims abstract description 214
- 125000001072 heteroaryl group Chemical group 0.000 title claims abstract description 37
- 230000004071 biological effect Effects 0.000 title abstract description 5
- 125000003118 aryl group Chemical group 0.000 title description 25
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 title description 3
- 125000005046 dihydronaphthyl group Chemical group 0.000 title description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 149
- -1 5,6,7,8-tetrahydronaphthyl Chemical group 0.000 claims abstract description 107
- 150000001875 compounds Chemical class 0.000 claims description 885
- 125000000217 alkyl group Chemical group 0.000 claims description 338
- 229910052739 hydrogen Inorganic materials 0.000 claims description 166
- 239000001257 hydrogen Substances 0.000 claims description 165
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 149
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 125
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 88
- 125000003342 alkenyl group Chemical group 0.000 claims description 73
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 66
- 125000000304 alkynyl group Chemical group 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 51
- 125000004076 pyridyl group Chemical group 0.000 claims description 45
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 34
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical group C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims description 32
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 30
- 125000002541 furyl group Chemical group 0.000 claims description 29
- 125000001544 thienyl group Chemical group 0.000 claims description 29
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 24
- 229910052717 sulfur Inorganic materials 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 125000005103 alkyl silyl group Chemical group 0.000 claims description 21
- 125000001624 naphthyl group Chemical group 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 125000000335 thiazolyl group Chemical group 0.000 claims description 15
- KEIFWROAQVVDBN-UHFFFAOYSA-N 1,2-dihydronaphthalene Chemical group C1=CC=C2C=CCCC2=C1 KEIFWROAQVVDBN-UHFFFAOYSA-N 0.000 claims description 14
- 125000002883 imidazolyl group Chemical group 0.000 claims description 14
- 125000002971 oxazolyl group Chemical group 0.000 claims description 14
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 14
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 14
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 14
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- 125000005016 hydroxyalkynyl group Chemical group 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 4
- 125000004001 thioalkyl group Chemical group 0.000 claims description 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 3
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 229910007161 Si(CH3)3 Inorganic materials 0.000 claims 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 3
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 claims 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims 1
- 125000004434 sulfur atom Chemical group 0.000 claims 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 175
- 238000000034 method Methods 0.000 description 139
- 238000002360 preparation method Methods 0.000 description 128
- 239000000243 solution Substances 0.000 description 122
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 117
- 238000006243 chemical reaction Methods 0.000 description 115
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 107
- 229940050390 benzoate Drugs 0.000 description 107
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 98
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 81
- 239000007787 solid Substances 0.000 description 75
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 72
- 239000000203 mixture Substances 0.000 description 71
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 64
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 58
- 239000005711 Benzoic acid Substances 0.000 description 55
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 55
- 235000010233 benzoic acid Nutrition 0.000 description 55
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 49
- 239000007864 aqueous solution Substances 0.000 description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 41
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 40
- 239000000377 silicon dioxide Substances 0.000 description 38
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 37
- 239000003153 chemical reaction reagent Substances 0.000 description 37
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 37
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 36
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 35
- 239000012267 brine Substances 0.000 description 34
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- 230000015572 biosynthetic process Effects 0.000 description 32
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 32
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 235000019441 ethanol Nutrition 0.000 description 30
- 239000003921 oil Substances 0.000 description 30
- 229940125904 compound 1 Drugs 0.000 description 28
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 27
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 26
- 238000000746 purification Methods 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 24
- 239000002253 acid Substances 0.000 description 23
- RCXZVAFZECFUGZ-UHFFFAOYSA-N ethyl 4-[2-(8,8-dimethyl-5-oxo-6,7-dihydronaphthalen-2-yl)ethynyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(C(=O)CCC2(C)C)C2=C1 RCXZVAFZECFUGZ-UHFFFAOYSA-N 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 21
- 230000000694 effects Effects 0.000 description 20
- 235000019439 ethyl acetate Nutrition 0.000 description 20
- 229910052786 argon Inorganic materials 0.000 description 19
- 201000010099 disease Diseases 0.000 description 19
- 150000002923 oximes Chemical class 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 230000000875 corresponding effect Effects 0.000 description 18
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 16
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 16
- 229910000027 potassium carbonate Inorganic materials 0.000 description 16
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 16
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 229940125782 compound 2 Drugs 0.000 description 15
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- SXKBXIQTBJQJHN-UHFFFAOYSA-N 4-[2-(8,8-dimethyl-5-oxo-6,7-dihydronaphthalen-2-yl)ethynyl]benzoic acid Chemical compound C1=C2C(C)(C)CCC(=O)C2=CC=C1C#CC1=CC=C(C(O)=O)C=C1 SXKBXIQTBJQJHN-UHFFFAOYSA-N 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 14
- 150000002148 esters Chemical class 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- 125000001424 substituent group Chemical group 0.000 description 14
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 13
- HKLPOHJGESDTSC-UHFFFAOYSA-N ethyl 4-[2-(5,5-dimethyl-8-oxo-6,7-dihydronaphthalen-2-yl)ethynyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C2C(C)(C)CCC(=O)C2=C1 HKLPOHJGESDTSC-UHFFFAOYSA-N 0.000 description 13
- RKJFWYTUBCPBEP-UHFFFAOYSA-N ethyl 4-[2-[5,5-dimethyl-8-(trifluoromethylsulfonyloxy)-6h-naphthalen-2-yl]ethynyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C2C(C)(C)CC=C(OS(=O)(=O)C(F)(F)F)C2=C1 RKJFWYTUBCPBEP-UHFFFAOYSA-N 0.000 description 13
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 12
- 239000012230 colorless oil Substances 0.000 description 12
- 235000001968 nicotinic acid Nutrition 0.000 description 12
- 239000011664 nicotinic acid Substances 0.000 description 12
- IAYMXLZAYMHPKJ-UHFFFAOYSA-N 4-[2-(8,8-dimethyl-5-phenyl-7h-naphthalen-2-yl)ethynyl]benzoic acid Chemical compound C12=CC=C(C#CC=3C=CC(=CC=3)C(O)=O)C=C2C(C)(C)CC=C1C1=CC=CC=C1 IAYMXLZAYMHPKJ-UHFFFAOYSA-N 0.000 description 11
- 102000052812 Ornithine decarboxylases Human genes 0.000 description 11
- 108700005126 Ornithine decarboxylases Proteins 0.000 description 11
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000011592 zinc chloride Substances 0.000 description 11
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 description 10
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 10
- HEUBMCOZJZSHGR-UHFFFAOYSA-N 6-ethynyl-4,4-dimethyl-2,3-dihydronaphthalen-1-one Chemical compound C1=C(C#C)C=C2C(C)(C)CCC(=O)C2=C1 HEUBMCOZJZSHGR-UHFFFAOYSA-N 0.000 description 10
- 239000007832 Na2SO4 Substances 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 238000005859 coupling reaction Methods 0.000 description 10
- YCBJOQUNPLTBGG-UHFFFAOYSA-N ethyl 4-iodobenzoate Chemical compound CCOC(=O)C1=CC=C(I)C=C1 YCBJOQUNPLTBGG-UHFFFAOYSA-N 0.000 description 10
- 229910052736 halogen Inorganic materials 0.000 description 10
- 230000002265 prevention Effects 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- 235000005074 zinc chloride Nutrition 0.000 description 10
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 9
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 9
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 9
- 150000001299 aldehydes Chemical class 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 9
- FQEHNJGWJQKFCA-UHFFFAOYSA-N ethyl 4-[2-(5,5-dimethyl-8-pent-1-ynyl-6h-naphthalen-2-yl)ethynyl]benzoate Chemical compound C1=C2C(C#CCCC)=CCC(C)(C)C2=CC=C1C#CC1=CC=C(C(=O)OCC)C=C1 FQEHNJGWJQKFCA-UHFFFAOYSA-N 0.000 description 9
- 150000002367 halogens Chemical group 0.000 description 9
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 9
- 238000000926 separation method Methods 0.000 description 9
- 235000017281 sodium acetate Nutrition 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 8
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- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
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- 229940061627 chloromethyl methyl ether Drugs 0.000 description 1
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- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
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- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 1
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- LHAIQOHRPPUYCO-UHFFFAOYSA-N ethyl 4-(3-bromophenyl)but-2-enoate Chemical class CCOC(=O)C=CCC1=CC=CC(Br)=C1 LHAIQOHRPPUYCO-UHFFFAOYSA-N 0.000 description 1
- DIEZILGFLCBIMS-UHFFFAOYSA-N ethyl 4-(4-bromophenyl)but-2-enoate Chemical compound CCOC(=O)C=CCC1=CC=C(Br)C=C1 DIEZILGFLCBIMS-UHFFFAOYSA-N 0.000 description 1
- MFJKKPLZXMOMBC-UHFFFAOYSA-N ethyl 4-[2-(5,5-dimethyl-8-pyridin-2-yl-6h-naphthalen-2-yl)ethynyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C2C(C)(C)CC=C(C=3N=CC=CC=3)C2=C1 MFJKKPLZXMOMBC-UHFFFAOYSA-N 0.000 description 1
- KHJIGFLSWTUOFS-UHFFFAOYSA-N ethyl 4-[2-(5-ethanethioyl-8,8-dimethyl-6,7-dihydro-5h-naphthalen-2-yl)ethynyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(C(CCC2(C)C)C(C)=S)C2=C1 KHJIGFLSWTUOFS-UHFFFAOYSA-N 0.000 description 1
- IMKDXBVEVLNHNC-UHFFFAOYSA-N ethyl 4-[2-(5-ethylsulfanyl-8,8-dimethyl-7h-naphthalen-2-yl)ethynyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(C(SCC)=CCC2(C)C)C2=C1 IMKDXBVEVLNHNC-UHFFFAOYSA-N 0.000 description 1
- IAGKNKQCINBSPM-UHFFFAOYSA-N ethyl 4-[2-(8,8-dimethyl-6,7-dihydro-5h-naphthalen-2-yl)ethynyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(CCCC2(C)C)C2=C1 IAGKNKQCINBSPM-UHFFFAOYSA-N 0.000 description 1
- OUOYKPXVHJQNQM-UHFFFAOYSA-N ethyl 4-[2-[8-(2-ethoxy-2-oxoethyl)-8-hydroxy-5,5-dimethyl-6,7-dihydronaphthalen-2-yl]ethynyl]benzoate Chemical compound C1=C2C(CC(=O)OCC)(O)CCC(C)(C)C2=CC=C1C#CC1=CC=C(C(=O)OCC)C=C1 OUOYKPXVHJQNQM-UHFFFAOYSA-N 0.000 description 1
- MQEKYOXGQGXWIO-UHFFFAOYSA-N ethyl 4-[2-[8-(4-tert-butylphenyl)-5,5-dimethyl-6h-naphthalen-2-yl]ethynyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C2C(C)(C)CC=C(C=3C=CC(=CC=3)C(C)(C)C)C2=C1 MQEKYOXGQGXWIO-UHFFFAOYSA-N 0.000 description 1
- AEOYJXLGKZJQDV-UHFFFAOYSA-N ethyl 4-[2-[8-(benzenesulfonyl)-5,5-dimethyl-6h-naphthalen-2-yl]ethynyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C2C(C)(C)CC=C(S(=O)(=O)C=3C=CC=CC=3)C2=C1 AEOYJXLGKZJQDV-UHFFFAOYSA-N 0.000 description 1
- ILDJJTQWIZLGPO-UHFFFAOYSA-N ethyl 6-chloropyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC=C(Cl)N=C1 ILDJJTQWIZLGPO-UHFFFAOYSA-N 0.000 description 1
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- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
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- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 1
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- 150000002500 ions Chemical class 0.000 description 1
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- 150000002642 lithium compounds Chemical class 0.000 description 1
- JDOZOOBCADNBIJ-UHFFFAOYSA-N lithium;2h-pyridin-2-ide Chemical compound [Li+].C1=CC=N[C-]=C1 JDOZOOBCADNBIJ-UHFFFAOYSA-N 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
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- QJPQVXSHYBGQGM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QJPQVXSHYBGQGM-UHFFFAOYSA-N 0.000 description 1
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- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
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- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- WMXCDAVJEZZYLT-UHFFFAOYSA-N tert-butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- NYBWUHOMYZZKOR-UHFFFAOYSA-N tes-adt Chemical class C1=C2C(C#C[Si](CC)(CC)CC)=C(C=C3C(SC=C3)=C3)C3=C(C#C[Si](CC)(CC)CC)C2=CC2=C1SC=C2 NYBWUHOMYZZKOR-UHFFFAOYSA-N 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
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- A61P11/00—Drugs for disorders of the respiratory system
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- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/32—Oximes
- C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
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Definitions
- the present invention relates to novel compounds having retinoid-like activity. More specifically, the present invention relates to compounds having an acetylene portion which is substituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl and by a substituted aryl or substituted heteroaryl group having an acid function.
- the acid function may also be converted to an alcohol, aldehyde or ketone or
- retinoid-like activity is well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and
- skin-related diseases including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of
- glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin.
- Retinoid compounds are also useful for the prevention and treatment of cancerous and
- precancerous conditions including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi's sarcoma.
- retinoid compounds can be used as agents to treat diseases of the eye, including, without
- proliferative vitreoretinopathy PVR
- retinal detachment dry eye and other corneopathies
- cardiovascular diseases including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty
- retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T- Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil R , diseases associated with the immune system, including use of the present compounds as immunosuppressants and
- immunostimulants modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
- the present invention covers compounds of Formula
- X is S or O
- R 1 is hydrogen or alkyl of 1 to 10 carbons
- R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
- o is an integer having the value 0 - 4;
- R 4 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenyl-C 1 - C 10 alkyl, napthyl-C 1 - C 10 alkyl; CN, or (CH 2 ) p CO 2 R 8 where p is an integer between 0 to 10;
- R 5 is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenyl-C 1 - C 10 alkyl, napthyl-C 1 - C 10 alkyl; Si(R 2 ) 3 , COR 14 , camphanoyl, C(R 15 ) (R 16 )XR 17 ;
- Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
- A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and
- B is hydrogen, COOH or a pharmaceutically
- CH 2 OR 1:L CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, -COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or tri-lower alkylsilyl, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10
- R 11 is lower alkyl, phenyl or lower alkylphenyl
- R 12 is lower alkyl
- R 13 is divalent alkyl radical of 2-5 carbons
- R 14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenyl-C 1 - C 10 alkyl, napthylC 1 - C 10 alkyl; R 15 and R 16 are hydrogen or lower alkyl of 1 to 6 carbons, R 17
- R 16 and R 17 jointly form a ring having a total of 4 to 5 carbons and the X heteroatom;
- R 1 is hydrogen or alkyl of 1 to 10
- R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
- o is an integer having the value 0 - 4;
- Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
- A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
- B is hydrogen, COOH or a pharmaceutically
- R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
- R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons
- R 8 is phenyl or lower alkylphenyl
- R 9 and R 10 independently are hydrogen, an alkyl group of l to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
- R 11 is lower alkyl, phenyl or
- X is O or S
- R 1 is hydrogen or alkyl of 1 to 10
- R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
- o is an integer having the value 0 - 4;
- Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
- A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
- B is hydrogen, COOH or a pharmaceutically
- R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
- R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
- R 9 and R 10 independently are hydrogen, an alkyl group of l to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
- R 11 is lower alkyl, phenyl or lower alkylphenyl
- R 12 is lower alkyl
- R 13 is divalent alkylsilyl
- R 19 is independently hydrogen, alkyl of l to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group
- phenyl consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenyl-C 1 - C 10 alkyl, naphthylC 1 - C 10 alkyl; CN, CHO, CH(OR 12 ) 2 , CHOR 13 O,
- R 1 is hydrogen or alkyl of 1 to 10
- R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
- o is an integer having the value 0 - 4;
- Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
- A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
- B is hydrogen, COOH or a pharmaceutically
- R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
- R 8 is an alkyl group of 1 tt 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
- R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
- R 11 is lower alkyl, phenyl or lower alkylphenyl
- R 12 is lower alkyl
- R 13 is di
- the wavy line represents a single valence bond around which the configuration can be syn or anti
- Z is OR 1 , R 1 is phenyl, benzyl, lower alkyl or lower alkoxy substituted phenyl, OSi(R 2 ) 3 , OCOR 14 , OC(R 15 )(R 16 )XR 17 , N(R 14 ) 2 , NHCON(R 14 ) 2 , NHCSN(R 14 ) 2 , where X is O or S; R 14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenyl-C 1 - C 10 alkyl, naphthylC 1 - C 10 alkyl; R 15 and R 16 are hydrogen
- R 16 and R 17 jointly form a ring having a total of 4 to 5 carbons and the X heteroatom;
- R 1 is hydrogen or alkyl of 1 to 10
- R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
- o is an integer having the value 0 - 4;
- Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
- A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
- B is hydrogen, COOH or a pharmaceutically
- R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
- R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
- R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
- R 11 is lower alkyl, phenyl or lower alkylphenyl
- R 12 is lower alkyl
- R 13 is divalent alkyl
- R 14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenyl-C 1 - C 10 alkyl, naphthyl-C 1 - C 10 alkyl, or R 14 is COR 8 , or the two R 14 groups together with the N jointly form a 5 or 6 membered ring,
- R 1 is hydrogen or alkyl of 1 to 10
- R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus; m is an integer having the value of 0 - 3;
- o is an integer having the value 0 - 3;
- Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R 2 groups;
- A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
- B is hydrogen, COOH or a pharmaceutically
- R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
- R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
- R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
- R 11 is lower alkyl, phenyl or lower alkylphenyl
- R 12 is lower alkyl
- R 13 is divalent
- X is O, S, SO or SO 2 and
- R 20 is Si(R 2 ) 3 , R 14 , COR 14 , SO 2 R 21 , where R 14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenylC 1 - C 10 alkyl, napthyl-C 1 - C 10 alkyl, or R 20 is
- R 21 is alkyl of 1 to 10 carbons
- fluoroalkyl of 1 to 10 carbons or carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl and phenyl-C 1 - C 10 alkyl, and
- R 1 is hydrogen or alkyl of 1 to 10
- R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus; m is an integer having the value of 0 - 3;
- o is an integer having the value 0 - 3;
- Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
- A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
- B is hydrogen, COOH or a pharmaceutically
- R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
- R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
- R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
- R 11 is lower alkyl, phenyl or lower alkylphenyl
- R 12 is lower alkyl
- R 13 is divalent alkyl
- R 22 is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenyl-C 1 - C 10 alkyl, naphthyl-C 1 - C 10 alkyl, C 1 - C 10 -alkenylphenyl having 1 to 3 double bonds, C 1 - C 10 -alkynylphenyl having 1 to 3 triple bonds, phenyl-C 1 - C 10 alkenyl having 1 to 3 double bonds, phenyl-C 1 - C 10 alkynyl having 1 to 3 triple bonds, hydroxy alky
- this invention relates to the use of the compounds of Formula 1 through Formula 7 for the treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic
- keratoses inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage
- the compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant
- hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias,
- the present compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty
- PVR proliferative vitreoretinopathy
- retinal detachment retinal detachment
- dry eye and other corneopathies as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty
- TPA tissue plasminogen activator
- Krohn's disease neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and
- Minoxidil diseases associated with the immune system, including use of the present compounds as
- immunosuppressants and immunostimulants modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
- This invention also relates to a pharmaceutical formulation
- a pharmaceutical formulation comprising a compound of Formula l through Formula 7 in admixture with a pharmaceutically
- this invention relates to processes for making a compound of Formula 1 through Formula 7 which process comprises reacting a compound of Formula 8 with a compound of Formula 9, in the presence of cuprous iodide and Pd(PQ 3 ) 2 Cl 2 (Q is phenyl) or a similar complex, or reacting the zinc salt of the compound shown in Formula 8 with a compound of Formula 9 in the presence of Pd(PQ 3 ) 4 (Q is phenyl) or similar complex.
- the symbol STHN the symbol STHN
- Formulas 1 through 7 or said tetrahydronaphthalene or dihydronaphthalene nucleus is appropriately substituted to provide such precursors of compounds of the Formulas 1 through 7 from which the target compounds can be readily obtained by organic reactions well known in the art.
- X 1 is halogen
- B 1 is H
- B' is either the desired B group of Formulas 1 through 7, or B' is a precursor from which the B group can be readily obtained by reactions well known in the art.
- the present invention relates to such reactions performed on the compounds of Formula 1 through 7 which cause transformations of the A-B group or of the substituents on the tetrahydro- or
- alkyl refers to and covers any and all groups which are known as normal alkyl, branched-chain alkyl and cycloalkyl.
- alkenyl refers to and covers normal alkenyl, branch chain alkenyl and
- alkynyl refers to and covers normal alkynyl, and branch chain alkynyl groups having one or more triple bonds.
- alkyl groups having 1 to 6 carbons in case of normal lower alkyl, and as applicable 3 to 6 carbons for lower branch chained and cycloalkyl groups.
- Lower alkenyl is defined similarly having 2 to 6 carbons for normal lower alkenyl groups, and 3 to 6 carbons for branch chained and cyclo- lower alkenyl groups.
- Lower alkynyl is also defined similarly, having 2 to 6 carbons for normal lower alkynyl groups, and 4 to 6 carbons for branch chained lower alkynyl groups.
- esters refers to and covers any compound falling within the definition of that term as classically used in organic chemistry. It includes organic and inorganic esters. Where B (of Formula 1 through 7) is -COOH, this term covers the products derived from treatment of this function with alcohols or thiols preferably with aliphatic alcohols having 1-6 carbons.
- ester is derived from compounds where B is -CH 2 OH
- this term covers compounds derived from organic acids capable of forming esters including phosphorous based and sulfur based acids, or compounds of the formula -CH 2 OCOR 11 where R 11 is any substituted or unsubstituted aliphatic, aromatic, heteroaromatic or aliphatic aromatic group, preferably with 1-6 carbons in the aliphatic portions.
- esters are derived from the saturated
- Particularly preferred aliphatic esters are those derived from lower alkyl acids and alcohols. Also preferred are the phenyl or lower alkyl phenyl esters.
- amides include the unsubstituted amides and all aliphatic and aromatic mono- and di- substituted amides.
- preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms or the cyclic or saturated aliphatic-cyclic radicals of 5 to 10 carbon atoms.
- amides are those derived from substituted and unsubstituted lower alkyl amines. Also preferred are mono- and disubstituted amides derived from the
- Acetals and ketals include the radicals of the formula-CK where K is (-OR) 2 .
- R is lower alkyl.
- K may be -OR 7 O- where R 7 is lower alkyl of 2-5 carbon atoms, straight chain or branched.
- a pharmaceutically acceptable salt may be prepared for any compounds in this invention having a
- a pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or
- salts may be derived from organic or inorganic bases.
- the salt may be a mono or polyvalent ion.
- the inorganic ions sodium, potassium, calcium, and
- Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar
- salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri- acid may also be used.
- the compounds of the present invention may have trans and cis (E and Z) isomers.
- the compounds of the present invention may contain one or more chiral centers and therefore may exist in
- oxime and related compounds of the present invention may exist in syn and anti isomeric forms.
- the scope of the present invention is intended to cover all such isomers per se, as well as mixtures of cis and trans isomers, mixtures of syn and anti isomers, mixtures of diastereomers and racemic mixtures of enantiomers
- the preferred compounds of the invention are those where Y is phenyl, pyridyl, thienyl or furyl. Even more preferred are compounds where Y is phenyl or pyridyl. As far as substititutions on the Y (phenyl) and Y (pyridyl) groups are concerned, compounds are preferred where the phenyl group is 1,4 (para)
- the A-B group of the preferred compounds is
- the aromatic portion of the tetrahydronaphthalene or dihydronaphthalene moiety is preferably substituted only by the acetylene function.
- R 2 substituent other than hydrogen
- R 3 substituent other than hydrogen
- the R 1 substituent of the compounds of the invention is preferably lower alkyl, and even more preferably methyl.
- R 4 substituent is preferably hydrogen, CN or CH 2 COOR 8 where R 8 is
- R 5 substituent is preferably hydrogen, alkyl, cycloalkyl, of the
- R 5 is hydrogen, cyclohexyl, trimethylsilyl, -CH 2 OCH 3 (methoxymethyl), 2'-tetrahydropyranyl, acetyl, benzoyl or camphanoyl.
- Specific preferred compounds in accordance with Formula 1 and their synthesis are described below in the section of this application titled "Specific Examples”. The presently roost
- X is sulphur and R 18 is an alkyl group; even more preferably X is sulphur and the two R 18 groups jointly represent methylene groups which together with the two sulphur atoms and the C 5 carbon of the tetrahydronaphthalene nucleus form a 6 membered ring.
- Specific preferred compounds in accordance with Formula 2 and their synthesis are described below in the section of this application titled "Specific Examples”. The
- the R 19 groups preferably are hydrogen, alkyl of 1 to 10 carbons, cyano (CN) or COOR 8 . Even more preferably the R 19 groups are H, CN, COOEt or lower alkyl.
- the two R 19 groups jointly form a -(CH 2 ) q - radical, (q is an integer having the values of 3 to 7) whereby a cycloalkyl ring is formed, most preferably a
- the Z group preferably represents OR 1 , where the R 1 group is preferably hydrogen or lower alkyl.
- R 1 group is preferably hydrogen or lower alkyl.
- Z is
- R 14 groups are hydrogen or lower alkyl, even more
- R 20 group is preferably R 14 , COR 14 , SO 2 R 21 or Si(R 2' ) 3 where R 14 is preferably phenyl, benzyl or lower alkyl, even more preferably ethyl, R 21 is preferably
- fluorinated lower alkyl even more preferably CF 3 , and R 2 , is preferably lower alkyl, even more preferably methyl.
- Specific preferred compounds in accordance with Formula 6 and their synthesis are described below in the section of this application titled "Specific Examples”. The presently most preferred compounds of the invention in accordance with Formula 6 are
- R 22 is preferably hydrogen, alkyl of 1 - 10 carbons, alkynyl of 2 to 10 carbons having 1 triple bond, alkylphenyl having 1 to 10 carbons in the alkyl group, phenylalkyl having 1 to 10 carbons in the alkyl group,
- phenylalkynyl having 2 to 10 carbons in the alkynyl group CH 2 CO 2 R 8 , hydroxyalkyl having 1 to 10 carbons in the alkyl group, hydroxyalkynyl having 2 to 10 carbons in the alkynyl group, cyano (CN), CONH 2 or heteroaryl.
- heteroaryl groups 5 or 6 membered rings having 1 or 2 heteroatoms are particularly preferred.
- Compounds where the R 22 group is 2-thiazolyl, 2-furyl, 2-thienyl or 2-pyridyl are especially preferred.
- the compounds of this invention may be any organic compound having the same properties as the compounds of this invention.
- the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds by injection. In certain cases, it may be useful to formulate these compounds in suppository form or as extended release formulation for deposit under the skin or intramuscular injection.
- medicaments can be added to such topical formulation for such secondary purposes as treating skin dryness; providing protection against light; other medications for treating dermatoses; medicaments for preventing infection, reducing irritation, inflammation and the like.
- Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoic acid-like compounds will be effected by administration of the therapeutically effective dose of one or more compounds of the instant invention.
- a therapeutic concentration will be that concentration which effects reduction of the particular condition, or retards it expansion.
- the compound potentially may be used in prophylactic manner to prevent onset of a particular condition.
- a useful therapeutic or prophylactic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient's susceptibility to treatment. Accordingly, no single concentration will be uniformly useful, but will require modification depending on the particularities of the disease being treated. Such concentrations can be arrived at through routine experimentation. However, it is anticipated that in the treatment of, for example, acne, or similar dermatoses, that a formulation containing between 0.01 and 1.0 milligrams per milliliter of formulation will constitute a therapeutically effective concentration for total application. If administered systemically, an amount between 0.01 and 5 mg per kg per day of body weight would be expected to effect a therapeutic result in the treatment of many diseases for which these compounds are useful.
- retinoic acid-like activity of these compounds is confirmed through the classic measure of retinoic acid activity involving the effects of retinoic acid on ornithine decarboxylase.
- the original work on the correlation between retinoic acid and decrease in cell proliferation was done by Verma & Boutwell, Cancer Research, 1977, 37,2196-2201. That reference discloses that ornithine decarboxylase (ODC) activity increased precedent to polyamine biosynthesis. It has been established elsewhere that increases in polyamine synthesis can be correlated or associated with cellular proliferation. Thus, if ODC activity could be
- TPA 12-0-tetradecanoylphorbol-13-acetate
- IC 80 is that concentration of the test compound which causes 80% inhibition in the
- IC 60 concentration of the test compound which causes 60% inhibition in the ODC assay.
- the compounds of this invention can be made by the synthetic chemical pathways illustrated here.
- the synthetic chemist will readily appreciate that the conditions set out here are specific embodiments which can be generalized to any and all of the compounds represented by Formulas 1 through 7.
- a zinc salt (or other suitable metal salt) of the compounds of Formula 12 can be coupled with the reagents of Formula 9 in the presence of Pd(PPh 3 ) 4 or similar complex.
- the coupling reaction with the reagent X 1 -Y(R 2 )-A-B' (Formula 9) is conducted at room or moderately elevated temperature.
- coupling between an ethynylaryl derivative or its zinc salt and a halogen substituted aryl or heteroaryl compound, such as the reagent of Formula 9, is described in United States Patent No. 5,264,456, the specification of which is expressly incorporated herein by reference.
- compounds of Formula 13 are compounds of the invention within the scope of Formula 2, or a derivative thereof protected in the B' group, from which the protecting group can be readily removed by reactions well known in the art.
- the compounds of Formula 13 can also be converted into ketals or thioketals, within the scope of Formula 2, by reactions generally well known in the art.
- the compounds of Formula 13 can also be converted into further compounds of the invention by such
- the halogen substitituted aryl or heteroaryl compounds of Formula 9 can, generally speaking, be obtained by reactions well known in the art.
- An example of such compound is ethyl 4-iodobenzoate which is obtainable, for example, by esterification of 4-iodobenzoic acid.
- Another example is ethyl 6-iodonicotinate which can be obtained by conducting a halogen exchange reaction on 6-chloronicotinic acid, followed by esterification.
- derivatization of compounds of Formula 13 and/or the synthesis of aryl and heteroaryl compounds of Formula 9 which can thereafter be reacted with compounds of Formula 12 to yield compounds of the invention the following well known and published general principles and synthetic methodology can be employed.
- Carboxylic acids are typically esterified by refluxing the acid in a solution of the appropriate alcohol in the presence of an acid catalyst such as hydrogen chloride or thionyl chloride.
- an acid catalyst such as hydrogen chloride or thionyl chloride.
- the carboxylic acid can be condensed with the
- aromatic or heteroaromatic carboxylic acids are subjected to homologation by successive treatment under Arndt-Eistert conditions or other homologation
- derivatives which are not carboxylic acids may also be homologated by appropriate procedures.
- the homologated acids can then be
- Compounds of Formula 9, (or of the invention as set forth in Formulas 1 through 7, as applicable) where A is an alkenyl group having one or more double bonds can be made for example, by synthetic schemes well known to the practicing organic chemist; for example by Wittig and like reactions, or by introduction of a double bond by elimination of halogen from an alpha-halo-arylalkyl-carboxylic acid, ester or like carboxaldehyde.
- Compounds of Formula 9 (or of the invention as set forth in Formulas 1 through 7, as applicable) where the A group has a triple (acetylenic) bond can be made by reaction of a corresponding aromatic methyl ketone with strong base, such as lithium diisopropyl amide, reaction with diethyl chlorophosphate and subsequent addition of lithium diisopropylamide.
- strong base such as lithium diisopropyl amide
- an ester of Formula 13 (or other compounds of the invention as set forth in Formulas 1 through 7, as applicable) may be dissolved in a polar solvent such as an alkanol, preferably under an inert atmosphere at room temperature, with about a three molar excess of base, for example, lithium hydroxide or potassium hydroxide.
- a polar solvent such as an alkanol
- base for example, lithium hydroxide or potassium hydroxide
- the amide may be formed by any appropriate
- amidation means known in the art from the corresponding esters or carboxylic acids.
- One way to prepare such compounds is to convert an acid to an acid chloride and then treat that compound with ammonium hydroxide or an appropriate amine.
- the ester is treated with an alcoholic base solution such as ethanolic KOH (in approximately a 10% molar excess) at room
- Alcohols are made by converting the corresponding acids to the acid chloride with thionyl chloride or other means (J. March, "Advanced Organic Chemistry", 2nd Edition, McGraw-Hill Book Company), then reducing the acid chloride with sodium borohydride (March, Ibid, pg. 1124), which gives the corresponding alcohols.
- esters may be reduced with lithium aluminum hydride at reduced temperatures. Alkylating these alcohols with appropriate alkyl halides under Williamson reaction conditions (March, Ibid, pg. 357) gives the corresponding ethers. These alcohols can be converted to esters by reacting them with appropriate acids in the presence of acid catalysts or dicyclohexylcarbodiimide and dimethylaminopyridine.
- Aldehydes can be prepared from the corresponding primary alcohols using mild oxidizing agents such as pyridinium dichromate in methylene chloride (Corey, E. J., Schmidt, G., Tet. Lett.. 399, 1979). or dimethyl sulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D., Tetrahedron. 1978. 34, 1651).
- mild oxidizing agents such as pyridinium dichromate in methylene chloride (Corey, E. J., Schmidt, G., Tet. Lett.. 399, 1979). or dimethyl sulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D., Tetrahedron. 1978. 34, 1651).
- Ketones can be prepared from an appropriate aldehyde by treating the aldehyde with an alkyl
- Acetals or ketals can be prepared from the
- halogenated aromatic or heteroaromatic compounds preferably where the halogen is I.
- the 7,8-dihydro-naphthalen-5(6H)-one derivatives of Formula 13 are reduced with a mild reducing agent such as sodium borohydride, to yield the corresponding 5-hydroxy-5,6,7,8-tetrahydronaphthalene derivatives of Formula 14.
- the 5-hydroxy function of the compounds of Formula 14 is then acylated with a suitable acylating agent (such as a carboxylic acid chloride or anhydride), or converted into an ether with a suitable reagent (such as an alkyl bromide under basic conditions, or
- the compounds of Formula 15 are compounds of the invention (or protected derivatives thereof) within the scope of Formula 1.
- Formula 15 can be "deprotected” or otherwise converted into further compounds of the invention by reactions well known in the art, as described above.
- the compounds of Formula 13 can also be reacted with a Reformatsky reagent derived from an a halocarboxylic acid ester (such as ethyl bromoacetate), or with a Grignard reagent, optionally followed by acylation or ether formation on the resulting tertiary hydroxyl group on the 5-position of the tetrahydronaphthalene nucleus, to yield compounds of Formula 16.
- a Reformatsky reagent derived from an a halocarboxylic acid ester (such as ethyl bromoacetate), or with a Grignard reagent, optionally followed by acylation or ether formation on the resulting tertiary hydroxyl group on the 5-position of the tetrahydronaphthalene nucleus, to yield compounds of Formula 16.
- the compounds of Formula 13 are reacted with cyanotrimethylsilane in the presence of boron trifluoroetherate to yield compounds in accordance with Formula 16.
- the compounds of Formula 16 are compounds of the invention within the scope of Formula 1, (or protected derivatives thereof) and can be converted into further homologs and derivatives within the scope of the invention.
- Reaction Scheme 2 illustrates another synthetic route to the compounds of the invention in accordance with Formula 1. 6- or 7-Bromo substituted 1,2,3,4-tetrahydro naphthalene derivatives of Formula 17
- the zinc salts of the compounds of Formula 18 can also be coupled with the reagents of Formula 9, in the presence of Pd(PPh 3 ) 4 or similar complex.
- Compounds of Formula 19 are then reacted with a suitable brominating agent (such as N-bromosuccinimide (NBS) and benzoyl peroxide in carbontetrachloride) to yield the corresponding 5-bromo-5,6,7,8-tetrahydronaphthalene derivatives of Formula 20.
- a suitable brominating agent such as N-bromosuccinimide (NBS) and benzoyl peroxide in carbontetrachloride
- the 5-bromo substituent of the compounds of Formula 20 can be subjected to nucleophilic substitution reactions with nucleophilic reagents having the formula R 5 XH, in the presence of base.
- the R 5 and X groups are defined as in connection with Formula 1, typically R 5 XH is the salt of a thiocarboxylic acid (such as potassium thioacetate) or the sodium derivative of an alcohol or thiol.
- R 5 XH is the salt of a thiocarboxylic acid (such as potassium thioacetate) or the sodium derivative of an alcohol or thiol.
- the compounds of Formula 21 can be converted into further homologs and derivatives, as is described above in connection with compounds of Formulas 13, 15 and 16.
- Compound F is brominated with a suitable brominating agent (such as N.-bromosuccinimide (NBS) and benzoyl peroxide in carbontetrachloride) to yield the
- R 5 and X groups are defined as in connection with Formula 1; typically R 5 XH is the salt of a thiocarboxylic acid (such as potassium thioacetate) or the sodium derivative of an alcohol (such as the sodium salt of cyclohexanol), or thiol.
- R 5 XH is the salt of a thiocarboxylic acid (such as potassium thioacetate) or the sodium derivative of an alcohol (such as the sodium salt of cyclohexanol), or thiol.
- the product of the latter reaction is a 6- or 7-bromo tetrahydronaphthalene derivative of Formula 23 which has the desired R 5 X substituent in the 4-position.
- the 6- or 7- bromo compound of Formula 23 is then reacted with trimethylsilylacetylene, followed by base (such as potassium carbonate) to yield the 6- or 7-ethynyl-1,2,3,4-tetrahydronaphthalene derivatives of Formula 24.
- base such as potassium carbonate
- the latter two reactions involving introduction of the ethynyl group into the 6 or 7 position of the tetrahydronaphthalene nucleus are conducted under conditions substantially similar to the analogous reactions described above in connection with Reaction Schemes 1 and 2.
- the ethynyl compounds of Formula 24 are then coupled with the reagent X 1 -Y(R 2 )-A-B'
- this coupling reaction can be conducted with 6- or 7- substituted ethynyl compounds which either already have a substituent desired for the present invention in the 4- position (as in Reaction Scheme 3) or have a precursor suitable for introduction of such desired substituent (as in Reaction Schemes 1 and 2).
- reaction step determines the nature of the R 1
- Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F).
- Compound F is in the scope of Formula 17, and in accordance with Reaction Schemes 2 and 3 serves as the starting material in the synthesis of several preferred compounds of the
- Compound F is oxidized with chromium
- Compound G is covered by Formula 10 and in accordance with
- Reaction Scheme 1 serves as a starting material in the synthesis of several preferred compounds of the
- Formula 27 are then coupled with the aromatic or heteroaromatic reagent X 1 -Y(R 2 )-A-B « (Formula 9) in the presence of cuprous iodide, a suitable catalyst, typically Pd(PPh 3 ) 2 Cl 2 , an acid acceptor, such as diethylamine, under inert gas (argon) atmosphere, as described above in connection with Reaction Scheme 1, to yield compounds of Formula 28.
- a suitable catalyst typically Pd(PPh 3 ) 2 Cl 2
- an acid acceptor such as diethylamine
- Reaction Scheme 7 illustrates synthesis of those compounds of Formula 3 wherein one of the R 19 groups is hydrogen and the other is a carboxylic acid ester (or derivative thereof).
- the starting compounds for these syntheses are compounds of Formula 30, which are within the scope of Formula 1 and can be obtained in
- Formula 13 are reacted with a reagent of the formula H 2 N-Z (Formula 32), where Z is defined as in connection with Formula 4 , to yield compounds of Formula 4.
- a reagent of the formula H 2 N-Z (Formula 32), where Z is defined as in connection with Formula 4 , to yield compounds of Formula 4.
- reagent H 2 N-Z is a primary amine (Z is R 1 , phenyl or benzyl) then the reaction between the compounds of Formula 13 and the primary amine is the formation of an imine. The latter reaction is usually conducted in a polar (alcoholic) solvent.
- Further reagents, in accordance with Formula 32 are those where Z is NHCON(R 14 ) 2 (formation of semicarbazone), NHCSN(R 14 ) 2 (formation of
- the semicarbazones, thiosemicarbazones and hydrazones corresponding to Formula 4 can be prepared under conditions which are well known in the art for the formation of such derivatives of ketone compounds. Usually these
- the hydrochloride salt of of the reagent is reacted with the compound of Formula 13 in an alcoholic solvent, in the presence of sodium acetate.
- an oxime derivative of the Formula 33 is first prepared in accordance with the reaction described above.
- the oxime derivative of Formula 33 is thereafter reacted with 3,4-dihydro-2H-pyran (DHP) in an inert solvent (such as
- tetrahydrothiopyranyl can be prepared in reaction steps analogous to the ones described above for the preparation of compounds of Formula 34.
- the oxime derivatives of Formula 33 can also be reacted with an appropriate reagent (such as an acyl chloride R 14 COCl) to introduce the R 14 CO group, to provide the compounds of Formula 35.
- an appropriate reagent such as an acyl chloride R 14 COCl
- the compounds of Formula 4 can also be obtained, generally speaking, by first forming an oxime, alkoxyoxime, imine, hydrazone, semicarbazone etc. from the ketone compounds of Formula 10 (see Reaction Scheme 1) and thereafter performing the synthetic steps of replacing the 6 or 7-bromo
- Compounds of Formula 36 where the NH 2 group is not substituted comprise the presently preferred compounds of Formula 5.
- Compounds of Formula 5 where R 14 is an alkyl, alkenyl, alkynyl or aryl group (as such groups are defined in connection with Formula 5) are prepared by reaction of compounds of Formula 36 with a reagent of the formula R 14 -X 1 , where X 1 is halogen. When R 14 is an alkyl group then the reagent R 14 -X 1 is an alkyl halide.
- alkenyl, alkynyl or aryl group (as such groups are defined in connection with Formula 5) can also be obtained from the 5-oxo 2- or 3- (aryl or
- R 14 NH 2 corresponding amine
- R 8 CO acyl
- the compounds of Formula 5 can also be obtained, generally speaking, by first forming the 5-amino, 5-alkylamino or 5-acylamido derivative from the ketone compounds of Formula 10 (see Reaction Scheme 1) and thereafter performing the synthetic steps of replacing the 6 or 7-bromo substituents in these compounds with an ethynyl group, and subsequently coupling the ethynyl compounds with the reagent X 1 -Y(R 2 )-A-B' (Formula 9).
- the ketone derivatives of Formula 13 are reacted with a reagent which "enolizes” the ketone function of the tetrahydronaphthalene nucleus.
- the resulting "enol” compound then reacts with a reagent which introduces the R 20 group into the enol function.
- the group R 20 is defined in connection with Formula 6.
- Suitable reagents for the purpose of introducing the R 20 function include a reactive leaving group L.
- the reagents used in this reaction have the general formula R 20 -L, R 14 -CO-L, R 14 -L, and R 21 -L, where the R 14 and R 21 groups are defined as in connection with Formula 6.
- Examples of the reagents, and/or reaction conditions which are used for the synthesis of the preferred compounds of the invention within the scope of Formula 6 include: reacting compounds of Formula 13 with sodium bis (trimethylsilyl) amide and 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine in an inert ether type solvent such as tetrahydrofuran at low temperatures (-78 °C and 0 °C) to obtain the 5-trifluoromethylsulfonyloxy-7,8-dihydronaphthalene derivative; reacting compounds of Formula 13 with acetic anhydride and p-toluenesulfonic acid at elevated temperature (80 °C) to obtain the 5-acetoxy-7,8-dihydronaphthalene derivative; and reacting compounds of Formula 13 with cyanotrimethylsilane in the presence of zinc iodide at ambient temperature to obtain the 5-trimethylsilyloxy-7,8-dihydron
- Compounds of Formula 38, obtained in the above- described manner are such compounds of Formula 6 where the X is oxygen.
- Compounds of Formula 6 where X is sulfur can be obtained by analogous reactions of the 5-thio analogs of the oxo compounds of Formula 13.
- Compounds of Formula 6 where X is S and R 20 is R 14 are preferably obtained by reacting compounds of Formula 13 with titanium tetrachloride and a thiol of the formula R 14 SH in an inert ether type solvent (such as
- the thienol ether compounds of Formula 38A can be oxidized to sulfoxides or with a suitable oxidizing agent, such as 3-chloroperoxybenzoic acid (MCPBA) to the corresponding sulfones of Formula 38B.
- MCPBA 3-chloroperoxybenzoic acid
- the compounds of Formula 6 can also be obtained, generally speaking, by first forming the "enolized” and acylated, alkylated or sulfonylated etc. derivative from the ketone compounds of Formula 10 (see Reaction Scheme 1) and thereafter performing the synthetic steps of replacing the 6 or 7-bromo substituents in these compounds with an ethynyl group, and subsequently coupling the ethynyl compounds with the reagent X 1 -Y(R 2 )-A-B' (Formula 9).
- Reaction Scheme 11 discloses synthetic steps for the preparation of those compounds of Formula 7 where the R 22 group is alkyl, alkenyl, alkynyl, carbocyclic aryl or heteroaryl, as these groups are broadly defined in Formula 7.
- R 22 group is alkyl, alkenyl, alkynyl, carbocyclic aryl or heteroaryl, as these groups are broadly defined in Formula 7.
- 5-trifluoromethylsulfonyloxy 2- or 3- (aryl or heteroaryl) ethynyl 7,8-dihydronaphthalene compounds of Formula 39 serve as starting materials.
- the compounds of Formula 39 can be obtained from the 5-oxo 2- or 3- (aryl or heteroaryl) ethynyl 5,6,7,8-tetrahydronaphthalene compounds of Formula 13 by reaction with sodium
- Formula 39 are reacted with an organometal derivative derived from the alkane, alkene, alkyne, or aryl or heteroaryl compound R 22 H, such that the formula of the organometal derivative is R 22 Met (Met stands for metal), preferably R 22 Li.
- the reaction with the organometal derivative, preferably lithium derivative of the formula R 22 Li is usually conducted in an inert ether type solvent (such as tetrahydrofuran) in the presence of either (1) cuprous cyanide (cuCN) and lithium chloride (Licl), or in the presence of zinc chloride (ZnCl 2 ) and tetrakis(triphenylphosphine)-palladium(O) (Pd(PPh 3 ) 4 ).
- the organolithium reagent R 22 Li if not commercially available, can be prepared from the compound R 22 H (or its halogen derivative R 22 -X 1 where X 1 is halogen) in an ether type solvent in accordance with known practice in the art.
- lithium salts derived from straight and branch chained alkanes such as methyl lithium, butyllithium, t-butyllithium
- lithium salts derived from carbocyclic aryl compounds such as phenyl lithium
- lithium salts derived from heteroaryl compounds such as 2-thiazolyllithium, 2-furyl lithium, 2-thienyllithium, and 2-pyridyllithium.
- dimethylformamide or without solvent, in the presence of a mild base (such as diethylamine), cuprous iodide (CuI), and bis (triphenylphosphine) palladium(II)
- a mild base such as diethylamine, cuprous iodide (CuI), and bis (triphenylphosphine) palladium(II)
- the reaction is typically conducted in the temperature range of ambient to 70 °C.
- 5,6,7,8-tetrahydronaphthalene compounds of Formula 42 serve as the starting materials.
- Compounds of Formula 42 are within the scope of Formula 1, and can be prepared in accordance with the procedures set forth for the preparation of compounds of Formula l.
- R 22 is defined as in connection with Formula 7, and R 24 is hydrogen, or trialkylsilyl (preferably trimethylsilyl), or any other group which is suitable to form a leaving group including the R 24 O- element, in the elimination
- the product of the elimination reaction is a compound of Formula 7.
- the reaction is conducted under conditions which are known in the art of organic chemistry to cause formation of double bonds by elimination, for example in refluxing pyridine in the presence of excess phosphorous oxychloride (POCl 3 ), or in a neutral hydrocarbon type solvent (such as benzene) in the presence of (methoxycarbonylsulfamoyl) triethylammonium hydroxide (Burgess reagent).
- Reaction Scheme 12 is presently preferred for the preparation of compounds of Formula 7 where the R 22 group is hydrogen, cyano (CN) and CH 2 COOEt.
- the elimination reaction which results in compounds where R 22 is CH 2 COOEt also gives rise to isomers where the double bond is exterior to the condensed 6-membered ring. The latter compounds are within the scope of Formula 3 and are not shown in this reaction scheme.
- Compound B was converted into the title compound (oil) using 255 ml (255 mmol) of diisobutylaluminum hydride (DIBAL-H, 1M in hexane), 85.8 g (250 mmol) of (carbethoxymethylene) triphenylphosphorane and 1.7 g of 10% Pd/C.
- DIBAL-H diisobutylaluminum hydride
- reaction mixture was sealed in a pressure tube and placed in a preheated oil bath (100 °C) for 24 hours.
- the reaction mixture was then filtered through Celite, washed with Et 2 O and the filtrate concentrated in vacuo to give crude 6-2-(trimethylsilyl)ethynyl-3, 4-dihydro-4,4-dimethylnaphthalen-1(2H)-one.
- a solution of 2-lithiothiazole was prepared by the addition of 41.2 mg (0.42 ml, 0.63 mmol) of n-butyl-lithium (1.5M solution in hexanes) to a cold solution (-78 °C) of 53.4 mg (0.63 mmol) of thiazole in 1.0 ml of THF. The solution was stirred at for 30 minutes and then a solution of 113.9 mg (0.84 mmol) of zinc chloride in 1.5 ml of THF was added.
- Ethyl 4-[(5-acetoxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 126) Employing the same general procedure as for the preparation of ethyl 4-[(5-acetoxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 105), 90.0 mg (0.26 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95943828A EP0800517A1 (en) | 1994-12-29 | 1995-12-14 | Acetylenes disubstituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity |
JP52102396A JP2002504066A (en) | 1994-12-29 | 1995-12-14 | Acetylene having retinoid-like biological activity, disubstituted with a 5- or 8-substituted tetrahydronaphthyl or dihydronaphthyl group and an aryl or heteroaryl group |
AU45204/96A AU698527B2 (en) | 1994-12-29 | 1995-12-14 | Acetylenes disubstituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity |
Applications Claiming Priority (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/366,167 US5618943A (en) | 1994-12-29 | 1994-12-29 | Acetylenes disubstituted with a 5 OXO substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
US08/366,193 US5648514A (en) | 1994-12-29 | 1994-12-29 | Substituted acetylenes having retinoid-like biological activity |
US08/366,169 US5599967A (en) | 1994-12-29 | 1994-12-29 | Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl of heteroaryl group having retinoid-like biological activity |
US08/366,172 US5543534A (en) | 1994-12-29 | 1994-12-29 | Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity |
US08/366,182 | 1994-12-29 | ||
US08/366,169 | 1994-12-29 | ||
US08/366,172 | 1994-12-29 | ||
US08/366,167 | 1994-12-29 | ||
US08/366,193 | 1994-12-29 | ||
US08/366,182 US5489584A (en) | 1994-12-29 | 1994-12-29 | Acetylenes disubstituted with a 5-amino or substituted 5-amino substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
US08/366,168 US5514825A (en) | 1994-12-29 | 1994-12-29 | Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
US08/366,183 | 1994-12-29 | ||
US08/366,183 US5618931A (en) | 1994-12-29 | 1994-12-29 | Acetylenes disubstituted with a 5 substituted dihydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
US08/366,168 | 1994-12-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996020930A1 true WO1996020930A1 (en) | 1996-07-11 |
Family
ID=27569724
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1995/016367 WO1996020930A1 (en) | 1994-12-29 | 1995-12-14 | Acetylenes disubstituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0800517A1 (en) |
JP (1) | JP2002504066A (en) |
AU (1) | AU698527B2 (en) |
CA (1) | CA2208844A1 (en) |
WO (1) | WO1996020930A1 (en) |
Cited By (15)
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WO1998039284A1 (en) * | 1997-03-06 | 1998-09-11 | Allergan Sales, Inc. | Aryl- and heteroarylcyclohexenyl substituted alkenes having retinoid agonist, antagonist or inverse agonist type biological activity |
WO2000068191A1 (en) * | 1999-05-07 | 2000-11-16 | Allergan Sales, Inc. | Oxygen, sulfur and nitrogen substituted cyclohexene and cyclohexane derivatives having retinoid-like biological activity |
WO2002018361A2 (en) * | 2000-08-29 | 2002-03-07 | Allergan, Inc. | Compounds having activity as inhibitors of cytochrome p450rai |
JP2004509955A (en) * | 2000-09-28 | 2004-04-02 | アラーガン、インコーポレイテッド | Methods for providing and using compounds (retinoids) having activity as cytochrome P450 RAI inhibitors |
FR2847167A1 (en) * | 2002-11-15 | 2004-05-21 | Galderma Res & Dev | Method for treating disorders associated with TGF-beta signal deficiency, e.g. cicatrization disorders, ulcers, cancers or graft rejection, comprises administration of retinoic acid receptor-Gamma antagonists |
WO2004045595A1 (en) * | 2002-11-15 | 2004-06-03 | Galderma Research & Development, S.N.C. | USE OF AN RAR RECEPTOR ANTAGONIST FOR POTENTIATING THE ACTION OF TGFβ |
WO2006027236A1 (en) * | 2004-09-09 | 2006-03-16 | Bayer Schering Pharma Aktiengesellschaft | Alkylidene tetrahydronaphthalene derivatives, method for their production and their use as anti-inflammatory agents |
US7638515B2 (en) | 2003-10-08 | 2009-12-29 | Bayer Schering Pharma Aktiengesellschaft | Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents |
US7659297B2 (en) | 2003-10-08 | 2010-02-09 | Bayer Schering Pharma, AG | Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents |
US7662821B2 (en) | 2003-10-08 | 2010-02-16 | Bayer Schering Pharma Ag | Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents |
US7880042B2 (en) | 2006-03-15 | 2011-02-01 | Bayer Schering Pharma Ag | Tetrahydronaphthalene derivatives, methods for the production thereof, and the use thereof as antiphlogistics |
JP2011031054A (en) * | 1997-06-13 | 2011-02-17 | Baxter Internatl Inc | Method for treating biological tissue to mitigate calcification |
US7998986B2 (en) | 2001-12-21 | 2011-08-16 | Exelixis Patent Company Llc | Modulators of LXR |
US8013001B2 (en) | 2001-12-21 | 2011-09-06 | Exelixis, Inc. | Modulators of LXR |
US8097627B2 (en) | 2004-04-05 | 2012-01-17 | Bayer Pharma AG | Multiply-substituted tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents |
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US7226951B2 (en) * | 2003-12-17 | 2007-06-05 | Allergan, Inc. | Compounds having selective cytochrome P450RAI-1 or selective cytochrome P450RAI-2 inhibitory activity and methods of obtaining the same |
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- 1995-12-14 JP JP52102396A patent/JP2002504066A/en active Pending
- 1995-12-14 AU AU45204/96A patent/AU698527B2/en not_active Ceased
- 1995-12-14 CA CA002208844A patent/CA2208844A1/en not_active Abandoned
- 1995-12-14 WO PCT/US1995/016367 patent/WO1996020930A1/en not_active Application Discontinuation
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WO1998039284A1 (en) * | 1997-03-06 | 1998-09-11 | Allergan Sales, Inc. | Aryl- and heteroarylcyclohexenyl substituted alkenes having retinoid agonist, antagonist or inverse agonist type biological activity |
JP2011031054A (en) * | 1997-06-13 | 2011-02-17 | Baxter Internatl Inc | Method for treating biological tissue to mitigate calcification |
WO2000068191A1 (en) * | 1999-05-07 | 2000-11-16 | Allergan Sales, Inc. | Oxygen, sulfur and nitrogen substituted cyclohexene and cyclohexane derivatives having retinoid-like biological activity |
US6465647B1 (en) | 1999-05-07 | 2002-10-15 | Allergan, Inc. | Oxygen, sulfur and nitrogen substituted cyclohexene and cyclohexane derivatives having retinoid-like biological activity |
WO2002018361A2 (en) * | 2000-08-29 | 2002-03-07 | Allergan, Inc. | Compounds having activity as inhibitors of cytochrome p450rai |
WO2002018361A3 (en) * | 2000-08-29 | 2003-07-31 | Allergan Inc | Compounds having activity as inhibitors of cytochrome p450rai |
JP2004507531A (en) * | 2000-08-29 | 2004-03-11 | アラーガン、インコーポレイテッド | Compounds having activity as cytochrome P450 RAI inhibitors |
AU2001286471B2 (en) * | 2000-08-29 | 2006-09-07 | Allergan, Inc. | Compounds having activity as inhibitors of cytochrome P450RAI |
JP2004509955A (en) * | 2000-09-28 | 2004-04-02 | アラーガン、インコーポレイテッド | Methods for providing and using compounds (retinoids) having activity as cytochrome P450 RAI inhibitors |
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US7662821B2 (en) | 2003-10-08 | 2010-02-16 | Bayer Schering Pharma Ag | Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents |
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US8097627B2 (en) | 2004-04-05 | 2012-01-17 | Bayer Pharma AG | Multiply-substituted tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents |
WO2006027236A1 (en) * | 2004-09-09 | 2006-03-16 | Bayer Schering Pharma Aktiengesellschaft | Alkylidene tetrahydronaphthalene derivatives, method for their production and their use as anti-inflammatory agents |
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Also Published As
Publication number | Publication date |
---|---|
AU698527B2 (en) | 1998-10-29 |
CA2208844A1 (en) | 1996-07-11 |
AU4520496A (en) | 1996-07-24 |
JP2002504066A (en) | 2002-02-05 |
EP0800517A1 (en) | 1997-10-15 |
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