IE913569A1 - Acetylenes disubstituted with a phenyl group and a¹2-substituted chromanyl, thiochromanyl or 1,2,3,4 -¹tetrahydroquinolinyl group having retinoid-like activity - Google Patents
Acetylenes disubstituted with a phenyl group and a¹2-substituted chromanyl, thiochromanyl or 1,2,3,4 -¹tetrahydroquinolinyl group having retinoid-like activityInfo
- Publication number
- IE913569A1 IE913569A1 IE356991A IE356991A IE913569A1 IE 913569 A1 IE913569 A1 IE 913569A1 IE 356991 A IE356991 A IE 356991A IE 356991 A IE356991 A IE 356991A IE 913569 A1 IE913569 A1 IE 913569A1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- formula
- hydrogen
- lower alkyl
- derivative
- Prior art date
Links
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims description 45
- 230000000694 effects Effects 0.000 title abstract description 19
- 125000002534 ethynyl group Chemical class [H]C#C* 0.000 title description 23
- 125000003016 chromanyl group Chemical class O1C(CCC2=CC=CC=C12)* 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 159
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 68
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 41
- 239000001257 hydrogen Substances 0.000 claims abstract description 39
- 150000002148 esters Chemical class 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 150000001408 amides Chemical class 0.000 claims abstract description 16
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 16
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 16
- 150000002367 halogens Chemical class 0.000 claims abstract description 14
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 10
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 8
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 75
- 238000000034 method Methods 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 230000008569 process Effects 0.000 claims description 13
- 239000007818 Grignard reagent Substances 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 150000004795 grignard reagents Chemical class 0.000 claims description 10
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 208000017520 skin disease Diseases 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000009738 saturating Methods 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 71
- 239000000243 solution Substances 0.000 description 69
- 238000006243 chemical reaction Methods 0.000 description 68
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 42
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 40
- -1 PHENYL GROUP Chemical group 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 239000002253 acid Substances 0.000 description 33
- 239000002904 solvent Substances 0.000 description 31
- 229910001868 water Inorganic materials 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 22
- 235000019341 magnesium sulphate Nutrition 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 20
- 229910052786 argon Inorganic materials 0.000 description 20
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- 239000000377 silicon dioxide Substances 0.000 description 20
- 238000003818 flash chromatography Methods 0.000 description 19
- 125000001424 substituent group Chemical group 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 230000000875 corresponding effect Effects 0.000 description 16
- 239000003921 oil Substances 0.000 description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 14
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 13
- 150000001299 aldehydes Chemical class 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical group C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 239000000284 extract Substances 0.000 description 11
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 10
- 150000001298 alcohols Chemical class 0.000 description 10
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 150000002576 ketones Chemical class 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 102000052812 Ornithine decarboxylases Human genes 0.000 description 8
- 108700005126 Ornithine decarboxylases Proteins 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 150000001241 acetals Chemical class 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical compound CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
- IVHBQBNIGBXJKX-UHFFFAOYSA-N 6-bromo-3,4-dihydro-2h-thiochromene Chemical compound S1CCCC2=CC(Br)=CC=C21 IVHBQBNIGBXJKX-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 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 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229940127271 compound 49 Drugs 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical class SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 5
- WPWNEKFMGCWNPR-UHFFFAOYSA-N 3,4-dihydro-2h-thiochromene Chemical group C1=CC=C2CCCSC2=C1 WPWNEKFMGCWNPR-UHFFFAOYSA-N 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 5
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical class C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 229940126142 compound 16 Drugs 0.000 description 5
- 229940127204 compound 29 Drugs 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 229940052303 ethers for general anesthesia Drugs 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000011905 homologation Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 235000011149 sulphuric acid Nutrition 0.000 description 5
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 4
- FTBCOQFMQSTCQQ-UHFFFAOYSA-N 4-bromobenzenethiol Chemical compound SC1=CC=C(Br)C=C1 FTBCOQFMQSTCQQ-UHFFFAOYSA-N 0.000 description 4
- GOUNZOPMXKRIGV-UHFFFAOYSA-N 6-ethynyl-3,4-dihydro-2h-thiochromene Chemical class S1CCCC2=CC(C#C)=CC=C21 GOUNZOPMXKRIGV-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229940125961 compound 24 Drugs 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- YCBJOQUNPLTBGG-UHFFFAOYSA-N ethyl 4-iodobenzoate Chemical compound CCOC(=O)C1=CC=C(I)C=C1 YCBJOQUNPLTBGG-UHFFFAOYSA-N 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 150000003509 tertiary alcohols Chemical class 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- XSBSVRQTQZUILE-UHFFFAOYSA-N 3,4-dihydrothiochromen-2-one Chemical compound C1=CC=C2SC(=O)CCC2=C1 XSBSVRQTQZUILE-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- FDTGUDJKAXJXLL-UHFFFAOYSA-N acetylene Chemical compound C#C.C#C FDTGUDJKAXJXLL-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical group 0.000 description 3
- 239000011260 aqueous acid Substances 0.000 description 3
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 229940125833 compound 23 Drugs 0.000 description 3
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 3
- DMSHWWDRAYHEBS-UHFFFAOYSA-N dihydrocoumarin Natural products C1CC(=O)OC2=C1C=C(OC)C(OC)=C2 DMSHWWDRAYHEBS-UHFFFAOYSA-N 0.000 description 3
- 229940043279 diisopropylamine Drugs 0.000 description 3
- 239000012259 ether extract Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 150000002373 hemiacetals Chemical class 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 3
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 229930002330 retinoic acid Natural products 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 239000012049 topical pharmaceutical composition Substances 0.000 description 3
- 229960001727 tretinoin Drugs 0.000 description 3
- 150000003751 zinc Chemical class 0.000 description 3
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 2
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 2
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 2
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 2
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 2
- WKALQROSCJBFLA-UHFFFAOYSA-N 1-(2,2,4,4-tetramethyl-3h-chromen-6-yl)ethanone Chemical compound O1C(C)(C)CC(C)(C)C2=CC(C(=O)C)=CC=C21 WKALQROSCJBFLA-UHFFFAOYSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- NHDVFXNUAUYRHR-UHFFFAOYSA-N 2,2,4,4-tetramethyl-3h-chromene Chemical compound C1=CC=C2OC(C)(C)CC(C)(C)C2=C1 NHDVFXNUAUYRHR-UHFFFAOYSA-N 0.000 description 2
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 2
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- IOSGANIYBODQTB-UHFFFAOYSA-N 2-ethynylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C#C IOSGANIYBODQTB-UHFFFAOYSA-N 0.000 description 2
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 2
- VMUXSMXIQBNMGZ-UHFFFAOYSA-N 3,4-dihydrocoumarin Chemical compound C1=CC=C2OC(=O)CCC2=C1 VMUXSMXIQBNMGZ-UHFFFAOYSA-N 0.000 description 2
- AYLNUQHJHYECII-UHFFFAOYSA-N 3-methyl-2-(3-methylphenyl)but-2-enoic acid Chemical compound CC(C)=C(C(O)=O)C1=CC=CC(C)=C1 AYLNUQHJHYECII-UHFFFAOYSA-N 0.000 description 2
- BDUBTLFQHNYXPC-UHFFFAOYSA-N 3-methylbut-2-enoyl chloride Chemical compound CC(C)=CC(Cl)=O BDUBTLFQHNYXPC-UHFFFAOYSA-N 0.000 description 2
- GHICCUXQJBDNRN-UHFFFAOYSA-N 4-iodobenzoic acid Chemical compound OC(=O)C1=CC=C(I)C=C1 GHICCUXQJBDNRN-UHFFFAOYSA-N 0.000 description 2
- JXECCEUIYMEVLB-UHFFFAOYSA-N 6-bromo-4,4-dimethyl-3h-thiochromen-2-one Chemical compound C1=C(Br)C=C2C(C)(C)CC(=O)SC2=C1 JXECCEUIYMEVLB-UHFFFAOYSA-N 0.000 description 2
- YKWBOJNHBUFTPV-UHFFFAOYSA-N 6-ethynyl-3,4-dihydro-2h-chromene Chemical class O1CCCC2=CC(C#C)=CC=C21 YKWBOJNHBUFTPV-UHFFFAOYSA-N 0.000 description 2
- 208000002874 Acne Vulgaris Diseases 0.000 description 2
- 238000006218 Arndt-Eistert homologation reaction Methods 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 2
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- 229940127007 Compound 39 Drugs 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 238000000023 Kugelrohr distillation Methods 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 206010000496 acne Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 229940125807 compound 37 Drugs 0.000 description 2
- 229940127573 compound 38 Drugs 0.000 description 2
- 229940126540 compound 41 Drugs 0.000 description 2
- 229940125936 compound 42 Drugs 0.000 description 2
- 229940125844 compound 46 Drugs 0.000 description 2
- 229940126545 compound 53 Drugs 0.000 description 2
- 229940127113 compound 57 Drugs 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 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 2
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical group [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- YCJZWBZJSYLMPB-UHFFFAOYSA-N n-(2-chloropyrimidin-4-yl)-2,5-dimethyl-1-phenylimidazole-4-carboxamide Chemical compound CC=1N(C=2C=CC=CC=2)C(C)=NC=1C(=O)NC1=CC=NC(Cl)=N1 YCJZWBZJSYLMPB-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- FFACJJSUQMXDRE-UHFFFAOYSA-N phenyl 3-methylbut-2-enoate Chemical compound CC(C)=CC(=O)OC1=CC=CC=C1 FFACJJSUQMXDRE-UHFFFAOYSA-N 0.000 description 2
- WRAQQYDMVSCOTE-UHFFFAOYSA-N phenyl prop-2-enoate Chemical class C=CC(=O)OC1=CC=CC=C1 WRAQQYDMVSCOTE-UHFFFAOYSA-N 0.000 description 2
- 229920000768 polyamine Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 150000004492 retinoid derivatives Chemical class 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- AOLHNYRECBIZFH-UHFFFAOYSA-N (2-ethynyl-2-methyl-3,4-dihydrothiochromen-6-yl)-trimethylsilane Chemical compound CC1(SC2=CC=C(C=C2CC1)[Si](C)(C)C)C#C AOLHNYRECBIZFH-UHFFFAOYSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- CCAMMGLODBTYJS-UHFFFAOYSA-N 1-(2,2,4,4,7-pentamethyl-3h-chromen-6-yl)ethanone Chemical compound C1=C(C)C(C(=O)C)=CC2=C1OC(C)(C)CC2(C)C CCAMMGLODBTYJS-UHFFFAOYSA-N 0.000 description 1
- LWLOEQYNKSEPEC-UHFFFAOYSA-N 1-(2,2,4,4-tetramethyl-7-propyl-3h-chromen-6-yl)ethanone Chemical compound O1C(C)(C)CC(C)(C)C2=C1C=C(CCC)C(C(C)=O)=C2 LWLOEQYNKSEPEC-UHFFFAOYSA-N 0.000 description 1
- DMHULXKTLIWNNC-UHFFFAOYSA-N 1-(2,2-diethyl-4,4-dimethyl-3h-chromen-6-yl)ethanone Chemical compound CC(=O)C1=CC=C2OC(CC)(CC)CC(C)(C)C2=C1 DMHULXKTLIWNNC-UHFFFAOYSA-N 0.000 description 1
- BAXUMNKQKVFPNU-UHFFFAOYSA-N 1-(3,4-dihydro-2h-chromen-6-yl)ethanone Chemical class O1CCCC2=CC(C(=O)C)=CC=C21 BAXUMNKQKVFPNU-UHFFFAOYSA-N 0.000 description 1
- KTIUCRYMBJEVAW-UHFFFAOYSA-N 1-(7-hexyl-2,2,4,4-tetramethyl-3h-chromen-6-yl)ethanone Chemical compound O1C(C)(C)CC(C)(C)C2=C1C=C(CCCCCC)C(C(C)=O)=C2 KTIUCRYMBJEVAW-UHFFFAOYSA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- HYTUSMXEQPPOAO-UHFFFAOYSA-N 2,2,4,4,7-pentamethyl-3h-chromene Chemical compound O1C(C)(C)CC(C)(C)C=2C1=CC(C)=CC=2 HYTUSMXEQPPOAO-UHFFFAOYSA-N 0.000 description 1
- IVBNQUYXRAJUPL-UHFFFAOYSA-N 2-(3,4-dihydro-2h-thiochromen-6-yl)ethynyl-trimethylsilane Chemical compound S1CCCC2=CC(C#C[Si](C)(C)C)=CC=C21 IVBNQUYXRAJUPL-UHFFFAOYSA-N 0.000 description 1
- UVYFPTLHZWDMJA-UHFFFAOYSA-N 2-(4-hydroxy-2,4-dimethylpentan-2-yl)-5-methylphenol Chemical compound CC1=CC=C(C(C)(C)CC(C)(C)O)C(O)=C1 UVYFPTLHZWDMJA-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- SZRMMGWBOCHZHV-UHFFFAOYSA-N 2-ethynyl-4-(2,4,4-trimethyl-2,3-dihydrothiochromen-6-yl)benzoic acid Chemical compound C=1C=C2SC(C)CC(C)(C)C2=CC=1C1=CC=C(C(O)=O)C(C#C)=C1 SZRMMGWBOCHZHV-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical group N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- PHUAHCFKROIBHD-UHFFFAOYSA-N 3-methylbut-2-enethioic s-acid Chemical compound CC(C)=CC(S)=O PHUAHCFKROIBHD-UHFFFAOYSA-N 0.000 description 1
- VQVDMHKSWDUCTO-UHFFFAOYSA-N 4,4,7-trimethyl-3h-chromen-2-one Chemical compound O1C(=O)CC(C)(C)C=2C1=CC(C)=CC=2 VQVDMHKSWDUCTO-UHFFFAOYSA-N 0.000 description 1
- ZBSFDCKGUFSQLN-UHFFFAOYSA-N 4,4-dimethyl-3h-chromen-2-one Chemical compound C1=CC=C2C(C)(C)CC(=O)OC2=C1 ZBSFDCKGUFSQLN-UHFFFAOYSA-N 0.000 description 1
- ITIBFNPMXOMRRJ-UHFFFAOYSA-N 4-(5-bromo-2-sulfanylphenyl)-2,4-dimethylpentan-2-ol Chemical compound CC(C)(O)CC(C)(C)C1=CC(Br)=CC=C1S ITIBFNPMXOMRRJ-UHFFFAOYSA-N 0.000 description 1
- DAAVTHZTVIEOBN-UHFFFAOYSA-N 4-[2-(2,2,4,4,7-pentamethyl-3h-thiochromen-6-yl)ethynyl]benzoic acid Chemical compound CC1=CC=2SC(C)(C)CC(C)(C)C=2C=C1C#CC1=CC=C(C(O)=O)C=C1 DAAVTHZTVIEOBN-UHFFFAOYSA-N 0.000 description 1
- KFXCYOSJSWUOEO-UHFFFAOYSA-N 4-[2-(2,2,4,4-tetramethyl-3h-chromen-6-yl)ethynyl]benzoic acid Chemical compound C=1C=C2OC(C)(C)CC(C)(C)C2=CC=1C#CC1=CC=C(C(O)=O)C=C1 KFXCYOSJSWUOEO-UHFFFAOYSA-N 0.000 description 1
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 1
- FVVPVSIIRRDWSQ-UHFFFAOYSA-N 5-(5-bromo-2-sulfanylphenyl)-3-ethyl-5-methylhexan-3-ol Chemical compound CCC(O)(CC)CC(C)(C)C1=CC(Br)=CC=C1S FVVPVSIIRRDWSQ-UHFFFAOYSA-N 0.000 description 1
- QGBXGWZCNVMPQB-UHFFFAOYSA-N 6-bromo-2,2,4,4-tetramethyl-3h-thiochromene Chemical compound BrC1=CC=C2SC(C)(C)CC(C)(C)C2=C1 QGBXGWZCNVMPQB-UHFFFAOYSA-N 0.000 description 1
- LARUSCVLGHSTRG-UHFFFAOYSA-N 6-bromo-2,4,4-trimethyl-2,3-dihydrothiochromene Chemical compound BrC1=CC=C2SC(C)CC(C)(C)C2=C1 LARUSCVLGHSTRG-UHFFFAOYSA-N 0.000 description 1
- SOKNYUIGDZEGJA-UHFFFAOYSA-N 6-bromo-2,4,4-trimethyl-3h-thiochromen-2-ol Chemical compound C1=C(Br)C=C2C(C)(C)CC(C)(O)SC2=C1 SOKNYUIGDZEGJA-UHFFFAOYSA-N 0.000 description 1
- FOPSVDSLPQNWOK-UHFFFAOYSA-N 6-bromo-2,4,4-trimethylthiochromene Chemical compound BrC1=CC=C2SC(C)=CC(C)(C)C2=C1 FOPSVDSLPQNWOK-UHFFFAOYSA-N 0.000 description 1
- NWAXNFJPPQCTBR-UHFFFAOYSA-N 6-bromo-3,3-dimethyl-4h-thiochromen-2-one Chemical compound BrC1=CC=C2SC(=O)C(C)(C)CC2=C1 NWAXNFJPPQCTBR-UHFFFAOYSA-N 0.000 description 1
- HMJHMPZSRPPFGE-UHFFFAOYSA-N 6-bromo-3,4-dihydrothiochromen-2-one Chemical compound S1C(=O)CCC2=CC(Br)=CC=C21 HMJHMPZSRPPFGE-UHFFFAOYSA-N 0.000 description 1
- WFMXKSXWEVNOCZ-UHFFFAOYSA-N 6-ethynyl-2,2,4,4,7-pentamethyl-3h-chromene Chemical compound O1C(C)(C)CC(C)(C)C2=C1C=C(C)C(C#C)=C2 WFMXKSXWEVNOCZ-UHFFFAOYSA-N 0.000 description 1
- ZOESRTXRNMZJQF-UHFFFAOYSA-N 6-ethynyl-2,2,4,4-tetramethyl-3h-chromene Chemical compound C#CC1=CC=C2OC(C)(C)CC(C)(C)C2=C1 ZOESRTXRNMZJQF-UHFFFAOYSA-N 0.000 description 1
- GMBKZKWUROHJFG-UHFFFAOYSA-N 6-ethynyl-2,2,4,4-tetramethyl-3h-thiochromene Chemical compound C#CC1=CC=C2SC(C)(C)CC(C)(C)C2=C1 GMBKZKWUROHJFG-UHFFFAOYSA-N 0.000 description 1
- CKSLWUUBKLNBEK-UHFFFAOYSA-N 6-ethynyl-2,4,4-trimethyl-2,3-dihydrothiochromene Chemical compound C#CC1=CC=C2SC(C)CC(C)(C)C2=C1 CKSLWUUBKLNBEK-UHFFFAOYSA-N 0.000 description 1
- 206010000503 Acne cystic Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000004031 Carboxy-Lyases Human genes 0.000 description 1
- 108090000489 Carboxy-Lyases Proteins 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 208000002506 Darier Disease Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 206010023369 Keratosis follicular Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 238000006959 Williamson synthesis reaction Methods 0.000 description 1
- UYIFTLBWAOGQBI-RRKYFUOXSA-N [(13s)-17-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate Chemical compound C([C@]1(C2CCC1O)C)CC(C1=CC=3)C2CCC1=CC=3OC(=O)C1=CC=CC=C1 UYIFTLBWAOGQBI-RRKYFUOXSA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 150000000475 acetylene derivatives Chemical class 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- FXORZKOZOQWVMQ-UHFFFAOYSA-L dichloropalladium;triphenylphosphane Chemical compound Cl[Pd]Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 FXORZKOZOQWVMQ-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005837 enolization reaction Methods 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- YDJDSUNRSIVGMI-UHFFFAOYSA-N ethyl 2-(4-iodophenyl)acetate Chemical compound CCOC(=O)CC1=CC=C(I)C=C1 YDJDSUNRSIVGMI-UHFFFAOYSA-N 0.000 description 1
- DFCMAJHJFMODLG-UHFFFAOYSA-N ethyl 3-(4-iodophenyl)propanoate Chemical compound CCOC(=O)CCC1=CC=C(I)C=C1 DFCMAJHJFMODLG-UHFFFAOYSA-N 0.000 description 1
- RNMSKHCWXQYXTB-UHFFFAOYSA-N ethyl 3-[4-[2-(2,2,4,4,7-pentamethyl-3h-chromen-6-yl)ethynyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OCC)=CC=C1C#CC(C(=C1)C)=CC2=C1OC(C)(C)CC2(C)C RNMSKHCWXQYXTB-UHFFFAOYSA-N 0.000 description 1
- SKOSJROJZWWZFU-UHFFFAOYSA-N ethyl 4-(4-iodophenyl)butanoate Chemical compound CCOC(=O)CCCC1=CC=C(I)C=C1 SKOSJROJZWWZFU-UHFFFAOYSA-N 0.000 description 1
- TTXZWOBETHGPDJ-UHFFFAOYSA-N ethyl 4-[2-(2,2,4,4,7-pentamethyl-3h-chromen-6-yl)ethynyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C#CC(C(=C1)C)=CC2=C1OC(C)(C)CC2(C)C TTXZWOBETHGPDJ-UHFFFAOYSA-N 0.000 description 1
- PUDSSRXSODRCCJ-UHFFFAOYSA-N ethyl 4-[2-(2,2,4,4-tetramethyl-3h-thiochromen-6-yl)ethynyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SC(C)(C)CC2(C)C)C2=C1 PUDSSRXSODRCCJ-UHFFFAOYSA-N 0.000 description 1
- LEEACEKPIMIWGN-UHFFFAOYSA-N ethyl 4-[2-(7-ethyl-2,2,4,4-tetramethyl-3h-chromen-6-yl)ethynyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C#CC(C(=C1)CC)=CC2=C1OC(C)(C)CC2(C)C LEEACEKPIMIWGN-UHFFFAOYSA-N 0.000 description 1
- RLDLHBDTPXHWQB-UHFFFAOYSA-N ethyl 4-[2-(7-hexyl-2,2,4,4-tetramethyl-3h-chromen-6-yl)ethynyl]benzoate Chemical compound CCCCCCC1=CC=2OC(C)(C)CC(C)(C)C=2C=C1C#CC1=CC=C(C(=O)OCC)C=C1 RLDLHBDTPXHWQB-UHFFFAOYSA-N 0.000 description 1
- KYRMTBHGXKOPHD-UHFFFAOYSA-N ethyl 5-[4-[2-(2,2,4,4,7-pentamethyl-3h-chromen-6-yl)ethynyl]phenyl]pentanoate Chemical compound C1=CC(CCCCC(=O)OCC)=CC=C1C#CC(C(=C1)C)=CC2=C1OC(C)(C)CC2(C)C KYRMTBHGXKOPHD-UHFFFAOYSA-N 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 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
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910001410 inorganic ion Inorganic materials 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 201000004607 keratosis follicularis Diseases 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- MHCFAGZWMAWTNR-UHFFFAOYSA-M lithium perchlorate Chemical compound [Li+].[O-]Cl(=O)(=O)=O MHCFAGZWMAWTNR-UHFFFAOYSA-M 0.000 description 1
- 229910001486 lithium perchlorate Inorganic materials 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- BVVVHFMUHKWXBP-UHFFFAOYSA-N s-(4-bromophenyl) 3-methylbut-2-enethioate Chemical compound CC(C)=CC(=O)SC1=CC=C(Br)C=C1 BVVVHFMUHKWXBP-UHFFFAOYSA-N 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000036620 skin dryness Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- NRUVOKMCGYWODZ-UHFFFAOYSA-N sulfanylidenepalladium Chemical compound [Pd]=S NRUVOKMCGYWODZ-UHFFFAOYSA-N 0.000 description 1
- 230000008833 sun damage Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical class C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- HOILYHAZMVVXPG-UHFFFAOYSA-N trimethyl-[2-(2,2,3,3-tetramethyl-4h-thiochromen-6-yl)ethynyl]silane Chemical compound C[Si](C)(C)C#CC1=CC=C2SC(C)(C)C(C)(C)CC2=C1 HOILYHAZMVVXPG-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/14—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 6 and unsubstituted in position 7
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Ophthalmology & Optometry (AREA)
- Nutrition Science (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Pyrane Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Retinoid-like activity is exhibited by compounds of formula (I), where X is S, O; R1, R2 and R3 are hydrogen or lower alkyl; R4 and R5 are hydrogen or lower alkyl with the proviso that R4 and R5 cannot both be hydrogen, R6 is hydrogen, lower alkyl, lower alkenyl, lower cycloalkyl or halogen; n is 0 - 5, and B is H, -COOH or a pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative, or -CHO or an acetal derivative, or -COR1 or a ketal derivative where R1 is -(CH2)mCH3 where m is 0-4, or a pharmaceutically acceptable salt thereof.
Description
ACETYLENES DISUBSTITUTED WITH A PHENYL GROUP AND A 2SUBSTITUTED CHROMANYL. THIOCHROMANYL OR 1,2,3.4 - TETRAHYDROQUINOLINYL GROUP HAVING RETINOID-LIKE ACTIVITY Background Cross-reference to Related Application 1. This application is a continuation-in-part of pending application serial number 408,488, filed on September 19, 1989, and assigned to the same assignee as this application.
Field of the Invention 2. This invention relates to novel compounds having retinoid-like activity. More specifically, the invention relates to compounds having an ethynylbenzoic acid portion and a second portion which is a 2-substituted tetrahydro15 quinolinyl, thiochromanyl, or chromanyl group. The acid function may also be converted to an alcohol, aldehyde or ketone or derivatives thereof, or may be reduced to -CH3.
Related Art Carboxylic acid derivatives useful for inhibiting the degeneration of cartilage of the general formula 4-(2-(4,4-dimethyl-6-X)-2-methylvinyl)benzoic acid where X is tetrahydroquinolinyl, chromanyl or thiochromanyl are disclosed in European Patent Application 0133795 published January 9, 1985. See also European Patent Application 176034A published April 2, 1986 where tetrahydronaphthalene compounds having an ethynylbenzoic acid group are disclosed, and United States Patent No. 4,739,098 where three olefinic units from the acid-containing moiety of retinoic acid are replaced by an ethynylphenyl functional30 ity.
Summary of the Invention This invention covers compounds of Formula 1 wherein X is S, 0; R1-R3 are hydrogen or lower alkyl, R4 and Rg are hydrogen or lower alkyl with the proviso that R4 and Rg cannot both be hydrogen; Rg is lower alkyl, lower alkenyl, lower cycloalkyl having 1 to 6 carbons, or halogen; n is 0-5; and B is H, -COOH or a pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative, or -CHO or an acetal deriva15 tive, or -COR^ or a ketal derivative where Rj is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons.
In a second aspect, this invention relates to the use of the compounds of Formula 1 for treating dermatoses, such as acne, Darier's disease, psoriasis, icthyosis, eczema, atopic dermatitis and epithelial cancers. These compounds are also useful in the treatment of arthritic diseases and other immunological disorders (e.g. lupus erythematosus), in promoting wound healing, in treating dry eye syndrome and in reversing the effects of sun damage to skin.
This invention also relates to a pharmaceutical formulation comprising a compound of Formula 1 in admixture with a pharmaceutically acceptable excipient.
In another aspect, this invention relates to the 30 process for making a compound of Formula 1 which process comprises reacting a compound of Formula 2 with a compound of Formula 3 in the presence of cuprous iodide and Pd(PQ3)2Cl2 (Q is phenyl) or a similar complex 1:3 Formula 2 Formula 3 where Rg-R6 are the same as described above, X' is a halogen, preferably I; and n is the same as defined above; and B is H, or a protected acid, alcohol, aldehyde or ketone, giving the corresponding compound of Formula 1; or to the process of making a compound of Formula 1 which consists of reacting a zinc salt of Formula 4 with a compound of Formula 3 in the presence of Pd(PQ3)4 (Q is phenyl) or a similar complex.
Formula 4 ZnCI where R^Rg, and X, are the same as defined above, giving the corresponding compound of Formula 1; or homologating a compound of the Formula 5 Formula 5 where n is 0-4 to give an acid of Formula 1; or converting an acid of Formula 1 to a salt; or forming an acid addition salt; converting an acid of Formula 1 to an ester; or converting an acid of Formula 1 to an amide; or reducing an acid of Formula 1 to an alcohol or aldehyde ; or converting an alcohol of Formula 1 to an ether or ester; or oxidizing an alcohol of Formula l to an aldehyde; or converting an aldehyde of Formula 1 to an acetal; or converting a ketone of Formula 1 to a ketal.
General Embodiments Definitions The term ester" as used here refers to and covers 30 any compound falling within the definition of that term as classically used in organic chemistry. Where B (of FormuIE 913569 la 1) is -COOH, this term covers the products derived from treatment of this function with alcohols, preferably with aliphatic alcohols having 1-6 carbons. Where the ester is derived from compounds where B is -CH2OH, this term covers compounds of the forumula -CH2OOCR where R is any substituted or unsubstituted aliphatic, aromatic or aliphatic aromatic group, preferably with 1-6 carbons in the aliphatic portions.
Preferred esters are derived from the saturated aliphatic alcohols or acids of ten or fewer carbon atoms or the cyclic or saturated aliphatic cyclic alcohols and acids of 5 to 10 carbon atoms. Particularly preferred aliphatic esters are those derived from lower alkyl acids or alcohols.
Here, and where ever else used, lower alkyl means having 1-6 carbon atoms and includes straight as well as branched chain alkyl groups.
Also preferred are the phenyl or lower alkylphenyl esters.
Preferred ethers are derived from the saturated alcohols defined hereinabove in relation to the preferred esters. Also preferred are the phenyl or lower alkylphenyl ethers.
Amide has the meaning clasically accorded that term in organic chemistry. In this instance it includes 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 aliphaticcyclic radicals of 5 to 10 carbon atoms. Particularly preferred amides are those derived from lower alkyl amines. Also preferred are mono and disubstituted amides derived from the phenyl or lower alkylphenyl amines. Unsubstituted amides are also preferred.
Acetals and ketals include the radicals of the formula -CK where k is (-OR)2· Here, R is lower alkyl. Also, K may be -ORjO- where R^ is lower alkyl of 2-5 carbon atoms, straight chain or branched.
A pharmaceutically acceptable salt may be prepared for any compound of this invention having a functionality capable of forming such salt, for example an acid or an amine functionality. A pharmaceutically acceptable salt may be any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
Such a salt may be derived from any organic or inorganic acid or base. The salt may be a mono or polyvalent ion. Of particular interest where the acid function is concerned are the inorganic ions, sodium, potassium, calcium, and magnesium. Organic amine 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 molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide. Preferred 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 preferred compounds of this invention are those where the ethynyl group and the B group are attached to the 1 and-4 positions respectively of a benzene ring (i.e. where the phenyl moiety of the compound is para substituted) n is 0; and B is -COOH, an alkali metal salt or organ30 ic amine salt, or a lower alkyl ester thereof, or -CH2OH and the lower alkyl esters and ethers thereof, or -CHO and acetal derivatives thereof. The more preferred compounds shown in Formula 6 are: ethyl 4 - [(2,2,4,4-tetramethylthiochroman-6-yl)-ethynyl] benzoate (Compound 1 X = S, Rg = H, R4 = CH3, Rg ~ CHg, R = C2H5); 4-((2,2,4,4-tetramethylthiochroman-6-yl)-ethynyl] benzoic 5 acid (Compound 2, X = S, Rg = H, R4 = CHg, Rg = CH3, R H) ; ethyl 4-[(2,2,4,4-tetramethylchroman- 6 - yl) - ethynyl] benzoate (Compound 3, X=0, Rg=H, R4= CHg, Rg = CHg, R" = C2H5) ; 4-[(2,2,4,4-tetramethylchroman-6-yl)-ethynyl] benzoic acid (Compound 4, X = 0, Rg = H, R4 = CH3, Rg = CHg, R = H); ethyl 4-((2,2,4,4,7-pentamethylthiochroman-6-yl)-ethynyl] benzoate (Compound 5, X = S, Rg = CH3, R4 = CH3, Rg = CH3, R = C2H5); 4-[(2,2,4,4,7-pentamethylthiochroman—6-yl)-ethynyl] benzoic acid (Compound 6, X = S, R3 = CH3, R4 = CH3, Rg = CH3, R = H) ethyl 4-((2,2,4,4,7-pentamethylchroman-6-yl)-ethynyl] benzoate (Compound 7, X = 0, Rg = CHg, R4 = CHg, Rg = CHg, R = C2H5); 4-((2,2,4,4,7-pentamethylchroman-6-yl)-ethynyl] benzoic acid (Compound 8, X = 0, Rg = CHg, R4 = CHg, Rg = CHg, R" = H) ethyl-4[(2,4,4,trimethyl-6-thiochromanyl) 25 ethynyl]benzoate (Compound 56, X = S, Rg = H, R4 = H, Rg = CHg, R = C2H5) 4-(2,4,4,trimethyl-6-thio-chromany1)-ethynyl benzoic acid (Compound 57, X = S, Rg - H, R4 = H, Rg = CHg, R = H) II Formula 6 The compounds of this invention may be administered systemically or topically, depending on such considerations as the condition to be treated, need for site-specific treatment, quantity of drug to be administered, and similar considerations.
In the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in certain cases such as treatment of severe cystic acne, oral administration may also be used. Any common topical formulation such as a solution, suspension, gel, ointment, or salve and the like may be used. Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania. For topical application, these compounds could also be administered as a powder or spray, particularly in aerosol form.
If the drug is to be administered systemically, it may be confected as a powder, pill, tablet or the like, or as a syrup or elixir for oral administration. For intravenous or intraperitoneal administration, 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 in suppository form or as an extended release formulation for deposit under the skin or intermuscular injection.
Other 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, preventing infection, 10 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 its expansion. In certain instances, the drug potentially could be used in a prophylactic manner to prevent onset of a particular condition. A given therapeutic 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, a given therapeutic concentration will be best determined at the time and place through routine experimentation. However, it is anticipated that in the treatment, of, for example, acne, or other such dermatoses, that a formulation containing between 0.001 and 5 percent by weight, preferably about 0.01 to 1% will usually con30 stitute a therapeutically effective concentration. If administered systemically, an amount between 0.01 and 100 mg per kg body weight per day, but preferably about 0.1 to 10 mg/kg, will effect a therapeutic result in most in10 IE 913559 stances The retionic acid like activity of these compounds was confirmed through the classic measure of retionic acid activity involving the effects of retionic acid on orni5 thine 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 10 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 inhibited, cell hyperproliferation could be modulated. Although all causes for ODC activity in15 crease are unknown, it is known that 12-0-tetradecanoylphorbol-13-acetate (TPA) induces ODC activity. Retinoic acid inhibits this induction of ODC activity by TPA. The compounds of this invention also inhibit TPA induction of ODC as demonstrated by an assay essentially following the 2o procedure set out in Cancer Res.. 35: 1662-1670, 1975.
By way of example of retinoic acid-like activity it is noted that in the assay conducted essentially in accordance with the method of Verma & Boutwell, ibid, the following examples of the preferred compounds of the present invention (Compounds 1, 3 and 7) attained an 80% inhibition of TPA induced ODC activity at the following concentrations (IC80): Compound IC80 cone (nmols) 1.2 0.1 1.0 2.2 .24 IE 913559 Specific Embodiments The compounds of this invention can be made by a number of different synthetic chemical pathways. To illustrate this invention, there is here outlined a series of steps which have been proven to provide the compounds of Formula 1 when such synthesis is followed in fact and in spirit. 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 Formula 1. Furthermore, the synthetic chemist will readily appreciate that the herein described synthetic steps may be varied and or adjusted by those skilled in the art without departing from the scope and spirit of the invention.
Compounds of Formula 1 where X is -S- and R4 and R5 are hydrogen or lower alkyl, with the proviso that R4 and R5 both are not hydrogen, are prepared as per Reaction Scheme I 20 Reaction Scheme I a ia n (CH2)n-B in Reaction Scheme I, Ri-R3 are hydrogen or a lower alkyl group, R6 is defined as above in connection with Formula 1, n is 0-5 and B is H, or a protected acid, alcohol, aldehyde or ketone. X» is Cl, Br or I when n is 0 but preferably be Br or I when n is 1-5.
Compounds of Formula 1 where X is oxygen and R4 and R5 are hydrogen or lower alkyl, with the proviso that R4 and Rj both are not hydrogen, are prepared as per Reaction Scheme 2.
(CH2)n-B 28a In Reaction Scheme 2 the definitions of R^-Rg, η, B and X* are the same as in Reaction Scheme 1.
A general description of the synthetic steps outlined in Reaction Schemes 1 and 2 is as follows.
In Reaction Scheme 1 the 4-bromo-thiophenol (Compound 9) is acylated with an acylating agent, such as an acid chloride (Compound 10) derived from an appropriately substituted acrylic acid. The acylation is conducted in an inert solvent (such as tetrahydrofuran) in the presence of strong base (for example sodium hydrdride). The resulting thioester (Compound 11) which contains the olefinic bond of the acrylic acid moiety is ring closed in the presence of a Friedel Crafts type catalyst (such as aluminum chloride) by stirring in a suitable solvent such as methylene chloride. The resulting 2-oxo-6-bromothiochroman (Compound 12) is usually isolated in crystalline form.
The R4 and/or R5 substituents (both of which cannot be hydrogen in accordance with the invention) are introduced by treating the 2-oxo-6-brorao-thiochroman (Compound 12) with a Grignard reagent, bearing the alkyl substituents and Rs (such as methylmagnesium bromide when R4 and R5 are methyl). When the Grignard reagent (such as methylmagnesium bromide) is in excess, the thiochroman ring is opened and the tertiary alcohol derivative of the 4-bromo thiophenol (Compound 13) is formed.
Ring closure of the thiophenol derivative (Compound 10 13) which has the desired R^, R2, R3, R4 and R5 substituents, is affected by heating in acidic conditions, preferably by heating Compound 13 in aqueous acid. The resulting 6-bromothiochroman which bears the desired alkyl (or hydrogen) substituents, R^, R2, R3, R4 and Rs is shown as Compound 14 in Reaction Scheme 1.
To introduce the acetylene (ethyne) portion into the molecule, the substituted 6-bromothiochroman 14 is reacted with trimethylsilylacetylene in the presence of cuprous iodide and a suitable catalyst, typically having the formula Pd(PQ3)2Cl2 (Q is phenyl). The reaction is typically conducted in the presence of bis(triphenylphosphine) palladium (II) chloride catalyst, an acid acceptor, (such as triethylamine) under an inert gas (argon) atmosphere, by heating in a sealed tube. The resulting 6-trimethylsi25 lylethynylthiochroman is shown as Compound 15 in Reaction Scheme 1.
As is shown on Reaction Scheme 1, the trimethylsilyl moiety is removed from the 6-trimethylsilylethynyl-thiochroman 15 in the next synthetic step, to provide the ring substituted 6-ethynyl-thiochroman derivative (Compound 16). The latter reaction is conducted under basic conditions, preferably under an inert gas atmosphere.
In order to introduce the phenyl or substituted phenyl substituent on the acetylene (ethyne) portion of Compound 16, Compound 16 is coupled with the reagent X’-Q(CH2)n-B (Formula 3, Q is a di- or multi-substituted phenyl residue) where the symbols η, X' and B have the same meaning as defined in connection with Formula 3. In other words, the phenyl or substituted phenyl substituent is introduced into the 6-ethynyl-thiochroman 16 by reacting the latter with a halogen substituted phenyl compound (Formula 3) in which the benzene nucleus either has the desired substituent [(CH2)n-B] or wherein the actual substituent (CH2)n-B can be readily converted to the desired substituent by means of organic reactions well known in the art.
Coupling of the 6-ethynyl-thiochroman 16 with the reagent X»-Q-(CH2)n-B is affected directly in the presence of cuprous iodide, a suitable catalyst, typically of the formula Pd(PQ3)2Cl2 and an acid acceptor, such as triethylamine, by heating in a sealed tube under an inert gas (argon) atmosphere.
The resulting disubstituted acetylene compound (Compound 18) may be the target compound made in accordance with the invention, or maybe readily converted into the target compound by such steps as salt formation, esterification, deesterification, homologation, amide formation and the like. These steps are further discussed below.
Compound 18 may also be obtained by first converting the 6-ethynyl-thiochroman derivative 16 into the corresponding metal salt, such as a zinc salt, (Compound 17) and thereafter coupling the salt 17 with the reagent X'-Q(CH2)n-B (Formula 3 Q is phenyl or substituted phenyl residue) in the presence of a catalyst having the formula Pd(PQ3)4 (Q is phenyl), or similar complex.
Derivatization of Compound 18 is indicated in Reaction Scheme 1 as conversion to homologs and derivatives, Compounds 19.
More specifically with respect to either derivatiza5 tion or deblocking of protected functionalities in Compound 18, or with respect to the preparation of phenyl derivatives of the formula X*-Q-(CH2)n-B, (which after coupling either directly yield the compounds of the invention, or are readily converted into them) the following is noted.
Where a protected phenyl derivatives is needed to couple with the compounds of Formula 2 (Compounds 16 in Reaction Scheme 1), such may be prepared from their corresponding acids, alcohols, ketones or aldehydes. These starting materials, the protected acids, alcohols, aldehydes or ketones, are all available from chemical manufacturers or can be prepared by published methods. 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. Alternatively, the carboxylic acid can be condensed with the appropriate alcohol in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine. The ester is recovered and purified by conventional means.
Acetals and ketals are readily made by the method described in March, Advanced Organic Chemistry, 2nd Edition, McGraw-Hill Book Company, p 810). Alcohols, aldehydes and ketones all may be protected by forming respectively, ethers and esters, acetals or ketals by known methods such as those described in McOmie, Plenum Publishing Press, 1973 and Protecting Groups. Ed. Greene, John Wiley & Sons, 1981.
To increase the value of n before effecting a couIE 913569 pling reaction, where such compounds are not available from a commercial source, the phenyl derivatives where B is -COOH are subjected to homologation by successive treatment under Arndt-Eistert conditions or other homolo5 gation procedures. Alternatively, phenyl derivatives where B is different from COOH, may also be homologated by appropriate procedures. The homologated acids can then be esterified by the general procedure outlined in the preceding paragraph.
An alternative means for making compounds where n is - 5 is to subject the compounds of Formula 1, where B is an acid or other function, to homologation, using the Arndt-Eistert method referred to above, or other homologation procedures.
The acids and salts derived from Formula 1 are readily obtainable from the corresponding esters. Basic saponification with an alkali metal base will provide the acid. For example, an ester of Formula 1 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, potassium hydroxide.
The solution is stirred for an extended period of time, between 15 and 20 hours, cooled, acidified and the hydrolysate recovered by conventional means.
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.
For example, the acid is treated with an alcoholic base solution such as ethanolic KOH (in approximately a 10% molar excess) at room temperature for about 30 minutes.
The solvent is removed and the residue taken up in an organic solvent such as diethyl ether, treated with a dialkyl fonnamide and then a 10-fold excess of oxalyl chloride. This is all effected at a moderately reduced temperature between about -10 degrees and +10 degrees C.
The last mentioned solution is then stirred at the reduced temperature for 1-4 hours, preferably 2 hours. Solvent removal provides a residue which is taken up in an inert inorganic solvent such as benzene, cooled to about 0 degrees C and treated with concentrated ammonium hydrox10 ide. The resulting mixture is stirred at a reduced temperature for 1-4 hours. The product is recovered by conventional means.
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. Alternatively, esters may be reduced with lithium aluminum hydride at reduced temperatures. Alkylating these alcohols with appropriate alky 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 dicyclohexlcarbodiimide and dimethlaminopyridine.
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).
Ketones can be prepared from an appropriate aldehyde by treating the aldehyde with an alkyl Grignard reagent or similar reagent followed by oxidation.
Acetals or ketals can be prepared from the corresponding aldehyde or ketone by the method described in March, Ibid, p 810.
Compounds where B is H can be prepared from the corresponding halogenated benzene compounds, preferably where the halogen is I.
With reference to Reaction Scheme 2, phenol, or a IQ phenol substituted in the 3 (meta) position by an alkyl substituent (R3) (Compound 20) is acylated with an acylating agent, such as an acid chloride (Compound 10) derived from an appropriately substituted acrylic acid. In Reaction Scheme 2, just as in Reaction Scheme 1, the R^ and R2 substituents of the target compounds are introduced through this acrylic acid derivative 10. The acylation with the acid chloride 10 is preferably conducted in the presence of a strong base (e.g. sodium hydride) in an inert solvent (such as.tetrahydrofuran). The resulting 2o substituted phenyl-acrylate is shown in Reaction Scheme 2 as Compound 21.
The substituted phenyl-acrylate 21 is ring closed under Friedel Crafts type reaction conditions (A1C13 catalyst, in an inert solvent, such as methylene chloride) to provide the 2-oxo-chroman compound (Compound 22) which bears, in the 4-position, the R^ and R2 substituents and in the 6-position the R3 substituent (as applicable).
Just like the analogous 2-oxo-thiochroman 12 in Reaction Scheme 1, the 2-oxo-chroman 22 of Reaction scheme 2 is treated with a Grignard reagent to introduce the R4 and R5 substituents. As it was noted out above, R4 and Rs both cannot be hydrogen. When R4 and R5 are methyl, the Grignard reagent is preferably methylmagnesium chloride (dissolved in tetrahydrofuran, THF). A solution of Compound 22 in a suitable solvent, for example in dry diethylether is added to this Grignard reagent. The resulting phenol containing a tertiary alcohol side chain, (that is a molecule in which the chroman ring had been opened) is shown in Reaction Scheme 2 as Compound 23.
Compound 23 which already has the desired R^, R2 , R3, R4 and Rs substituents, is ring closed under acidic conditions, (e.g. by heating in aqueous sulfuric acid) to provide the chroman derivative (Compound 24). It should be noted that up to this point in the synthetic sequence (which is preferably but not necessarily exclusively used for making the compounds of the invention) similar or analogous steps are involved for making both the thiochro15 man (Reaction Scheme 1) and chroman derivatives (Reaction Scheme 2), the only difference being that in Reaction Scheme 2 the starting phenol derivative does not have a halogen (such as a bromo) substituent.
Because of the lack of the halogen substituent in the preferred synthetic sequence for preparing the chroman compounds of the invention, the preferred and herein illustrated steps (Reaction Scheme 2) for introducing the acetylene (ethyne) group into the 6-position of the chroman moiety are different from the steps utilized for introducing the acetylene moiety into the analogous thiochroman (Reaction Scheme X).
Thus, in Reaction Scheme 2 an acetyl group is introduced into the 6-position of the chroman derivative 24 under Friedel-Crafts type conditions. This acetylation is preferably conducted with acetyl chloride, in nitromethane solvent, in the presence of aluminum chloride. The resulting 6-acetyl-chroman derivative is Compound 25.
The acetylenic (triple) bond is introduced into the molecule by converting the 6-acetyl moiety of chroman 25 to an acetylene moiety. This is accomplished, preferably, by treatment with lithium diisopropylamide (at low temper5 ature, such as - 78 degrees C) which causes enolization of the acetyl group. The intermediate enol compound (not shown in Reaction Scheme 2) is esterified by treatment with diethylchlorophosphate (or the like) and is again reacted at reduced temperature (e.g. - 78 degrees C) with lithium diisopropylamide, to form the triple bond (presumably by an elimination reaction) and to yield the 6-ethynyl-chroman derivative (Compound 26).
It is noted at this point that the present invention is not intended to be limited or bound by the above-men15 tioned and other theories of reaction mechanisms. Brief description of theory of reaction mechanisms (where applicable) are given to further enable and facilitate the work of a skilled artisan in the field to modify and adjust the synthetic conditions to fit particular specific intermediates and to make the several compounds of the invention, without departing from the scope and spirit of the invention.
Referring back again to Reaction Scheme 2, the 6ethynyl-chroman derivative 26 may be converted into the target compounds of the invention in synthetic steps which are analogous to the conversion of 6-ethynyl-thiochromans (Compound 16) into the corresponding target thiochroman derivatives (See Reaction Scheme 1). Briefly, Compound 26 is preferably heated with a reagent X'-Q-(CH2)n-B (Formula 3 Q is phenyl or substituted phenyl residue) in the presence of cuprous iodide, a suitable catalyst, typically of the formula Pd(PQ3)2 Cl2 (Q is phenyl or the like) and an acid acceptor, such as triethylamine. This coupling reaction, yields the target chroman compounds, (Compound 28) or such derivatives which are readily converted into the target compounds by protection, deprotection, esterification, homologation etc., as is discussed in connection with Reaction Scheme 1. The homologs are indicated, as a group, as Compound 28a in Reaction Scheme 2.
Alternatively, the 6-ethynyl-chroman compounds 26 may first be converted to the corresponding metal (zinc) salt (Compound 27) and thereafter coupled with the reagent χ·-Q-(CH2)n~B (Formula 3 Q is phenyl substituted phenyl residue) under conditions which are similar to the conditions described in Reaction Scheme 1 for coupling of Compounds 18 with the same reagent.
REACTION SCHEME 3 Br Br t Br REACTION SCHEME H Br Br Referring to Reaction Scheme 3 substituted 6-bromo thio chroman 14, where the R* or R5 substituent is alkyl and the other is hydrogen can be made by treating the 2oxo-6-bromo-thiochroman (Compound 12) with a Grignard 20 reagent. As in Reaction Scheme 1 the 2-oxo-thiochroman 12 is subjected to an excess of Grignard reagent, bearing the alkyl substituents R4 or Rs (such as methylmagnesium bromide when R4 or R5 is methyl). However, the reaction temperature is controlled to and maintained at a relative25 ly low temperature (such as -14 degrees C) and the duration of the reaction is kept relatively short (0.5 hours). A hemiacetal derivative of 4-bromothiophenol (Compound 49) is formed, in this controlled Grignard reaction, as shown in Reaction Scheme 3. Cyclization of the thiophenol derivative Compound 49 is affected by heating in acidic conditions, preferably by aqueous acid, to give the unsaturated thio olefin (Compound 50). The 6-bromothioolefin (Compound 50) is reduced by hydrogenation in the presence of palladium sulfide-on-carbon catalyst at increased pressure (approximately 30 psi). The resulting 6-bromothiochroman which bears the desired hydrogen and alkyl substituents R^, R2 , R3, R4 and R5 with one of R4 or Rs being hydrogen, is shown as Compound 14.
Again, referring to 6-bromo-thio chroman, 14, in Reaction Scheme 4 the R4 and Rs substituents, both of which are alkyl but not identical with one another in this example, are introduced by treating the hemiacetal derivative (Compound 49) with a different Grignard reagent than previously used, as shown in Scheme 4. In this Grignard reaction the thio chroman ring is opened and the tertiary alcohol derivative of 4-bromo-thiophenol, 13, is formed. Ring closure of the thiophenol derivative 13 which has the desired Rx, R2, R3, R4 and Rs substituents, is affected by heating in acidic conditions, preferably by heating with aqueous acid. The resulting 6-bromo thiochroman which bears the desired alkyl and hydrogen substituents Rx, R2, R3, R4 and Rg is shown as Compound 14.
REACTION SCHEME 5 REACTION SCHEME & In Reaction Scheme 5, just as in Reaction Scheme 3, one of the R4 or Rg substituents is alkyl and the other is hydrogen. Just like the analogous 2-oxo-thiochroman 12 in Reaction Scheme 3, the 2-oxochroman 22 of Reaction Scheme 5 is treated with Grignard reagent to introduce the R4 and R5 substituents. With controlled reaction temperature and time, the resulting hemiacetal derivative can be isolated as Compound 51, as shown in Reaction Scheme 5. Under acidic conditions, (e.g. by heating in agueous acid) the hemiacetal 51 is cyclized to form the corresponding olefin derivative (Compound 52). The olefin derivative can then be reduced using the same conditions as described in connection with Reaction Scheme 3 for the reduction of Compound 49, or by a more general reducing procedure. The resulting chroman derivative is shown as Compound 24 in Reaction Scheme 5. It should be noted that up to this point in the synthetic sequence (which is preferably but not necessarily exclusively used for making the compounds of the invention) similar or analogous steps are involved for making both the thio-chroman (Reaction Scheme 3) and the chroman derivatives (Reaction scheme 5) the only difference being that in Reaction Scheme 5 the starting lactone does not have a halogen (such as a bromo substitu10 ent).
Referring to Reaction Scheme 6, in Compound 24 of that scheme the R4 and R5 substituents are alkyl but are not identical. The R4 and Rs alkyl substituents are introduced by treating Compound 51 with a different Grig15 nard reagent than previously used to form the tertiary alcohol (Compound 23). The tertiary alcohol 23 which already has the desired R1# R2, R3, R4 and Rs substituents, is ring closed under acidic conditions, as described above, to provide the chroman derivative (Compound 24).
In order to obtain the final acetylenic products where the R4 or Rs substituent is alkyl and the other is hydrogen, or where the R4 and Rs substituents are alkyl but not identical to one another, Compounds 14 and 24 are subjected to substantially the same reaction procedures as outlined in Reaction Scheme 1 and Reaction Scheme 2.
The following examples of specific compounds of the invention, and specific examples of the synthetic steps in which the compounds and certain intermediates are made, are set out to illustrate the invention, not to limit its scope.
Specific Examples Ethvl-4-iodobenzoate (Compound 29) To a suspension of 10 g (40.32 mmol) of 4-iodobenzoic acid in 100 ml absolute ethanol was added 2 ml thionyl chloride and the mixture was then heated at reflux for 3 hours. Solvent was removed in vacuo and the residue was dissolved in 100 ml ether. The ether solution was washed with saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was then removed in vacuo and the residue kugelrohr distilled (100 degrees C; 0.55 mm) to give the title compound as a colorless oil, PMR (CDC13): & 1.42 (3H, t, J'7 HZ), 4,4 (2H, q, J'7 Hz), 7.8 (4H).
In the same manner, but substituting for 4-iodobenzoic acid the appropriate acid, the following examples of compounds can be prepared: ethyl 4-iodophenylacetate; ethyl 3-(4-iodophenyl)propionate; ethyl 4-(4-iodophenyl)butanoate; and ethyl 5-(4-iodohenyl)pentanoate.
S-(4-bromopenvl) 3,3-dimethvlthioacrvlate (Compound 30) To an ice bath cooled solution of 1.92 g (80 mmol) of NaH (obtained from a 60% suspension in mineral oil by 3 x 15 ml hexane wash) in 30 ml of dry THF was added slowly under argon a solution of 15.1 g (80 mmol) of 4-bromothiophenol in 60 ml of dry THF over 1 h. The mixture was stirred at 0 degrees C for a further 30 min and then treated with a solution of 10.1 g (85 mmol) of dimethylacryloyl chloride in 30 ml of dry THF. The cooling bath was then removed and the mixture then stirred at room temperature for 40 h. The reaction mixture was poured into 200 ml of water containing 2 ml of glacial acetic acid and the organic layer was separated. The organic layer was washed with 2 x 75 ml of water and then dried (MgSO4). The solvent was removed in vacuo to give the title compound as a yellow oil. PMR (CDC13): & 1.91 (3H, s), 2.14 (3H, s), 6.03-6.06 (1H, m) , 7.28 (2H, d, J-8.6 Hz), 7.53 (2H, d, J-8.6 Hz). 4, 4-Dimethvl-6-bromo-2-oxo-thiochroman (Compound 31) To a stirred, ice-cooled suspension of 15.9 g (119 mmol) of aluminum chloride in 140 ml of methylene chloride 5 was added under nitrogen a solution of 21.64 g (79.9 mmol) of S-(4-bromophenyl) 3,3-dimethyl-thioacrylate (Compound ) in 100 ml of methylene chloride. The mixture was then stirred at room temperature for 72 h and then poured into 250 g of an ice and brine mixture. The mixture was ex10 tracted with methylene chloride and the combined organic extracts were washed with saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue recrystallized from hexanes to give the title compound as white crystals. PMR (CDC13): & 1.40 (6H, s), 2.67 (2H, s), 7.31-7.40 (3H, m). MS exact mass, m/e 269.9714 (calcd. for C11H11 SOBr, 269.9714). 4-Bromo-2-(1,1.3-trimethvl-3-hvdroxvbutyl1 thiophenol (Compound 32) To 3.49 g (32.8 mmol) of lithium perchlorate was added under argon 35 ml of 3.0M (105 mmol) methyl magnesium bromide in ether. The above mixture was treated dropwise with stirring with a solution of 2.961 g (10.926 mmol) of 4,4-dimethyl-6-bromo-2-oxo-thiochroman (Compound 31) and the reaction mixture was then heated at reflux for 70 h. The reaction mixture was then allowed to cool and poured onto a mixture of 100 g of ice and 8 ml of conc. H2SO4. The organic layer was separated and the aqueous layer was extracted with 2 x 25 ml of ether. The organic layers were combined and washed successively with 2 x 25 ml of saturated NaHCO3 solution, 25 ml of water and 25 ml of saturated NaCl solution and then dried (MgSO4). The solvent was removed in-vacuo and the residue purified by flash chromatography to give the title compound as a pale yellow oil. PMR (CDClg): & 1.05 (6H, s), 1.52 (6H, s), 2.30 (2H, s), 3.71 (IH, s), 7.22 (1H, dd, J-8.5 Hz, 2.1 Hz), 7.28 (IH, d, J-8.5 Hz), 7.35 (1H, d, J-2.1 Hz) Using ethyl magnesium bromide, instead of methyl 5 magnesium bromide, provides the corresponding 4-bromo-2(1,1 dimethyl 3-ethyl-3-hydroxypentyl)-thiophenol. 2.2.4.4- Tetramethvl-6-bromothiochroman (Compound 33) A mixture of 500 mg (1.49 mmol) of 4-bromo-2-(1,1,3trimethyl-3-hydroxybutyl) thiophenol (Compound 32) and 8 ml of 20 percent aqueous H2SO4 was heated at reflux for 24 h. The mixture was extracted with hexanes, the organic extracts were combined and washed successively with water, saturated NaHCOg, water again, saturated NaCl and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; hexanes) to give the title compound as a colorless oil. PMR (CDClg): & 1.35 (6H, s) , 1.40 (6H, s) , 1.93 (2H, s) , 7.17 (IH, dd, J-8.4 Hz, 2.1 Hz), 7.23 (IH, d, J-8.4 Hz), 7.26 (IH, d, J-2.1 Hz). MS exact mass, m/e 284.0221 (calcd. for CggHgy S Br, 284.0234) · 2.2.4.4- Tetramethvl-6-trimethvlsilvlethvnvl-thiochroman (Compound 34) A solution of 600 mg (2.11 mmol) of 2,2,4,4-tetramethyl-6-bromothiochroman (Compound 33) in 1.5 ml of triethylamine was placed in a heavy-walled tube and degassed and then treated under argon with 1.4 g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. The reaction mixture was degassed again, then placed under argon and the tube was sealed. The mixture was heated at 100 degrees C for 24 h, allowed to cool to room temperature and then treated with a further 1.4 g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was then degassed, placed under argon and then heated in the sealed tube at 100 degrees C for 96 h. The mixture was cooled to room temperature and extracted with 3 x 10 ml of ether. The organic extracts were combined, washed successively with 25 ml of water and 25 ml of saturated sodium chloride solution and then dried (MgSO4).
The solvent was removed in vacuo and the residue purified by flash chromatography (silica; hexanes followed by 3% ethyl acetate in hexanes) to give the title compound as a yellow, crystalline solid. PMR (CDC13): & 0.23 (9H, s), 1.36 (6H, s), 1.39 (6H, s), 1.94 (2H, s), 7.17 (IH, dd, J-8.2 HZ, 1.8 HZ), 7.25 (IH, d, J-1.8 Hz), 7.30 (IH, d, J-8.2 Hz). MS exact mass, m/1 302.1519 (calcd. for S Si, 382.1524). 2,2,4,4-Tetramethvl-6-ethvnvlthiochroman (Compound 35) To a solution of 527.6 mg (1.75 mmol) of 2,2,4,42o tetramethyl-6-trimethylsilylethynylthiochroman (Compound 34) in 4 ml of isopropanol was added, under argon, 4 ml of IN KOH solution. The reaction mixture was stirred at room temperature for 20 h and the isopropanol was then removed under vacuum. The residue was extracted with ether and the combined ether extracts were washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo to give the title compound as a yellow oil. PMR (CDC13): & 1.34 (6H, s), 1.37 (6H, s), 1.91 (2H, s), 2.99 (IH, s), 7.17 (IH, dd, J-8.1 30 Hz, 1.8 Hz), 7.26 (IH, d, J-1.8 Hz), 7.30 (IH, d, J-8.1 Hz). MS exact mass, m/e 230.1122 (calcd. for C15H18S, 230.1129) Ethvl 4-Γ(2,2.4,4-tetramethvl-thlochroman-6-vl)-ethvnvl] benzoate (Compound 1) A solution of 110.7 mg (0.481 mmol) of 2,2,4,4tetramethyl-6-ethynylthiochroman (Compound 35) and 142.3 mg (0.516 mmol) of ethyl 4-iodobenzoate (Compound 29) in 2 ml of triethylamine was placed in a heavy walled glass tube and degassed under argon. The mixture was then treated with a finely ground mixture of 42 mg (0.221 mmol) of cuprous iodide and 63 mg (0.09 mmol) of bis (triphenylphosphine) palladium (II) chloride. The reaction mixture was degassed under argon again and the tube was sealed.
The mixture was stirred at room temperatures for 40 hours. The triethylamine was removed under vacuum and the residue purified by flash chromatography (silica, 3% ethyl acetate in hexanes) to give the title compound as a pale yellow solid. PMR (CDC13) 1 : & 1.37- •1.42 (15H, m), 1.96 (2H, s), 4.38 (2H, q, J-7.0 Hz) , 7.25 (1H, dd, J-8.2 Hz, 1.8 Hz), 7.33 (1H, d, J-1.8 HZ) , 7.37 (1H, d, J-8.2 Hz), 7.65 (2H, d, J-8.6 Hz) , 8.01 (2H, d, J- 8.6 Hz). MS exact mass, m/e 378.1636 (calcd. for C24H26O2S, 378.165.3).
Using the method for the preparation of Compound 1, but substituting the appropriate ethynylthiochroman (Compound 16 in Reaction Scheme 1) and the appropriate halo substituted phenyl ester (Formula 3, prepared for example as specifically described for Compound 29) the following compounds of the invention may be prepared: ethyl 4-((2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl]benzoate; ethyl 4-((2,2,4,4-tetramethyl-7-ethylthiochroman-6yl)-ethynyl]benzoate ? ethyl 4-((2,2,4,4-tetramethyl-7-propylthiochroman-6yl)-ethynyl]benzoate; ethyl 4-((2,2,4,4-tetramethyl-7-hexylthiochroman-6yl)-ethynylJ benzoate; ethyl 2-(4-((2,2,4,4-tetramethylthiochroman-6yl)ethynyl)-phenyl]acetate; ethyl 2-((4-(2,2,4,4,7-pentamethylthiochroraan-6y1)ethynyl)-phenyl]acetate; ethyl 2-[4(2,2,4,4-tetramethyl-7-ethylthiochroman-6y1)-ethynyl) phenyl]acetate; ethyl 2-(4(2,2,4,4-tetramethyl-7-hexylthiochroman-6y1)-ethynyl) phenyl]acetate; ethyl 3-(4-(2,2,4,4-tetramethylthiochroman-2-yl)10 ethynyl)phenyl]propionate; ethyl 3-(4-(2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl) phenyl]propionate; ethyl 3-(4-2(2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl)15 ethynyl)phenyl]propionate; ethyl 3-(4-(2,2,4,4-tetramethyl-7-hexylthiochroman-6yl)-ethynyl)phenylJpropionate; ethyl 5-(4-(2,2,4,4-tetramethylthiochroman-6yl)ethynyl)20 phenyl]pentanoate; ethyl 5-(4-(2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl) phenyl]pentanoate; ethyl 5-(4-(2,2,4,4-tetramethyl-7-ethylthiochroman-6y1)-ethynyl) phenyl]pentanoate; The positional isomers of the above-noted examples (and of analogous compounds) can also be prepared in accordance with the foregoing procedures or by apparent modifications of such procedures.
Phenyl 3.3-dimethvlacrvlate (Compound 37) To an ice bath cooled solution of 1.29 g (54 mmol) of NaH (obtained from a 60% suspension in mineral oil by 3x10 ml hexane wash) in 20 ml of dry THF was added slowly under oxygen a solution of 5 g (53 mmol) of phenol in 50 ml of dry THF. The mixture was then treated with a solution of 7 g (59 mmol) of dimethylacryloyl chloride in 30 ml of dry THF. The cooling bath was then removed and the mixture was stirred for a further 2.5 h. The reaction mixture was then poured into 150 ml of water containing 1 ml of glacial acetic acid. The mixture was extracted with 150 ml ether and the ether extract washed with saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography χθ (silica; 5% ether in hexanes) to give the title compound as a yellow oil. PMR (CDC13)): & 1.99 (3H, s), 2.24 (3H, s) , 5.93 (1H, broad s), 7.10 (2H, d, J-7.8 Hz) 7.22 (1H, t, J-7.8 Hz), 7.38 (2H, t, J-7.8 Hz). 4,4-Dimethvl-2-oxo-chroman (Compound 38) To a stirred, ice-cooled suspension of 10.4 g (78 mmol) of aluminum chloride in 160 ml of methylene chloride was added slowly under argon a solution of 7 g (39.8 mmol) of phenyl 3,3-dimethylacrylate (Compound 37) in 40 ml of methylene chloride. The cooling bath was removed and the 2q mixture stirred for a further 42 h. The mixture was poured into a mixture of ice and brine and the organic layer separated. The aqueous layer was extracted with methylene chloride and the organic extracts were combined and washed with saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 10% ether in hexane) to give the title compound as a colorless oil.
PMR (CDC13: & 1.30 (6H, s), 2.56 (2H, s), 7.06 (1H, dd, J-8.0 Hz, 1.4 HZ), 7.16 (1H, td, J-8.0 Hz, 1.4 Hz), 7.26 30 (1H, td, J-8.0 HZ, 1.7 Hz), 7.33 (1H, dd, J-8.0 Hz, 1.7 Hz). MS exact mass, m/e 176.0852 (calcd. for cnHi2°2' 176.0837. 2-(1.1.3-Trimethyl-3-hvdroxvbutvl)phenol (Compound 39) To 11 ml of 3.0 M (33 mmol) methyl magnesium chloride in THF, cooled in an ice bath, was added, under nitrogen, a solution of 1.96 g (11.1 mmol) of 4,4-dimethyl-2-oxo5 chroman (Compound 38) in 35 ml of dry ether. The cooling bath was then removed and the mixture stirred at room temperature for 72 h. The reaction mixture was then poured onto a mixture of 100 g of ice and 3 ml of cone. H2SO4 and stirred until the magnesium salts were dis10 solved. The organic layer was separated and the aqueous layer extracted with 2x50 ml of ether. The organic layers were combined and washed successively with water, saturated NaHCO3 and saturated NaCl solutions and then dried (MgSO4). The solvent was removed in vacuo and the residue 15 was purified by flash chromatography (silica; 20% ethyl acetate in hexanes) to give the title compound as a pale yellow solid. PMR (CDC13): & 1.13 (6H, s) , 1.48 (6H, s) , 1.89 (1H, s) , 2.23 (2H, s) , 6.60 (1H, dd, J-7.9 Hz, 1.4 Hz), 6.83 (1H, s), 6.84 (1H, 2o td, J-7.9 Hz, 1.4 Hz), 7.07 (1H, td, J-7.9 Hz, 1.6 Hz), 7.31 (1H, dd, J-7.9 Hz, 1.6 Hz). MS exact mass, m/e 208.1458 (calcd. for C13H20O2, 208.1464). 2,2.4.4-Tetramethvl-chroman (Compound 40) A mixture of 2.98 g (14.3 mmol) of 2-(1,1,3-trimeth25 yl~3-hydroxybutyl) phenol (Compound 39) and 40 ml of 20% aqueous H2SO4 was heated at reflux, under nitrogen, for 4 h. The mixture was stirred at room temperature for a further 72 h and then diluted with 50 ml of water. The mixture was extracted with 3x20 ml of hexanes. The organ30 ic extracts were then combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was then removed in vacuo to give the title compound as a colorless oil. PMR (CDC13): & 1.36 (6H, s), 1.37 (6H, s), 1.83 (2H, s) , 6.71 (1H, dd, J-8.2 HZ, 1.5 Hz) 6.92 (1H, td, J-8.2 Hz, 1.5 Hz), 7.09 (1H, td, J-8.2 Hz, 1.5 Hz), 7.29 (1H, dd, J-8.2 Hz, 1.5 Hz) . 2,2,4.4-Tetramethvl-6-acetvl-chroman (compound 41) To an ice bath cooled solution of 2 g (10.53 mmol) of 2,2,4,4-tetramethylchroman (Compound 40) in 25 ml of nitromethane was added, under nitrogen, 941 mg (11.99 mmol) of acetyl chloride followed by 1.59 g (11.92) mmol) of aluminum chloride. The cooling bath was then removed and the mixture stirred at room temperature for 16 h. The mixture was then cooled again in an ice bath and treated with 25 ml of conc. HCl. The mixture was then filtered and the residue washed with methylene chloride. The filtrate was concentrated in vacuo and the resultant residue was purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a yellow oil. PMR (CDC13): & 1.38 (6H, s) , 1.39 (6H, S) , 1.87 (2H, s) , 2.56 (3H, s), 6.83 (1H, d, J-8.7 HZ), 7.71 20 (1H, dd, J-8 .7 HZ, 2.1 HZ), 7.98 (1H, d, J-2.1 HZ) . MS exact mass, m/e 232.1468 (calcd. for C13H20°2' 232. 1464). 2,2.4.4-Tetramethvl-6-ethvnyl-chroman (Compound 42) To a cooled (-78 degrees C) solution of 522 mg (5.17 mmol) of diisopropylamine in 8 ml of dry THF was added slowly, under nitrogen, 3.23 ml of 1.6 M (5.17 mmol) nbutyl lithium in hexane. The mixture was stirred at - 78 degrees C. for 40 minutes and then treated with a solution of 1.24 g (5.17 mmol) of 2,2,4,4-tetramethyl-6-acetylchroman (Compound 41) in 2 ml of dry THF. The mixture was stirred at - 78 degrees C for a further 1 h and then treated with 895 mg (5.19 mmol) of diethylchlorophosphate. The reaction mixture was allowed to warm to room temperature and transferred by double-ended needle into a soluIE 913569 tion of lithium diisopropylamide in THF at -78 degrees C [prepared as described above from 1.04 g (10.34 mmol of diisopropylamine and 6.46 ml of 1.6 M (10.34 mmol) of nbutyl lithium in hexane]. The cooling bath was removed and the mixture was stirred at room temperature for 16 h. The mixture was then treated with 10 ml of ice water and acidified to a pH of 2 with 10% HCl. The organic layer was separated and the aqueous layer was extracted with 3x30 ml of pentane. The organic extracts were combined and washed successively with 2x30 ml of dilute HCl, water, 3x30 ml of saturated NaHCO3 solution and saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (silica; 2% ethyl acetate in hexane) to give the title compound as a pale yellow oil. PMR (CDC13): & 1.31 (6H, s) , 1.32 (6H, s), 1.50 (2H, s), 3.00 (1H, s) , 6.72 (1H, d, J-8.4 Hz), 7.20 (1H, dd, J-8.4 Hz, 2.1 Hz), 7.42 (1H, d, J-2.1 Hz). MS exact mass, m/e 2.14.1251 (calcd. for C15H18O, 214.1357) Ethyl 4-((2,2,4,4-tetramethvlchroman-6-vl-ethvnvl1 benzoate Compound 3) A solution of 233 mg (1.088 mmol) of 2,2,4,4-tetramethyl-6-ethynyl-chroman (Compound 42) and 308 mg (1.087 mmol) of ethyl 4-iodo-benzoate (Compound 29) in 1 ml of triethylamine was placed in a heavy-walled tube and degassed under argon. The mixture was treated with a finely ground mixture of 50 mg (0.263 mmol) of cuprous iodide and 100 mg (0.142 mmol) of bis (triphenylphosphine) palladium (II) chloride and the tube was then sealed. The reaction 30 mixture was then heated at 55 degrees C for 48 hours. The triethylamine was removed in vacuo and the residue was purified by flash chromatography (silica, 5% ethyl acetate in hexans) to give the title compound as yellow oil. PMR (CDClg) : & 1.33 (6H, s) , 1.34 (6H, s) , 1.37 (3H, t, J-7.2 HZ), 1.83 (2H, S), 4.35 (2H, q, J-7.2 Hz), 6.75 (IH, d, J-8.4 Hz), 7.24 (IH, dd, J-8.4 Hz, 2.1 Hz), 7.46 (IH, d, J-2.1 Hz), 7.54 (2H, d, J-8.1 Hz), 7.99 (2H, d, J-8.1 Hz) MS exact mass, m/e 362.1880 (calcd. for C24H26°3' 362.1881). 3-Methvl-phenvl-3.3-dimethvlacrvlate (Compound 44) A 60% suspension of sodium hydride (3.22 g; 81 mmol) in mineral oil was washed with 3x10 ml of hexane and then jg treated with 30 ml of dry THF. This mixture was cooled in an ice-bath and then treated with a solution of 8.6 g (79.5 mmol) of m-cresol in 80 ml of dry THF. The reaction mixture was stirred for 10 min and then treated with a solution of 10.5 g (88.5 mmol) of dimethylacryloyl chlo15 ride in 40 ml of dry THF. The reaction mixture was stirred at room temperature for 96 h and then poured into a mixture of 150 ml of water and 1 ml of glacial acetic acid. The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with 20 2x50 ml of ether. The organic layers were combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a pale yellow oil. PMR (CDClg): & 1.95 (3H, d, J-1.3 HZ), 2.21 (3H, d, J-1.2 Hz), 2.34 (3H, S), 5.90 (IH, broad S), 6.86 - 6.93 (2H, m), 7.01 (IH, d, J-7.2 HZ), 7.24 (IH, t, J-7.2 Hz). 2-(1,1,3-Trimethy1-3-hydroxybutyl·) 5-methvl-phenol (Com39 pound 45) To an ice-bath cooled suspension of 13 g (97.5 mmol) of aluminum chloride in 200 ml of methylene chloride was added dropwise under argon a solution of 9.0 g (47.4 mmol) of 3-methyl-phenyl-3,3-dimethylacrylate (Compound 44) in 100 ml of methylene chloride. The reaction mixture was stirred at 0 degrees C for a further 30 min and then at room temperature for 15 h. The reaction mixture was poured into 200 ml of an ice water/salt mixture and the organic layer was separated. The aqueous layer was extracted with 50 ml of ether. The organic layers were combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was 10 removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexane) to give an approximately 2.5:1 mixture of isomeric products, 4,4,7trimethyl-2-oxo-chroman and 4,4,5-trimethyl-2-oxo-chroraan as a pale yellow oil. To a solution of 3.8 g (20 mmol) of this mixture of isomeric 2-oxo-chromans in 60 ml of ether at 0 degrees C was added under argon 20 ml of 3.0 M (60 mmol) of methyl magnesium bromide in ether. The reaction mixture was stirred at room temperature for 48 h and then poured onto a mixture of ice and 1 ml of cone. H2SO4. The 2o organic layer was separated and the aqueous layer extracted with 2x50 ml of ether. The organic layers were combined and washed successively with water, saturated NaHC03 solution, water again and then saturated NcCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (silica; 15 % ethyl acetate in hexanes) to give the title compound as a colorless oil. PMR (CDC13): & 1.14 (6H, s), 1.45 (6H, s), 2.19 (3H, s), 2.21 (2H, s), 6.39 (IH, d, J-1.8 HZ), 6.67 (IH, dd, J-7.9 Hz, 1.8 Hz), 7.16 (IH, d, J-7.9 30 HZ), 7.44 (IH, s) . 2.2,4,4,7-Pentamethvl-chroman (Compound 46) To 2.16 g (11.7 mmol) of 2-(1,1,3-trimethyl-3hydroxybutyl) 5-methyl-phenol (Compound 45) was added under nitrogen 50 ml of 20% aqueous sulfuric acid. The reaction mixture was heated at reflux for 13 h and then cooled. The organic layer was separated and the aqueous layer was extracted with ether. The organic extracts were combined and washed successively with water, saturated NaHCOg solution, water again and saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo to give the title compound as a yellow oil. PMR (CDC13): & 1.32 (6H, s), 1.34 (6H, s), 1.81 (2H, s) , 2.26 (3H, s) , 6.63 (1H, s), 6.72 (1H, d, J-7.9 Hz), 7.15 (1H, d, J-7.9 HZ) . 2.2.4.4.7- Pentamethvl-6-acetvl-chroman (Compound 47) To an ice-bath cooled solution of 1.96 g (9.6 mmol) of 2,2,4,4,7-pentamethyl-chroman (Compound 46) in 30 ml of nitromethane was added under argon 1.059 g (13.5 mmol) of acetyl chloride followed by 1.9 g (14.3 mmol) of aluminum chloride. The reaction mixture was stirred at room temperature for 14 h and then cooled in an ice-bath and treated with 25 ml of cone. HCl. The mixture was warmed 2o to room temperature and diluted with ether and water. The organic layer was separated and the aqueous layer extracted with ether. The organic extracts were combined and washed successively with water, saturated NaHCO3 solution, water again, and saturated NaCl solution, and then dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (silica; 5% ethyl acetate in hexanes) to give the title compound as a pale yellow oil. PMR (CDC13): & 1.36 (6H, s), 1.37 (6H, s), 1.86 (2H, S), 2.49 (3H, s), 2.56 (3H, s), 6.65 (1H, s), 7.74 (1H, s). 2.2.4.4.7- Pentamethvl-6-ethynyl-chroman (Compound 48) To a solution of 455 mg (4.5 mmol) of disopropylamine in 5 ml of dry THF at -78 degrees C was added under argon ml of 1.5 M n-BuLi in hexane. The mixture was stirred at -78 degrees C for a further 45 min and then treated with a solution of 1.07 g (4.3 mmol) of 2,2,4,4,7-pentamethyl-6-acetyl-chroman (Compound 47) in 4 ml of dry THF.
The reaction mixture was stirred at -78 degrees C for 1 h and then treated with 776 mg (4.5 mmol) of diethyl chlorophosphate. The mixture was allowed to warm to room temperature and then transferred by a double-ended needle into a solution of lithium diisopropyl amide in 10 ml dry THF at -78 degrees C which was prepared as described above using 910 mg (9.0 mmol) of diisopropylamine and 6 ml of 1.5 M (9.0 mmol) n-BuLi in hexane. The mixture was stirred at room temperature for 15 h and then poured into 10 ml of iced water. The mixture was acidified to pH=2 with 10% HCl solution. The organic layer was separated and the aqueous layer extracted with pentane. The organic extracts were combined and washed successively with water, saturated NaHCO3 and saturated NaCl solutions and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by Kugelrohr distillation (82 degrees C, 0.3 mm) to give the title compound as a pale yellow oil. PMR (CDC13): & 1.32 (6H, s), 1.34 (6H, s), 1.81 (2H, s) , 2.36 (3H, S) , 3.18 (1H, s), 6.64 (1H, s), 7.40 1H (s) . MS exact mass, m/e 228.1520 (calcd. for C16H2qO, 228.1514).
Ethvl 4-Γ (2,2,4,4.7-pentamethvlchroman-6- vl)-ethvr>vn benzoate (Compound 7) Nitrogen was bubbled for 15 min through a solution of 200 mg. (0.877 mmol) of 2,2,4,4,7-pentamethyl-6-ethynylchroman (Compound 48) and 245.3 mg (0.888 mmol) of ethyl 4-iodobenzoate (Compound 29) in 2 ml of triethylamine.
The mixture was then placed under an argon atmosphere and treated with a finely ground mixture of 50 mg (0.2625 mmol) of cuprous iodide and 100 mg (0.1425 mmol) of bis(triphenylphosphine) palladium (II) chloride. The reaction vessel was then fitted with a reflux condenser and the mixture was heated at 55 degrees C under argon for 72 hours. The triethylamine was then removed under vacuum and the residue purified by flash chromatography (silica, 5% ethyl acetate in hexane) to give the title compound as a yellow oil. PMR (CDC13) : & 1.32 (12H, s), 1.37 (3H, t, J-7.0 Hz), 1.80 (2H, s) 2.40 (3H, s), 4.36 (2H, q, J-7.0 Hz), 6.66 (1H, s, 7.42 (1H, s), 7.54 (2H, d, J-8.6 Hz), 7.99 (2H, d, J-8.6 Hz). MS exact mass, m/e 376.2 038 (calcd. for C25H28O3, 376.2038). 2, 4,4-Trimethvl-6-Bromo-2-Hvdroxy-thiochroman. (Compound 49) To a solution of 68g (182.5 mmol) of cerium chloride 15 (dried on a high vacuum line at 135 degrees C for four days) in 160 ml THF and 62 ml of 3M (186 mmol) methyl magnesium bromide in ether was added to a solution of 5g (18.45 mmol) of 4-4 dimethyl-6-bromo-2-oxo-thiochroman and 20ml of dry THF at -14 degrees C. The mixture was stirred for 0.5 hours and then poured onto 300 ml of ice/water mixture containing 10 ml of concentrated sulfuric acid.
The layers were separated and the aqueous layer was extracted with 100 ml of ether. The organic layers were combined and washed with 2X250 ml of water, 1 X 100 ml of saturated sodium chloride solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica: 10% EtOAc/Hexanes) to give the title compound as a yellow oil. PMR (CDC13): & 1.35(3H, S) 1.47(3H, S), 1.71(3H, s), 2.09-2.18 (AB dou30 blet), 2.42 (1H, s), 7.17 - 7.24 (2H, m), 7.27 (1H, d, J = 8.1 Hz). 2,4,4, Trimethvl-6-Bromo-(4H)-1-benzothiopvran (Compound 50) A mixture of 2.03g (7.1 mmol) of 2,4,4-trimethyl-6bromo-2-hydroxy thiochroman (Compound 49) and 20 ml of 20% aqueous sulfuric acid was heated at reflux for 4 hours.
The mixture was extracted with ether. The combined organ5 ic extracts were washed with 2 X 25 ml H20 and 1 X 25 ml of saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; hexanes) to give the title compound as a colorless oil. PMR (CDC13): & 1.34 (6H, s), 2.00(3H, d, J = 1.4Hz), 5.45(1H, d, J = 1.4Hz), 7.19-7.38 (3H, m). 2.4,4-trimethvl-6-bromo-thiochroman (Compound 53) A solution of 500 mg (1.9 mmol) of 2,4,4-trimethyl-6bromo-(4H)-1-benzothiopyran (Compound 50) in 5 ml of ethyl 15 acetate was treated with 500 mg of 10% palladium sulfide on carbon and then shaken under an atmosphere (30 psi) of hydrogen in a Parr apparatus for 24 hours. The mixture was filtered through celite and the solvent was removed in-vacuo. The residue was purified by flash chromatogra20 Phy (silica; hexanes) to give the title compound as a colorless oil. PMR (CDC13): & 1.21 (3H, s), 1.33 (3H, d, J = 6.6Hz), 1.36 (3H, s), 1.64-1.89 (2H, m), 3.37-3.50 (1H, m) , 7.10 (1H, dd, J = 8.4 Hz, 2.1Hz), 7.19 (1H, d, 8.4 HZ), 7.20 (1H, d, 2.1 Hz) 2,4,4-trimethyl-6-trimethvlsilvl-ethvnvl-thiochroman (Compound 54) A solution of 201 mg (74 mmol) of 2,4,4-trimethyl-6bromo-thiochroman (Compound 53) in 1 ml of distilled triethylamine was placed in a heavy walled tube and de30 gassed. The mixture was then treated under argon with 0.53 ml (3.72 mmol) of trimethylsilylacetylene and a powdered mixture of 52 mg (0.074 mmol) of bis-triphenylhosphine palladium (II) chloride and 28 mg (0.15 mmol) of cuprous idodide. The reaction mixture was placed under argon and the tube was sealed. The mixture was heated at 55 degrees C for 72 hours. The mixture was cooled to room temperature and filtered through celite and the residue washed with CH2C12. The filtrate was concentrated invacuo and the residue was purified by flash chromatography (silica; hexanes) to give the title compound as a yellow oil. PMR (CDCl-j) : & 0.24 (9H, s) , 1.22 (3H, s) , 1.33 (3H, d, J = 6.6 HZ), 1.37 (3H, s), 1.71 (1H, t, J - 13.0 Hz) 1.86 (1H, dd, J - 13.0 Hz, 3.0 Hz) 3.38 - 3.50 (1H, m), 7.07 (1H, dd, J = 8.1 HZ, 1.8Hz), 7.18 (1H, d, J = 1.8 Hz), 7.26 (1H, d, J = 8.1 Hz) 2.4,4-trimethvl-6-ethvnvl-thiochroman (Compound 55) To a solution of 186 mg (0.647 mmol) of 2,4,4-tri15 methyl-6-trimethylsilyl ethynyl thiochroman (Compound 54) was added 11 ml of ethanolic KOH solution. The reaction mixture was stirred at room temperature for 16 hours. The ethanol was then removed in-vacuo and the residue was extracted with ether. The ether extracts were combined and washed with water and saturated sodium chloride solution and then dried (MgSO4). The solvent was removed invacuo and the residue purified by Kugelrohr distillation to give the title compound as a colorless oil. PMR (CDC13): & 1.21 (3H, s), 1.32 (3H, d, J = 6 Hz), 1.40 (3H, s,) 1.70 (1H, t, J - 13.0 Hz), 1.88 (1H, dd, J - 13.0 Hz, 3.0 Hz), 3.0 (1H, s, ), 3.39-3.51 (1H, m), 7.13 (1H, dd, J = 9.1 Hz,. 2.1 HZ), 7.21 (1H, d, J - 2.1 Hz) 7.28 (1H, d, J - 9.0 Hz).
Ethyl-4Γ f2.4,4-trimethyl-6-thiochromanvl)-ethvnvll benzo30 ate (Compound 56) A solution of 55 mg (0.26 mmol) of 2,4,4-trimethyl-6ethynyl-thiochroman (Compund 55) and 70.5 mg (0.26 mmol) of ethyl 4-iodo benzoate (29) in 1.5 ml of distilled triethylamine was placed in a heavy walled tube. Argon was bubbled through the mixture for 20 minutes under slightly reduced pressure. To the mixture was added 18 mg (0.051 mmol) of bis triphenylphosphine palladium (II) chloride and 9.7 mg (0.051 mmol) of cuprous iodide. The tube was then sealed and the mixture was stirred at 55 degrees C for 72 hours. The mixture was then cooled to room temperature. The reaction mixture was diluted wth CH2C12 and treated with a small amount of silica. The solvent was then removed in-vacuo and the residue was subjected to flash chromatography (silica; 1.5% EtOAc/Hexanes) to give the title compound as a white crystalline solid. PMR(CdCl3): 1.25 (3H, s) , 1.35 (3H, d, J = 6.6 Hz), 1.37-1.44 (6H, m), 1.75 (1H, t, J = 13 Hz), 1.88 (1H, dd, J = 13 Hz, 3.5 Hz), 3.40-3.50 (1H, m), 4.38 (2H, q, J = 7Hz), 7.17 (1H, dd, J = 8.1 Hz, 1.8 Hz), 7.26 (1H, d, J = 1.5 Hz), 7.33 (1H, J = 8.1 Hz), 7.55 (2H, d, J = 8.4 Hz, 8.01 (2H, d, J = 8.4 Hz). 4-(2,4,4-trimethvl-6-thiochromanvl)-ethynyl benzoic acid (Compound 57) A mixture of 37 mg (0.102 mmol) of ethyl 4(2,4,4trimethyl-6-thiochromanyl)-ethynyl)benzoate (Compound 56) and 11 ml of ethanolic potassium hydroxide solution was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was taken up with water and then acidified with IN HCl. The mixture was extracted with three portions of ether. The organic extracts were combined and then washed with water and saturated NaCl solution and dried (MgSO4). The solvent was removed ip30 vacuo to give the title compound as an orange solid. PMR (CDC13): 1.17 (3H, s), 1.26 (3H, d, J = 6.3 Hz), 1.34 (3H, s), 1.58 (1H, t, J = 13.1 Hz), 1.92 (1H, dd, J = 13.1 Hz, 2.4 Hz), 3.33-3.48 (1H, m), 7.20 (1H, d, J = 8.1 Hz), 7.21 (IH, s), 7.45 (1H, d, J = 8.1 Hz) , 7.62 (2H, d, 8.4 Hz), 7.95 (2H, d, J = 8.4 Hz).
Following the procedures set forth above, with such modificiation and/or application of standard synthetic organic procedures which will be readily apparent to a synthetic organic chemist of ordinary skill, in light of the present disclosure, the following further examples of compounds can be prepared: 2.2.4.4- tetramethyl-6-acetyl-7-ethylchroman; 2,2,4,4-tetramethyl-6-acetyl-7-propylchroman; 2.2.4.4- tetramethyl-6-acetyl-7-butylchroman; 2.2.4.4- tetramethyl-6-acetyl-7-pentylchroman; 2,2,4, 4-tetramethyl-6-acetyl-7-hexylchroman; 2,2-diethyl-4,4-dimethyl-6-acetyl-chroman; 2,2-diethyl,-4,4,7-trimethyl-6-acetyl-chroman; ethyl 4-[(2,2,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl]benzoate; ethyl 4-((2,2,4,4-tetramethyl-7-propylchroman-6-yl)ethynyl]benzoate; ethyl 4-[(2,2,4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl]benzoate; ethyl [2-(4-(2,2,4,4-tetramethylchroman-6-yl)ethynyl)phenyl]acetate; ethyl [2-(4-(2,2,4,4,7-pentamethylchroman-6-yl)ethynyl )-phenyl]acetate; ethyl [2-(4-(2,2,4,4-tetramethyl-7-ethylchroman-6-yl) ethynyl) phenyl]acetate; ethyl [2-(4-(2,2,4,4-tetramethyl-7-hexylchroman-6-yl) ethynyl) phenyl]acetate; ethyl 3-[4-((2,2,4,4-tetramethylchroman-2-y1) IE 913569 ethynyl) phenyl]propionate; ethyl 3-[4-((2,2,4,4,7-pentamethylchroman-6-yl)ethynyl)-phenyl]propionate; ethyl 3-[4-(2,2,4,4-tetramethyl-7-ethylchroman-6-yl)5 ethynyl)phenyl]propionate; ethyl 3-[4-(2,2,4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl)phenylpropionate; ethyl -[4-((2,2,4,4-tetramethylchroman-6-yl)ethynyl)10 phenyl]pentanoate; ethyl 5-[4-((2,2,4,4,7-pentamethylchroman-6-yl)ethynyl) phenyl]pentanoate; ethyl -(4-((2,2,4,4-tetramethyl-7-ethylchroman-6-yl) 15 ethynyl)phenyl]pentanoate; ethyl 5-(4-((2,2,4,4-tetramethylchroman-6-yl-ethynyl) phenyl]pentanoate; ethyl 4-(2,2-diethyl-4,4-dimethylchroman-6-yl)ethynyl]benzoate; and ethyl 4-(2,2-diethyl-4,4,7-trimethylchroman-6-yl)ethynyl]benzoate.
The positional isomers of the above-listed examples can also be prepared in accordance with the foregoing procedures or by such modifications thereof which will be readily apparent to the practicing chemist in light of the foregoing disclosure.
Examples of Formulation for Topical Administration Preferably the compounds of the invention may be administered topically using various formulations. Such formulations may be as follows: Ingredient Weight/Percent Solution Retinoid (active ingredient) 0.1 ΒΗΤ Ο .1 Alcohol USP 58.0 Polyesthylene Glycol 400 NF 41.8 Gel Retinoid (active ingredient) 0.1 BHT 0.1 Alcohol USP 97.8 Hydroxypropyl Cellulose 2.0
Claims (41)
1. A compound of the formula 10 where X is S or 0; R l' r 2 an ^ r 3 independently are hydrogen or lower alkyl; R 4 and Rg are hydrogen or lower alkyl with the proviso 15 (i) that R 4 and Rg both are not hydrogen (ii) that R 4 and Rg are not identical with one another n is an integer from 0-5; R 6 is hydrogen, lower alkyl, lower alkenyl or 20 lower cycloalkyl having 1 to 6 carbons, or halogen; B is hydrogen, COOH or a pharmaceutically acceptable salt, ester or amide thereof, - CH 2 OH or an ether or ester derivative thereof, or CHO or an acetal derivative thereof or -COR” or a ketal derivative thereof where 25 R is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons.
2. A compound of Claim 1 where X is S.
3. A compound of Claim 2 where n is 0, 1, or 2.
4. A compound of Claim 3 where n is 0.
5. A compound of Claim 3 where B is COOH or a pharmaceutically acceptable salt, ester or amide thereof.
6. A compound of Claim 3 where R 3 is hydrogen or methyl.
7. A compound of Claim 2 where R 4 is H.
8. A compound of Claim 1 where X is 0.
9. A compound of Claim 8 where the phenyl ring is disubstituted in the 1, 4 positions and n is 0, 1, or 2.
10. A compound of Claim 9 where n is 0.
11. A compound of Claim 9 where B is COOH or a pharmaceutically acceptable salt, ester or amide thereof.
12. A compound of Claim 9 where R 3 is hydrogen or methyl.
13. A compound of Claim 9 where R 4 is H.
14. One or more compounds set forth in Claim 1, comprised in and admixed with a pharmaceutical composition including a pharmaceutically acceptable excipient.
15. One or more compounds set forth in claim 1, comprised in and admixed with a pharmaceutical composition as set forth in Claim -14, said composition being useful for treating skin disorders in a mammal.
16. A compound of Claim 2 where R 4 is lower alkyl and R 5 is lower alkyl, and R 4 and Rj are different.
17. A compound of Claim 8 where R 4 is lower alkyl and R g is lower alkyl, and R 4 and Rj are different.
18. A compound of the formula R, where R x , R 2 , and R 3 independently are hydrogen or lower alkyl; R 4 and R 5 are hydrogen or lower alkyl with the provisos 10 (i) that R 4 and R g both are not hydrogen (ii) that R 4 and R 5 are not identical with one another. n is an integer between 0 to 5, and B is COOH or 15 a pharmaceutically acceptable salt, ester or amide thereof, -CH 2 0H or an ether or ester derivative thereof, or CHO or an acetal derivative thereof, or COR· or a ketal derivative thereof, where R” is an alkyl, cycloalkyl or alkenyl grop having 1-5 carbons.
19. A compound of Claim 18 wherein n is 0.
20. A compound of Claim 19 where B is COOH or a pharmaceutically acceptable salt or an ester derrivative thereof.
21. A compound of Claim 19 where R x , R 2 , are methyl, R 4 is hydrogen and Rg is methyl.
22. A compound of Claim 21 where R 3 is H or CH 3 .
23. A compound of Claim 21 where B is COOH or a pharmaceutically acceptable salt thereof.
24. The compound of Claim 23 where R 3 is H or a pharmaceutically acceptable salt thereof.
25. The compounds of Claim 21 where B is COOC 2 H 5 .
26. The compound of Claim 25 where R 3 is H. where X is S or 0; R l' r 2 an ^ r 3 are independently hydrogen or lower alkyl; R 4 is lower alkyl; 1° R 6 is hydrogen, lower alkyl, lower alkenyl or lower cycloalkyl having 1 to 6 carbons or halogen; n is an integer from 0 to 5; B is hydrogen, COOH or a pharmaceutically acceptable salt, ester or amide thereof, -CH 2 OH or an ether or ester 15 derivative thereof, or CHO or an acetal derivative thereof, or -COR” or a ketal derivative thereof where R” is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, the process comprising the steps of: reacting a compound of formula (ii) 25 where R^, R 2 and R 3 are defined as above, and Y is halogen when X is S and Y is hydrogen when X is 0, with a Grignard reagent having the formula R 4 -Mg-X* where X’ is halogen, to obtain a compound of formula (iii) 35 where R^, R 2 , R 3 , R 4 , X and Y are defined as above; converting the compound of formula (iii) to a compound of formula (iv) where R^, R 2 , R 3 , R 4 , X and Y are defined as above; 45 saturating the compound of formula (iv) to provide a compound of formula (v) where R 1# R 2 , R 3 , R 4 , X and Y are defined as above; converting the compound of formula (v) into the 55 compound of formula (i), said steps of converting (v) into (i) including a step of reacting a compound of formula (vi) where R x , R 2 , R 3 , R 4 and X are defined as above, with a 65 compound of formula (vii) X’ •l· /’V_ic W (VU) where X' is halogen, and R 6 , B and n are defined as above
27. 28. The process of Claim 27 where X is S.
28. 29. The process of Claim 28 where R 4 is CH 3 .
29. 30. The process of Claim 29 where R x and R 2 are methyl.
30. 31. The process of Claim 30 where R 3 is H.
31.
32. The process of Claim 27 where X is 0.
33. A process for synthesizing a compound of the formula (i) where X is S or 0; R l' r 2 and r 3 are independently hydrogen or lower 10 alkyl; R 4 and Rj are lower alkyl, with the proviso that R 4 and Rj are not the same; R 6 is hydrogen, lower alkyl, lower alkenyl or lower cycloalkyl having 1 to 6 carbons or halogen; 15 n is an integer from 0 to 5; B is hydrogen, COOH or a pharmaceutically acceptable salt, ester or amide thereof, -CH 2 OH or an ether or ester derivative thereof, or CHO or an acetal derivative thereof, or -COR” or a ketal derivative thereof where R” is an 20 alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, the process comprising the steps of: reacting a compound of formula (ii) where R x , R 2 and R 3 are defined as above, and Y is halogen when X is S and Y is hydrogen when X is O, with a Grignard 30 reagent having the formula R^-Mg-X· where X· is halogen, to obtain a compound of formula (iii) (Ul) X HO where R^, R 2 , R 3 , R 4 , X and Y are defined as above? reacting the compound of formula (iii) with a Grignard reagent having the formula Rg-Mg-X' where Rg and X* are defined as above, to obtain a compound of formula (iv) 45 where R x , R 2 , R 3 , R 4 , Rg, X and Y are defined as above? converting the compound of formula (iv) to a compound of formula (v, where R x , R 2 , R 3 , R 4 , Rg, X and Y are defined as above; converting the compound of formula (v) into the compound of formula (i), said steps of converting (v) into 55 (i) including a step of reacting a compound of formula (vi) (VI) R where R^, R 2 , R 3 , Rg, R 5 and X are defined as above, with a compound of formula (vii) X*- Λ (CH2) n B (VII) 65 where X’ is halogen, ; and Rg and n are defined as above.
34. The process of Claim 33 where X is S.
35. The process of Claim 33 where X is 0.
36. A compound according to any one of Claims 1 to 26 for use in medicine.
37. A compound according to any one of Claims 1 to 26 for use in treating skin disorders in a mammal.
38. The use of a compound as defined in any one of Claims 1 to 26 for the manufacture of a medicament for the treatment of skin disorders.
39. A method of preparing a compound of the formula (I) substantially as described herein with reference to the Examples.
40. A compound of the formula (I) substantially as described herein with reference to the Examples. - 59
41. A compound of formula (I) whenever prepared by a method as claimed in any of claims 27 to 35 or 39.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US59488290A | 1990-10-09 | 1990-10-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
IE913569A1 true IE913569A1 (en) | 1992-04-22 |
Family
ID=24380813
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE356991A IE913569A1 (en) | 1990-10-09 | 1991-10-16 | Acetylenes disubstituted with a phenyl group and a¹2-substituted chromanyl, thiochromanyl or 1,2,3,4 -¹tetrahydroquinolinyl group having retinoid-like activity |
Country Status (12)
Country | Link |
---|---|
EP (1) | EP0553156A4 (en) |
JP (1) | JPH06501948A (en) |
AU (1) | AU652189B2 (en) |
CA (1) | CA2092178A1 (en) |
FI (1) | FI931625A (en) |
HU (1) | HUT63405A (en) |
IE (1) | IE913569A1 (en) |
IL (1) | IL99617A0 (en) |
PL (1) | PL168679B1 (en) |
PT (1) | PT99188A (en) |
WO (1) | WO1992006084A1 (en) |
ZA (1) | ZA918026B (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE144258T1 (en) * | 1991-02-13 | 1996-11-15 | Allergan Inc | 7-PHENYLETHYNYL-SUBSTITUTED CHROMANES AND THIOCHROMANES WITH RETINOID-LIKE BIOLOGICAL ACTIVITY |
FR2691149B1 (en) * | 1992-05-18 | 1994-07-08 | Adir | NOVEL THIOCHROMANIC COMPOUNDS, PROCESSES FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
US5451603A (en) * | 1993-03-11 | 1995-09-19 | Zymogenetics, Inc. | 3,4-diarylchromans for treatment of dermatitis |
EP0889032A4 (en) * | 1996-03-18 | 2000-01-05 | Eisai Co Ltd | Fused-ring carboxylic acid derivatives |
US6740676B2 (en) * | 2002-03-19 | 2004-05-25 | Allergan, Inc. | 4-[(8-ethynyl, 8-vinyl or 8-ethynyl-methyl)-6-chromanoyl]-benzoic and 2-[4-[(8-ethynyl, 8-vinyl or 8-ethynyl-methyl)-6-chromanoyl]-phenyl]-acetic acid, their esters and salts having cytochrome p450rai inhibitory activity |
BR112012001680A2 (en) | 2009-07-16 | 2015-09-01 | Stiefel Laboratories | Tazarotene derivatives |
CN107176945B (en) | 2016-03-11 | 2021-06-08 | 中国科学院上海有机化学研究所 | Retinoid compound, preparation method, intermediate and application thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4810804A (en) * | 1987-03-26 | 1989-03-07 | Allergan, Inc. | Acetylenes disubstituted with a phenyl group and a heterobicyclic group having retinoid-like activity |
US4980369A (en) * | 1989-09-19 | 1990-12-25 | Allergan, Inc. | Acetylenes disubstituted with a phenyl group and a 2-substituted chromanyl or thiochromanyl group having retinoid-like activity |
ATE144258T1 (en) * | 1991-02-13 | 1996-11-15 | Allergan Inc | 7-PHENYLETHYNYL-SUBSTITUTED CHROMANES AND THIOCHROMANES WITH RETINOID-LIKE BIOLOGICAL ACTIVITY |
-
1991
- 1991-09-24 HU HU931030A patent/HUT63405A/en unknown
- 1991-09-24 EP EP19910917856 patent/EP0553156A4/en not_active Withdrawn
- 1991-09-24 CA CA002092178A patent/CA2092178A1/en not_active Abandoned
- 1991-09-24 JP JP3516762A patent/JPH06501948A/en active Pending
- 1991-09-24 AU AU87210/91A patent/AU652189B2/en not_active Ceased
- 1991-09-24 PL PL91299061A patent/PL168679B1/en unknown
- 1991-09-24 WO PCT/US1991/006901 patent/WO1992006084A1/en not_active Application Discontinuation
- 1991-10-01 IL IL99617A patent/IL99617A0/en unknown
- 1991-10-08 ZA ZA918026A patent/ZA918026B/en unknown
- 1991-10-09 PT PT99188A patent/PT99188A/en not_active Application Discontinuation
- 1991-10-16 IE IE356991A patent/IE913569A1/en not_active Application Discontinuation
-
1993
- 1993-04-08 FI FI931625A patent/FI931625A/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
JPH06501948A (en) | 1994-03-03 |
FI931625A (en) | 1993-06-07 |
AU652189B2 (en) | 1994-08-18 |
AU8721091A (en) | 1992-04-28 |
FI931625A0 (en) | 1993-04-08 |
EP0553156A4 (en) | 1993-11-18 |
IL99617A0 (en) | 1992-08-18 |
HUT63405A (en) | 1993-08-30 |
ZA918026B (en) | 1992-06-24 |
HU9301030D0 (en) | 1993-07-28 |
WO1992006084A1 (en) | 1992-04-16 |
PL168679B1 (en) | 1996-03-29 |
EP0553156A1 (en) | 1993-08-04 |
PT99188A (en) | 1992-09-30 |
CA2092178A1 (en) | 1992-04-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5162546A (en) | Acetylenes disubstituted with a phenyl group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity | |
EP0419131B1 (en) | Acetylenes disubstituted with a phenyl group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity | |
US5677323A (en) | Acetylenes disubstituted with a heteroaromatic group and a 2-substituted chromanyl, thiochromanyl or 1, 2, 3, 4, -tetrahydroquinolinyl group having retinoid-like activity | |
US5616597A (en) | Acetylenes disubstituted with a heteroaromatic group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4--tetrahydroquinolinyl group having retinoid-like activity | |
US5045551A (en) | Acetylenes disubstituted with a heteroaromatic group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity | |
EP0571546B1 (en) | Chroman and thiochromans with phenylethynyl substituents at the 7-position having retinoid-like biological activity | |
AU652830B2 (en) | Chromans and thiochromans with heteroarylethynyl substituents at the 7-position having retinoid-like biological activity | |
US5399561A (en) | Acetylenes disubstituted with a phenyl or heteroaryl group and a 2-oxochromanyl, 2-oxothiochromanyl or 2-oxo-1,2,3,4-tetrahydro-quinolinyl group having retinoid-like biological activity | |
EP0636127B1 (en) | Disubstituted acetylenes bearing heterobicyclic groups and heteroaromatic or phenyl groups having retinoid like activity | |
AU652189B2 (en) | Chromans and thiochromans with retinoid-like activity | |
AU657100B2 (en) | Acetylenes disubstituted with a heteroaromatic group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FC9A | Application refused sect. 31(1) |