CA2078771A1 - 2(5h)-furanones substituted in the 5 and or in the 4 position, as anti-inflammatory agents - Google Patents
2(5h)-furanones substituted in the 5 and or in the 4 position, as anti-inflammatory agentsInfo
- Publication number
- CA2078771A1 CA2078771A1 CA002078771A CA2078771A CA2078771A1 CA 2078771 A1 CA2078771 A1 CA 2078771A1 CA 002078771 A CA002078771 A CA 002078771A CA 2078771 A CA2078771 A CA 2078771A CA 2078771 A1 CA2078771 A1 CA 2078771A1
- Authority
- CA
- Canada
- Prior art keywords
- compounds
- cancelled
- alkyl
- acid
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000002260 anti-inflammatory agent Substances 0.000 title description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 34
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 150000001345 alkine derivatives Chemical class 0.000 claims abstract description 6
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 5
- -1 n-octyl Chemical group 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 150000002431 hydrogen Chemical group 0.000 claims description 7
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical group C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 9
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 84
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 239000000203 mixture Substances 0.000 description 33
- 101150041968 CDC13 gene Proteins 0.000 description 32
- 239000000243 solution Substances 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- 239000003921 oil Substances 0.000 description 26
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 23
- 239000002253 acid Substances 0.000 description 23
- 238000001704 evaporation Methods 0.000 description 23
- 230000008020 evaporation Effects 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 17
- 239000003208 petroleum Substances 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 239000000377 silicon dioxide Substances 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 235000019341 magnesium sulphate Nutrition 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 101000939348 Homo sapiens NEDD8-activating enzyme E1 regulatory subunit Proteins 0.000 description 7
- 102100029781 NEDD8-activating enzyme E1 regulatory subunit Human genes 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000011981 lindlar catalyst Substances 0.000 description 5
- FGJIDQWRRLDGDB-CPIXEKRISA-N manoalide Chemical compound C=1([C@@H](O[C@H](CC=1)C=1[C@@H](OC(=O)C=1)O)O)CC\C=C(/C)CCC1=C(C)CCCC1(C)C FGJIDQWRRLDGDB-CPIXEKRISA-N 0.000 description 5
- FGJIDQWRRLDGDB-GMKZXUHWSA-N manoalide Natural products CC(=CCCC1=CC[C@@H](O[C@H]1O)C2=CC(=O)O[C@H]2O)CCC3=C(C)CCCC3(C)C FGJIDQWRRLDGDB-GMKZXUHWSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- DUAZKLYNTLDKQK-UHFFFAOYSA-N 5-hydroxy-2(5h)-furanone Chemical group OC1OC(=O)C=C1 DUAZKLYNTLDKQK-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 108010058864 Phospholipases A2 Proteins 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 238000012746 preparative thin layer chromatography Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 229910021653 sulphate ion Inorganic materials 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 108090000312 Calcium Channels Proteins 0.000 description 3
- 102000003922 Calcium Channels Human genes 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 102100037611 Lysophospholipase Human genes 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 150000001241 acetals Chemical class 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- FMVJYQGSRWVMQV-UHFFFAOYSA-N ethyl propiolate Chemical compound CCOC(=O)C#C FMVJYQGSRWVMQV-UHFFFAOYSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000003844 furanonyl group Chemical group 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 150000002596 lactones Chemical class 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- MOOYVEVEDVVKGD-UHFFFAOYSA-N oxaldehydic acid;hydrate Chemical compound O.OC(=O)C=O MOOYVEVEDVVKGD-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- MFGALGYVFGDXIX-UHFFFAOYSA-N 2,3-Dimethylmaleic anhydride Chemical compound CC1=C(C)C(=O)OC1=O MFGALGYVFGDXIX-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- NZQQBWRIUYNRIK-UHFFFAOYSA-N 2-hydroxy-3-octyl-2h-furan-5-one Chemical compound CCCCCCCCC1=CC(=O)OC1O NZQQBWRIUYNRIK-UHFFFAOYSA-N 0.000 description 2
- UJEDMBIYBKULKV-UHFFFAOYSA-N 4-oxo-6-phenylhex-2-ynoic acid Chemical compound OC(=O)C#CC(=O)CCC1=CC=CC=C1 UJEDMBIYBKULKV-UHFFFAOYSA-N 0.000 description 2
- 241000256844 Apis mellifera Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 239000007995 HEPES buffer Substances 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000003810 Jones reagent Substances 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102000014384 Type C Phospholipases Human genes 0.000 description 2
- 108010079194 Type C Phospholipases Proteins 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 239000003659 bee venom Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000012267 brine Substances 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
- 230000004094 calcium homeostasis Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229950005499 carbon tetrachloride Drugs 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 210000005069 ears Anatomy 0.000 description 2
- 230000002500 effect on skin Effects 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- VAKLLTRIQRTOFA-UHFFFAOYSA-N ethyl 4-hydroxytridec-2-ynoate Chemical compound CCCCCCCCCC(O)C#CC(=O)OCC VAKLLTRIQRTOFA-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- YFHXZQPUBCBNIP-UHFFFAOYSA-N fura-2 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=3OC(=CC=3C=2)C=2OC(=CN=2)C(O)=O)N(CC(O)=O)CC(O)=O)=C1 YFHXZQPUBCBNIP-UHFFFAOYSA-N 0.000 description 2
- 150000002241 furanones Chemical class 0.000 description 2
- 210000001156 gastric mucosa Anatomy 0.000 description 2
- 210000000224 granular leucocyte Anatomy 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- JXYZHMPRERWTPM-UHFFFAOYSA-N hydron;morpholine;chloride Chemical compound Cl.C1COCCN1 JXYZHMPRERWTPM-UHFFFAOYSA-N 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
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- 238000012986 modification Methods 0.000 description 2
- WTEVQBCEXWBHNA-YFHOEESVSA-N neral Chemical compound CC(C)=CCC\C(C)=C/C=O WTEVQBCEXWBHNA-YFHOEESVSA-N 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 208000004124 rheumatic heart disease Diseases 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 210000004989 spleen cell Anatomy 0.000 description 2
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- KYWIYKKSMDLRDC-UHFFFAOYSA-N undecan-2-one Chemical compound CCCCCCCCCC(C)=O KYWIYKKSMDLRDC-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QGVLYPPODPLXMB-UBTYZVCOSA-N (1aR,1bS,4aR,7aS,7bS,8R,9R,9aS)-4a,7b,9,9a-tetrahydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-1,1a,1b,4,4a,7a,7b,8,9,9a-decahydro-5H-cyclopropa[3,4]benzo[1,2-e]azulen-5-one Chemical compound C1=C(CO)C[C@]2(O)C(=O)C(C)=C[C@H]2[C@@]2(O)[C@H](C)[C@@H](O)[C@@]3(O)C(C)(C)[C@H]3[C@@H]21 QGVLYPPODPLXMB-UBTYZVCOSA-N 0.000 description 1
- KESXQHZIRZKRKH-QGQXVBDASA-N (e,2e)-2-[3-hydroxy-3-(2-hydroxy-5-oxo-2h-furan-3-yl)propylidene]-6-methyl-8-(2,6,6-trimethylcyclohexen-1-yl)oct-5-enal Chemical compound C=1C(=O)OC(O)C=1C(O)C\C=C(C=O)/CC\C=C(/C)CCC1=C(C)CCCC1(C)C KESXQHZIRZKRKH-QGQXVBDASA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XHRSIAZYSQZOHJ-UHFFFAOYSA-N 2-methoxy-3-octyl-2h-furan-5-one Chemical compound CCCCCCCCC1=CC(=O)OC1OC XHRSIAZYSQZOHJ-UHFFFAOYSA-N 0.000 description 1
- ZUXNHFFVQWADJL-UHFFFAOYSA-N 3,4,5-trimethoxy-n-(2-methoxyethyl)-n-(4-phenyl-1,3-thiazol-2-yl)benzamide Chemical compound N=1C(C=2C=CC=CC=2)=CSC=1N(CCOC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 ZUXNHFFVQWADJL-UHFFFAOYSA-N 0.000 description 1
- XMZQWZJMTBCUFT-UHFFFAOYSA-N 3-bromopropylbenzene Chemical compound BrCCCC1=CC=CC=C1 XMZQWZJMTBCUFT-UHFFFAOYSA-N 0.000 description 1
- YGCZTXZTJXYWCO-UHFFFAOYSA-N 3-phenylpropanal Chemical compound O=CCCC1=CC=CC=C1 YGCZTXZTJXYWCO-UHFFFAOYSA-N 0.000 description 1
- SBOSBRODDJVOFH-UHFFFAOYSA-N 4-bromo-2-methoxy-3-octyl-2h-furan-5-one Chemical compound CCCCCCCCC1=C(Br)C(=O)OC1OC SBOSBRODDJVOFH-UHFFFAOYSA-N 0.000 description 1
- RFDVNYRMMNTEAQ-UHFFFAOYSA-N 4-ethyl-5-hydroxy-5-methylfuran-2-one Chemical compound CCC1=CC(=O)OC1(C)O RFDVNYRMMNTEAQ-UHFFFAOYSA-N 0.000 description 1
- BUUXFKHAWLGSRB-UHFFFAOYSA-N 4-hydroxy-6-phenylhex-2-ynoic acid Chemical compound OC(=O)C#CC(O)CCC1=CC=CC=C1 BUUXFKHAWLGSRB-UHFFFAOYSA-N 0.000 description 1
- HHEWBBHHLOBGAI-UHFFFAOYSA-N 4-hydroxytridec-2-ynoic acid Chemical compound CCCCCCCCCC(O)C#CC(O)=O HHEWBBHHLOBGAI-UHFFFAOYSA-N 0.000 description 1
- LUXOYEZTEWTGMD-UHFFFAOYSA-N 4-oxohept-2-enoic acid Chemical compound CCCC(=O)C=CC(O)=O LUXOYEZTEWTGMD-UHFFFAOYSA-N 0.000 description 1
- MKNUCQYYCNBENU-UHFFFAOYSA-N 4-oxotridec-2-enoic acid Chemical compound CCCCCCCCCC(=O)C=CC(O)=O MKNUCQYYCNBENU-UHFFFAOYSA-N 0.000 description 1
- NAABUVBQPIPNFQ-UHFFFAOYSA-N 4-oxotridec-2-ynoic acid Chemical compound CCCCCCCCCC(=O)C#CC(O)=O NAABUVBQPIPNFQ-UHFFFAOYSA-N 0.000 description 1
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/28—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/60—Two oxygen atoms, e.g. succinic anhydride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Compounds of formula (1), and compounds of formula (2) in which R1 is H, alkyl of 1 to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds; R2 is H, alkyl of 1 to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds; R3 is H, alkyl of 1 to 20 carbons, arylalkyl, or halogene, and X is H or alkyl of 1 to 20 carbons, CO-X*, CO-O-X*,, CO-NH-X*,, or PO(OX*,)2 or PO(OX*,)X*,, where X*, independently is H, alkyl of 1 to 20 carbons, phenyl, or substituted phenyl, are disclosed. However, in the compounds of the invention illustrated by formula (2), R1 and R3 both cannot be hydrogen. The compounds have anti-inflammatory activity.
Description
WO 91/1605~ 2 ~ ~ 8 7 7 ~ PCI'/US91~02005 2 ~5H) -FlJ~AN0NE:8 ~UB81~TU~5!ED ~N T~ 5 AND OR IN T~}~ 4 ' -PO8I~ION, A8 ANT~ TORY AGENTR
BAC~GRO~ND OF T~ ION
1. Field of the InventiQn The present invention is directed to novel 2(5H)-furanones substituted in the S position and or in the 4 position, which compounds are active as anti-inflammatory agents. The present invention is also directed to pharmaceutical compositions which comprise one or more of 10 the novel compounds of the invention, to the methods of using these pharmaceutical compositions, and to the chemical processes of making the novel compounds.
2. Brief Description of the Prior Art Manoali~e is a compound isolated from a marine sponge 15 ~E. D. de Silva et al., ~etrahedron Letters 21:1611-1614 (1980)] which has anti-inflammatory, immunosuppressive and analgesic properties. Manoalide (Co~poun~ 1) the structure of which is shown below, includes a 5-hydroxy-2(5H)-furanone moiety, attached in the 4-position of the 20 furanone ring to the rest of the molecule. Certain analogs of manolide, such as -co-~no~ (Co~poun~ 2) and dehydro-s-co-~a~o~lide (Compou~d 3) also have anti-inflammatory activity. For further description of the biological activity of ~anoalide and some of its 25 derivatives reference is made to United States Patent Nos.
4,447,445, 4,786,651, 4,789,749 and to European Patent Application No. 0 133 376 (published on February 20, 1985).
. ~ - ~ ;- . .
WO91/16055 PCT/USsl/02~s _ 2~g77~
S ~b~H
manoalldQ
dehydro-seco- ~OH
Compound 1 ~
Compound 3 ~;~OH
seco manoalide p~--OH
Compound 2 Synthetic analogs of manoalide, particularly analogs having various sub~tituents on the furanone moiety of manoalide, are describ~d in s~veral applications for United States Lett~r~ Patent by the same inventor as in the pre~ent application, the following of which have been allowed and ara expected to i~u~ as United States Letters Patent:
Serial No. 259,225 filed on October 18, 1988;
Serial No. 281,126 ~iled on Dec~mb~r 7, 1988.
Publi~h~d Europo~n Patent Applicatlon No. 0 295 056 -disclose~ 4 ~ub~tituted 5-hydroxy-2(SH)-furanones having , . ... . ,.. .~ ,. .. - . . ., - ~ - ,. . , . . .,: . , -WO91/16055 2 ~ 7 ~ 7 7 ~ PCT/USg1/02~5 anti-inflammatory, immunosuppressive and anti-proliferative activity where the substituents in the 4 position are a variety 1-hydroxyalkyl, l-acyloxy-alkyl and l-carbamoyloxy-alkyl groups.
United States Patent No. 4,855,320 discloses 5-arylalkyl-4-alkoxy-2(5H)-furanones as anti-convulsive and anti-epileptic agents.
Published European Patent Application No. 0 209 274 discloses 4-alkyl-5-hydroxy-2~5H)-furanones as anti-10 inflammatory and anti-allergy agents.
Chemical Abstracts Volume 107 236559t (1987) .
discloses 4-acyloxy 5-hydroxy-2(5H)-furanones.
~MMARY OP T~E INV~NT~ON
The present invention covers compounds of ~or~ula 1, and compound-~ of Formula 2 R~ ~ R~ R~ ~
For~ula 1 Yor~ul~ 2 - .. . . -. , : , WO9tJ1605~ 2 ~ ~ 8 ~ ~ ~ PCT/US91/02~5-_ ~n which Rl is H, alkyl of l to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds:
R2 is H, alkyl of l to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds;
10 R3 is H, alkyl of 1 to 20 ~arbons, arylalkyl, or halogene, and X is H or alkyl of l to 20 carbons, C0-S~, CO-O~
CO-NH-~, PO(OS~)2 or PO(OS ,)~ ,, where S ,independently is ~, alXyl of 1 to 20 carbons, phenyl, or substituted 15 phenyl. However, in the compounds of the invention illustrated by Formula 2, both ~ and ~3 cannot be hydrogen.
The present invention also covers salts of the above-defined compounds, formed with pharmaceutically acceptable 20 acids or bases, as applicable.
In a second aspect the present invention relates to pharmaceutical formulations comprising one or more compounds o~ Yor~ula 1 or of Yor~ula 2, or both, (or pharmaceutically acceptable salts thereof) in ad~ixture -25 with ~ pharmaceutically acceptable excipient, for the purpo-~ of tre~ting certain conditions, ~yndro~es or diseases in ma~mals, including humans. Th~ compound~ of the invention have anti-infl~mmatory, i~munosuppressant and anti-prolifQrative activity. ThQrQfor~, the compounds 30 are uBeful for treating in ~ammal8 (including human~) inflam~ation, rh~u~toid arthriti~, o~teo~rthrlti~, rheumatic carditis, ocular and dermal infl~mmatory diseasQs~ autoi~mune diseas~. such a~ allergic di eases, .. ~ . .. . . .. .
:. . ~
WO91/1605~ 2 ~ ~ 8 7 7 ~ PCT/US9t/02005 bronchial asthma and myasthenia gra~is, and for suppressing unwanted immune responses and retarding proliferation of cell.
. ~ R,CHO ~HC_Ca~Et E~ULl ~ R~ OH)C--CCOaEt Formula 3 4 . Formula 4 1. H2 / Llndlar .
catalyst 2. acld :
=
o~o~Rl Formula 1 R2 ~ Ra = H
R-~ctlon Sch~m- 1 In still another a~pect, the present invention relates to the processes of making the compounds of .
For~ula 1 and of ~o~ula 2. In general tercs, these processes, shown in R-~ction ~oh-u- 1, 2, 3 ~n~ ~ comprise the steps of reacting an aldehyde o~ ~o~ula 3 with a .... ,, . ~ ........ .. . .
, ~ . . . . . . .
WO91/160S5 2 ~ ~ 3 ~ 7 ~ PCT/US91/02005 -lithium or magnesium salt derived fro~ a propiolate ester, , such as ethyl propiolate (Co~poun~ 4), to yield an Rl-substituted 4-hydroxy --ynoate of For~ula 4 (Rl defined as in conn~ction with For~ula 1 and Fo~ula 2).
Hydroganation over a "poisoned" catalyst (Lindlar catalyst) converts th~ acetylenic (triple) bond into an olephinic (double) bond. This is followed by acid catalyzed cyclization to yield compounds of For~ula 1 where R2 and ~3 ar~ hydrogen.
~c~ol~c=cc~ KOH , R,C~OH)C_CCO~N
Formub ~ Formub S
. :
Jon-~
r-~-nt R,COC----CC02H
Formul~ 6 , H2 / Llndbr o~l~ly~t ¦ R~COCH=CHCO,H ¦
¦ cycll2~tlon R~ccllon Sch-m 2 ~,.
D,C;~R, O 01~ :
Formub 2 R~ ~ R~ H ~ - -... : : ~ . .. . - . :. : .~ ., , -W091/16055 2 ~ 7 ~ 7 7 ~ PCT/US91/02~S
In order to obtain compounds of For3ul~ 2, as is shown in Re~ct~o~ 80heme 2, the intermediate Rl-substituted 4-hydroxy--ynoate of For~ula ~ is saponified to obtain the corresponding free carboxylic acid of ~ormula 5, which is thereafter oxidized (typically with Jones reagent) to yield the corresponding Rl-substituted 4-oxo-alkynoic acid of For~ul~ 6. The intermediate of Formula 6 is hydrogenated over a "poisoned" catalyst, typically Lindlar catalyst, to yield an alkenoic acid intermediate which cyclizes, usually spontanously, to provide compounds of Fo~mula 2 where R2, R3 and ~ are hydrogen. As is shown in R-~otion 8ch~m- 2, the compounds of Formu~a 2 can be reduced with a mild redu~ing agent, such as sodium borohydride to provide the corresponding compounds-of ~ormul~ l. A theoretical explanation for this reaction (although the present inventors do not wish to be bound by theory) is that the carbon in the 5-position of the 5-hydroxy-2(SH)-furanone molecule is an "aldehydic" carbon, ring closed with the carboxylic acid group in the "2-position" of the ring, and that the aldehydic carbon is reduced with 80diu~ borhydridQ to a primary alcohol, which, thereafter., ring closes w~th the carboxylic acid to for~ a lactone of Yor~ula ~.
Compounds Or ~or~ula 2 where the S substituent is other than hydrogen, can be obtained by acylation, carbamate formation (through rQaction with isocyanate) phosphorylation and the like, in accordance with procQdures which are within the sXill of the practicing organic chemist.
.
' - - . . ' . ~
' :: '. ' . , ' ' ' . ' ~ , ' :
, , . -. . , : . . ~
' . : ,- . .. ' : ' ' .: . ' :
WO 91/16055 2 ~3 7 8 7 r~t ~ pcr/us9l/o2oo5 ~
R~COCH2R2 ~CHOCO2H acld ~¦ R~coCR2=cHco2H ¦
Formula 7 ~ Formula 8 S ~ '' / heat ~/
10 ~, , XO~( ~, NllrH~ D~, ;
Formula 2 Formula 2 Formula 1 X = alkyl R3 = X = H R3 = H
R3 = H
Br2 . , L~R H2O / acid ~ ~ 1 20 o ox O OH
Formula 2 Formula 2 X = alkyl Reactlon Scheme 3 WO91/16055 2 ~3 7 g ~ 7 ~ PCT/US91/02005 In order to obtain compounds of Formula 2 where neither R~ nor ~2 are hydrogen, a ketone of Formul~ 7 (which bears the desired Rl and R2 groups) is condensed under acidic condition with glyoxylic acid (Compoun~ S), as is shown in ~eAct~o~ 8chQ~- 3. An inter~ediate condensation product of Formula 8 usually is not isolated because it cyclizes during the condition of the condensation reaction to form the furanones of For~ul~ 2 where the Rl and R2 groups are derived from the starting ketone of For~ula 7 and where S is hydrogen. Reduction of the 5-hydroxy-2(5H)-furanone compound of For~uls 2 (S is ~) with sodium borohydride, as shown in ~e~ctlon 8ch-~e 3 results in "removal" of the 5-hydroxy group and yields the corresponding compound of For~ula l.
Referring still to R-actlon 8c~ 3, compounds of Formul~ 2 where Rl is hydrogen, are obtained when the starting material of Formul- 7 is an aldehyde rather than a ketone, (in Formula 7 Rl-H). In this case, the condensation reaction with glyoxylic acid (Co~pound 5) is usually performed in the presence of morpholine hydrochloride. An alkyl substitutent for the 5-hydroxy function (in Formula 2 ~alkyl) is introduced into the molecule by reacting the 5-hydroxy-2(5H)-furanone derivative of For~ul- 2 with the appropriate alcohol (SO~) in the presence of acid. The resulting 5-alkoxy-2(5H)-furanone derivative Or Tor~ul~ 2 where R3 i5 hydrogen, is brominated to yield the corresponding 3-bromo-5-alkoxy-2(5H)-furanone derivative Or For~ula 2. The alkoxy substituent can be replaced wit~ OH by reaction with agueous acid.
.: . . . . . ~ - -.
2 ~ ~ 8 7 7 ~L
WO 91/160S5 PCI-/US91/02005 _ R~ ~ CH5Cil,1 BuLI ,~c~CR,' Formula 9 Formula 10 Formula 11 RlMgBr H2 ~ ~ ~ ~
R~ R2 R3 R2 O~OH O~OH
ls Formula 2 Formula 2 Na B H4 NaBH4 ,, ~ ~
Formula 1 Formula :
Reaction Scheme 4 W O 91/16055 2 ~ r~ ~ 7 7 ~ PC~r/US91/02005 Re~ct~on 8c~me ~ summarizes a reaction sequence, in which compounds of the invention can be prepared where neither R2 nor R3 are hydrogen. In accordance with this scheme, a di-substituted maleic acid anhydride (For~ul~ 9) S is reacted with the lithium salt of an alkyne (Forsul~ 10) to provide a 5-alkynyl substituted 5-hydroxy-2(5H)-furanone derivative (Formul~ 11). In Formul~ 10 -CC-R~
symbolizes such a precursor of the group Rl which is readily converted by hydrogenation and or other reactions within the skill of the practicing organic chemist, into the group R~ defined in connection with Formula 1 and -Formul~ 2. Reactlon 8c~-m- ~ show~ a hydrogenation step in which the olephinic bond of the intermediate of Formul~
11 is partially or fully saturated to provide compounds of Formul- 2. Reduction of the compounds of Fon~ul~ 2 with sodium borohydride provides compounds of Formula:l.
Another process of preparing compounds of the invention where neither R2 nor ~3 are hydrogen, involves the react~on a di-substituted maleic acid anhydride of Formula 9 with a Grignard reagent of the formula Rl-MgBr to provide compounds of ror~ul~ 2 where S is hydrogen.
Reduction of the~e compounds with sodiu~ borohydride, yields compounds of Yor~ul~ ~.
In anothe~ general aspect, the processes leading to the compounds of the invention ~ay involve performance of routin~ chemical reactions (~uch as e~terification, saponlfication of esters, oxidation of alcohols to ketones or aldehydes, formation o~ acetals, ketal , and lactones from aldehydes or keton~s, and th~ like) which are well known to the practicing synthetlc organic chemist.
When it i5 desired to ~ubstitut~, for example acylate, the 5-hydroxy function of th~ compound3 of Formula 2, an S group (as defined in connection with .: :
.- . . ~ . .
. , .
. . , . ~ .. ,; .. .
2~7877P
W091/16055 PCT/US91/02~5.
these formulas) can be introduced into the 5-hydroxy-2(5H)-furanone compounds by conventional means.
As it was illustrated in connection with R-~ct~o~ schQme 3, introduction of an ~ alkyl group into the compounds of Formul~ 2 in reality is formation of an acetal, which can be accomplished by treating the respecting 5-hydroxy-2(SH)-furanone with an alcohol 20H in the presence of acid.
General Emb~dim~
10 Definitions The terms "ester", "amine", "amide", "ether"
"acetal", "lactone" and all other terms and terminology used here, (unless specifically defined in the present description) refer to and cover any compounds falling within the respective term as that term is classically used in organic chemistry.
Unless specifically noted otherwise, preferred esters are derived fro~ the saturated aliphatic alcohols or acids of ten or.fewer carbon atoms or from 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 alcohol~. Also preferred are the phenyl or lower alkylphenyl esters.
The term ~alkyl" as used in the pre6ent description and claim~ includes straight chain alkyl.group~, branched chain alkyl group~, cycloalkyl groups, alkyl .ubstituted cycloalkyl groups, and cycloalkyl ~ubstituted alkyl groups. Unles~ the nu~ber of carbons i~ otherwise specified, ~10WQr alkyl~ means the ~ormer bro~d definition of "al~yl" groups ~ut with tha re~triction that ~he group has 1 to 6 carbon atoms.
The term "long chain alkyl" ~l~o ~e~n~ the for~er broAd def~nition o~ "alkyl" groups ~ut with the . . . . . . .
.
' WO91/16055 2 ~ 7 o 7 7 ~ PCT/US91/02005 restriction that the group has no less than 4 carbon atoms, and no more than approximately 2~ carbon atoms.
Unless specifically noted otherwise, preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms, or the cyclic or saturated aliphatic-cyclic radicals of 5 to lO carbon atoms.
Some of the compounds of the invention (~or~ula 1) contain a non-equilibrating chiral center in the 5 position of the furan ring. Other compounds of the invention may contain one or more additional chiral centers. Accordingly, the compounds of the invention may be prepared as mixtures of enantiomeric compounds (where the enantiomers ~ay or ~ay not be present in equal amounts) or ~s optically pure enantiomers. When there is more than one chiral center, the compounds of the invention may also be prepared as mixtures of diastereomers, or as pure diastereomers, and each diastereomer itself may be a mixture of enantiomers in 1:1, or other, ratios. Alternatively, each diastereomeric compound may be sterically and optically pure. However, all of the abovo-noted form~, including optically pure enantiomers and mixtur~s thereof, a~ well as all diasterQomers, are within scope of the pre3ent invention.
Som~ of the compound~ of the invention, for example tho~e which contain olephinic doubl~ bond~ in the side chain~, may have Çi~ and tran~ storQoi~om~rfi. The scope of the invention includes both pur~ ster~oisomers as well a~ mixtures thereof.
A pharmacQuticalIy acc-pt~bl~ salt may be prepared for ~ny compound of this invention having a functionality capable of forming such salt, for ex~mle an acid or an amine functionality. A pharmac~utically acceptable salt -- .. . . : .
. :
2 ~ 7 ~
W O 91/16055 PC~r/US91/02005 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 trialkylamines or ethanol amines. Sal~s may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen suf~iciently basic as to be capable of forming acid addition ~alts, such may be formed with any inorganic or organic acids or alkylating agsnt such as methyl iodide. Preferred salts are those for~ed with inorganic acids such as hydrochloric acid, sulfuric acid or pho~phoric acid. Any of a number of simple org~nic acid~ such as mono-, di- or tri-acid may also bQ usQd.
The prefQrred compounds of the present invention are, with referencQ to ror~ula 2 and with re~p~ct to the OS
substituent in thQ 5-position of the furanone moiety, tho~e where thQ sub~tituent is hydroxy, ~thoxy or 25 ac~tyloxy (~ i~ H, or CH30 or CH3CO). -Wlth r sp~ct to the Rl susbtituQnt in th~ 5 position of th~ 2(5H)-furanone molecule, th~ prQferred compounds in accordance with ~he pr~sent invention are those where ~1 is hydrogen, long chain alkyl, or ~rylalkyl. Compounds ar~ particularly pr-ferr~d in thi8 rQg~rd whQre th~ ~1 group i~ long chain alkyl which i~ fitraight chain-d, or where the ~ i8 ~rylalkyl containing a straight ~lXyl chain of 3 carbons.
-: ., , : . ... ,-.. , ... .. ,. .... , ~.. - .. ,~: - ... .. ~ . -WO91/16055 2~7~77 1 PCT/US91/02005 With respect to the ~2 substituent in the 4-position of the 2(~H)-furanone molecule, the compounds of the invention are preferred where ~2 is hydrogen, or alkyl group, particularly straight chain alkyl With respect to position 3 of the 2(5~)-furanones of the invention, compounds are preferred where ~3 is H, methyl or bromo The most preferred compounds of the invention are those listed just below with reference to Formul~ 1 or 10 Formul~ 2 Formula 1, compoun~ 6 ~1=C~3(CH2)8~ R2-H~ and R3 H;
Formula 2 Co~poun~ 7 R1=CH3(CH2)g~ R2 H, R3 H
S-H
Formul~ 1, compoun~ 8 ~1=(CH2)3-c6H5~R2=cH3~ and 15 R3-C~3;
' P ~ 9 R1 H~ R2-CH3(CH2)7~ R3=Br and SSH, and ~or~ul~ ', Co~poun~ lO Rl'H~ R23C~3(CH2)7 and R3 H
The compounds of the present inv~ntion are useful in pharmaceutical compositions to produce anti-inflammatory, immunosuppres~ant and anti-proliferative activity The diseases, syndromes or conditions of mammals (including humans) which can be treated with pharmaceutical compositions containing one or more co~pounds of the invention (or salt~ thereof) include inflammation, rheumatoid arthriti~, osteoarthritis, rheumatic carditis, ocular and dermal $nflammatory diseasQs, autoimmune di~ease~ 3uch as allergic disaases, bronchial asth~a and myasthenia gravi~, unwanted immune r~pon~es and unwanted proli~eration of cell~, psoria~i~, acne, atopic diseases and allorgic con~unctiviti~
The activ~ty o~ the compounds o~ this invention is demonstrated by ~nhibition of the enzyme phospholipase A2 .. . . . . . . ....................... .
.. .. . .
. - .. - . .. .. . ., ~, . . ~ . . ~
WOsl/16055 2 ~ ~ ~ 7 7 ~ PCT/US91/02005 ~
.~ vitro and by reduction of inflammation in the mouse ear anti-inflammatory assay in vivo.
Activity of compounds of this invention may also be demonstrated by inhibition of phosphoinositide-specific phospholipase C. This activity has been reported for manoalide and may indicate anti-inflammatory utility.
Bennett et al, Molecular PharmacolQgy 32:587-593 (1987).
Activity of the compounds may also be demonstrated by inhibition of ornithine decarboxylase, a rate limiting enzyme in cellular growth, which indicates use in treating psoriasis and neoplasis.
The compounds also modify calcium homeostasis. This activity i8 shown by effect on intracellular calcium levels in experiments using gastric glands, spleen cells, epithelial cells, GH3 cells, etc. Calcium is inhibited from entering through the plasma membrane calcium channels and calcium release from intracellular stores is also blocked. Modification of calcium homeostasis is expected to have application in diseases of the nervous ~ystem involving modification of membrane lipids or transmitter release (Parkinson's, Alzheimer's), di~eas~s of the cardiovascular sy~tem involving application of cardiac or vascular smooth muscle contractility and platelet aggregation (hypertension, cardiac infarction and atherosclerosi~), diseases of the ga~troint~stinal tract such a8 ul¢er disease, diarrhea, motility due to secretion of acid or Cl , diseases of the kidney involving renal handling of fluid an~ electrolytes tmetabolic acidosi~, alk~lo~is), and di~eas~ of abnormal growth (neopla~ia, psoria~is).
The compounds of thiQ invention hav~ acti~ity which i~ si~ilar to that o~ manoalide, th~t i8 the co~pounds app~ar to be devoid of the endo~rine propertie~ of the . , ~ , . , -. . . . .. ..
... . ... , . ~, , , : , ..
- . . .. . . . , :
.: .: ~ . .
.. . . . .
- . ~ ..... ,. . ~, ;: , - . . ~
WO91/16055 PCT/US9t/02~5 2~7~7 ~
glucocorticoids while having anti-inflammatory and immunosuppressive properties.
In the method~ of this invention, the compounds of the invention are administered to mammals, includi~g humans, in an effective amount to produce the desired activity, preferably in an amount of about 0.05 to lOO mg per day per kilogram of body weight. The amount of the compound depends upon the disease or condition being treated, the severity thereof, the route of ad~inistration lG and the nature of the host. The compounds may be administered topically, orally, parenterally or by other standard routes of administration.
Pha~maceutical compositions of this invention comprise compounds of Yormula 1 and of For~ul~ 2, and pharmaceutical carriers suitable for the route of ad~inistration. Standard methods for formulating pharmaceutical compositions o~ this type may be found in Reminaton's Pha~se~dh~LL~ ~ ss~ Mack Publishing Company, Easton, PA.
For topical administration, the pharmaceutical composition may be in the for~ of ~ salve, crea~, ointment, spray, powder or the like. Standard pharmaceutical carriers for such compositions may be used.
Preferably, compo~itionQ for topical administration will contain 0.05-5% of the active ingredient.
A typic~l cream formulation may contain the following: -Inaredient - P~rts by Weiaht -Water/glycol mixture 50-99 (15% or ~ore glycol) Fatty ~lcohol 1-20 Non-ionid surfactant 0-lO
M~neral oil 0-lO ;
, ~
. . ...... . . , . . : . . , . ,., -W091/160S5 2 ~ 7 8 7 7 L PCT/US9t/0200s.~
Typical pharmaceutical adjuvants 0-5 Active ingredient 0.05-5 A typical ointment formulation ~ay contain the following:
Inaredients ~ s by Weiht White petrolatum 40-94 Mineral oil 5-20 Glycol solvent 1-15 Surfactant 0-10 Stabilizer O-lo Active ingredient 0.05-5 For oral ad~inistration, suitable pharmaceutical carriexs include mannitol, lacto~e, ~tarch, ~agnesiu~
stearate, talcum, glucose and magne ium carbonate. Oral compositions ~ay be in the form of tablets, capsules, powd~rs, solutions, suspensions, su6tained release formulations, and the like.
A typical tablet or capsule may contain the following:
Inaredients P~çent w~w Lactose, ~pray-dri~d 40-99 Magnesium ste~rat~ 1-2 Cornstarch 10-20 Active ingredient 0.001-20 Parenteral compo~ition~ are prepared in conventional suspen~ion or solution ~orms, a~ emuls~ons or as solid ~ :
forms ~or reconstruction. Suitable carriers are water, saline, dextro--, Hank' 8 solution, ~inger'~ solution, glyc-rol! and the like. Parent~ral administration i~
usually by in~ction which ~ay be ~ubcutaneous, intramuscular or intravenous.
., . .. . ;
WO91/16055 2 ~ ~ ~ 7 7~ PCT/US91/02005 The compounds of this invention may be combined with other known anti-infla~matory/immunosuppressive agents such as steroids or non-steroidal anti-inflammatory agents (NSAID) in the pharmaceutical compositions and methods deecribed herein.
The assay procedures by which useful biological activity of the compounds of the invention can be demonstrated, are described below.
Calcium Channel (mobilization~ Inhibition Assay Polymorphonuclear leukocytes (PMNa), gastric glands, GH3 cells, A431 cells, spleen cells, hu~an ~eratinocytes corneal cells, etc. were loaded with the Ca2+ sensitive fluorescent dye, Fura-2. The appropriate cell type was chosen and the potency and e~ficacy of the anti-inflammatory furanones on calcium mobilization, calcium channel inhibition wa~ quantitated. The methods used for A431 cells listed below are representative of those used for other cells.
A431 cell~ were detached using a 5-10 min trypsin-EDTA trea~ment wherQas GH3 cell~ were treated 2 to 5 minwith a 1% pancreatin solution. Cells were immediately washed twice in a 20mM HEPES bu~fer (pH 7.4) containing 120mM NaCl, 6 mM KCl, 1 ~M MgS04, 1 mg/ml gluco~e and mg/ml pyruvatQ and 1.4mM calcium (mediu~ A).
Approximately 5 x 106 cell~ w~re suspQnded in medium A and incubated with 4uM fura-2-AM for 15 ~in ~t 37C.
After washing the ~ura-2 loaded cells, the uptake of dye was checked using fluorescence microscopy and found to be evenly ~istributed in the cyto801 0~ all cells.
Fluore~cenc~ waB continucusly r~cordsd with a Perkin-Elmer LS-5 spQctrofluorom~ter. The excltation w~velength was set at 340n~ and emicsion wavelength ~et at 500nm. The cell suspension was continually stirred, maintained at ~ . - - .. .. . . . . . . ......... . . . . ................ .
.. .. : . - - . . , . ~ . . . : . . ~ .
W091/16055 2 ~ 7 ~ 7 7 ~ PCT/US9t/02~5 ~
37C and equilibrated for approximately 5 min before addition of various agents. [ca2+i was calculated using the following formula:
tca2+]i = 220 X F - Fmin Fmax - F
All fluorescence values were measured relative to a EGTA-quenched signal determined as follows: F was the relative fluorescence measurement of the ~ample. FmaX was determined by lysing the cells with digitonin (lOOug/ml) in DMSO. After FmaX was determined the pH was adjusted to 8, with NaOH and Ca2+ chQlated with 3mM EGTA to totally quench the fura-2 sis ~1 and obtain Fmin.
When quin-2- was used, cell~ were incubated with lOuM
quin-2- at 37C for 1 hour, wa~hed and th~n used.
is Mouse ~ an~i-Inflam~tory Assay Test compound and phorbol ~yrist~te ~cetate (PMA) are topically applied simultaneously to the pinnae o~ the left ears of mice. PMA alone is applied to the right ear.
Three hours and 20 minute~ after application, the mice are sacrificed, left and ri~ht e~r~ remo~ed, and standard sized bores taken. Edema (inflammation) is m~asured as the diffQrence ~n weight between left and right ears [Van Arman, C.G., Clin Phar~col ~h~ (1974) 16:900-904].
Inhibition o~ PhoQpholipase A2 Th efSect of compounds of thi~ invention on bee vonom phospholipa~ A2 i d~termin~d by the following procedure:
a. Bee venom pho~pholipasQ A2 in lO uM HEPES (pH
7.4) with 1 mM CaC12 i~ incubat~d with v~hicl~ or test ~gent for l.O hour ~t 41.
b. 1.36 mM pho~photidylcholine, 2.76 mM Triton X-:. .. : . ~ -- ~ , .. :, ~.
WO 91/16055 2 ~ ~ ~ 7 7 ~ PCT/US91/02005 loo ?
are dispersed in buffer by sonication and then mixed with L-3 phosphotidylcholine, l-palmitoyl-s (1-14C) palmitoyl for 10 min.
c. Start the reaction by the addition sf enzyme (0.495 units/ml).
d. Incubation for 15 sec. at 41.
e. Reaction is terminated by addition of 2.5 ~1 of isopropanol: n-heptane: 0.5 M H2SO4 (40:10:1;
v:v:v: ) .
f. 2.0 ml n-heptane and 1.0 ml H2O added; mixture centrifuged.
g. 2.0 ml n-heptane removed and treated with 200-300 mg of silica gel HR60.
h. Samples centrifuged; 1 ml of n-heptane SN
removed and added to 10 ml scintillation fluid.
i. Samples counted on a scintillation counter.
Inhikition.of Phos _ cific Phospholi~ase C
The ef~ect of compound~ o~ this in~ention on phosphoino~itide-~pecific phospholipase C ~ay be determined by procedures described by Bennett et al, Molecular Pharmacology 32:587-593 (1987).
Activ~ty Data In the above-de cribed pho~pholipase A2 assay the -- compounds of the invention we~e found to provide 50%
inhibition (IC50) o~ bee vsnom phospholipa~e A2 at the following concentrations (in micromol0~ indicat~d in ~1- 1. ' ' ~'..
wO91/16055 2 0 7 ~ 7 ~ ~ PCT/US91/02~5 ~
T~ble 1 Phospholipase A2 Assay.
Compound name or number IC50 (um) l 0.03 *Data for Compoun~ l (monoalide) are provided for comparison.
In the above-described phospholipase A2 assay compounds of the invention which are listed in ~abl- 2 were found to provide the following percentage (%) inhibition of bee venom phospholipase A2 at lO0 micromolar concentration.
~4b~0_2 .
The compounds of the present invention can be made by the synthetic chemical pathways which are illustrated above in general terms, and in the ~pecific examples as well. The ~ynthstic che~ist will readily appreciate that the conditions described here in general terms, and specifically, can be generalized to any and all co~pounds repr-sented by ~or~ul~ ~ or by For~ul~ 2, as applicable.
Furthermore, th~ synthetic ch~mist will readily appreciate that the hereln dQscribed ~ynt~etic step~ may be varied or adjusted by tho~e ~killed in the ~rt wlthout departing from the soope and spirit o~ the invQntion. Therefore, the following examples o~ spec~ic compounds of the invention, and spec$fic examples of the synthetic steps in which the compound~ and cert~in intermediates are made, , ~ ~}
- . , : . .
-, . . . . . . .. . .
.. : ...... :; : : , . .. . . . : . . . .
WO91/16055 2 ~ 7 ~ 7 71 PCT/US91/02005 are set out to illustrate the invention, not to limit its scope.
Specifi~ E~mp~es Example 1 Ethyl 4-hydroxy-6-phenylhex-1-ynoate (Compoun~ 11) n-Butyl lithium (a 1.6 M solution in hexane; 6.7 ml, 10.7 mmol) was added dropwise to a solution of ethyl propiolate (1.04 g, 10. 6 mmol ) in tetrahydrofuran (10 ml) at -78 under argon. After 10 minutes, a solution of hydrocinnamaldehyde (1.42 g, 10.6 mmol) in tetrahydrofuran (5 ml) was added. Stirring was continued at -78C for 2 hours and acetic acid (1 ml) was added. on warming up to 0, the reaction mixture was poured into water.
Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts a~forded an oil, which was flash chromatographed with silica using 30% ethyl ether/petroleum ether. Fractions with Rf of about 0.28 on evaporation afforded the title ~ster as a light yellow oil.
1 NMR (CDC13) 1.34 (m, 3H), 2.10 (m, 2H), 2.40 (br, lH), 2.83 (t, 2H, J - 8.3 Hz), 4.25 (q, 2H, J s 7.3 Hz), 4.50 (t, lH, J ~ 7.0 Hz) and 7.29 (m, 5H).
LRNS m/e (% abundance) 233 (M++1, 2), 232 (M+, 7), 186 (24), 185 (42), 170 (51), 169 (30), 158 (24), 142 (37), 141 (100) and 105 (84).
BAC~GRO~ND OF T~ ION
1. Field of the InventiQn The present invention is directed to novel 2(5H)-furanones substituted in the S position and or in the 4 position, which compounds are active as anti-inflammatory agents. The present invention is also directed to pharmaceutical compositions which comprise one or more of 10 the novel compounds of the invention, to the methods of using these pharmaceutical compositions, and to the chemical processes of making the novel compounds.
2. Brief Description of the Prior Art Manoali~e is a compound isolated from a marine sponge 15 ~E. D. de Silva et al., ~etrahedron Letters 21:1611-1614 (1980)] which has anti-inflammatory, immunosuppressive and analgesic properties. Manoalide (Co~poun~ 1) the structure of which is shown below, includes a 5-hydroxy-2(5H)-furanone moiety, attached in the 4-position of the 20 furanone ring to the rest of the molecule. Certain analogs of manolide, such as -co-~no~ (Co~poun~ 2) and dehydro-s-co-~a~o~lide (Compou~d 3) also have anti-inflammatory activity. For further description of the biological activity of ~anoalide and some of its 25 derivatives reference is made to United States Patent Nos.
4,447,445, 4,786,651, 4,789,749 and to European Patent Application No. 0 133 376 (published on February 20, 1985).
. ~ - ~ ;- . .
WO91/16055 PCT/USsl/02~s _ 2~g77~
S ~b~H
manoalldQ
dehydro-seco- ~OH
Compound 1 ~
Compound 3 ~;~OH
seco manoalide p~--OH
Compound 2 Synthetic analogs of manoalide, particularly analogs having various sub~tituents on the furanone moiety of manoalide, are describ~d in s~veral applications for United States Lett~r~ Patent by the same inventor as in the pre~ent application, the following of which have been allowed and ara expected to i~u~ as United States Letters Patent:
Serial No. 259,225 filed on October 18, 1988;
Serial No. 281,126 ~iled on Dec~mb~r 7, 1988.
Publi~h~d Europo~n Patent Applicatlon No. 0 295 056 -disclose~ 4 ~ub~tituted 5-hydroxy-2(SH)-furanones having , . ... . ,.. .~ ,. .. - . . ., - ~ - ,. . , . . .,: . , -WO91/16055 2 ~ 7 ~ 7 7 ~ PCT/USg1/02~5 anti-inflammatory, immunosuppressive and anti-proliferative activity where the substituents in the 4 position are a variety 1-hydroxyalkyl, l-acyloxy-alkyl and l-carbamoyloxy-alkyl groups.
United States Patent No. 4,855,320 discloses 5-arylalkyl-4-alkoxy-2(5H)-furanones as anti-convulsive and anti-epileptic agents.
Published European Patent Application No. 0 209 274 discloses 4-alkyl-5-hydroxy-2~5H)-furanones as anti-10 inflammatory and anti-allergy agents.
Chemical Abstracts Volume 107 236559t (1987) .
discloses 4-acyloxy 5-hydroxy-2(5H)-furanones.
~MMARY OP T~E INV~NT~ON
The present invention covers compounds of ~or~ula 1, and compound-~ of Formula 2 R~ ~ R~ R~ ~
For~ula 1 Yor~ul~ 2 - .. . . -. , : , WO9tJ1605~ 2 ~ ~ 8 ~ ~ ~ PCT/US91/02~5-_ ~n which Rl is H, alkyl of l to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds:
R2 is H, alkyl of l to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds;
10 R3 is H, alkyl of 1 to 20 ~arbons, arylalkyl, or halogene, and X is H or alkyl of l to 20 carbons, C0-S~, CO-O~
CO-NH-~, PO(OS~)2 or PO(OS ,)~ ,, where S ,independently is ~, alXyl of 1 to 20 carbons, phenyl, or substituted 15 phenyl. However, in the compounds of the invention illustrated by Formula 2, both ~ and ~3 cannot be hydrogen.
The present invention also covers salts of the above-defined compounds, formed with pharmaceutically acceptable 20 acids or bases, as applicable.
In a second aspect the present invention relates to pharmaceutical formulations comprising one or more compounds o~ Yor~ula 1 or of Yor~ula 2, or both, (or pharmaceutically acceptable salts thereof) in ad~ixture -25 with ~ pharmaceutically acceptable excipient, for the purpo-~ of tre~ting certain conditions, ~yndro~es or diseases in ma~mals, including humans. Th~ compound~ of the invention have anti-infl~mmatory, i~munosuppressant and anti-prolifQrative activity. ThQrQfor~, the compounds 30 are uBeful for treating in ~ammal8 (including human~) inflam~ation, rh~u~toid arthriti~, o~teo~rthrlti~, rheumatic carditis, ocular and dermal infl~mmatory diseasQs~ autoi~mune diseas~. such a~ allergic di eases, .. ~ . .. . . .. .
:. . ~
WO91/1605~ 2 ~ ~ 8 7 7 ~ PCT/US9t/02005 bronchial asthma and myasthenia gra~is, and for suppressing unwanted immune responses and retarding proliferation of cell.
. ~ R,CHO ~HC_Ca~Et E~ULl ~ R~ OH)C--CCOaEt Formula 3 4 . Formula 4 1. H2 / Llndlar .
catalyst 2. acld :
=
o~o~Rl Formula 1 R2 ~ Ra = H
R-~ctlon Sch~m- 1 In still another a~pect, the present invention relates to the processes of making the compounds of .
For~ula 1 and of ~o~ula 2. In general tercs, these processes, shown in R-~ction ~oh-u- 1, 2, 3 ~n~ ~ comprise the steps of reacting an aldehyde o~ ~o~ula 3 with a .... ,, . ~ ........ .. . .
, ~ . . . . . . .
WO91/160S5 2 ~ ~ 3 ~ 7 ~ PCT/US91/02005 -lithium or magnesium salt derived fro~ a propiolate ester, , such as ethyl propiolate (Co~poun~ 4), to yield an Rl-substituted 4-hydroxy --ynoate of For~ula 4 (Rl defined as in conn~ction with For~ula 1 and Fo~ula 2).
Hydroganation over a "poisoned" catalyst (Lindlar catalyst) converts th~ acetylenic (triple) bond into an olephinic (double) bond. This is followed by acid catalyzed cyclization to yield compounds of For~ula 1 where R2 and ~3 ar~ hydrogen.
~c~ol~c=cc~ KOH , R,C~OH)C_CCO~N
Formub ~ Formub S
. :
Jon-~
r-~-nt R,COC----CC02H
Formul~ 6 , H2 / Llndbr o~l~ly~t ¦ R~COCH=CHCO,H ¦
¦ cycll2~tlon R~ccllon Sch-m 2 ~,.
D,C;~R, O 01~ :
Formub 2 R~ ~ R~ H ~ - -... : : ~ . .. . - . :. : .~ ., , -W091/16055 2 ~ 7 ~ 7 7 ~ PCT/US91/02~S
In order to obtain compounds of For3ul~ 2, as is shown in Re~ct~o~ 80heme 2, the intermediate Rl-substituted 4-hydroxy--ynoate of For~ula ~ is saponified to obtain the corresponding free carboxylic acid of ~ormula 5, which is thereafter oxidized (typically with Jones reagent) to yield the corresponding Rl-substituted 4-oxo-alkynoic acid of For~ul~ 6. The intermediate of Formula 6 is hydrogenated over a "poisoned" catalyst, typically Lindlar catalyst, to yield an alkenoic acid intermediate which cyclizes, usually spontanously, to provide compounds of Fo~mula 2 where R2, R3 and ~ are hydrogen. As is shown in R-~otion 8ch~m- 2, the compounds of Formu~a 2 can be reduced with a mild redu~ing agent, such as sodium borohydride to provide the corresponding compounds-of ~ormul~ l. A theoretical explanation for this reaction (although the present inventors do not wish to be bound by theory) is that the carbon in the 5-position of the 5-hydroxy-2(SH)-furanone molecule is an "aldehydic" carbon, ring closed with the carboxylic acid group in the "2-position" of the ring, and that the aldehydic carbon is reduced with 80diu~ borhydridQ to a primary alcohol, which, thereafter., ring closes w~th the carboxylic acid to for~ a lactone of Yor~ula ~.
Compounds Or ~or~ula 2 where the S substituent is other than hydrogen, can be obtained by acylation, carbamate formation (through rQaction with isocyanate) phosphorylation and the like, in accordance with procQdures which are within the sXill of the practicing organic chemist.
.
' - - . . ' . ~
' :: '. ' . , ' ' ' . ' ~ , ' :
, , . -. . , : . . ~
' . : ,- . .. ' : ' ' .: . ' :
WO 91/16055 2 ~3 7 8 7 r~t ~ pcr/us9l/o2oo5 ~
R~COCH2R2 ~CHOCO2H acld ~¦ R~coCR2=cHco2H ¦
Formula 7 ~ Formula 8 S ~ '' / heat ~/
10 ~, , XO~( ~, NllrH~ D~, ;
Formula 2 Formula 2 Formula 1 X = alkyl R3 = X = H R3 = H
R3 = H
Br2 . , L~R H2O / acid ~ ~ 1 20 o ox O OH
Formula 2 Formula 2 X = alkyl Reactlon Scheme 3 WO91/16055 2 ~3 7 g ~ 7 ~ PCT/US91/02005 In order to obtain compounds of Formula 2 where neither R~ nor ~2 are hydrogen, a ketone of Formul~ 7 (which bears the desired Rl and R2 groups) is condensed under acidic condition with glyoxylic acid (Compoun~ S), as is shown in ~eAct~o~ 8chQ~- 3. An inter~ediate condensation product of Formula 8 usually is not isolated because it cyclizes during the condition of the condensation reaction to form the furanones of For~ul~ 2 where the Rl and R2 groups are derived from the starting ketone of For~ula 7 and where S is hydrogen. Reduction of the 5-hydroxy-2(5H)-furanone compound of For~uls 2 (S is ~) with sodium borohydride, as shown in ~e~ctlon 8ch-~e 3 results in "removal" of the 5-hydroxy group and yields the corresponding compound of For~ula l.
Referring still to R-actlon 8c~ 3, compounds of Formul~ 2 where Rl is hydrogen, are obtained when the starting material of Formul- 7 is an aldehyde rather than a ketone, (in Formula 7 Rl-H). In this case, the condensation reaction with glyoxylic acid (Co~pound 5) is usually performed in the presence of morpholine hydrochloride. An alkyl substitutent for the 5-hydroxy function (in Formula 2 ~alkyl) is introduced into the molecule by reacting the 5-hydroxy-2(5H)-furanone derivative of For~ul- 2 with the appropriate alcohol (SO~) in the presence of acid. The resulting 5-alkoxy-2(5H)-furanone derivative Or Tor~ul~ 2 where R3 i5 hydrogen, is brominated to yield the corresponding 3-bromo-5-alkoxy-2(5H)-furanone derivative Or For~ula 2. The alkoxy substituent can be replaced wit~ OH by reaction with agueous acid.
.: . . . . . ~ - -.
2 ~ ~ 8 7 7 ~L
WO 91/160S5 PCI-/US91/02005 _ R~ ~ CH5Cil,1 BuLI ,~c~CR,' Formula 9 Formula 10 Formula 11 RlMgBr H2 ~ ~ ~ ~
R~ R2 R3 R2 O~OH O~OH
ls Formula 2 Formula 2 Na B H4 NaBH4 ,, ~ ~
Formula 1 Formula :
Reaction Scheme 4 W O 91/16055 2 ~ r~ ~ 7 7 ~ PC~r/US91/02005 Re~ct~on 8c~me ~ summarizes a reaction sequence, in which compounds of the invention can be prepared where neither R2 nor R3 are hydrogen. In accordance with this scheme, a di-substituted maleic acid anhydride (For~ul~ 9) S is reacted with the lithium salt of an alkyne (Forsul~ 10) to provide a 5-alkynyl substituted 5-hydroxy-2(5H)-furanone derivative (Formul~ 11). In Formul~ 10 -CC-R~
symbolizes such a precursor of the group Rl which is readily converted by hydrogenation and or other reactions within the skill of the practicing organic chemist, into the group R~ defined in connection with Formula 1 and -Formul~ 2. Reactlon 8c~-m- ~ show~ a hydrogenation step in which the olephinic bond of the intermediate of Formul~
11 is partially or fully saturated to provide compounds of Formul- 2. Reduction of the compounds of Fon~ul~ 2 with sodium borohydride provides compounds of Formula:l.
Another process of preparing compounds of the invention where neither R2 nor ~3 are hydrogen, involves the react~on a di-substituted maleic acid anhydride of Formula 9 with a Grignard reagent of the formula Rl-MgBr to provide compounds of ror~ul~ 2 where S is hydrogen.
Reduction of the~e compounds with sodiu~ borohydride, yields compounds of Yor~ul~ ~.
In anothe~ general aspect, the processes leading to the compounds of the invention ~ay involve performance of routin~ chemical reactions (~uch as e~terification, saponlfication of esters, oxidation of alcohols to ketones or aldehydes, formation o~ acetals, ketal , and lactones from aldehydes or keton~s, and th~ like) which are well known to the practicing synthetlc organic chemist.
When it i5 desired to ~ubstitut~, for example acylate, the 5-hydroxy function of th~ compound3 of Formula 2, an S group (as defined in connection with .: :
.- . . ~ . .
. , .
. . , . ~ .. ,; .. .
2~7877P
W091/16055 PCT/US91/02~5.
these formulas) can be introduced into the 5-hydroxy-2(5H)-furanone compounds by conventional means.
As it was illustrated in connection with R-~ct~o~ schQme 3, introduction of an ~ alkyl group into the compounds of Formul~ 2 in reality is formation of an acetal, which can be accomplished by treating the respecting 5-hydroxy-2(SH)-furanone with an alcohol 20H in the presence of acid.
General Emb~dim~
10 Definitions The terms "ester", "amine", "amide", "ether"
"acetal", "lactone" and all other terms and terminology used here, (unless specifically defined in the present description) refer to and cover any compounds falling within the respective term as that term is classically used in organic chemistry.
Unless specifically noted otherwise, preferred esters are derived fro~ the saturated aliphatic alcohols or acids of ten or.fewer carbon atoms or from 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 alcohol~. Also preferred are the phenyl or lower alkylphenyl esters.
The term ~alkyl" as used in the pre6ent description and claim~ includes straight chain alkyl.group~, branched chain alkyl group~, cycloalkyl groups, alkyl .ubstituted cycloalkyl groups, and cycloalkyl ~ubstituted alkyl groups. Unles~ the nu~ber of carbons i~ otherwise specified, ~10WQr alkyl~ means the ~ormer bro~d definition of "al~yl" groups ~ut with tha re~triction that ~he group has 1 to 6 carbon atoms.
The term "long chain alkyl" ~l~o ~e~n~ the for~er broAd def~nition o~ "alkyl" groups ~ut with the . . . . . . .
.
' WO91/16055 2 ~ 7 o 7 7 ~ PCT/US91/02005 restriction that the group has no less than 4 carbon atoms, and no more than approximately 2~ carbon atoms.
Unless specifically noted otherwise, preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms, or the cyclic or saturated aliphatic-cyclic radicals of 5 to lO carbon atoms.
Some of the compounds of the invention (~or~ula 1) contain a non-equilibrating chiral center in the 5 position of the furan ring. Other compounds of the invention may contain one or more additional chiral centers. Accordingly, the compounds of the invention may be prepared as mixtures of enantiomeric compounds (where the enantiomers ~ay or ~ay not be present in equal amounts) or ~s optically pure enantiomers. When there is more than one chiral center, the compounds of the invention may also be prepared as mixtures of diastereomers, or as pure diastereomers, and each diastereomer itself may be a mixture of enantiomers in 1:1, or other, ratios. Alternatively, each diastereomeric compound may be sterically and optically pure. However, all of the abovo-noted form~, including optically pure enantiomers and mixtur~s thereof, a~ well as all diasterQomers, are within scope of the pre3ent invention.
Som~ of the compound~ of the invention, for example tho~e which contain olephinic doubl~ bond~ in the side chain~, may have Çi~ and tran~ storQoi~om~rfi. The scope of the invention includes both pur~ ster~oisomers as well a~ mixtures thereof.
A pharmacQuticalIy acc-pt~bl~ salt may be prepared for ~ny compound of this invention having a functionality capable of forming such salt, for ex~mle an acid or an amine functionality. A pharmac~utically acceptable salt -- .. . . : .
. :
2 ~ 7 ~
W O 91/16055 PC~r/US91/02005 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 trialkylamines or ethanol amines. Sal~s may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen suf~iciently basic as to be capable of forming acid addition ~alts, such may be formed with any inorganic or organic acids or alkylating agsnt such as methyl iodide. Preferred salts are those for~ed with inorganic acids such as hydrochloric acid, sulfuric acid or pho~phoric acid. Any of a number of simple org~nic acid~ such as mono-, di- or tri-acid may also bQ usQd.
The prefQrred compounds of the present invention are, with referencQ to ror~ula 2 and with re~p~ct to the OS
substituent in thQ 5-position of the furanone moiety, tho~e where thQ sub~tituent is hydroxy, ~thoxy or 25 ac~tyloxy (~ i~ H, or CH30 or CH3CO). -Wlth r sp~ct to the Rl susbtituQnt in th~ 5 position of th~ 2(5H)-furanone molecule, th~ prQferred compounds in accordance with ~he pr~sent invention are those where ~1 is hydrogen, long chain alkyl, or ~rylalkyl. Compounds ar~ particularly pr-ferr~d in thi8 rQg~rd whQre th~ ~1 group i~ long chain alkyl which i~ fitraight chain-d, or where the ~ i8 ~rylalkyl containing a straight ~lXyl chain of 3 carbons.
-: ., , : . ... ,-.. , ... .. ,. .... , ~.. - .. ,~: - ... .. ~ . -WO91/16055 2~7~77 1 PCT/US91/02005 With respect to the ~2 substituent in the 4-position of the 2(~H)-furanone molecule, the compounds of the invention are preferred where ~2 is hydrogen, or alkyl group, particularly straight chain alkyl With respect to position 3 of the 2(5~)-furanones of the invention, compounds are preferred where ~3 is H, methyl or bromo The most preferred compounds of the invention are those listed just below with reference to Formul~ 1 or 10 Formul~ 2 Formula 1, compoun~ 6 ~1=C~3(CH2)8~ R2-H~ and R3 H;
Formula 2 Co~poun~ 7 R1=CH3(CH2)g~ R2 H, R3 H
S-H
Formul~ 1, compoun~ 8 ~1=(CH2)3-c6H5~R2=cH3~ and 15 R3-C~3;
' P ~ 9 R1 H~ R2-CH3(CH2)7~ R3=Br and SSH, and ~or~ul~ ', Co~poun~ lO Rl'H~ R23C~3(CH2)7 and R3 H
The compounds of the present inv~ntion are useful in pharmaceutical compositions to produce anti-inflammatory, immunosuppres~ant and anti-proliferative activity The diseases, syndromes or conditions of mammals (including humans) which can be treated with pharmaceutical compositions containing one or more co~pounds of the invention (or salt~ thereof) include inflammation, rheumatoid arthriti~, osteoarthritis, rheumatic carditis, ocular and dermal $nflammatory diseasQs, autoimmune di~ease~ 3uch as allergic disaases, bronchial asth~a and myasthenia gravi~, unwanted immune r~pon~es and unwanted proli~eration of cell~, psoria~i~, acne, atopic diseases and allorgic con~unctiviti~
The activ~ty o~ the compounds o~ this invention is demonstrated by ~nhibition of the enzyme phospholipase A2 .. . . . . . . ....................... .
.. .. . .
. - .. - . .. .. . ., ~, . . ~ . . ~
WOsl/16055 2 ~ ~ ~ 7 7 ~ PCT/US91/02005 ~
.~ vitro and by reduction of inflammation in the mouse ear anti-inflammatory assay in vivo.
Activity of compounds of this invention may also be demonstrated by inhibition of phosphoinositide-specific phospholipase C. This activity has been reported for manoalide and may indicate anti-inflammatory utility.
Bennett et al, Molecular PharmacolQgy 32:587-593 (1987).
Activity of the compounds may also be demonstrated by inhibition of ornithine decarboxylase, a rate limiting enzyme in cellular growth, which indicates use in treating psoriasis and neoplasis.
The compounds also modify calcium homeostasis. This activity i8 shown by effect on intracellular calcium levels in experiments using gastric glands, spleen cells, epithelial cells, GH3 cells, etc. Calcium is inhibited from entering through the plasma membrane calcium channels and calcium release from intracellular stores is also blocked. Modification of calcium homeostasis is expected to have application in diseases of the nervous ~ystem involving modification of membrane lipids or transmitter release (Parkinson's, Alzheimer's), di~eas~s of the cardiovascular sy~tem involving application of cardiac or vascular smooth muscle contractility and platelet aggregation (hypertension, cardiac infarction and atherosclerosi~), diseases of the ga~troint~stinal tract such a8 ul¢er disease, diarrhea, motility due to secretion of acid or Cl , diseases of the kidney involving renal handling of fluid an~ electrolytes tmetabolic acidosi~, alk~lo~is), and di~eas~ of abnormal growth (neopla~ia, psoria~is).
The compounds of thiQ invention hav~ acti~ity which i~ si~ilar to that o~ manoalide, th~t i8 the co~pounds app~ar to be devoid of the endo~rine propertie~ of the . , ~ , . , -. . . . .. ..
... . ... , . ~, , , : , ..
- . . .. . . . , :
.: .: ~ . .
.. . . . .
- . ~ ..... ,. . ~, ;: , - . . ~
WO91/16055 PCT/US9t/02~5 2~7~7 ~
glucocorticoids while having anti-inflammatory and immunosuppressive properties.
In the method~ of this invention, the compounds of the invention are administered to mammals, includi~g humans, in an effective amount to produce the desired activity, preferably in an amount of about 0.05 to lOO mg per day per kilogram of body weight. The amount of the compound depends upon the disease or condition being treated, the severity thereof, the route of ad~inistration lG and the nature of the host. The compounds may be administered topically, orally, parenterally or by other standard routes of administration.
Pha~maceutical compositions of this invention comprise compounds of Yormula 1 and of For~ul~ 2, and pharmaceutical carriers suitable for the route of ad~inistration. Standard methods for formulating pharmaceutical compositions o~ this type may be found in Reminaton's Pha~se~dh~LL~ ~ ss~ Mack Publishing Company, Easton, PA.
For topical administration, the pharmaceutical composition may be in the for~ of ~ salve, crea~, ointment, spray, powder or the like. Standard pharmaceutical carriers for such compositions may be used.
Preferably, compo~itionQ for topical administration will contain 0.05-5% of the active ingredient.
A typic~l cream formulation may contain the following: -Inaredient - P~rts by Weiaht -Water/glycol mixture 50-99 (15% or ~ore glycol) Fatty ~lcohol 1-20 Non-ionid surfactant 0-lO
M~neral oil 0-lO ;
, ~
. . ...... . . , . . : . . , . ,., -W091/160S5 2 ~ 7 8 7 7 L PCT/US9t/0200s.~
Typical pharmaceutical adjuvants 0-5 Active ingredient 0.05-5 A typical ointment formulation ~ay contain the following:
Inaredients ~ s by Weiht White petrolatum 40-94 Mineral oil 5-20 Glycol solvent 1-15 Surfactant 0-10 Stabilizer O-lo Active ingredient 0.05-5 For oral ad~inistration, suitable pharmaceutical carriexs include mannitol, lacto~e, ~tarch, ~agnesiu~
stearate, talcum, glucose and magne ium carbonate. Oral compositions ~ay be in the form of tablets, capsules, powd~rs, solutions, suspensions, su6tained release formulations, and the like.
A typical tablet or capsule may contain the following:
Inaredients P~çent w~w Lactose, ~pray-dri~d 40-99 Magnesium ste~rat~ 1-2 Cornstarch 10-20 Active ingredient 0.001-20 Parenteral compo~ition~ are prepared in conventional suspen~ion or solution ~orms, a~ emuls~ons or as solid ~ :
forms ~or reconstruction. Suitable carriers are water, saline, dextro--, Hank' 8 solution, ~inger'~ solution, glyc-rol! and the like. Parent~ral administration i~
usually by in~ction which ~ay be ~ubcutaneous, intramuscular or intravenous.
., . .. . ;
WO91/16055 2 ~ ~ ~ 7 7~ PCT/US91/02005 The compounds of this invention may be combined with other known anti-infla~matory/immunosuppressive agents such as steroids or non-steroidal anti-inflammatory agents (NSAID) in the pharmaceutical compositions and methods deecribed herein.
The assay procedures by which useful biological activity of the compounds of the invention can be demonstrated, are described below.
Calcium Channel (mobilization~ Inhibition Assay Polymorphonuclear leukocytes (PMNa), gastric glands, GH3 cells, A431 cells, spleen cells, hu~an ~eratinocytes corneal cells, etc. were loaded with the Ca2+ sensitive fluorescent dye, Fura-2. The appropriate cell type was chosen and the potency and e~ficacy of the anti-inflammatory furanones on calcium mobilization, calcium channel inhibition wa~ quantitated. The methods used for A431 cells listed below are representative of those used for other cells.
A431 cell~ were detached using a 5-10 min trypsin-EDTA trea~ment wherQas GH3 cell~ were treated 2 to 5 minwith a 1% pancreatin solution. Cells were immediately washed twice in a 20mM HEPES bu~fer (pH 7.4) containing 120mM NaCl, 6 mM KCl, 1 ~M MgS04, 1 mg/ml gluco~e and mg/ml pyruvatQ and 1.4mM calcium (mediu~ A).
Approximately 5 x 106 cell~ w~re suspQnded in medium A and incubated with 4uM fura-2-AM for 15 ~in ~t 37C.
After washing the ~ura-2 loaded cells, the uptake of dye was checked using fluorescence microscopy and found to be evenly ~istributed in the cyto801 0~ all cells.
Fluore~cenc~ waB continucusly r~cordsd with a Perkin-Elmer LS-5 spQctrofluorom~ter. The excltation w~velength was set at 340n~ and emicsion wavelength ~et at 500nm. The cell suspension was continually stirred, maintained at ~ . - - .. .. . . . . . . ......... . . . . ................ .
.. .. : . - - . . , . ~ . . . : . . ~ .
W091/16055 2 ~ 7 ~ 7 7 ~ PCT/US9t/02~5 ~
37C and equilibrated for approximately 5 min before addition of various agents. [ca2+i was calculated using the following formula:
tca2+]i = 220 X F - Fmin Fmax - F
All fluorescence values were measured relative to a EGTA-quenched signal determined as follows: F was the relative fluorescence measurement of the ~ample. FmaX was determined by lysing the cells with digitonin (lOOug/ml) in DMSO. After FmaX was determined the pH was adjusted to 8, with NaOH and Ca2+ chQlated with 3mM EGTA to totally quench the fura-2 sis ~1 and obtain Fmin.
When quin-2- was used, cell~ were incubated with lOuM
quin-2- at 37C for 1 hour, wa~hed and th~n used.
is Mouse ~ an~i-Inflam~tory Assay Test compound and phorbol ~yrist~te ~cetate (PMA) are topically applied simultaneously to the pinnae o~ the left ears of mice. PMA alone is applied to the right ear.
Three hours and 20 minute~ after application, the mice are sacrificed, left and ri~ht e~r~ remo~ed, and standard sized bores taken. Edema (inflammation) is m~asured as the diffQrence ~n weight between left and right ears [Van Arman, C.G., Clin Phar~col ~h~ (1974) 16:900-904].
Inhibition o~ PhoQpholipase A2 Th efSect of compounds of thi~ invention on bee vonom phospholipa~ A2 i d~termin~d by the following procedure:
a. Bee venom pho~pholipasQ A2 in lO uM HEPES (pH
7.4) with 1 mM CaC12 i~ incubat~d with v~hicl~ or test ~gent for l.O hour ~t 41.
b. 1.36 mM pho~photidylcholine, 2.76 mM Triton X-:. .. : . ~ -- ~ , .. :, ~.
WO 91/16055 2 ~ ~ ~ 7 7 ~ PCT/US91/02005 loo ?
are dispersed in buffer by sonication and then mixed with L-3 phosphotidylcholine, l-palmitoyl-s (1-14C) palmitoyl for 10 min.
c. Start the reaction by the addition sf enzyme (0.495 units/ml).
d. Incubation for 15 sec. at 41.
e. Reaction is terminated by addition of 2.5 ~1 of isopropanol: n-heptane: 0.5 M H2SO4 (40:10:1;
v:v:v: ) .
f. 2.0 ml n-heptane and 1.0 ml H2O added; mixture centrifuged.
g. 2.0 ml n-heptane removed and treated with 200-300 mg of silica gel HR60.
h. Samples centrifuged; 1 ml of n-heptane SN
removed and added to 10 ml scintillation fluid.
i. Samples counted on a scintillation counter.
Inhikition.of Phos _ cific Phospholi~ase C
The ef~ect of compound~ o~ this in~ention on phosphoino~itide-~pecific phospholipase C ~ay be determined by procedures described by Bennett et al, Molecular Pharmacology 32:587-593 (1987).
Activ~ty Data In the above-de cribed pho~pholipase A2 assay the -- compounds of the invention we~e found to provide 50%
inhibition (IC50) o~ bee vsnom phospholipa~e A2 at the following concentrations (in micromol0~ indicat~d in ~1- 1. ' ' ~'..
wO91/16055 2 0 7 ~ 7 ~ ~ PCT/US91/02~5 ~
T~ble 1 Phospholipase A2 Assay.
Compound name or number IC50 (um) l 0.03 *Data for Compoun~ l (monoalide) are provided for comparison.
In the above-described phospholipase A2 assay compounds of the invention which are listed in ~abl- 2 were found to provide the following percentage (%) inhibition of bee venom phospholipase A2 at lO0 micromolar concentration.
~4b~0_2 .
The compounds of the present invention can be made by the synthetic chemical pathways which are illustrated above in general terms, and in the ~pecific examples as well. The ~ynthstic che~ist will readily appreciate that the conditions described here in general terms, and specifically, can be generalized to any and all co~pounds repr-sented by ~or~ul~ ~ or by For~ul~ 2, as applicable.
Furthermore, th~ synthetic ch~mist will readily appreciate that the hereln dQscribed ~ynt~etic step~ may be varied or adjusted by tho~e ~killed in the ~rt wlthout departing from the soope and spirit o~ the invQntion. Therefore, the following examples o~ spec~ic compounds of the invention, and spec$fic examples of the synthetic steps in which the compound~ and cert~in intermediates are made, , ~ ~}
- . , : . .
-, . . . . . . .. . .
.. : ...... :; : : , . .. . . . : . . . .
WO91/16055 2 ~ 7 ~ 7 71 PCT/US91/02005 are set out to illustrate the invention, not to limit its scope.
Specifi~ E~mp~es Example 1 Ethyl 4-hydroxy-6-phenylhex-1-ynoate (Compoun~ 11) n-Butyl lithium (a 1.6 M solution in hexane; 6.7 ml, 10.7 mmol) was added dropwise to a solution of ethyl propiolate (1.04 g, 10. 6 mmol ) in tetrahydrofuran (10 ml) at -78 under argon. After 10 minutes, a solution of hydrocinnamaldehyde (1.42 g, 10.6 mmol) in tetrahydrofuran (5 ml) was added. Stirring was continued at -78C for 2 hours and acetic acid (1 ml) was added. on warming up to 0, the reaction mixture was poured into water.
Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts a~forded an oil, which was flash chromatographed with silica using 30% ethyl ether/petroleum ether. Fractions with Rf of about 0.28 on evaporation afforded the title ~ster as a light yellow oil.
1 NMR (CDC13) 1.34 (m, 3H), 2.10 (m, 2H), 2.40 (br, lH), 2.83 (t, 2H, J - 8.3 Hz), 4.25 (q, 2H, J s 7.3 Hz), 4.50 (t, lH, J ~ 7.0 Hz) and 7.29 (m, 5H).
LRNS m/e (% abundance) 233 (M++1, 2), 232 (M+, 7), 186 (24), 185 (42), 170 (51), 169 (30), 158 (24), 142 (37), 141 (100) and 105 (84).
5-~2-Ph~ny~a~hy~-2f5H)-furanone (Compou~ 12) A ~olution of ethyl 4-hydroxy-6-phenylhex-1-ynoate (Compo~d 11, 585 mg, 2.5 mmol) in ether (12 ml) was hydrogen~ted over ~indlar catalyst (50 ~g) at roo~
temperature for 3 hour~. The ~ixturQ wa8 ~ltered through celite and the filtrate was refluxed w~th 2M hydrochloric acid (1 ml) for 2-1/2 hours. On cooling, the mixture was . ~ . . . , . . . . . . . . , .~ - , .
. , .. . ,. ,- . . . -, .
. . , .. , . , : .
Wosl/l6o55 2 ~ ~ ~ 7 7 ~ PCT/US9l~02005-~ 1 dried (magnesium sulphate) and evaporated to dryness to give an oil, which was purified by preparative thin layer chromatography (tlc, 20x20 cm, 2000u silica plate:
developed with 30% ethyl ether/petroleum ether). The title furanone was obtained as colorless prisms (recrystallized from ether): mp 66-7.
lH NMR (CDC13) 1.98-2.16 (m, 2H), 2.86 (m, 2H), 5.08 (m, lH), 6.16 (dd, lH, J = 6.0 Hz, 1.6 Hz), 7.36 (m, 5H) and 7.45 (dd, lH, J s 6.0 Hz, 1.6 Hz).
13C NMR (CDC13) 31.3, 34.9, 82.3, 121.5, 126.3, 128.5, 128.6, 140.2, 156.1 and 172.9.
HRMS exact mass calculated for C12H1202 (M+) 188.0837, found 188.0841.
Exam~le_~
4-Hy~oxy-6-phenylhex-2-ynoic acid (Co~pou~ 13) A solution of potassium hydroxide t377 mg, 6.7 mmol) in 95% ethanol (lo ml) was added to a solution of ethyl 4-hydroxy-6-phenylhex-1-ynoate (Co~pou~ 11, 1.04 g, 4.5 mmol) in the ~ame solvent tlO ~1) at 0, and the reaction mixture was stirred at room temperature for 15 hours.
After most o~ the sol~ent was removed, the residue was dissolved in water (ca. 15 ml) and ex*racted with dichloromethane (discarded). After the extraction the aqueous phas~ w~ acid~fied to pH 1 with dilute hydrochloric acid ~nd extra~ted thorou~hly with ethyl acetate. Ev~poration of the dried (magnesium sulphate) extracts gave the titl~ ac~d ~8 a pale yellow oil (which cryst~llizes 810wly on standing), which w~s used directly in the next step.
lH NMR (CDC13) 2.16 (m, 2H), 2.85 (m, 2H), 4.52 (dd, lH, J - 11.3 Hz, 6.6 Hz), 5.10 tbr, 2H) ~nd 7.31 (~, 5H).
LRMS ~/e (% ~bundance) 204 (M+, 6), 142 (42), 141 (75), 134 (21), 133 (11), 131, (10), 118 (34), 11~ (32), I
Wo9l/l6055 2~o771 Pcr/lls9l/n2l)os 115 (21) and 105 (100).
4-Keto-6-phenylhex-2-ynoic acid (Co~pou~ ) A solution of Jones Reagent (a 2.67 M solution in sulphuric: acid; 2.07 ml, 5.5 mmol) was added dropwise to a s solution of 4-hydroxy-6-phenylhex-2-ynoic acid (~ompound 13, 750 mg, 3.7 mmol) in acetone (12 ml) at 0 and the reaction mixture was maintained at 0 for 70 minutes. The mixture was quenched with ethanol (2 ml) and extracted with ethyl ether. Evaporation of the dried (magnesium 10 sulphate) extracts gave the title acid as a yellow oil which was used directly in the next step.
1 NMR (CDC13) 3.02 (s, 4H), 7.30 (~n, 5H) and 8.80 (br, lH, exchanged with D20).
5-Hydroxy-5-(2-Dhenylethyl)-2-furanone (Compou~ 15) A solution of 4-keto-6-phenylhex-2-ynoic acid (Co~pou~ , 228 mg, 1.1 mmol) in ethyl ether t8 ml) was hydrogena~ed over Lindlar catalyst (20 mg) at 0 ~or 80 minutes. The mixture was filt~red through celite and the filtrate, after evaporat~on to dryness, was purified by 20 preparative tlc (20x20 cm, lOOOu silica plate; developed with 60% ethyl ether/hexane). The title furanone was obtained a~ a colorless oil.
lH N~ (CDC13) 2.31 (dd, 2H, J -- 10.8 H2, 5.5 Hz), 2.78 (dd, 2H, J - 10.8 Hz, 5.5 Hz), 4.80 (br, lH), 6.11 (d, lH, J - 5.8 Hz), 7.20 (m, 5H) and 7.28 (d, lH, J s 5.8 Hz).
13C N~ tC~C13) 29.7, 39.1, 107.8, 123.1, 126.4, 128.3, 128.7, 140.3, 154.3 and 171Ø
HRMS exact mass calculated for C12H1203 (H+) ,, ;
204.07`86, found 204.0792.
EXZ~ 3 2~hY1 4-hydrox~lftridec-2 vno~te (Co~pou~ld ~6) Methylmagnesi~L~ bromide (a 3M ~olution in WO91/160~5 2 ~ ~ 3 ~ 7 ~ PCT/US91/02005 _ tetrahydrofuran; 7.8 ml, 23.4 mmol) was added dropwise to a solution of ethyl propiolate (Compoun~ ~, 2.25 g, 22.9 mmol) in tetrahydrofuran (10 ml) at -78 under argon.
After 10 minutes, a solution of decyl aldehyd~ (3.58 g, 22.9 mmol) in tetrahydrofuran (2 ml) was added. Stirring was continued for 1 hour while the cooling bath was warmed to room temperature. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl ether. Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 30% ethyl ether/petroleum ether. Fractions with Rf of about 0.31 qave, after evaporation, the title ester as a deep, yellow oil.
lH NMR (CDC13) 0.88 (t, 3~, J ~ 6.4 Hz), 1.27 (br s, 14H), 1.75 (m, 2H) and 4.25 (q, 2H, J - 6.4 Hz).
LRMS m/e % abundance) 255 (M++l, 5), 254 (M+, 5), 237 (6), 209 (8), 181 (12~, 179 (11), 163 (13), 152 (12), 151 (13), 137 (16), 130 (19), 128 (100), 100 (66) and 71 (35).
5-~Q~yl-2~5H)-fu~none (Co~poun~ 6) A solution of ethyl 4-hydroxytridec-2-ynoate (Compou~ 16, 230.6 ml, 1.02 mmol) in ether (10 ~1) was hydrogenated o~er Lindlar catalyst (20 mg) at 0 for 1 hour. The mixture was filtered through celite and after evaporation the filtratQ gav- a residue, which was flash 2S chromatographed on silica u~ing 60% athyl ether/petroleum ether. Fractions with ~f of about 0.18 gave after evaporation a colorles~ oil (157 mg, 59%) identified by lH
NMR as Qthyl (~)-4-hydroxytridec-2-enoate: lH NMR (CDC13) 0.92 (t, 3H, J - 6.7 Hz), 1.31 (br ~, 14H), 1.55 (m, 2H), 4.97 (q, lH, J - 6.2 Hz), 5.91 (d~ 1~, J - 12.5 HZ) nnd 6.41 (dd, lH, J - 12.5 Hz, 7.3 HZ). Th~ oil on crystallization fro~ petroleu~ ~ther, in the presence of a drop of acetic acid, lactonized to give the title furanone .
:' . . . -.- . . ~ , ~
WO91/1605~ ~ 3 7 ~ 7 7 ~ PCT/US9l/02005 as a colorless oil.
lH NMR (CDC13) 0.92 (t~ 3H~ J = 6.7 Hz), 1.30 (br s, r 12H), 1.45 (m, 2H), 1.75 (m, 2H), 5.08 (m, lH~, 6.14 (dd, lH~ J = 5.9 Hz~ 2.6 Hz) and 7.48 (dd, 1~, J = 5.3 HZ~ 1.4 5 Hz).
13C NMR (CDC13) 14.1, 22.6, 25.0, 29.2, 29.3, 29.4, 31.8, 33.2~ 83.4, 121.5, 156.3 and 173.1.
HRMS m/e: exact mass calculated for C13H2202 (M+) 210.1620, found 210.1624.
10 ExamplÇ 4 4-Hydr~ytridec-~-ynoic acid (compoun~ 17) A solution of potassium hydroxide (885 mg, 15.8 mmol) in 95% ethanol (35 ml) was added to ethyl 4-hydroxytridec-2-ynoate (Co~poun~ 16, 2.68 g, 10.5 m~ol) in the same 15 solvent (5 ml) at 0. After ~tirring at room te~perature for 9 hours, most of the solvent was removed and water (20 ml) was added. ThQ mixture was extracted thorouqhy with dichloromethane (discarded), acidified to pH 1 with dilute hydrochloric acid and extracted with ethyl acetate.
20 Evaporation of the dr~ed (magnesium sulphat~) ethyl acetate extracts gave an off-whitQ solid, which on recrystallizat~on from petroleum ether (at -78) ga~e the title acid ~8 colorless p~isms: mp 65-6.
H NMR (CDC13) 0.93 (t, 3H, J ~ 5.7 Hz), 1.31 (br s, 12H), 1.50 (br, lH), 1.81 (~, 2H), 4.56 (dt, lH, J ~ 5.0 Hz, 1.9 ~z) and 5.00 (br, lH).
L~MS m/s ~% ~bundance) 226 IM+, 5), 137 (13), 124 (12), 121 (18), 107 (26), 100 (94), 97 (33), 95 (27), 93 (43) 85 (48), ~3 (63), 79 (55) ~nd 71 (75).
4-K~Q~id~c-2-ynQ~c-ac~ (Compou~ 18) r Jon~ re~gQnt (a 2.67 M ~olution ~n ~ulphuric acid;
1.32 ml, 3.5 mmol) was ~dded dropwi~e to a solution of 4-hydroxytridec-2-ynoic acid (~o~pou~ 17, 531.8 ~g, 2.4 2~i37~ ~
mmol) in acetone (lo ml) at o and the reaction mixture was maintained at 0 for 70 minutes. The mixture was quenched with ethanol (1 ml) and dried with magnesium sulphate. on evaporation, the title acid was obtained as a colorless oil.
lH NMR (CDC13) 0.87 (t, 3H, J = 6.6 Hz), 1.25 (br s, 12H), 1.67 (m, 2H), 2.64 (t, 2H, J = 7.2 Hz) and 4.90 (br, lH).
LRMS m/e (% abundance) 224 (M+, 5), 223 (12), 197 (36), 155 (37), 149 (14), 37 (21), 123 tl5), 111 (14), 109 (12) and 97 (34).
~-Hydroxy-5-nonyl-2-furanone (Compoun~ 7) A solution of 4-ketotridec-2-ynoic acid (Compound 18, 220 mg, 0.98 mmol) in ether (10 ml) was hydrogenated over Lindlar catalyst (10 mg) at 0 for 80 minutes. The mixture was filtered through celite and after evaporation to dryness the ~iltr~te gave an oil, which was purified by preparative tlc (20x20 cm, lOOOu silica plate; developed with 60% ethyl ether~petroleum ether). The title furanone was obtained as colorless pri~ms (recrystallized from petroleum ether): ~p 54-5.
lH NMR (CDC13) 0.88 (t, 3H, J ~ 7.5 Hz), 1.26 (br s, 12H), 1.40 (m, 2H), 1.98 (m, 2H), 6.12 (d, lH, J = 6.4 Hz) and 7.16 (d, lH, J ~ 6.4 Hz).
13C NMR (CDC13) 14.1, 22.6, 23.4, 29.3, 29.4, 31.8, 37.5, 108.5, 123.0, 154.5 and 170.8.
HRMS m/e: exact mass calculated 20r C13H2203 (M+) 226.1569, found 226.1568.
Ex~m~J~-5 5-Hydroxy-5-met~yL-4-octyl-2-furanQne (Co~pou~
A mixture o~ 2-undecanone (lO g, 58.7 ~ol), glyoxylic acid monohydrate (Co~pou~ 5, 5.15 g, 56 m~ol) and 85% phosphoric acid (10 ml) was war~ed at 80 for 18 - , , , -.
-;; : , ,. . ~ .~ - , 2 ~ 7 ~
wogl/l60ss PCT/US91/02005 hours. On cooling to room temperature, the mixture was diluted with ethyl ether/dichloro~ethane (50 ml each) and washed thoroughly with brine. Evaporation of the dried lmagnesium sulphate) organic phase gave a yellow oil which on crystallization from ethyl ether/petroleum ether gave 4-ketotridec-2-enoic acid as colorless prisms.
lH NMR (CDCl3~ 0.96 (t, 3H, J = 7.4 Hz), 1.34 (br s, 12H), 1.72 (p, 2H, J = 7.1 Hz), 2.73 (t, 2~, J = 7.1 Hz), 6.74 (d, lH, J = 15.7 Hz) and 7.22 (d, lH, J = 15.7 Hz).
The mother liguor from the above recrystallization was concentrated down and was flash chromatographed on silica using 40% ethyl acetate/petroleum ether. Fractions with Rf of about 0.1 gave, after evaporation, the title furanone as a pale yellow oil.
a5 lH NMR (CDC13) 0.92 (t, 3H, J = 7.4 Hz), 1.30 (br s, 12H), 2.45 (s, 3H), 2.79 (t, 2H, J = 7.5 Hz) and 6.56 (s, lH).
13C NMR (CDCl3) 14.1, 22.7, 26.7, 27.0, 29.2, 29.3, 29.8, 31.9, 124.5, 158.0, 171.3 and 200Ø
HRMS m/e: exact mass calculated for C13H2203 (M+) 226.1569, found 226.1559.
Exam~le 6 5-Methyl-4-octvl-2~5H~-furanone (Compou~d 20) Sodium borohydride (214 mg, 5.7 ~mol) was added to a solution of 5-hydroxy-5-~ethyl-4-octyl-2-furanone (Compoun~ 19, 640 mg, 2.8 mmol) in tetrahydrofuran (15 ml). After ~tirring at room temperature for 80 minutes, moæt of the'solvent was removed and water (lO ml) waæ
added. Extraction (dichloromethane) and Qvaporation of the drisd'(m2gnesium sulphate) sxtract~ gave a residue, which was flash chro~atographed on sil~ca u ing 60% ethyl ether/petroleum Qther. Fract~on~ with R~ of about 0.23 were evaporated to yield the title furanone as a colorless ... . .
WO 91/l~OS~ 2 ~ ~ 3 7 7 ~ PCT/US91/02005 _ oil, which crystallized slowly on storage at -70.
lH NMR (CDC13) 0.85 (t, 3N, J = 5.4 Hz), 1.26 (br s, loH), 1.33 (d, 3H, J = 6.9 Hz), 1.47 (m, 2H), 2.26 (m, lH), 2.83 (m, lH0, 4.33 (q, lH, J = 6.2 Hz) and 5.99 (s, lH).
13C MMR (CDC13) 14.1, 22.4, 22.6, 29.2, 29.3, 29.5, 29.8, 31.9, 71.1, 113.0, 169.2 and 171.8.
HRMS m/e exact mass calculated for C13H2202 (M+) 210.1620, found 210.1617.
Exam~le 7 (Comoun~ 21) A mixture of 2-pentanone (17.1 g, 198 mmol), glyoxylic acid monohydrate (Co~pou~ 5, 8.05 g 88 mmol) and about 85% phosphoric acid (12 ml) was warmed at ca.
80 for 19 hour~. on coolin~ to room temperature the mixture was diluted with ethyl ether/dichloromethane (loO
ml, 1:1) and washed thoroughly wit~ brine. Evaporation of the dried (magnesium sulphate) organic phase gave a yellow viscous oil, which on crystallization from ethyl ether/petroleum ether gave 4-keto-hept-2-enoic acid as colorles~ prisms: mp 100-2.
lH NMR (CDC13) 1.01 (t, 3H, J - 7.9 Hz), 1.73 (p, 2H, J s 7.1. Hz), 2.70 (t, 2H, J - 7.3 Hz), 6.73 (lH, d, J =
15.8 Hz) and 7.19 (d, lH, J 3 15.8 Hz).
HRMS m/e: exact mass calculated for C7H1003 (M+) 142.0630, found 142.0622.
The mother liquor from the above crystallization was evaporated to dryness and extracted thoroughly with petrol~um ether. The combined extract3 were concentrated and cooled to -20 to give the t~tle ~uranone as colorless prisms: mp 37-8.
lH NMR tC~C13) 1.09 (t, 3H, J ~ 7.8 Hz), 2.46 (s, ; - . : - -WO91/160~5 2 ~ ~ 3 7 7 ~ PCT/US91/02005 3H), 2.83 (q, 2~), J = 7.8 Hz) and 6.S7 (s, lH).
13C NMR (CDC13) 13.6, 20.4, 26.6, 124.6, 158.7, 171.2 and 199.9.
HRMS m/e: exact mass calculated for C7H1003(M+) 142.0630, found 142.0622.
Example 8 4-~h~1-5-methYl-2f5H~-furanone (Co~poun~ 22) Sodium borohydride (646 mg, 17 mmol) was added to a solution of 4-ethyl-5-hydroxy-5-methyl-2-furanone (compoun~ 21, 1.21 g, 8.5 ~mol) in tetrahydrofuran (10 ml) at room temperature. After 1/2 hour, most of the solvent was removed and water (10 ml) was added. Extraction (ethyl acetate) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 60S ethyl ether/petroleum ether. Fractions with Rf of about 0.23 gave after evaporation, a pale yellow oil, which slowly crystallized on storage at -20. Recrystallization from ethyl ether/petroleum ether afforded the title furanone as colorless prisms: mp 86-7.
1H NMR (CDC13) 1.16 (t, 3~, J - 7.2 Hz), 1.39 (d, 3H, J z 5.4 Hz), 2.36 (m, lH), 2.84 (m, lH), 4.41 (q, 2H, J =
temperature for 3 hour~. The ~ixturQ wa8 ~ltered through celite and the filtrate was refluxed w~th 2M hydrochloric acid (1 ml) for 2-1/2 hours. On cooling, the mixture was . ~ . . . , . . . . . . . . , .~ - , .
. , .. . ,. ,- . . . -, .
. . , .. , . , : .
Wosl/l6o55 2 ~ ~ ~ 7 7 ~ PCT/US9l~02005-~ 1 dried (magnesium sulphate) and evaporated to dryness to give an oil, which was purified by preparative thin layer chromatography (tlc, 20x20 cm, 2000u silica plate:
developed with 30% ethyl ether/petroleum ether). The title furanone was obtained as colorless prisms (recrystallized from ether): mp 66-7.
lH NMR (CDC13) 1.98-2.16 (m, 2H), 2.86 (m, 2H), 5.08 (m, lH), 6.16 (dd, lH, J = 6.0 Hz, 1.6 Hz), 7.36 (m, 5H) and 7.45 (dd, lH, J s 6.0 Hz, 1.6 Hz).
13C NMR (CDC13) 31.3, 34.9, 82.3, 121.5, 126.3, 128.5, 128.6, 140.2, 156.1 and 172.9.
HRMS exact mass calculated for C12H1202 (M+) 188.0837, found 188.0841.
Exam~le_~
4-Hy~oxy-6-phenylhex-2-ynoic acid (Co~pou~ 13) A solution of potassium hydroxide t377 mg, 6.7 mmol) in 95% ethanol (lo ml) was added to a solution of ethyl 4-hydroxy-6-phenylhex-1-ynoate (Co~pou~ 11, 1.04 g, 4.5 mmol) in the ~ame solvent tlO ~1) at 0, and the reaction mixture was stirred at room temperature for 15 hours.
After most o~ the sol~ent was removed, the residue was dissolved in water (ca. 15 ml) and ex*racted with dichloromethane (discarded). After the extraction the aqueous phas~ w~ acid~fied to pH 1 with dilute hydrochloric acid ~nd extra~ted thorou~hly with ethyl acetate. Ev~poration of the dried (magnesium sulphate) extracts gave the titl~ ac~d ~8 a pale yellow oil (which cryst~llizes 810wly on standing), which w~s used directly in the next step.
lH NMR (CDC13) 2.16 (m, 2H), 2.85 (m, 2H), 4.52 (dd, lH, J - 11.3 Hz, 6.6 Hz), 5.10 tbr, 2H) ~nd 7.31 (~, 5H).
LRMS ~/e (% ~bundance) 204 (M+, 6), 142 (42), 141 (75), 134 (21), 133 (11), 131, (10), 118 (34), 11~ (32), I
Wo9l/l6055 2~o771 Pcr/lls9l/n2l)os 115 (21) and 105 (100).
4-Keto-6-phenylhex-2-ynoic acid (Co~pou~ ) A solution of Jones Reagent (a 2.67 M solution in sulphuric: acid; 2.07 ml, 5.5 mmol) was added dropwise to a s solution of 4-hydroxy-6-phenylhex-2-ynoic acid (~ompound 13, 750 mg, 3.7 mmol) in acetone (12 ml) at 0 and the reaction mixture was maintained at 0 for 70 minutes. The mixture was quenched with ethanol (2 ml) and extracted with ethyl ether. Evaporation of the dried (magnesium 10 sulphate) extracts gave the title acid as a yellow oil which was used directly in the next step.
1 NMR (CDC13) 3.02 (s, 4H), 7.30 (~n, 5H) and 8.80 (br, lH, exchanged with D20).
5-Hydroxy-5-(2-Dhenylethyl)-2-furanone (Compou~ 15) A solution of 4-keto-6-phenylhex-2-ynoic acid (Co~pou~ , 228 mg, 1.1 mmol) in ethyl ether t8 ml) was hydrogena~ed over Lindlar catalyst (20 mg) at 0 ~or 80 minutes. The mixture was filt~red through celite and the filtrate, after evaporat~on to dryness, was purified by 20 preparative tlc (20x20 cm, lOOOu silica plate; developed with 60% ethyl ether/hexane). The title furanone was obtained a~ a colorless oil.
lH N~ (CDC13) 2.31 (dd, 2H, J -- 10.8 H2, 5.5 Hz), 2.78 (dd, 2H, J - 10.8 Hz, 5.5 Hz), 4.80 (br, lH), 6.11 (d, lH, J - 5.8 Hz), 7.20 (m, 5H) and 7.28 (d, lH, J s 5.8 Hz).
13C N~ tC~C13) 29.7, 39.1, 107.8, 123.1, 126.4, 128.3, 128.7, 140.3, 154.3 and 171Ø
HRMS exact mass calculated for C12H1203 (H+) ,, ;
204.07`86, found 204.0792.
EXZ~ 3 2~hY1 4-hydrox~lftridec-2 vno~te (Co~pou~ld ~6) Methylmagnesi~L~ bromide (a 3M ~olution in WO91/160~5 2 ~ ~ 3 ~ 7 ~ PCT/US91/02005 _ tetrahydrofuran; 7.8 ml, 23.4 mmol) was added dropwise to a solution of ethyl propiolate (Compoun~ ~, 2.25 g, 22.9 mmol) in tetrahydrofuran (10 ml) at -78 under argon.
After 10 minutes, a solution of decyl aldehyd~ (3.58 g, 22.9 mmol) in tetrahydrofuran (2 ml) was added. Stirring was continued for 1 hour while the cooling bath was warmed to room temperature. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl ether. Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 30% ethyl ether/petroleum ether. Fractions with Rf of about 0.31 qave, after evaporation, the title ester as a deep, yellow oil.
lH NMR (CDC13) 0.88 (t, 3~, J ~ 6.4 Hz), 1.27 (br s, 14H), 1.75 (m, 2H) and 4.25 (q, 2H, J - 6.4 Hz).
LRMS m/e % abundance) 255 (M++l, 5), 254 (M+, 5), 237 (6), 209 (8), 181 (12~, 179 (11), 163 (13), 152 (12), 151 (13), 137 (16), 130 (19), 128 (100), 100 (66) and 71 (35).
5-~Q~yl-2~5H)-fu~none (Co~poun~ 6) A solution of ethyl 4-hydroxytridec-2-ynoate (Compou~ 16, 230.6 ml, 1.02 mmol) in ether (10 ~1) was hydrogenated o~er Lindlar catalyst (20 mg) at 0 for 1 hour. The mixture was filtered through celite and after evaporation the filtratQ gav- a residue, which was flash 2S chromatographed on silica u~ing 60% athyl ether/petroleum ether. Fractions with ~f of about 0.18 gave after evaporation a colorles~ oil (157 mg, 59%) identified by lH
NMR as Qthyl (~)-4-hydroxytridec-2-enoate: lH NMR (CDC13) 0.92 (t, 3H, J - 6.7 Hz), 1.31 (br ~, 14H), 1.55 (m, 2H), 4.97 (q, lH, J - 6.2 Hz), 5.91 (d~ 1~, J - 12.5 HZ) nnd 6.41 (dd, lH, J - 12.5 Hz, 7.3 HZ). Th~ oil on crystallization fro~ petroleu~ ~ther, in the presence of a drop of acetic acid, lactonized to give the title furanone .
:' . . . -.- . . ~ , ~
WO91/1605~ ~ 3 7 ~ 7 7 ~ PCT/US9l/02005 as a colorless oil.
lH NMR (CDC13) 0.92 (t~ 3H~ J = 6.7 Hz), 1.30 (br s, r 12H), 1.45 (m, 2H), 1.75 (m, 2H), 5.08 (m, lH~, 6.14 (dd, lH~ J = 5.9 Hz~ 2.6 Hz) and 7.48 (dd, 1~, J = 5.3 HZ~ 1.4 5 Hz).
13C NMR (CDC13) 14.1, 22.6, 25.0, 29.2, 29.3, 29.4, 31.8, 33.2~ 83.4, 121.5, 156.3 and 173.1.
HRMS m/e: exact mass calculated for C13H2202 (M+) 210.1620, found 210.1624.
10 ExamplÇ 4 4-Hydr~ytridec-~-ynoic acid (compoun~ 17) A solution of potassium hydroxide (885 mg, 15.8 mmol) in 95% ethanol (35 ml) was added to ethyl 4-hydroxytridec-2-ynoate (Co~poun~ 16, 2.68 g, 10.5 m~ol) in the same 15 solvent (5 ml) at 0. After ~tirring at room te~perature for 9 hours, most of the solvent was removed and water (20 ml) was added. ThQ mixture was extracted thorouqhy with dichloromethane (discarded), acidified to pH 1 with dilute hydrochloric acid and extracted with ethyl acetate.
20 Evaporation of the dr~ed (magnesium sulphat~) ethyl acetate extracts gave an off-whitQ solid, which on recrystallizat~on from petroleum ether (at -78) ga~e the title acid ~8 colorless p~isms: mp 65-6.
H NMR (CDC13) 0.93 (t, 3H, J ~ 5.7 Hz), 1.31 (br s, 12H), 1.50 (br, lH), 1.81 (~, 2H), 4.56 (dt, lH, J ~ 5.0 Hz, 1.9 ~z) and 5.00 (br, lH).
L~MS m/s ~% ~bundance) 226 IM+, 5), 137 (13), 124 (12), 121 (18), 107 (26), 100 (94), 97 (33), 95 (27), 93 (43) 85 (48), ~3 (63), 79 (55) ~nd 71 (75).
4-K~Q~id~c-2-ynQ~c-ac~ (Compou~ 18) r Jon~ re~gQnt (a 2.67 M ~olution ~n ~ulphuric acid;
1.32 ml, 3.5 mmol) was ~dded dropwi~e to a solution of 4-hydroxytridec-2-ynoic acid (~o~pou~ 17, 531.8 ~g, 2.4 2~i37~ ~
mmol) in acetone (lo ml) at o and the reaction mixture was maintained at 0 for 70 minutes. The mixture was quenched with ethanol (1 ml) and dried with magnesium sulphate. on evaporation, the title acid was obtained as a colorless oil.
lH NMR (CDC13) 0.87 (t, 3H, J = 6.6 Hz), 1.25 (br s, 12H), 1.67 (m, 2H), 2.64 (t, 2H, J = 7.2 Hz) and 4.90 (br, lH).
LRMS m/e (% abundance) 224 (M+, 5), 223 (12), 197 (36), 155 (37), 149 (14), 37 (21), 123 tl5), 111 (14), 109 (12) and 97 (34).
~-Hydroxy-5-nonyl-2-furanone (Compoun~ 7) A solution of 4-ketotridec-2-ynoic acid (Compound 18, 220 mg, 0.98 mmol) in ether (10 ml) was hydrogenated over Lindlar catalyst (10 mg) at 0 for 80 minutes. The mixture was filtered through celite and after evaporation to dryness the ~iltr~te gave an oil, which was purified by preparative tlc (20x20 cm, lOOOu silica plate; developed with 60% ethyl ether~petroleum ether). The title furanone was obtained as colorless pri~ms (recrystallized from petroleum ether): ~p 54-5.
lH NMR (CDC13) 0.88 (t, 3H, J ~ 7.5 Hz), 1.26 (br s, 12H), 1.40 (m, 2H), 1.98 (m, 2H), 6.12 (d, lH, J = 6.4 Hz) and 7.16 (d, lH, J ~ 6.4 Hz).
13C NMR (CDC13) 14.1, 22.6, 23.4, 29.3, 29.4, 31.8, 37.5, 108.5, 123.0, 154.5 and 170.8.
HRMS m/e: exact mass calculated 20r C13H2203 (M+) 226.1569, found 226.1568.
Ex~m~J~-5 5-Hydroxy-5-met~yL-4-octyl-2-furanQne (Co~pou~
A mixture o~ 2-undecanone (lO g, 58.7 ~ol), glyoxylic acid monohydrate (Co~pou~ 5, 5.15 g, 56 m~ol) and 85% phosphoric acid (10 ml) was war~ed at 80 for 18 - , , , -.
-;; : , ,. . ~ .~ - , 2 ~ 7 ~
wogl/l60ss PCT/US91/02005 hours. On cooling to room temperature, the mixture was diluted with ethyl ether/dichloro~ethane (50 ml each) and washed thoroughly with brine. Evaporation of the dried lmagnesium sulphate) organic phase gave a yellow oil which on crystallization from ethyl ether/petroleum ether gave 4-ketotridec-2-enoic acid as colorless prisms.
lH NMR (CDCl3~ 0.96 (t, 3H, J = 7.4 Hz), 1.34 (br s, 12H), 1.72 (p, 2H, J = 7.1 Hz), 2.73 (t, 2~, J = 7.1 Hz), 6.74 (d, lH, J = 15.7 Hz) and 7.22 (d, lH, J = 15.7 Hz).
The mother liguor from the above recrystallization was concentrated down and was flash chromatographed on silica using 40% ethyl acetate/petroleum ether. Fractions with Rf of about 0.1 gave, after evaporation, the title furanone as a pale yellow oil.
a5 lH NMR (CDC13) 0.92 (t, 3H, J = 7.4 Hz), 1.30 (br s, 12H), 2.45 (s, 3H), 2.79 (t, 2H, J = 7.5 Hz) and 6.56 (s, lH).
13C NMR (CDCl3) 14.1, 22.7, 26.7, 27.0, 29.2, 29.3, 29.8, 31.9, 124.5, 158.0, 171.3 and 200Ø
HRMS m/e: exact mass calculated for C13H2203 (M+) 226.1569, found 226.1559.
Exam~le 6 5-Methyl-4-octvl-2~5H~-furanone (Compou~d 20) Sodium borohydride (214 mg, 5.7 ~mol) was added to a solution of 5-hydroxy-5-~ethyl-4-octyl-2-furanone (Compoun~ 19, 640 mg, 2.8 mmol) in tetrahydrofuran (15 ml). After ~tirring at room temperature for 80 minutes, moæt of the'solvent was removed and water (lO ml) waæ
added. Extraction (dichloromethane) and Qvaporation of the drisd'(m2gnesium sulphate) sxtract~ gave a residue, which was flash chro~atographed on sil~ca u ing 60% ethyl ether/petroleum Qther. Fract~on~ with R~ of about 0.23 were evaporated to yield the title furanone as a colorless ... . .
WO 91/l~OS~ 2 ~ ~ 3 7 7 ~ PCT/US91/02005 _ oil, which crystallized slowly on storage at -70.
lH NMR (CDC13) 0.85 (t, 3N, J = 5.4 Hz), 1.26 (br s, loH), 1.33 (d, 3H, J = 6.9 Hz), 1.47 (m, 2H), 2.26 (m, lH), 2.83 (m, lH0, 4.33 (q, lH, J = 6.2 Hz) and 5.99 (s, lH).
13C MMR (CDC13) 14.1, 22.4, 22.6, 29.2, 29.3, 29.5, 29.8, 31.9, 71.1, 113.0, 169.2 and 171.8.
HRMS m/e exact mass calculated for C13H2202 (M+) 210.1620, found 210.1617.
Exam~le 7 (Comoun~ 21) A mixture of 2-pentanone (17.1 g, 198 mmol), glyoxylic acid monohydrate (Co~pou~ 5, 8.05 g 88 mmol) and about 85% phosphoric acid (12 ml) was warmed at ca.
80 for 19 hour~. on coolin~ to room temperature the mixture was diluted with ethyl ether/dichloromethane (loO
ml, 1:1) and washed thoroughly wit~ brine. Evaporation of the dried (magnesium sulphate) organic phase gave a yellow viscous oil, which on crystallization from ethyl ether/petroleum ether gave 4-keto-hept-2-enoic acid as colorles~ prisms: mp 100-2.
lH NMR (CDC13) 1.01 (t, 3H, J - 7.9 Hz), 1.73 (p, 2H, J s 7.1. Hz), 2.70 (t, 2H, J - 7.3 Hz), 6.73 (lH, d, J =
15.8 Hz) and 7.19 (d, lH, J 3 15.8 Hz).
HRMS m/e: exact mass calculated for C7H1003 (M+) 142.0630, found 142.0622.
The mother liquor from the above crystallization was evaporated to dryness and extracted thoroughly with petrol~um ether. The combined extract3 were concentrated and cooled to -20 to give the t~tle ~uranone as colorless prisms: mp 37-8.
lH NMR tC~C13) 1.09 (t, 3H, J ~ 7.8 Hz), 2.46 (s, ; - . : - -WO91/160~5 2 ~ ~ 3 7 7 ~ PCT/US91/02005 3H), 2.83 (q, 2~), J = 7.8 Hz) and 6.S7 (s, lH).
13C NMR (CDC13) 13.6, 20.4, 26.6, 124.6, 158.7, 171.2 and 199.9.
HRMS m/e: exact mass calculated for C7H1003(M+) 142.0630, found 142.0622.
Example 8 4-~h~1-5-methYl-2f5H~-furanone (Co~poun~ 22) Sodium borohydride (646 mg, 17 mmol) was added to a solution of 4-ethyl-5-hydroxy-5-methyl-2-furanone (compoun~ 21, 1.21 g, 8.5 ~mol) in tetrahydrofuran (10 ml) at room temperature. After 1/2 hour, most of the solvent was removed and water (10 ml) was added. Extraction (ethyl acetate) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 60S ethyl ether/petroleum ether. Fractions with Rf of about 0.23 gave after evaporation, a pale yellow oil, which slowly crystallized on storage at -20. Recrystallization from ethyl ether/petroleum ether afforded the title furanone as colorless prisms: mp 86-7.
1H NMR (CDC13) 1.16 (t, 3~, J - 7.2 Hz), 1.39 (d, 3H, J z 5.4 Hz), 2.36 (m, lH), 2.84 (m, lH), 4.41 (q, 2H, J =
7.2 Hz) and 6.04 (s, lH).
13C NMR ~CDC13) 13.8, 22.3, 22.8, 71.0, 112~9~ 17~3 and 171.7.
HRMS m/e: exact mass calculated for C7H10O2(M+) 126.0681, found 126.0683.
Exam~Ç_ r9~
3.4-Dimethyl-5-hydroxy-5-~1-octvnyl)-2-furanone (Compou~d 23) n-Butyl lithium (a 1.6 M solution in hexane; 6.78 ml, 10.9 mmol) was added dropwise to a solution of l-octyne (1.13 g, 10 mmol) in tetrahydrofuran (7 ml) at 78 under , ,. ~, ~ , .. ..
.
~' . ~ , ' . .
Wosl/16055 2 ~ ~ 3 7 ~ ~ PCT/US91/0~005_ argon. After 20 minutes, the solution was cannulated dropwise, under argon, to a solution of 2,3-dimethylmaleic anhydride (1.30 g, 10.3, mmol) in tetrahydrofuran (15 ml) cooled at -78. Stirring was continued for 2 hours while the cooling bath attained room temperature. The mixture was quenched with dilute hydrochloric acid, diluted with water (10 ~1) and extracted with ethyl acetate.
Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 30% ethyl ether/petroleum ether. Fractions with Rf of about 0.18 on evaporation afforded a light yellow viscous oil, which crystallized out slowly on storage at -20. Recrystallization from petroleum ether gave the title furanone as colorless prisms: mp 55-6C.
lH NMR (CDC13) 0.85 (t, 3H, J - 7.4 Hz), ~.24 (m, 6H), 1.49 (p, 2H, J = 7.9 Hz), 1.79 (s, 3H), 2.00 (s, 3H), 2.21 (t, 2H, J s 7.2 Hz) and 3.93 (br, lH).
13C NMR (CDC13) 8.4, 10.5, 13.9, 18.5, 22.4, 27.9, 28.4, 31.1, 74.5, 88.2, 98.0, 124.3, 156.9 and 172.1.
HRMS m/e: exact mass calculated for C14H2003 (M+) 237.1491, found 237.1498.
ExamDle 10 3.4-Dimethvl-5-hydroxy-5-(2-Dhenylp~opyl~-2-furanone (Co~poun~ 2~) A mixture o~ 3-phenyl-1-bromopropane (521 mg, 2.6 mmol) and magn~aium turnings (66 mg, 2.8 m~ol) in tetrahydrofuran (5 ml) was refluxed under argon for 90 minutes. After the reaction mixture had been cooled to -78, a ~olution o~ 2,3-dimethylmaleic anhydride (330 mg, 2.6 mmol) in ~etrahydro~uran (5 ml) wa3 added dropwise.
Stirring wa~ continu~d ovornight (ca. 17 hour8) while the cooling bath attained room temperature. The mixture was quenched with a saturated solution o~ am~oniu~ chloride , .. . . . .. .
. - - . , : . .
. : .
~ .
WO91/16055 2 8 ~ o ~ 7 ~ PCT/US91/02005 and extracted with ethyl acetate. Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 40~ ethyl acetate/petroleum ether. Fractions with Rf of about 0.32 on evaporation afforded the title furanone as a pale yellow oil, which on storaqe at -20 crystallized as colorless prisms: mp 62-3C.
lH NHR (CDC13) 1.48 (m, lH), 1.70 (m, lH), 1.79 (s, 3H), 1.89 (s, 3H), 2.05 (m, 2H), 2.65 (m, 2H) and 7.25 (m, 5H).
13C NMR (CDC13) 8.3, 10.6, 24.7, 35.4, 107.2, 125.1, 125.9, 128.4, 141.5, 158.1 and 172.6.
HRM3 m/e: exact mass calculated for C15H1803 (~+) 246.1256, found 246.1270.
15 ~ 11 3.4-Dimethyl-5-(2-phen~lpropyl)-2(5H)-furanone (Compound 8) Potassium borohydride (503 mg, 9.3 ~mol) was added to a solution of 3,4-dimethyl-5-hydroxy-5-(2-phenylpropyl)-2-furanone (Co~pou~ 24, 382 mg, 1.6 mmol) intetrahydrofuran (8 ml) and methanol (6 ml) at room temperature. After 7 hours, most of the ~olvent was removed and water (10 ml) was added. Extraction (ethyl acetate) and evaporation of the dr~ed (m~gnesium sulphate) extract~ gave ~n oil, which was pur~fied by preparative tlc ~20x20 cm, 2000u si-lica plate; developed with 30%--ethyl ether/petroleum ether). The title furanone was obta~n~d as colorl-~s prisms (recry~tallizsd from ethyl ether/petrol~um Qthar): mp 69-70.
lH NMR (CDC13) 1.50 tm, lH), 1-.77 (p, 2H, J ~ 6.8 HZ), 1.82 (g, 3H), 1.92 (~, 3H), 1.95 (m,-lH1, 2.67 (~, 2~), 4.74 (m, lH) and 7.25 (~, 5H). :
13C NMR (CDC13) 8.4, 11.9, 26.0, 31.5, 35.4, 82.9, . ..
. . .
Wo 91/16055 2 ~ 7 3 7 7 ~ PCr/USsl/02005 123.6, 125.9, 128.4, 141.5 and 158.9.
HRMS m/e: exact n~ass calculated for C15H1802 (M+) 230.1307, found 230.1311.
E~PD1e 12 4-Octyl-5-hYdroxy-2(5H)-furanone (Co~pou~ 25) A mixture of glyoxylic acid monohydrate (Co~pou~d 5, 1.19 g, 16.1 mmol), morpholine hydrochloride (1.81 g, 14.6 mmol), water (0.73 ml) and l-decanal (2.89 ml, 15.4 mmol) in dioxane (6 ml) was stirred at room temperature for 1 hour, followed by reflux for 25 hours. After cooling, most of the solvent was removed by evaporation and the residue wa~ extracted with ethyl eth~r. Evaporation of the dried (magnesium sulfate) extracts qave an oil, which was flash chromatographed with 30S ethyl acetate/hexane to give the title furanone.
1H N~ (CDC13): 0.89 (t, 3H, J - 6.6 Hz), 1.25 (br s, lOH), 1.60 (m, 2H), 2.40 (m, 2H), 4.70 (br, lH), 5.84 (s, lH) and 6.00 (8, lH).
4-octyl-~methQ~L-fur~ (Coupou~ 26) A mixture of 4-octyl-5-hydroxy-2(5H)-furanone (Co~pou~l~ 2S, 244 mg, 1.16 Dmol) and ~-toluenesulfonic acid (33 mg, 0.17 D~mol) ~nd m~ nol (5.8 ml) was stirred at room temperature for 2 d~y~. The ~ixture was diluted with ethyl ether and washed thoroughly wlth 5S sodium bicarbon~te solution. E~ por~tion of the dried (magnesium sul~at~) organic phase g~ve ~n oil, which was flash chromatographed on silica u~ing 10% ethyl ~cet~te/hexane to gi~- the title fur~none.
lH Nl~ (CDC13): 0.89 (t, 3H, J -- 7.5 Hz), 1.28 (br s, lOH), 1.60 (~, 2H), 2.35 (m, 2H), 3.56 (8, 3H), 5.64 (8, lH) ~nd 5.86 (8 lH).
3-Br~?~Q-4-octy~-5-~tl~ox~-2r5H)-~urarlpne (Co~pou~ 27) A solution of bro~ine (28 mlcroliter) in - . . : ~ .
:-WO 91/160~ PCI`/VS9t/02005 2~7a7 7:~
carbontetrachloride (0.2 ml) was added to a solution of 4-octyl-5-methoxy-2(5H)-furanone (100 mg, 0.45 mmol) in carbon tetrachloride (0.5 ml) at 0. The mixture was stirred at room temperature until all the starting - 5 material ~lsappeared (as monit13Fed by tlc). After cooling to 0, pyridine (86 microliter, 1.17 mmol) was added. The mixture was quenched with water and ~he layers were separated. ~vaporation of the dried (magnesium sulfate) organic phase gave an oil, which was purified by flash chromatography using 5~ ethyl acetate/hexane to give the title furanone.
1H NMR (CDC13): 0.89 (t, 3H, J - 6.8 Hz), 1.28 (br s, lSH), 1.60 tm, 2H), 2.50 (m, 2H), 3.58 (8, 3H) and 5.69 (s, 1~). \'`
3-Bromo-4-octyl-5-~ydroxy-2L~jHl-furano~ (Co~poun~ 9) A mixture of 3-bromo-4-octyl-5-methoxy-2(5H)-furanone (106 mg, 0.35 mmol) and conc~ntrated hydrochloric acid (0.21 ml) was r~fluxQd unt~l all thQ starting material disappeared as shown by tlc. After cooli~ng, the mixture was diluted with ethyl ~ther and wa~ neutral~zed by washing thoroughly with ~aturatQd potass~um bicarbonate solution.. Evaporation of the dried (magn~ium sulfate) organic phase gav~ n oil, which wa~ flash chromatographed on silica u~ing 10% ethyl acetate/hexane to give the title furanon~.
IR (C~C13): 3389, 1755 and 1651.
- lH NMR (CDC13): 0.87 (t, 3H, J - 7.2 Hz), 1.27 (br ~, lOH), 1.60 (m, 2H), 2.49 (t, 2H, J - 8.5 Hz), 4.50 (br, lH), and 6.05 (~, lH).
13C NMR (CDC13): 14.2, 22.7, 26.5, 27.8, 2g.2, 29.6, 31.8, 98.8, 112.1 and 163.9.
HRNS ~XACt ma~ calculat~d for C12~20~rO3 (M+H) 291.0596, tound 291.0590.
~,.
. . . : . . . :. : . . .. :: . . , . . . . :, : . , ,. .: .: . , : . . . : . . .
13C NMR ~CDC13) 13.8, 22.3, 22.8, 71.0, 112~9~ 17~3 and 171.7.
HRMS m/e: exact mass calculated for C7H10O2(M+) 126.0681, found 126.0683.
Exam~Ç_ r9~
3.4-Dimethyl-5-hydroxy-5-~1-octvnyl)-2-furanone (Compou~d 23) n-Butyl lithium (a 1.6 M solution in hexane; 6.78 ml, 10.9 mmol) was added dropwise to a solution of l-octyne (1.13 g, 10 mmol) in tetrahydrofuran (7 ml) at 78 under , ,. ~, ~ , .. ..
.
~' . ~ , ' . .
Wosl/16055 2 ~ ~ 3 7 ~ ~ PCT/US91/0~005_ argon. After 20 minutes, the solution was cannulated dropwise, under argon, to a solution of 2,3-dimethylmaleic anhydride (1.30 g, 10.3, mmol) in tetrahydrofuran (15 ml) cooled at -78. Stirring was continued for 2 hours while the cooling bath attained room temperature. The mixture was quenched with dilute hydrochloric acid, diluted with water (10 ~1) and extracted with ethyl acetate.
Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 30% ethyl ether/petroleum ether. Fractions with Rf of about 0.18 on evaporation afforded a light yellow viscous oil, which crystallized out slowly on storage at -20. Recrystallization from petroleum ether gave the title furanone as colorless prisms: mp 55-6C.
lH NMR (CDC13) 0.85 (t, 3H, J - 7.4 Hz), ~.24 (m, 6H), 1.49 (p, 2H, J = 7.9 Hz), 1.79 (s, 3H), 2.00 (s, 3H), 2.21 (t, 2H, J s 7.2 Hz) and 3.93 (br, lH).
13C NMR (CDC13) 8.4, 10.5, 13.9, 18.5, 22.4, 27.9, 28.4, 31.1, 74.5, 88.2, 98.0, 124.3, 156.9 and 172.1.
HRMS m/e: exact mass calculated for C14H2003 (M+) 237.1491, found 237.1498.
ExamDle 10 3.4-Dimethvl-5-hydroxy-5-(2-Dhenylp~opyl~-2-furanone (Co~poun~ 2~) A mixture o~ 3-phenyl-1-bromopropane (521 mg, 2.6 mmol) and magn~aium turnings (66 mg, 2.8 m~ol) in tetrahydrofuran (5 ml) was refluxed under argon for 90 minutes. After the reaction mixture had been cooled to -78, a ~olution o~ 2,3-dimethylmaleic anhydride (330 mg, 2.6 mmol) in ~etrahydro~uran (5 ml) wa3 added dropwise.
Stirring wa~ continu~d ovornight (ca. 17 hour8) while the cooling bath attained room temperature. The mixture was quenched with a saturated solution o~ am~oniu~ chloride , .. . . . .. .
. - - . , : . .
. : .
~ .
WO91/16055 2 8 ~ o ~ 7 ~ PCT/US91/02005 and extracted with ethyl acetate. Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 40~ ethyl acetate/petroleum ether. Fractions with Rf of about 0.32 on evaporation afforded the title furanone as a pale yellow oil, which on storaqe at -20 crystallized as colorless prisms: mp 62-3C.
lH NHR (CDC13) 1.48 (m, lH), 1.70 (m, lH), 1.79 (s, 3H), 1.89 (s, 3H), 2.05 (m, 2H), 2.65 (m, 2H) and 7.25 (m, 5H).
13C NMR (CDC13) 8.3, 10.6, 24.7, 35.4, 107.2, 125.1, 125.9, 128.4, 141.5, 158.1 and 172.6.
HRM3 m/e: exact mass calculated for C15H1803 (~+) 246.1256, found 246.1270.
15 ~ 11 3.4-Dimethyl-5-(2-phen~lpropyl)-2(5H)-furanone (Compound 8) Potassium borohydride (503 mg, 9.3 ~mol) was added to a solution of 3,4-dimethyl-5-hydroxy-5-(2-phenylpropyl)-2-furanone (Co~pou~ 24, 382 mg, 1.6 mmol) intetrahydrofuran (8 ml) and methanol (6 ml) at room temperature. After 7 hours, most of the ~olvent was removed and water (10 ml) was added. Extraction (ethyl acetate) and evaporation of the dr~ed (m~gnesium sulphate) extract~ gave ~n oil, which was pur~fied by preparative tlc ~20x20 cm, 2000u si-lica plate; developed with 30%--ethyl ether/petroleum ether). The title furanone was obta~n~d as colorl-~s prisms (recry~tallizsd from ethyl ether/petrol~um Qthar): mp 69-70.
lH NMR (CDC13) 1.50 tm, lH), 1-.77 (p, 2H, J ~ 6.8 HZ), 1.82 (g, 3H), 1.92 (~, 3H), 1.95 (m,-lH1, 2.67 (~, 2~), 4.74 (m, lH) and 7.25 (~, 5H). :
13C NMR (CDC13) 8.4, 11.9, 26.0, 31.5, 35.4, 82.9, . ..
. . .
Wo 91/16055 2 ~ 7 3 7 7 ~ PCr/USsl/02005 123.6, 125.9, 128.4, 141.5 and 158.9.
HRMS m/e: exact n~ass calculated for C15H1802 (M+) 230.1307, found 230.1311.
E~PD1e 12 4-Octyl-5-hYdroxy-2(5H)-furanone (Co~pou~ 25) A mixture of glyoxylic acid monohydrate (Co~pou~d 5, 1.19 g, 16.1 mmol), morpholine hydrochloride (1.81 g, 14.6 mmol), water (0.73 ml) and l-decanal (2.89 ml, 15.4 mmol) in dioxane (6 ml) was stirred at room temperature for 1 hour, followed by reflux for 25 hours. After cooling, most of the solvent was removed by evaporation and the residue wa~ extracted with ethyl eth~r. Evaporation of the dried (magnesium sulfate) extracts qave an oil, which was flash chromatographed with 30S ethyl acetate/hexane to give the title furanone.
1H N~ (CDC13): 0.89 (t, 3H, J - 6.6 Hz), 1.25 (br s, lOH), 1.60 (m, 2H), 2.40 (m, 2H), 4.70 (br, lH), 5.84 (s, lH) and 6.00 (8, lH).
4-octyl-~methQ~L-fur~ (Coupou~ 26) A mixture of 4-octyl-5-hydroxy-2(5H)-furanone (Co~pou~l~ 2S, 244 mg, 1.16 Dmol) and ~-toluenesulfonic acid (33 mg, 0.17 D~mol) ~nd m~ nol (5.8 ml) was stirred at room temperature for 2 d~y~. The ~ixture was diluted with ethyl ether and washed thoroughly wlth 5S sodium bicarbon~te solution. E~ por~tion of the dried (magnesium sul~at~) organic phase g~ve ~n oil, which was flash chromatographed on silica u~ing 10% ethyl ~cet~te/hexane to gi~- the title fur~none.
lH Nl~ (CDC13): 0.89 (t, 3H, J -- 7.5 Hz), 1.28 (br s, lOH), 1.60 (~, 2H), 2.35 (m, 2H), 3.56 (8, 3H), 5.64 (8, lH) ~nd 5.86 (8 lH).
3-Br~?~Q-4-octy~-5-~tl~ox~-2r5H)-~urarlpne (Co~pou~ 27) A solution of bro~ine (28 mlcroliter) in - . . : ~ .
:-WO 91/160~ PCI`/VS9t/02005 2~7a7 7:~
carbontetrachloride (0.2 ml) was added to a solution of 4-octyl-5-methoxy-2(5H)-furanone (100 mg, 0.45 mmol) in carbon tetrachloride (0.5 ml) at 0. The mixture was stirred at room temperature until all the starting - 5 material ~lsappeared (as monit13Fed by tlc). After cooling to 0, pyridine (86 microliter, 1.17 mmol) was added. The mixture was quenched with water and ~he layers were separated. ~vaporation of the dried (magnesium sulfate) organic phase gave an oil, which was purified by flash chromatography using 5~ ethyl acetate/hexane to give the title furanone.
1H NMR (CDC13): 0.89 (t, 3H, J - 6.8 Hz), 1.28 (br s, lSH), 1.60 tm, 2H), 2.50 (m, 2H), 3.58 (8, 3H) and 5.69 (s, 1~). \'`
3-Bromo-4-octyl-5-~ydroxy-2L~jHl-furano~ (Co~poun~ 9) A mixture of 3-bromo-4-octyl-5-methoxy-2(5H)-furanone (106 mg, 0.35 mmol) and conc~ntrated hydrochloric acid (0.21 ml) was r~fluxQd unt~l all thQ starting material disappeared as shown by tlc. After cooli~ng, the mixture was diluted with ethyl ~ther and wa~ neutral~zed by washing thoroughly with ~aturatQd potass~um bicarbonate solution.. Evaporation of the dried (magn~ium sulfate) organic phase gav~ n oil, which wa~ flash chromatographed on silica u~ing 10% ethyl acetate/hexane to give the title furanon~.
IR (C~C13): 3389, 1755 and 1651.
- lH NMR (CDC13): 0.87 (t, 3H, J - 7.2 Hz), 1.27 (br ~, lOH), 1.60 (m, 2H), 2.49 (t, 2H, J - 8.5 Hz), 4.50 (br, lH), and 6.05 (~, lH).
13C NMR (CDC13): 14.2, 22.7, 26.5, 27.8, 2g.2, 29.6, 31.8, 98.8, 112.1 and 163.9.
HRNS ~XACt ma~ calculat~d for C12~20~rO3 (M+H) 291.0596, tound 291.0590.
~,.
. . . : . . . :. : . . .. :: . . , . . . . :, : . , ,. .: .: . , : . . . : . . .
Claims
CLAIM REPLACEMENT SHEET
WHAT IS CLAIMED IS:
Claims 1 - 7 (Cancelled) Claims 8 - 10 (cancelled) 11. (Amended) Compounds of the formula wherein R2 is alkyl of 6 to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds;
R3 is halogen and X is H or alkyl of 1 to 20 carbons, CO-X*, CO-O-X*,, CO-NH-X*,, or PO(OX*,)2 or PO(OX*,)X~,, where X*, independently is H, alkyl of 1 to 20 carbons, phenyl, or substituted phenyl.
12. (Cancelled) 13. (Cancelled) 14. (Cancelled) 15. Compounds of Claim 11 wherein R2 is alkyl.
16. (Cancelled) 17. (Cancelled) 18. (Cancelled) 19. Compounds of Claim 11 wherein R3 is bromo.
20. Compounds of Claim 11 wherein X is hydrogen, CH3 or CH3CO.
21. (Amended) A pharmaceutical composition comprising an effective amount of one or more compounds of Claim 11 and a pharmaceutically acceptable excipient.
22. (Cancelled) 23. (Cancelled) 24. (Cancelled) 25. (Cancelled) 26. (Cancelled) 27. (Cancelled) 28. (Cancelled) 29. (Cancelled) 30. (Cancelled) 31. (Cancelled) 32. (Cancelled) 33. (Cancelled) 34. (Amended) Compounds of the formula wherein R2 is alkyl of 6 to 20 carbons;
R3 is [H, alkyl of 1 to 20 carbons, or halogene,]
halogen and X is H or alkyl of 1 to 20 carbons.
35. (Cancelled) 36. (Cancelled) 37. (Cancelled) 38. (Amended) Compounds of Claim 34 wherein X is hydrogen.
39. Compounds of Claim 34 wherein R3 is bromine.
40. Compounds of Claim 39 wherein R2 is n-octyl.
41. (Cancelled) 42. (Amended) The compound of Claim 40 wherein X is hydrogen.
WHAT IS CLAIMED IS:
Claims 1 - 7 (Cancelled) Claims 8 - 10 (cancelled) 11. (Amended) Compounds of the formula wherein R2 is alkyl of 6 to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds;
R3 is halogen and X is H or alkyl of 1 to 20 carbons, CO-X*, CO-O-X*,, CO-NH-X*,, or PO(OX*,)2 or PO(OX*,)X~,, where X*, independently is H, alkyl of 1 to 20 carbons, phenyl, or substituted phenyl.
12. (Cancelled) 13. (Cancelled) 14. (Cancelled) 15. Compounds of Claim 11 wherein R2 is alkyl.
16. (Cancelled) 17. (Cancelled) 18. (Cancelled) 19. Compounds of Claim 11 wherein R3 is bromo.
20. Compounds of Claim 11 wherein X is hydrogen, CH3 or CH3CO.
21. (Amended) A pharmaceutical composition comprising an effective amount of one or more compounds of Claim 11 and a pharmaceutically acceptable excipient.
22. (Cancelled) 23. (Cancelled) 24. (Cancelled) 25. (Cancelled) 26. (Cancelled) 27. (Cancelled) 28. (Cancelled) 29. (Cancelled) 30. (Cancelled) 31. (Cancelled) 32. (Cancelled) 33. (Cancelled) 34. (Amended) Compounds of the formula wherein R2 is alkyl of 6 to 20 carbons;
R3 is [H, alkyl of 1 to 20 carbons, or halogene,]
halogen and X is H or alkyl of 1 to 20 carbons.
35. (Cancelled) 36. (Cancelled) 37. (Cancelled) 38. (Amended) Compounds of Claim 34 wherein X is hydrogen.
39. Compounds of Claim 34 wherein R3 is bromine.
40. Compounds of Claim 39 wherein R2 is n-octyl.
41. (Cancelled) 42. (Amended) The compound of Claim 40 wherein X is hydrogen.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US51036490A | 1990-04-17 | 1990-04-17 | |
US510,364 | 1990-04-17 |
Publications (1)
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CA2078771A1 true CA2078771A1 (en) | 1991-10-18 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA002078771A Abandoned CA2078771A1 (en) | 1990-04-17 | 1991-03-25 | 2(5h)-furanones substituted in the 5 and or in the 4 position, as anti-inflammatory agents |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0524979A4 (en) |
JP (1) | JPH05506215A (en) |
AU (1) | AU7559691A (en) |
CA (1) | CA2078771A1 (en) |
IE (1) | IE911267A1 (en) |
WO (1) | WO1991016055A1 (en) |
Families Citing this family (18)
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US5268387A (en) * | 1992-04-24 | 1993-12-07 | Allergan, Inc. | Pharmaceutical compositions and method for administering 3 and 4-substituted 2(5H)-furanones to a mammal for inhibiting bone loss |
US6492413B2 (en) | 1993-01-15 | 2002-12-10 | G.D. Searle & Co. | 3.4-diaryl thiophenes and analogs thereof having use as antiinflammatory agents |
US5474995A (en) * | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
GB9602877D0 (en) * | 1996-02-13 | 1996-04-10 | Merck Frosst Canada Inc | 3,4-Diaryl-2-hydroxy-2,5- dihydrofurans as prodrugs to cox-2 inhibitors |
AU693110B2 (en) * | 1993-08-19 | 1998-06-25 | Warner-Lambert Company | Substituted 2(5H)furanone, 2(5H)thiophenone and 2(5H)pyrrolone derivatives, their preparation and their use as endothelin antagonists |
CN1143365A (en) * | 1994-01-10 | 1997-02-19 | 麦克弗罗斯特(加拿大)有限公司 | Phenyl-heterocycles as COX-2 inhibitors |
US5451686A (en) * | 1994-04-15 | 1995-09-19 | Allergan, Inc. | 3 and 5 alkyl and phenyl 4-(hydroxy or acyloxy)-alkyl substituted 2(5H)-furanones as anti-inflammatory agents |
US5639468A (en) * | 1995-06-07 | 1997-06-17 | University Of Southern California | Method for reducing or preventing post-surgical adhesion formation using manoalide and analogs thereof |
US5922759A (en) * | 1996-06-21 | 1999-07-13 | Warner-Lambert Company | Butenolide endothelin antagonists |
US5998468A (en) * | 1995-08-24 | 1999-12-07 | Warner-Lambert Company | Furanone endothelin antagonists |
US5981576A (en) * | 1995-10-13 | 1999-11-09 | Merck Frosst Canada, Inc. | (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors |
US6020343A (en) * | 1995-10-13 | 2000-02-01 | Merck Frosst Canada, Inc. | (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors |
GB9615867D0 (en) * | 1996-07-03 | 1996-09-11 | Merck & Co Inc | Process of preparing phenyl heterocycles useful as cox-2 inhibitors |
US5891892A (en) * | 1996-10-29 | 1999-04-06 | Warner-Lambert Company | Small molecule biaryl compounds as inhibitors of endothelin converting enzyme |
US6080876A (en) * | 1997-10-29 | 2000-06-27 | Merck & Co., Inc. | Process for making phenyl heterocycles useful as COX-2 inhibitors |
AU2008248465A1 (en) * | 2007-05-04 | 2008-11-13 | Aquapharm Bio-Discovery Ltd | Natural bioactive compounds |
FR2978963A1 (en) | 2011-08-11 | 2013-02-15 | Ascorbix | NOVEL DERIVATIVES OF FURANONES AND PHARMACEUTICAL COMPOSITION CONTAINING SAME |
RU2522598C1 (en) * | 2013-03-29 | 2014-07-20 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Кубанский государственный технологический университет" (ФГБОУ ВПО "КубГТУ") | Method of obtaining 2(5h)-furanone |
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US2359208A (en) * | 1941-03-21 | 1944-09-26 | Lilly Co Eli | beta-substituted-delta alpha,beta-gamma-butyrolactones and beta-substituted-beta-hydroxy-gamma-butyrolactones and the methods of preparing them |
US2359096A (en) * | 1941-03-21 | 1944-09-26 | Lilly Co Eli | beta-substituted-delta alpha, beta-gamma-butyrolactones and beta-substituted - beta - hydroxy-gamma-butyrolactones and methods of preparing them |
DE2538771A1 (en) * | 1975-09-01 | 1977-03-17 | Henkel & Cie Gmbh | Antimicrobial agents contg. (2)-furanone derivs. - used e.g. as cleansing agents and disinfectants for textiles, hospital equipment, breweries and bathing pools |
JPS6019902B2 (en) * | 1979-03-28 | 1985-05-18 | 三井東圧化学株式会社 | Dimer of isopropenylphenylmaleimide derivative |
US4874782A (en) * | 1985-07-01 | 1989-10-17 | Eli Lilly And Company | Furanone derivatives |
FR2603036B1 (en) * | 1986-08-22 | 1988-11-25 | Rhone Poulenc Agrochimie | 2,3-DIHYDROFURANNE DERIVATIVES, THEIR PREPARATION PROCESS, THEIR USE AS AN INTERMEDIATE FOR THE PREPARATION OF TETRAHYDROFURANNE |
-
1991
- 1991-03-25 JP JP91506660A patent/JPH05506215A/en active Pending
- 1991-03-25 CA CA002078771A patent/CA2078771A1/en not_active Abandoned
- 1991-03-25 AU AU75596/91A patent/AU7559691A/en not_active Abandoned
- 1991-03-25 WO PCT/US1991/002005 patent/WO1991016055A1/en not_active Application Discontinuation
- 1991-03-25 EP EP19910907029 patent/EP0524979A4/en not_active Ceased
- 1991-04-16 IE IE126791A patent/IE911267A1/en unknown
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JPH05506215A (en) | 1993-09-16 |
EP0524979A4 (en) | 1993-03-10 |
IE911267A1 (en) | 1991-10-23 |
AU7559691A (en) | 1991-11-11 |
EP0524979A1 (en) | 1993-02-03 |
WO1991016055A1 (en) | 1991-10-31 |
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