AP188A - Novel aryloxy alcohol benzenes, processes for their preparation as well as the pharmaceutical compositions containing them. - Google Patents
Novel aryloxy alcohol benzenes, processes for their preparation as well as the pharmaceutical compositions containing them. Download PDFInfo
- Publication number
- AP188A AP188A APAP/P/1990/000223A AP9000223A AP188A AP 188 A AP188 A AP 188A AP 9000223 A AP9000223 A AP 9000223A AP 188 A AP188 A AP 188A
- Authority
- AP
- ARIPO
- Prior art keywords
- formula
- vherein
- hydroxy
- lover
- given
- Prior art date
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- -1 aryloxy alcohol benzenes Chemical class 0.000 title claims abstract description 54
- 238000000034 method Methods 0.000 title claims abstract description 31
- 230000008569 process Effects 0.000 title claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 92
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 71
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- 229910052786 argon Inorganic materials 0.000 claims description 43
- 229910052727 yttrium Inorganic materials 0.000 claims description 42
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 230000009471 action Effects 0.000 claims description 15
- 150000002431 hydrogen Chemical group 0.000 claims description 14
- 239000003863 metallic catalyst Substances 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- IPBVNPXQWQGGJP-UHFFFAOYSA-N phenyl acetate Chemical compound CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 claims description 12
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 11
- 229910052783 alkali metal Inorganic materials 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical group 0.000 claims description 10
- 150000001340 alkali metals Chemical class 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 230000000903 blocking effect Effects 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000001117 sulphuric acid Substances 0.000 claims description 8
- 235000011149 sulphuric acid Nutrition 0.000 claims description 8
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- PURLWQWDGIIYBG-UHFFFAOYSA-N 1-ethoxy-4-fluorobenzene Chemical compound CCOC1=CC=C(F)C=C1 PURLWQWDGIIYBG-UHFFFAOYSA-N 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 5
- 125000000468 ketone group Chemical group 0.000 claims description 5
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 claims description 4
- 241000790917 Dioxys <bee> Species 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 125000005518 carboxamido group Chemical group 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 125000005188 oxoalkyl group Chemical group 0.000 claims description 4
- BGCBEZLNZOLTLR-UHFFFAOYSA-N phenoxymethylphosphane Chemical class PCOC1=CC=CC=C1 BGCBEZLNZOLTLR-UHFFFAOYSA-N 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims description 4
- 239000003981 vehicle Substances 0.000 claims description 4
- VLLSCJFPVSQXDM-UHFFFAOYSA-N 2-phenoxyacetonitrile Chemical compound N#CCOC1=CC=CC=C1 VLLSCJFPVSQXDM-UHFFFAOYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 150000004678 hydrides Chemical class 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- JVNCFFFHVBWVBR-UHFFFAOYSA-N 2-(1-hydroxyethyl)phenol Chemical compound CC(O)C1=CC=CC=C1O JVNCFFFHVBWVBR-UHFFFAOYSA-N 0.000 claims description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- 150000003935 benzaldehydes Chemical class 0.000 claims description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 2
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical class BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 125000005027 hydroxyaryl group Chemical group 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- PMOIAJVKYNVHQE-UHFFFAOYSA-N phosphanium;bromide Chemical compound [PH4+].[Br-] PMOIAJVKYNVHQE-UHFFFAOYSA-N 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims 3
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims 2
- JKSGBCQEHZWHHL-UHFFFAOYSA-N 2-phenoxyethylbenzene Chemical class C=1C=CC=CC=1OCCC1=CC=CC=C1 JKSGBCQEHZWHHL-UHFFFAOYSA-N 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 230000001079 digestive effect Effects 0.000 claims 1
- 125000002950 monocyclic group Chemical group 0.000 claims 1
- 125000000109 phenylethoxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])O* 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 22
- 239000005022 packaging material Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 11
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 102000004257 Potassium Channel Human genes 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 6
- 229960003883 furosemide Drugs 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 108020001213 potassium channel Proteins 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- 230000003276 anti-hypertensive effect Effects 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 239000001103 potassium chloride Substances 0.000 description 5
- 235000011164 potassium chloride Nutrition 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 208000004880 Polyuria Diseases 0.000 description 4
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical class [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 238000004220 aggregation Methods 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 210000001772 blood platelet Anatomy 0.000 description 4
- 230000001882 diuretic effect Effects 0.000 description 4
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- 230000000144 pharmacologic effect Effects 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- LJHOQCMUMBBCFZ-UHFFFAOYSA-N 2-phenoxyethanone Chemical compound O=[C]COC1=CC=CC=C1 LJHOQCMUMBBCFZ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
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- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- DESGWODFUXYGGQ-UHFFFAOYSA-N 2-(1-phenoxypropan-2-yl)phenol Chemical compound C=1C=CC=C(O)C=1C(C)COC1=CC=CC=C1 DESGWODFUXYGGQ-UHFFFAOYSA-N 0.000 description 2
- ILCAUMISWYFUPO-UHFFFAOYSA-N 4-[2-(4-fluorophenoxy)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC(CCOC=2C=CC(F)=CC=2)=C1 ILCAUMISWYFUPO-UHFFFAOYSA-N 0.000 description 2
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
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- 206010020772 Hypertension Diseases 0.000 description 2
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- 238000010521 absorption reaction Methods 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
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- HCZKYJDFEPMADG-UHFFFAOYSA-N nordihydroguaiaretic acid Chemical compound C=1C=C(O)C(O)=CC=1CC(C)C(C)CC1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-UHFFFAOYSA-N 0.000 description 2
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- ZJABPUSDYOXUKS-UHFFFAOYSA-N 1-(2-phenylmethoxyphenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1OCC1=CC=CC=C1 ZJABPUSDYOXUKS-UHFFFAOYSA-N 0.000 description 1
- ZPQBYVIOKMVZEX-UHFFFAOYSA-N 1-(chloromethylperoxy)-4-fluorobenzene Chemical compound FC1=CC=C(OOCCl)C=C1 ZPQBYVIOKMVZEX-UHFFFAOYSA-N 0.000 description 1
- KBZMEUGKRPOXQD-UHFFFAOYSA-N 1-[2-(4-fluorophenoxy)ethyl]-3-methylsulfonylbenzene Chemical compound CS(=O)(=O)C=1C=C(C=CC1)CCOC1=CC=C(C=C1)F KBZMEUGKRPOXQD-UHFFFAOYSA-N 0.000 description 1
- IVVNZDGDKPTYHK-UHFFFAOYSA-N 1-cyano-2-(3,3-dimethylbutan-2-yl)-3-pyridin-4-ylguanidine Chemical compound CC(C)(C)C(C)N=C(NC#N)NC1=CC=NC=C1 IVVNZDGDKPTYHK-UHFFFAOYSA-N 0.000 description 1
- IVVNZDGDKPTYHK-JTQLQIEISA-N 1-cyano-2-[(2s)-3,3-dimethylbutan-2-yl]-3-pyridin-4-ylguanidine Chemical compound CC(C)(C)[C@H](C)N=C(NC#N)NC1=CC=NC=C1 IVVNZDGDKPTYHK-JTQLQIEISA-N 0.000 description 1
- VIPWUFMFHBIKQI-UHFFFAOYSA-N 1-fluoro-4-methoxybenzene Chemical compound COC1=CC=C(F)C=C1 VIPWUFMFHBIKQI-UHFFFAOYSA-N 0.000 description 1
- 125000004098 2,6-dichlorobenzoyl group Chemical group O=C([*])C1=C(Cl)C([H])=C([H])C([H])=C1Cl 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/39—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups
- C07C205/42—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/43—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C305/00—Esters of sulfuric acids
- C07C305/22—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to carbon atoms of six-membered aromatic rings
- C07C305/24—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to carbon atoms of six-membered aromatic rings of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/02—Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
This invention has a subject matter novel aryloxy alkylbenzenes, their processes for production and the pharmaceutical compositions containing them.
Description
This invention relates to novel aryloxy alkyl bent of production as well as the pharmaceutical compositions - containing, them.
It has more precisely as subject matter as novel compounds, aryloxyethyl benzene substituted on one or both rings and specifically the aryloxyethyl benzene of the formula I
Ar - CH - CH - 0 - Ar' (I) wherein Ar is an aromatic mono- or bicyclic hydroxylated radical selected from the group consisting of
- phenyl derivatives having the formula (Z)p wherein X is a hydroxy, free esterified by a carboxylic or sulphonic organic acid, by phosphoric acid, or by sulphuric acid, or etherified by a lower alkyl or alkenyl radical
Z is a substituent selected from the group consisting of hydrogen, halogens, hydroxy, a lower alkoxy, an acyloxy, a phenyl lower alkyl, a lower alkyl, a lower alkyl substituted by a ((lower alkyl) oxy carbonyle), a (lower alkyl) substituted by a hydroxy carbonyle, a moiety -CCKCT^)^ CH^ wherein m is an integer of from 1 to 4, a moiety CHOH-(CH2)m,-CH2 wherein m' is an integer of from 1 to 4 a carboxamido group optionally substituted by one or two lower alkyl radicals, a phenyl and a phenoxy and the naphtalenic derivatives selected from the group consisting of the naphtyl derivatives of the formula
AP 0 0 0 1 8 8
wherein A is a free hydroxy or an esterified or etherified hydroxy group
Z is defined as above-given and p is an integer of from 1 to 3 and those of formula (Z)p
wherein A, Z and p are defined as above-given
Ar' is an aromatic mono- or bicyclic radical selected from the consisting of group
- the benzenic derivatives of formula
wherein Y is a hydrogen, a halogen, a (lower alkylene) dioxy, a hydroxy, a lower alkoxy, an acyloxy derivated from an organic carboxylic acid, a lower alkyl, a lower alkyl substituted by a (lower alkoxy) carbonyl, an oxo alkyl chain of the formula ^3 wherein m is an integer of from 1 to 4, or an hydroxy alkyl chain of the formula CHOH-(CH) -^,-CH-^ wherein m' is an integer of from 1 to 4
- the naphtalenic derivatives selected from the group consisting of naphtyl derivatives of formula
- »
- 3 wherein Y is defined as above-givent and n is an integer of from 1 to 4
- and the naphtalenic derivatives of formula
wherein Y and n are defined as above-given
R is a hydrogen, a hydroxy, the oxygen of a keto group or a lower alkyl radical
R^ is a hydrogen or a lower alkyl radical
This invention also relates to the optically-active isomers of a compound of formula I when R^ and/or R£ are different than hydrogen and when R is not a keto group.
Further when R and R^ are both substituents, it is possible to create a pair of diastereo isomers erythro and threo and further to resolve it into the optically-active isomers by means of a chiral reagent.
This invention also includes the salts of the compounds of formula I -when X is a hydroxy esterified by sulphuric acid or phosphoric acidwith a mineral or organic base.
Among the compounds of formula I according to this invention, the following groups may be more precisely cited :
- the hydroxyphenyl ethoxy benzenes of formula IA
x
- 4 wherein X is hydroxy, a hydroxy etherified by a lower alkyl or a lower alkenyl or esterified by an organic carboxylic or sulphonic acid, by phosphoric acid or by phosphoric acid and R, R^, Y, Z, n and p have the above-given definitions and as preferred compounds :
l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethane
- the metallic or organic base addition salts of l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethane such as the piperazine disalt or the sodium salt l-(2-hydroxy 5-carboxamido phenyl) (4-fluorophenoxy) ethane
wherein the definitions of the substituents X, Y, Z, R, remain unaltered
R^, n and p
- the compounds having the general formula Ic
wherein the definitions of the substituents Ζ, Υ, X, R, R^, n and p remain unaltered
- 5 - the compounds to having the formula Ιθ
wherein Z, Υ, X, R, Rj, n and p are defined as previously given
- the compounds according to this invention having the formula IE
(Y).
(ie’
AP 0 0 0 1 8 8 wherein R, R^, X, Y, Z, n and p have the above-given definitions As far as this invention is concerned, a lower alkyl radical is a hydrocarbon chain which may be straight or branched, having up to 6 carbon atoms such as a methyl, ethyl, isopropryl, secbutyl, tert-butyl, neopentyl or n-hexyl. A lower alkoxy radical includes an alkyl chain defined as above.
Among the various halogens, it may more particularly be cited fluorine or chlorine. However bromine and iodine are also of value.
A lower alkenyl radical is a hydrocarbon chain including a double bond, having from 2 to 6 carbon atoms. As lower alkenyl radicals, it may be cited an allyl, a methallyl, a but-2-enyl radical, an isopropenyl or a
3-methyl but-l-enyl radical.
A lower alkylene dioxy group has from 1 to 4 carbon atoms in the alkylene chain as for example methylenedioxy or ethylenedioxy.
When X and/or Y and /or Z are an acyl moiety, this moiety derives from
- 6 a lower alkyl carboxylic acid such as acetyl, propionyl, dipropyl acetyl, or from an aromatic cyclic acid such as a benzoyl, naphtoyl-1, 2,6-dichlorobenzoyl, 3,4,5-trimethoxybenzoyl, a veratroyl, a syringoyl, a O-carbethoxy syringoyl, a nicotinoyl or a furoyl; or from an aryl lower alkyl carboxylic acid such as a phenoxy acetyl, a dichlorophenoxyacetyl or a p-chlorophenoxy isobutyryl.
An aryl lower alkyl radical is defined as a monocyclic aryl radical bearing a hydrocarbonated side-chain of 1 to 6 carbon atoms such as for example benzyl, phenylethyl, ot-methylphenyl ethyl, 2,6-dichlorobenzyl,
2,3,5-1 r imethoxybenzy1.
When Z is an alkyl carboxylic side chain, the alkyl moiety has from 1 to 4 carbon atom. The carboxylic function may be free or esterified such a (methoxy carbonyl) methyl, an (ethoxy carbonyl) methyl or an (ethoxy carbonyl) ethyl.
The substituent Y may further be an alkyl radical substituted with an oxo group or a hydroxy group. A preferred example of such group is acetyl or hydroxy ethyl.
When R and/or are a lower alkyl radical, they are preferably a methyl or an ethyl.
From all the compound of formula I, mentionned hereabove, the presently preferred compounds are those for which X is a hydroxy, free, esterified, or etherified located in position ortho to the ethyloxy chain and those for which Y is a halogen and most preferably those for which Y is a fluorine.
The significance of Z may very broadly vary. The nature of this substituant is important but the number of the substituents Z plays a more reduced role.
This invention also extend to a process for producing a compound of genec,'ii formula I
- 7 (I)
- Ο \
Ar'-(Y)n which comprises the steps consisting of
- condensing a phenolic derivative of the formula II
Ar - X (II) (Z)p wherein Ar, X, Z are defined as above-given with an aryl aceto nitrile of the formula III „ 0 CH, CN
Ar' ^*2 (HI) <Y)n wherein Ar', Y and n have the above-given definitions in the presence of an acidic catalyst to produce a diaryl ethanone of the formula IV
AP 0 0 0 1 8 8 wherein z, Y, Ar, Ar', n and p have the above-given definitions and X is a free hydroxy rducing the latter by means of an alkali metal mixed hydride in the presence of a metalic catalyst or by reaction with a lower alkyl chloroformate and reduction of the intermediary so-produced compound by means of an alkali metal borohydride to obtain a compound of formula I.
This invention more particularly relates to a process for producing a compound of formula IA which comprises the steps of condensing a phenol of formula II.
A (Z)p
OH
X
IUA>
wherein Z, X and p have the above-given defintions with a phenoxyaceto nitrile of the formula
wherein Y and n have the above-given definitions in the presence of an acidic catalyst to produce the ethanone of general formula IV.
O
wherein Z, Y, n and p have the previous definitions and X is a free hydroxyl
- reducing the latter into a compound of general formula IA by means of an alkali metal mixed hydride in the presence of a metallic catalyst or by reaction with a lower alkyl chloroformate then reduction of the thus-formed intermediary compound with an alkali-metal borohydride which may be alkylated by means of an alkylating reagent in basic
- 9 medium or acylated by meeans of functional derivative of a carboxylic, sulphonic, sulphuric or phosphoric acid.
This process also includes another process for producing a compound of formula I which comprises the steps of blocking the phenolic function of a hydroxy acetophenone of formula V (Z)p - Ar Cf (V)
CO CH3 wherein Ar, Z and p are defined as previously given and X is a free hydroxyl using a easily-split reagent submitting the so-blocked phenol of formula VI ___OB (Z)p - Ar <7 (VI) — 0 CH3 wherein B is a leaving group
Z and p have the above-given definitions submitting the latter to the action of a brominating agent to produce an α-bromoketone of formula VII
OB (Z)p - Ar (VII)
CO CH2 Br wherein Z, Ar, B and p have the above-given meanings
- condensing this derivative with a phenolic derivative of formula
Ar’
AP 0 0 0 1 8 8 wherein Ar', Y and n are defined as previously indicated to produce a phenoxy ethanone of formula VIII (Z)p - Ar (VIII)
- 10 COCH. 0 Ar' - (Y) z n
X wherein the definitions of the substituents Y, Z, Ar, n and p remain unaltered and X is a hydroxy group blocked by an easily-split radical
- submitting the conpound of formula VIII to a hydrogenolysis in the presence of a metallic-catalyst or to an acidolysis to make free the hydroxy group and produce a phenoxy ethanone of formula IX
CH- 0 -, (Z)p - Ar z Ar' - (Y) (IX) '--OH n wherein Z, Y, Ar, Ar', n and p have the above-given meanings
- treating the latter with a reducing agent to produce the hydroxylated derivative thereof of formula X
CHOH - CH- 0 (Z)p - Ar Ar' - (Y) (X)
OH in which Z, Y, n, p, Ar and Ar' are defined as above-indicated and X is a free hydroxyl.
This process particularly applies for producing a compound of formula VIII.
A which comprises the steps of
- blocking the free hydroxyl of a hydroxy acetophenone of formula VA
X _ »
- 11 with an easily-split blocking reagent
- submitting this blocked phenolic derivative to the action of a brominating agent to produce the corresponding a-bromoketone
- condensing this bromoketone with a phenol of formula
wherein Y and n are defined as previously to obtain a phenoxy ethanone of formula VIA
(Y) n (VIA, wherein the meanings of the substituents Z, Y, p and n remain unchanged and X is blocked hydroxyl
AP 0 0 0 1 8 8
- submitting this compound to hydrogenation in the presence of a metallic catalyst or to an acidolysis, to make free the hydroxyl function and obtain a phenoxy ethanone of formula VIIA
wherein X is a hydroxy
,. *
- 12 and Ζ, Y, p and n are defined as previously indicated
- reducing the compound of formula VIIA by means of a reducing agent to produce the corresponding alkanol of formula VIIIA
wherein Ζ, Y, n and p are defined as previously given and X is a free hydroxyl
This invention also relates to another process for producing a compound of formula I wherein R is a lower alkyl radical, which comprises the steps of
- reacting a phenoxy ethanone of formula VIII (Z)p - Ar - CO CH. 0 - Ar' - (Y) (VIII) \χ ζ n wherein Ζ, Y, Ar, Ar', p and n have the above-given definitions and X is a blocked hydroxy group to the action of a triaryl alkyl phosphonium bromide under the conditions of the Wittig's reaction to produced an ethylenic derivative of formula XI
R
I (Z)p - Ar - C = CH - 0 - Ar' - (Y) (VI) ^X n wherein Ζ, Y, Ar, Ar', n and p are defined as above-given
X is a blocked hydroxy group and R is a lower alkyl radical
- 13 - submitting this compound to hydrogenation in the presence of a metallic catalyst to produce the «-alkylated derivative of formula I
R
I (Z)p - Ar - CH - CH-, - 0 - Ar' - (Y) (I) \x 2 n wherein Z, Y, Ar, Ar, n and p are defined as previously
X is a free hydroxy group and R is a lower alkyl radical which may, when desired, be alkylated or acylated under the conditions previously defined
This process more particularly applies for producing a compound of formula IA which comprises the steps of reacting a phenoxy ethanone of formula VI.
A
AP 0 0 0 1 8 β wherein Y, Z, n and p have the abobe-given definitions and X is a blocked phenolic group with a triaryl (lower alkyl) phosphonium bromide under the condtions of the Wittig's reaction to produce an ethylenic derivative of formula IX.
A
<IXA>
tri x
*
- 14 wherein Z, Y, n and p have the above-given definitions
R is a lower alkyl radical and X is blocked phenolic group
- and submitting this latter to hydrogenolysis in the presence of a metallic catalyst to produce an α-alkyl ethoxy derivative of formula I.
A
R
wherein Z, Y, n and p have the above-given definitions
X is a hydroxy and R is a lower alkyl radical which may when desired, be alkylated or acylated under the above-defined conditions.
This invention also includes another process for producing a conpound of formula I which comprises the step of reacting a substituted aryl aldehyde of formula X (Z)p - Ar - CHO (X) wherein Z and p are defined as above and X is a blocked phenolic group with a triaryl (phenoxy methyl) phosphonium salt under the conditions of the Wittig's reaction to produce an ethylenic conpound of the formula XII (XII) „ *
- 15 (Y) - Ar' - Ο - CH - CH - Ar - Z n s wherein Z, Ar, Ar', X, Y, n and p have the above-given definitions
- hydrogenating the latter by means of hydrogen in the presence of a metallic catalyst into a compound of formula I (Y)„ - Ar' - 0 - H, CH, - Ar - (Z)p (I) wherein the substituents Z, Ar, Ar', Y, n, p and X have the above-given definitions
This invention further includes another process for producing a compound of formula I wherein a substituted benzaldehyde of formula XA . CHO (Z)p (XA) wherein Z and p have the above-given definitions and X is a blocked phenolic function is reacted with a triaryl (phenoxy methyl) phosphonium salt under the conditions of the Wittig's reaction to produce an ethylenic derivative of formula XI.
A
AP 0 0 0 1 8 8
wherein Z, Y, n and p have the above-given definitions and X is a blocked phenolic group which is further hydrogenated into a compound of formula I by means „ *
- 16 of hydrogen in the presence of a metallic catalyst.
This invention also includes a process for producing a compound formula I which comprises the steps of blocking the reactive functions of a hydroxy aryl alkanol of formula XIII
R
I (Z)p - Ar - CH - CHOH - R. (XIII)
X wherein Z, Ar, R, R^ have the above-given definitions and X is a free hydroxyl by means of an easily-split reagent, then reacting the thus-blocked derivative with a phenolic derivative of formula XIV ___OH
Ar' —(XIV)
wherein Y, n and Ar' have the above-given definitions t to produce an aryloxy ethyl arylidenic derivative of formula XV (Z)p - Ar - CH - CH - 0 - Ar' - (Y) (XV) \χ wherein Z, Y, Ar, Ar', n and p have the above-given definitions R and R| the same or different each other are a hydrogen or a lower alkyl radical and X is a blocked phenolic group and to make free the hydroxy function by means of an alkaline agent to produce a compound of formula I
This process more precisely applies for producing a compound of formula IA which comprises the steps of blocking the reacting functions of a (hydroxyphenyl) ethanol of formula XIIA
- 17 R R.
wherein Z and p are defined as above
X is a hydroxy
R and R^ are a hydrogen or a lower alkyl by means of a ragent, which is easily split, contacting the thus-blocked derivative with a phenol of formula ΧΠΙΑ
wherein Y and n have the above-given definitions to produce a phenylethoxy phenyl of formula XIVA
AP 0 0 0 1 8 8 wherein Z, Y, n and p have the above-given definitions
R and R^ are hydrogen or a lower alkyl and X is a blocked phenolic group and making free the hydroxyl function by means of an alkaline agent to product a compound of formula IA
Thi invention has as a further subject matter the intermediates of formula IX.
A
,. r
- 18 R
X wherein Υ, Ζ, X, R, n and p have the above-given definitions and the compounds of formula XI 1^
CH = CH - O
wherein Ζ, Υ, X, n and p are defined a previously
It is a further subject matter of this invention, the pharmaceutical compositions containing as active ingredient at least one conpound of formula I in admixture or conjunction with an inert non-toxic pharmaceutically-acceptable carrier or vehicle.
The compounds of formula I acccording to this invention show very interesting phamacological properties and namely diuretic, antihypertensive, platelets, anti-aggregating properties and anti-lipoxygenase properties. These vascular properties are very peculiar due to the fact that their site of action is not exclusively renal. The compounds according to this invention inhibit the contractions induced by Noradrenaline and by the potassium salts.
»
- 19 The results of this testing imply the existence of an extra-renal site of action likely vascular, in the mechanism of hypertensive action of the compounds of formula I. The pharmacological testing and the obtained results allow to think that the way of action of the compound of formula I goes through the intra-cellular movement of Calcium into the muscular wall of the vessels.
As a result of the pharmacological properties the compounds according to this invention find a use in human and veterinary therapy as a platelet anti-aggregating mdecine or as an anti-hypertensive medecine. To these ends they are used in the form of pharmaceutical compositions which contain as active ingredient at least one compound of formula I in admixture or conjunction with an inert, non-toxic pharmaceuticallyacceptable vehicle or carrier.
For the therapeutic use, they are manufactured in those forms convenient for administration through parenteral, oral, rectal, permucous or percutaneous ways. It may be cited in this respect the injectible solutes or suspensions packed in ampuls, in multi-dosis flasks, or in the form of auto-injectible syringes, in the form of coated or uncoated tablets, dragees, solft gelatine capsules, powders, rectal suppositories, solutions in a polar solvent, or the transdermal preparations.
The carriers which are appropriate for such manners of administration are cellulose derivatives, micro-crystalline cellulose, earth-alkaline carbonates, magnesium phosphate, starches, chemically-modified starches or lactose.
For parenteral use, water, aqueous solutions, saline, glucose solutions and the like are the most conveniently used ones. For rectal way of administration, cacao butter or polyethylene glycol stearates are the preferred carriers.
AP 0 0 0 1 Θ 8
- 20 The dosology may vary within broad limits which are a function of the severity of the hypertensive disease, of the weight and the age of the patient and of the way of administration.
A a general rule, the unit dosage may range from 1 to 200 mg per intake and the daily dosage may range from 2 to 500 mg per day in the man.
The manner of administration may also be modulated as a function^ of the duration of the action of the compounds of formula I.
The following examples are merely intended to illustrate the invention without limiting it in any manner.
EXAMPLE I
1—(2—HYDROXY 5—METHOXY PHENYL) 2-FHENQXY ETHANE (Process A)
Step A : l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethanone
To a solution of 32.2 g (0,27 mol) of boron trichloride in 200 ml chloroethane cooled to 0°, they are successively added a solution of 28,4 g (0,23 mol) 4-methoxy phenol in 100 ml dichloroethane, 36,6 g (0,24 mol) phenoxy acetonitrile then 15,2 g (0,11 mol) aluminium chloride while stirring. The mixture is kept under stirring for 20 hours at room temperature. After hydrolysis in acidic conditions for 30 mn, and extraction, it is obtained after crystallisation from methanol, 26 g (ie a yield of 44%) phenoxy acetophenone. The pure compound melts at 128°C.
Step B : l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethane To 6,4 g (0,058 mol) of ethyl chloroformate at 0°C one adds a solution of 12.8 g l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethanone obtained at step A in 100 ml tetrahydrofuran in the presence of 6 g (0,058 mol) triethylamine. After one hour contact under stirring at room temperature, the thus formed „ *
- 21 triethylamine hydrochloride which has precipitated is filtered and the filtrate is dropwise added to a solution of
5.6 g (0,15 mol) sodium borohydride in 50 ml water at 5°C for 45 mn. After stirring at room temperature for 1,5 hour the reaction mixture is poured on ice, one proceeds to an acidic hydrolysis with hydrochloric acid then extracts with ether. The ethereous phases are separated, the solvent is evaporated off and 8.4 g of product recovered after purification by distillation under reduced pressure. The yield amounts to 69%. The melting point of the pure compound is 170eC.
Its piperazine disalt melts at 95eC
EXAMPLE II
1—(2-METBOKY PHENYL) 2-PHENOKY ETHANE g l-(2-hydroxy phenyl) 2-phenoxy ethane (ie 0,032 mol) and 16 g potassium carbonate (0,117 mol) in 100 ml acetonitrile are added with
4.9 g (0,039 mol) methyl sulphate. The whole mixture is heated to reflux for 5 hours. Thereafter the solvent is evaporated off and the residue extracted, 5,6 g (ie a yield of 80%) of the methoxy derivative are recovered as an only product.
EXAMPLE III l-(2-ACETOXY 5-METHOXY PHENYL) 2-PHENOXY ETHANE
To 4 g (0,016 mol) l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethane they are added 1.5 g (0,019 mol) acetyl chloride and 2 g (0,019 mol) triethylamine for acetylation. After stirring of the mixture for 1 hour at room temperature, the mixture is extracted with a solvent to provide 4 g (ie a yield of 85%) of the 2-acetoxylated derivative.
EXAMPLE IV
1—(2-SULFITO CKY PHENYL) 2-( 4-FLUOROPHENOXY) ETHANE AS THE POTASSIUM SALT
AP 0 0 0 1 8 8 „ *
- 22 In a three-neck flask, under Argon atmospher, 6.53 g (0,47 mol) potassium carbonate and 10 g (0,43 mol) l-(2-hydroxy phenyl) 2-(4-fluorophenoxy) ethanol are introduced with 100 ml acetonitrile. The mixture is stirred for 30 mn at 40°C then 8.97 g (0,645 mol) of the complex (SO^-triethylamine) are added. After stirring the mixture is cooled and the formed sulphate precipitates. After filtration 6.5 g of a white solid are recovered.
Melting point : 163°C
Yield : 42 % Λ
EXAMPLE V l-(2-PHOSPHCNYLQXY PHENYL) 2-(4-FLUOROPHENOXY) ETHANE
Step A : 2-(4-fluorophenoxy ethyl) phenyl phosphochloridate g (0,043 mol) of l-(2-hydroxy phenyl) 2-(4-fluorophenoxy) ethane are dissolved into 36 g POCl^ (0,235mol) and the mixture is heated to the reflux for 2,5 hours in the presence of 0.1 g Aluminium chloride. The mixture is concentrated then distilled. The formed phosphate distillates (Eb θ 2^ 210 220’C) - 9,71 g of an oily residue are thus recovered (yield - 64 %).
Step B : Hydrolysis of the phosphochloridate g (0,11 mol) of the phosphochloridate are hydrolysed in 10 ml water under stirring at 80°C. The reaction mixture is kept under stirring for three further hours. It is concentrated therafter under reduced pressure until dryness. By scratching in petroleum ether, a white solid weighing 3.1 g is recovered.
Yield : 86 %
MP : 80-82°
EXAMPLE VI
1-(2-HYDROXY PHENYL) 2-( 4-FLUOROPHENOKY) ETHANOL (Process B)
- 23 Step A : 1-(2-benzyloxy phenyl) 2-bromo ethanone
250 g (1,1 mol) of 2-benzyloxy acetophenone are dissolved in 1000 ml of dry tetrahydrofuran, the solution is cooled to O’C and then added portionwise to 500 g (1,32 mol) of phenyl trimethyl anilinium tribromide for 4 hours. The so-formed precipitate is filtered. The mixture is distilled off to dryness and the residue is used as such for the next step of the synthesis.
Weight : about 34 g Yield : 70 %
Step B : 1-(2-benzyloxy phenyl) 2-phenoxy ethanone
125 g of the α-bromoketone obtained in the preceding step are added to 57 g phenol (0,61 mol). 283 g (2 mol) of potassium carbonate in acetonitrile and the whole mixture is heated to reflux for 2 hours. After filtration of the mineral salts and evaporation off of the solvent the residue is taken up dichoroethane, washed with a N solution of sodium hydroxide then with water until the washings are neutral. The solvant is further dried and evaporated until dry to produce 104 g of the phenoxy benzylated derivative.
MP : 141°C Yield : 80 %
Step C : l-(2-hydroxy phenyl) 2-phenoxy ethane g (0,164 mol) of phenoxy benzylated derivative of step B are let to be hydrogenated under an atmospher of hydrogen in ethanol (1000 ml), preferably in the presence of 3 g of palladized charcoal at 10%. After absorption of the required amount of hydrogen, the catalyst is separated by filtration, Ethanol is evaporated off and the dry residue is crystallized to provide 34,7 g of phenolic derivative melting at 120°C.
The yield amounts to 92%
8 V 0 0 0 dV
.. *
- 24 Step D : 1-(2-hydroxy phenyl) 2-(4-fluorophenoxy) ethanol
To a solution of 5 g (0,02 mol) of 1-(2-hydroxy phenyl) 2-(4-fluorophenoxy) ethanone in methanol cooled to 0°, they are added dropwise 0.760 g (0.02 mol) of sodium borohydride. After return to room temperature, at the end of one hour,the reaction mixture is concentrated and poured on ice then is acidified at pH 4. The whole mixture is extracted with ether to recover 4.5 g of the hydroxy ethylated derivative as an oily residue.
The yield amounts to 90%
EXAMPLE VII
2-(2-HYDROXY PHENYL) 3-PHENOXY PROPANE
A solution of 53,5 g of triphenyl methyl phosphonium in 500 ml tetrahydrofuran under atmospher of argon, is added to 112,5 ml of a
1,6 M solution of butyl lithium in hexane at room temperature. After 4 hours of steering, l-(benzyloxy phenyl) 2-phenoxy ethanone dissolved in tetrahydrofuran is added dropwise and the mixture is heated over a night at reflux temperature.
After concentration of the solvent, the mixture is poured into water and is extracted with ether. The residue recovered after evaporating off the solvent, is submitted to a flash-chromatography on silica, with a mixture of eluents (Petroleum ether/isopropyl ether 90:10) to recover 37 g of propenylated derivative which melts at 57°C.
g of propenylated derivative is hydrogenated under hydrogen atmospher in the presence of palladized charcoal at 10% Palladium, in 400 ml ethanole under vigorous stirring at atmospheric pressure and at 50°C, for 20 hours.
After having separated the catalyst by filtration and evaporation of the filtrate, 16 g of 2-(2-hydroxy phenyl) 3-phenoxy propane are recovered (yield : 75%)
EXAMPLE VIII
1-(3—METHOXY 4-HYDROXY PHENYL) 2-(4-FLUOROPHENOXY) ETHANE _ »
- 25 Preparation of (chloromethyl) 4-fluorophenoxy ether :
g (0,47 mol), of 4-fluoroanisole are heated with 97 g (0,47 mol) phosphorous pentachloride at 120eC for 2 hours then the temperature is increased to 140® then to 160° as PCl^ distillates. One maintains still 2 further hours at this temperature after the distillation of PCl^ is achieved, then one distillates under reduced pressure (15 mm Hg) at a temperature of 100® to obtain 47 g of the chlorinated ether. The yield amounts to 75%.
Preparation of triphenyl 4-fluoroxy methyl) phosphonium chloride :
In 300 ml benzene, 42 g of chloromethylated ether (0,26 mol) and 81 g of triphenyl phosphine are introduced and the whole mixture is heated to reflux for a night. Afer evaporation of benzene, the salt of phosphonium is allowed to crystallyse from ether. 62 g of salt of phosphonium are recovered, melting at 248®C. The yield amounts to 57%.
Step A : 1-(3-methoxy 4-benzyloxy phenyl) 2-4-fluorophenoxy) ethene
12.2 g (0,029 mol) (4-fluorophenoxy methyl) triphenyl phosphonium chloride are dissolved in 100 ml tetrahydrofuran and the solution is cooled to 78®C under atmospher of argon. To this, 16 ml of a 1,6 H (i.e 0,026 mol) solution of butyl lithium in hexane are added dropwise. After 1 hour standing at this temperature, 5 g (0,02 mol) of 3-methoxy 4-benzyloxy benzaldehyde are added then the mixture is allowed to revert to room temperature in two hours. The mixture is then poured on ice, made acidic at pH 4 and extracted with ether. After evaporation of the solvent, the residue is filtered on silica and 6,2 g (86%) of the phenoxy ethene are recovered.
Step B : 1-( 3-methoxy 4-hydroxyphenyl) 2-( 4-fluorophenoxy) ethane
8.2 g (0,0225 mol) of phenoxy ethenic derivative of step A is put in a vessel for hydrogenation under atmospher of hydrogen, in ethanol, in the presence of 2 g of palladized charcoal at 10%. The mixture is kept under vigourous stirring
AP 0 0 0 1 8 8
- 26 for 12 hours. After filtration of the catalyst and having evaporated off the solvent, the residue is chromatographied on silica and after elution by a mixture of petroleum ether/ethyl acetate (90:10) to provide after evaporation of the solvent, 3.5 g of the saturated derivative in the form of an oily product
Yield :60 %
EXAMPLE IX (Method B)
1-(3-HYDRCKY PHENYL) 2-(4-FLUDROPHENQXY ETHANE)
Step A : l-(2-methyl sulphonyloxy ethyl) 3-(methylsulphonyloxy) benzene g (0,21 mol) of (3-hydroxy phenyl) ethanol in anhydrous pyridine are added dropwise to 41 ml (0,525 mol) methyl sulphonyl chloride at OeC, under stirring
After return to room temperature and standing at this temperature for 1,5 hour, the mixture is poured on ice. It is acidified then extracted with methylene chloride. The extract is washed with water until neutral, dried on sodium sulphate and evaporated to dryness. 53 g of di-methyl sulphonate are obtained. Yield : 86%
Step B : 1-( 3-methyl sulphonyloxy phenyl) 2-(4-fluorophenoxy) ethane A mixture made of 53 g (0,18 mol) of the dimethyl sulphonate of step A, 24,4 g (0,217 mol) of 4-fluorophenol and 28,8 g (0,217 mol) potassium carbonate are introduced into 350 ml acetone and heated to reflux under stirring for 9 hours. The mineral salts are thereafter filtered and the filtrate is evaporated off. The residue is taken up in water and extracted with ether. The organic phases are separated, washed with sodium hydroxide then with water until neutral and dried on sodium sulphate. The ethereous solution is evaporated off to obtain 46 g of dry residue (i.e a yield of 83%) of (3-methyl sulphonyl phenyl) 2-(4-fluorophenoxy) ethane, pure enough for the progress of the synthesis.
- 27 Step C : 1-(3-hydroxy phenyl) 2-(4-fluorophenoxy) ethane g (0,148 mol) of the methyl sulphonate of step B are allowed to be saponified by reflux in 2000 ml of a 2N solution of sodium hydroxide for 16 hours. After cooling, one acidifies with 5N ClH, extracts with ether and dries on sodium sulphate. The solvent is evaporated off and 25 g of crude product substantially containing a 3-hydroxy styrenic derivative are recovered. Using the Flash Chromatography and the elution with a mixture of petroleum ether/isopropyl ether (80:20) 11,68 g of pure (3-hydroxy phenyl) 2-(4-fluorophenyl) ethane are obtained as a crystaline form
MP : 64°
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TABLETS WITH 100 MG OF l-(2-HYDRGXY PHENYL) 2-( 4-FLUOROPHENOXY) ETHANE
- active ingredient ................ 100 g
- wheat starch ..................... 45 g
- Ma'is starch ...................... 55 g
- microcristalline cellulose powder. 12 g
- ethyl cellulose .................. 8 g
- magnesium stearate ............... 5 g for 1000 tablets finished at an average weight of 0.225 g
Pharmacological study of the compounds according to this invention :
A - DIURETIC ACTION
1. in the mice The compounds of formula I have been given to batches of 12 male mice weighing between 25 and 30 g each. The mice, divided by pairs, are prior syhmitt-pd to a load of liquid, constituted by the administration of the compound to be tested under a volume of 25 ml per kg, followed by administration of saline a 9 %0, the total volume to be given, being of 1 ml per mouse.
The diuresis is studied for 4 hours. The urinary volume is measured every hour. Potassium and sodium are dosed by spectrophotometry on the pooled urines.
2. in the rat
An overload of liquid is obtained in the rats of male sex weighing between 200 and 250 g and fastened for 18 hours before the testing.
The animals are located each in an individual cage for diuresis and receive by oral way an overload of 20 mlAg of saline at 0,9% containing the compound of formula I to be tested. The diuresis is measured for 5 hours. The volumes of urine are determined every hour. Dosages of sodium and potassium are performed by spectrophotometry.
Table I collects the main results obtained during this testing.
- 41 TABLE
PRODUCT of exaiqple | ||||||
Diuretic power en % R - RAT | Ratio Na/K en % R - RAT | |||||
S - MICE Minimal doses in i | (X) active xj/kg PO | S - MICE Minimal a< doses in mg, | (x, rtive dtg PO | |||
ex | 25 | R (12) | 190 % | R (12) | 46 | % |
S (25) | 10 % | S (25) | 50 | % | ||
ex | 26 | R (50) | 250 * | R (50) | 40 | % |
S (100) | 30 % | S (100) | 210 | % | ||
ex | 30 | R (12) | 170 % | R (12) | 40 | % |
S (25) | 40 % | S (25) | 210 | % | ||
ex | 36 | R (100) | 140 % | R (100) | 65 | % |
S (100) | 40 % | S (100) | 180 | % | ||
ex | 42 | R (12) | 190 * | R (12) | 60 | % |
S (100) | Inactive | Inactive | ||||
ex | 169 | R (12) | 70 % | R (12) | 85 | % |
S (100) | Inactive | S (100) | Inactive | |||
ex | 46 | R : Inactive | R : Inactive | |||
S : Inactive | S : Inactive | |||||
ex | 46 | R (25) | 80 % | R (25) | 80 | % |
S (100) | 20 % | S (100) | 130 | % | ||
ex | 172 | R (25) | 80 % | R (25) | 160 | % |
S (100) | 68 % | S (100) | 208 | % | ||
ex | 56 | R : Inactive | R : Inactive | |||
S : Inactive | S : Inactive | |||||
ex | 107 | R (25) | 140 % | R (25, | 60 | % |
S (100) | 80 * | S (100) | 220 | % | ||
ex | 134 | R (6) | 100 % | R (6) | 50 | % |
S (25) | 40 % | S (25) | 140 | % | ||
ex | 139 | R (25) | 32 % | R (25) | 80 | % |
S (25) | 40 % | S (25) | 80 | % | ||
ex | 163 | R (6) | 260 * | R (6) | 53 | % |
S (25) | 34 % | S (25) | 134 | % | ||
FUROSEMIDE | R (12) S (25) | 30 % 120 % | R (12) S (25) | 10 320 | % % |
8 V 0 0 0 dV
BAD ORIGINAL $
- 42 Β - ΑΝΠ-HYPERTENSIVE ACTION IN THE UNANESTHETIZED RAT
This study has been carried out in batches of males rats SHR (strain OKAMOTO) 16 weeks old. The arterial systolic pressure has be measured by the sphygomanometric process using an electrospohygmograph NARCO (biosystems) type PE 300. The determinations of the blood pressure have been performed 24 hours after the administration of a compound of formula I to be tested. The arterial systolic pressure is calculated from the average of 6 to 8 measurements.
The obtained results are gathered in Table II
It thus appears that the kinetic of the anti-hypertensive action is dissociated from that of the diuretic effect.
♦
- 43 TABLE II
PRODUCT | ANTI-HYPERTENSIVE ACTIVITY STUDIED in the RAT | |
A - Acute C - chronic (x) » dosis studied in MG/kg ΡΌ | Variation of the anti-hypertensive effect 24 heures after administration of the product | |
ex 25 | not tested | not tested |
ex 26 | not tested | not tested |
ex 30 | A - (7,5) A » (30) C - (15) | - 11 mmHg - 30 mmHg - 16 mmHg |
ex 36 | A - (100) C - (100) | not active - 20 mnHg |
ex 42 | not tested | not tested |
ex 169 | not tested | not tested |
ex 46 | not tested | not tested |
ex 48 | A (60) | - 24 mmHg |
ex 172 | A - (60) | - 16 mmHg |
ex 56 | not tested | not tested |
ex 107 | not tested | not tested |
ex 134 | A - (15) A - (60) C - (30) | - 11 nmHg - 37 mmHg - 26 mmHg |
ex 139 | A (60) | - 12 mmHg |
ex 163 | A - (10) A - (60) | - 19 mmHg - 33,5 mmHg |
FUROSEMIDE | FUROSEMIDE (60) HYDROCHLOROTHIAZIDE (60) | FUROSEMIDE not active HYDROCHLOROTHIAZIDE not active |
AP 0 0 0 1 8 8
BAD ORIGINAL $
C - BLOOD PLATELETS ΑΝΠ-AGGREGATING EFFECT
These studies have been carried out on plasmas reach in platelets, coming from rat blood. The aggregation is induced by adding Adenosine diphosphoric acid (ADP). The nephelometric curves showing the aggregation are obtained using an aggregometer type BORN, plasma being incubated at 37° under continuous stirring at 100 RPM (cf. Bom G.V.fc, and CROSS J, J.Physiol. 168 (1962) 178).
*
Table III collects the obtained results with the many tested compounds of formula I bad ORIGINAL
Ill
- * _ 45 TABLE
PLATELETS ΑΝΠ^AGGREGATING ACTIVITY IN VITRO (Aggrating agent is ADP)
PRODUCT | V at 50 | M at 50 |
TICLOPIDINE | 0,75 mM | 0,85 mM |
Ex 56 | 0,45 | 0,30 |
Ex 30 | 0,5-1 | 0,8 |
Ex 174 | 0,55 | 0,40 |
Ex 90 | 0,60 | 0,50 |
Ex 82 | 0,65 | 0,55 |
Ex 52 | 0,70 | 0,75 |
Ex 64 | 0,70 | 0,50 |
Ex 78 | 0,70 | 0,70 |
Ex 58 | 0,75 | 0,60 |
Ex 129 | 0,8 | 0,6 |
Ex 84 | 0,8 | 0,75 |
Ex 102 | 1,0 | 0,7 |
Ex 42 | 1,0 | 1,2 |
Ex 172 | 1,0 | 0,95 |
Ex 86 | 1,25 | 1,55 |
Ex 134 | 1,5 | 1,3 |
Ex 81 | 1,6 | 1 |
Ex 12 | 1,95 | 1,60 |
Ex 100 | 1,1 | |
Ex 169 | > 2 | inactive |
Ex 54 | > 2 | inactive |
Ex 36 | > 2 | inactive |
AP 0 0 0 1 8 8 f
These results are confirmed by the results obtained ex vivo in the rats receiving for 3 days a conpound of formula I by oral way.
It is stated an inhibiting efect on the platlets aggregation which is evidenced by a dobblening of the dosis of ADP needed in respect of the dosis given to the controls for obtaining an aggregation of 50%.
Ticlopidine tested as reference substance at the same dosis, give about the same results. ;
D - ACTION CN THE SYSTEMS OF TRANSPCREATICN OF SODIUM AH) POTASSIUM IONS IN THE HUMAN ERYTHROCYTS
This action has been studied according to the method described by
G. GARAY and cowork in Naunyn-Schmideberg's Arch. Pharmakol. 334 (1986) 202 and in Bioch. Pharm. 33 (1984) 2013.
The following results have been obtained and are collected in Table IV. They appear to be better than those obtained with Furosemide and
XIPAMIDE.
_ 47 _
TABLE
IV
PHARMACOLOGICAL ACTION ON THE TRANSPORT SYSTEMS of Na+ and K+ of the human erythrocyts
PRODUCTS | EFFECT ON THE TRANSPORT Na-K IC 50 fOl | EFFECT CN THE ANION EKCHANSH IC 50 fM |
ex 25 | > 600 | 120 |
ex 26 | 70 | 40 |
ex 30 | 170 | 4 |
ex 36 | > 600 | 0,8 |
ex 42 | 40 | 12 |
ex 169 | not active | not active |
ex 46 | 95 | 200 |
ex 41 | = 400 | 200 |
ex 172 | = 400 | 75 |
ex 56 | 95 | 200 |
ex 107 | not tested | not tested |
ex 134 | not active | not active |
ex 139 | not tested | not tested |
ex 163 | not tested | not tested |
BUMETANIDE | 0,66 | 300 |
FUROSEMIDE | 37 | 200 |
XIPAMIDE | - | 25 |
AP 0 0 0 1 8 8
-48 E - STUDY CN THE IMPACT OF ΊΉΕ COMPOUNDS OF FORMULA I ON THE POTASSIUM CHAM4ELS IN THE AORTA USING A MEASURE OF THE EFFLUX OF RUBIDIUM
The action of the compounds of formula I on the potassium Channels has been determined using Rubidium (Rb+) which is the homolog of potassium. The entry of Rb+ in pieces of aorta has been studied in initial speed after 5 mn and at 37°C. The content in Rb+ and K+ have measured using an apparatus of atomic absorption or by a high-performance flamrae photometer.
As an example, the compounds of example 1 and 4 have been studied using a dose-effect curve.
RESULTS
Figures 1 and 2 collect the obtained results.
The compound of example 1 has a very clear positive effect on the opening of the potassium channels. Its activity is far*higher than that of PINACIDIL but slightly weaker than that of CHROMAKALIM.
Compound of ex 1 is less active on the opening of potassium channels. On the other part, in contrast of Cromakalim and Pinacidil, the opening effect on the potassium channels of the compound of ex.l is not antagonized by GLIBENCLAMIDE. The same compound in contrast with those agents acting on the opening of the potassium channels -is glibenclamido-resistent- Its mechanism of action is not bound to the ATP-dependent potassium channel.
F - MEASUREMENT OF THE VASOCCNSTRICTICN INDUCED BY POTASSIUM CHLORIDE
a) Method
A vasoconstriction is caused in male rats of Wistar strain, weighing 200to 350 g by increasing doses of potassium chloride ranging from 20 to 60 mM.
_ 49 _
The rats are thereafter beheaded at the thoracic aorta and the diameter of the vessels is measured.
Curves 1 and 2 gather the obtained results compound of example 1 as the piperazine disalt shows an antagonist efect merely on the contraction induced by the weakest dosis of potassium chloride (C1K at 20 mM).
/
The mean inhibitory dosis (IC^q) has been calculated at 22 μΜ. The contraction induced by the highest dosis of potassium chloride (60 mM) is antagonized only by a strong dosis of the compound of example (IC5Q - 1,12 mM)
It thus appears that it exists a dissociation of the vaso-relaxing effect of the compound of example 1 after , vaso-constriction by potassium chloride depending on the utilized concentration as it has been previously shown only with the potassium agonists. In contrast thereof the calcium inhibitors induce a decontracting effect at both concentrations of the vaso-constricting agent to be administered.
G - ANTI-LIPCKYGENASE EFFECT
The anti-lipoxygenase effect has been studied using soja lipoxygenase in accordance to the method discribed by W.L SMITH and W.E LANDS (J. Biol. Chem. 247 (1972) 1038).
AP 0 0 0 1 8 8
The following results vhich have been obtained are gathered in Table V
TABLE V
PRODUCT | ΑΝΠ-LIPOTYGENASE ACTIVITY |
IC 50 pM | |
ex 25 | 6 |
ex 26 | 6 |
ex 30 | = 100 |
ex. 36 | Inactive |
ex 42 | not tested |
ex 169 | In&eti1£> |
ex 46 | 0,7 |
ex 48 | 30 |
ex 172 | not tested |
ex 56 | 25 |
ex 107 | 7 |
ex 134 | > 166 |
ex 139 | not tested |
ex 163 | not tested |
NDGA | 0,5 |
Claims (26)
- WHAT IS CLAIMED IS1·- Novel derivatives of phenoxyethyl benzene having the formula IR R,I fAr - CE - CH - 0 - Ar' (I) vherein Ar is an aromatic mono- or bicyclic hydroxylated radical selected from the group consisting of- phenyl derivatives having the formula vherein X is a hydroxy free, esterified by a carboxylic or sulphonic organic acid, by phosphoric acid, or by sulphuric acid, or etherified by a lover alkyl or alkenyl radicalZ is a substituent selected from the group consisting of hydrogen, halogens, hydroxy a lover alkoxy» an acyloxy, a phenyl lover alkyl, a lover alkyl, a lover alkyl substituted by a [(lover alkyl) oxycarbonyl, a (lover alkyl) substituted by a hydroxy carbonyl, a moiety CO(CH2)B CH3 vherein m is an integer of from 1 to 4, a moiety CB0H-(CB2)b,-CH3 vherein a' is an integer of from 1 to 4, a carboxamido group optionally substituted by one or tvo lover alkyl radicals, a phenyl and a phenoxy and the naphtalenic derivatives selected from the group consisting of the naphtyl derivatives of the formulaAP 0 0 0 1 8 8 vherein A is a free hydroxy or an esterified or etherified hydroxy- 40 Z is defined as above-given and p is an ineger of from 1 to 3 and those of formula (2),A vherein A, Z and p are defined as above-givenAr' is an aromatic mono- or bicyclic radical selected from the group consisting of- the benzenic derivatives of formulaV’· vherein 7 is a hydrogen, a halogen, a (lover alkylene)dioxy, a hydroxy, a lover alkoxy, an acyloxy derivated from in organic carboxylic acid, a lover alkyl, a lover alkyl substituted by a (lover alkyl) carbonyle, an oxo alkyl chain of the formula C0(CH3)a CHj vherein a is an integer of from 1 to 4, or an hydroxy alkyl chain of the formula CHOH-(CH3)a,-CH3 vherein m' is an integer of from 1 to 4.- the naphtalenic derivatives selected from the group consisting of naphtyl derivatives of formula vherein 7 is defined as above-given-Aland n is an integer of from 1 to 4- and the naphtalenic derivatives of formula vherein 7 and n are defined as above-givenR is a hydrogen, a hydroxy, the oxygene of a keto group of a lover alkyl radical is a hydrogen or a lover alkyl radical
- 2*- The optically active forms the compounds of claim 1° having the formula IAr - CH - CH - 0 - Ar' (I) vherein Ar is an aromatic mono- or bicyclic hydroxylated radical selected from the group consisting of- phenyl derivatives having the formulaAP 0 0 0 1 8 8 vherein X is a hydroxy free, esterified by a carboxylic or sulphonic organic acid, by phosphoric acid, or by sulphuric acid, or etherified by a lover alkyl or alkenyl radicalZ is a substituent selected from the group consisting of hydrogen, halogens, hydroxy a lover alkoxy, an acyloxy, a phenyl lover alkyl, a lover alkyl, a lover alkyl substituted by a [(lover alkyl) oxycarbonylL, a (lover alkyl) substituted by a hydroxy carbonyl, a moiety CO(CH2)B CH, vherein m is an integer of from 1- 42 .to 4, a moiety CH0H-(CH2)B,-CH3 vherein m' is an integer of from 1 to 4, a carboxamido group optionally substituted by one or two lever alkyl radicals, a phenyl and a phenoxy and the naphtalenic derivatives selected from the group consisting of the naphtyl derivatives of the formula vherein A is a free hydroxy or an esterified or etherified hydroxyZ is defined as above-given and p is an Integer of from 1 to 3 and those of formula vherein A, Z and p are defined as above-givenAr' is an aromatic mono- or bicydic radical selected from the group cconsisting of- the benzenic derivatives of formula vherein Y is a hydrogen, a halogen, a (lover alkylene)dioxy, a hydroxy, a lover alkoxy, an acyloxy derivated from in organic carboxylic acid, a lover alkyl, a lover alkyl substituted by a (lover alkyl) carbonyle, an oxo alkyl chain of the formula C0(CH2)b CH3 vherein n is an integer of from 1 to 4, or an hydroxy alkyl chain of the formula CH0H-(CH2)B,-CH3 vherein m' is an- 43 integer of from 1 to 4.- the naphtalenic derivatives selected, from the group consisting of naphtyl derivatives of formula vherein Y is defined as above-given and n is an integer of from 1 to 4- and the naphtalenic derivatives of formula vherein Y and n are defined as above-givenR is a hydrogen, a hydroxy, the oxygene of a keto group or a lover alkyl radicalRt is a hydrogen or a lover alkyl radical vith the restriction that E or Rx are different than hydrogen and represent either a hydroxy or a lover alkyl radical.
- 3*- The base addition salt of a compound of formula I according to claim 1° vith an alkali metal, an earth-alkali metal or an organic base, vhen X is a hydroxy esterified by a polyhydroxylic acid selected from the group consisting of sulphuric acid and phosphoric acid
- 4·- The compounds of formula I according to any of claims 1 to 3’ having the general formula IAAP 0 0 0 1 8 8 vhereir. X is hydrcxy, a hydroxy etherified by a lover alkyl of a lover alkenyl or esterified by an organic carboxylic or sulphonic acid, by phosphoric acid or by phosphoric acid and R, Rx, Υ, Ζ, n and p have the above-given definitions
- 5*- A compound according to any of claims 1 to 4’ being l-(2-hydroxy
- 6-methoxy phenyl) 2-phenoxy ethane.6*- A compound according to any of claims 1 to 5° selected from the group consisting of the metallic and the organic base adition salts of l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethane.
- 7*- A compound according to any of claims 1 to 4* being l-(2-hydroxy 5-carboxamido phenyl) (4-fluorophenoxy) ethane.
- 8*- The compounds of formula I according to any of claims 1 to 3' having the general formula I, vherein the definitions of the substituents X, Y, Z, R, Rx, n and p are the same as in claim 1°
- 9°- The compounds according to any of claims 1 to 3° having the generale formula Ic vherein the definitions of the substituents Z, Y, X, R, Rx, n and p the same as in claim 1°
- 10*- The compounds according to any of the claims 1 to 3* having the formula Is according to any of claims 1 to
- 11*- The compounds formula If <ID) in claim 1°3* having theAP 0 0 0 1 8 8R (I,) vherein R, Rx, X, Y, Z, n and p have definitions given in claim 1°
- 12·- A process for producing a compound of general formula I according to any of claims 1 to 11*CH./ (Z)--Ar P \CH,- 46 0.(I) vherein Ar is an aromatic mono- or bicyclic hydroxylated radical selected from the group consisting of- phenyl derivatives having the formula vherein X is a hydroxy free,- esterified by a carboxylic or sulphonic organic acid, by phosphoric acid, or by sulphuric acid,I I y.or etherified by a lover alkyl or alkenyl radicalZ is a substituent selected from the group consisting of hydrogen, halogens, hydroxy a lover alkoxy, an acyloxy, a phenyl lover alkyl, a lover alkyl, a lover alkyl substituted by a [(lover alkyl) oxycarbonyl L, a (lover alkyl) substituted by a hydroxy carbonyl, a moiety CH(CH2)B CH, vherein m in an integer of from 1 to 4, a moiety CHOH-(CH,)'-CH, vherein m' is an integer of from 1 to 4, a carboxamido group optionally substituted by one or tvo lover alkyl radicals, a phenyl and a phenoxy and the naphtalenic derivatives selected from the group consisting of the naphtyl derivatives of the formula vherein A is a free hydroxy or an esterified or etherified hydroxyZ is defined as above-given and p is an integer of from 1 to 3 »- 47 and those of formula vherein A, Z and p are defined as above-givenAr' is an aromtic mono- or bicyclic radical selected from the group consisting of- the benzenic derivatives of formula vherein 7 is a hydrogen, a halogen, a (lover alkylene)dioxy, a hydroxy, a lover alkoxy, an acyloxy derivated from in organic carboxylic acid, a lover alkyl, a lover alkyl substituted by a (lover alkyl) carbonyle, an oxo alkyl chain of the formula CO(CH2)B CHj vherein m is an integer of from 1 to 4, or an hydroxy alkyl chain of the formula CHOH-(CH2)b,-CH3 vherein m' is an integer of from 1 to 4.- the naphtalenic derivatives selected from the group consisting of naphtyl derivatives of formulaAP 0 0 0 1 8 8 vherein 7 is defined as above-given and n is an integer of from 1 to 4 „ V- 48 - and the naphtalenic derivatives of formula vherein Y and n are defined as above-givenR is a hydrogen, a hydroxy, the oxygene of a keto group or a love; alkyl radicalRx is a hydrogen or a lover alkyl radical vhich comprises the steps consisting of- condensing a phenolic derivative of the formula IIAr - X (II) '^-(Z)p vherein Ar, X, Z are defined as given in claim 1° vith an aryl aceto nitrile of the formula IIIOCB2 CNAr' (III) (T)„ vherein Ar', Y and n have the definitions given in claim 1° in the presence of an acidic catalyst to produce a diarylethanone of the formula IV (IV) »* vherein Ζ, Y, Ar, Ar', n and p the definitions given in claim 1* and X is a free hydroxyl group reducing the latter by means of an alkali metal mixed hycride in the presence of a aetalic catalyst or by reaction vith a lover alkyl chloroformate and reduction of the intermediate so-produced compound by means of an alkali metal borohydride to obtain a compound of formula I according to claim 1*
- 13*- A process for producing a compound of formula I according to any of claims 1 to 11° vhich comprises the steps of condensing a phenol of formula IIA <ΠΑ) vherein Ζ, X and p have the definitions given in claim 1° vith a phenoxy acetonitrile of the formula IIIA (Hix)COGO oo oa.vherein Y and n have the definitions given in claim 1* in the presence of an acidic catalyst, to produce the ethanone of generale formula IVA vherein Z, T, n and p have the definitions given in claim 1° and Z is a free hyroxyl- reducing the latter into a compound of general formula IA by means of an alkali metal mixed hydride in the presence of a metallic catalyst or by reaction vith a lover alkyl chloroformate then reduction of the thus-formed intermediate compound vith an alkali metal borohydride vhich may be alkylated by means of an alkylating reagent in basic medium or acylated by means of functional derivative of a carboxylic, sulphonic, sulphuric or phosphoric acid.
- 14*- A process for producing a compound of formula I according to any of claims 1 to 11* vhich comprises the steps of- bloking the phenolic function of a hydroxy acetophenone of formula VCO CH, vherein Ar, Z and p are defined as given in claim 1* and Z i a free hydroxyl uing an easily-split reagent submitting the so-blocked phenol of formula VIOB (Z)p - Ar (VI)CO CH,- 51 vherein B is a leaving groupZ and p have the definitions given in claim 1°- submitting the latter of the action of a brominating agent to produce an e-bromoketone of formula VII (Z)F (VII) vherein Z, Ar, B and p have the meaning given in claim 1*- condensing this derivative vith a phenolic derivative of formulaOHAr' (T).vherein Ar', Y and n are defined as indicated in claim 1° to produce a phenoxy ethanone of formula VIIICOCHj 0 Ar' - (Y)„ (Z)F - Ar (VIII) vherein the definitions of the substituents Y, Z, Ar, n and p remain the same that in claim 1° and X is a hydroxy group blocked by an easily-split radical- submitting the compound of formula VIII to hydrogenolysis in the presence of a metallic-catalyst or to an acidolysis, to make free the hydroxy group and produce a phenoxy ethanone of formula IX8 8 L 0 0 0 dV *»- 52 CO CBj 0 (2)ρ - ArAr' - (Y).(Π)OB vherein Z, Y, Ar, Ar', n and p have the sam meanings than in claim 1 0- treating the latter vith a reducing agent to produce the hydroxylated derivative thereof of formula X (Z)p - ArCBOB - CBjO ^Ar' - (Y)B OB (X) in vhich Z, Y, n, p, Ar and Ar' are defined as indicated in claim1· and X is a free hydroxyl
- 15*- A process for producing a compound of general formula I according to claims 1 to 3* vhich comprises the steps of- blocking the free hydroxyl of a hydroxy acetophenone of formula VAΧΛ (V*)CO CB, vith an easily-split blocking reagent- submitting this blocked phenolic derivative to the action of a brominating agent to produce the corresponding α-bromo ketone- condensing this bromoketone vith a phenol of formula »*- 53 OB evherein Y and n are defined as given in claim 1* to obtain a phenoxy ethanone of formula VIA vherein the meaning of the substituents Z, Y, p and n are the same than in claim 1* and X is a blocked hydroxyl- submitting this compound to hydrogenation in the presence of a metallic catalyst or to acidolysis, to make free the hydroxyl function and obtain a phenoxy ethanone of formula VIIA vherein X is a hydroxy and Z, Y, p and n are defined as given in claim 1°- reducing the compound of formula VIIA by means of a reducing agent to produce the corresponding alkanol of formula VIIIAOH vherein Z, and X is aY, n and p are defined as given in claim 1° free hydroxyl
- 16*- A process for producing a compound of formula I according to any of claims 1 to 3* vherein R is a lover alkyl radical vhich comprises the steps of submitting a phenoxy ethanone of formula VIII »· a;vherein Ζ, Y, Ar, Ar', p and n have the definitions given in claim 1* and X is a blocked hydroxy group to the action of a triaryl alkyl phosphonium bromide under the conditions of the Vittig's reaction to produced an ethylenic derivative of formula VIRI (Z)_ - Ar - C - · CH - 0 - Ar' - (Y)a (VI) \X vherein Ζ, Y, Ar, Ar', n and p are defined as given in claim 1*X is a blocked hydroxy group and R is a lover alkyl radical- submitting this compound to hydrogenolysis in the presence of a metallic catalyst to produce the α-alkylated derivative of formula I **- 55 RI (Z), - AR - CH - CH2 - 0 - AR' - (Y)„ (I) vherein z, y, ar, ar', n and p are defined as given in claim 1* x is a free hydroxy group vhich may, vhen desired, be alkylated or acylated under the conditions previously defined
- 17*- A process for producing a compound of formula i vherein r is a lover alkyl radical, according to any of claims 1 to 3* vhich comprises the steps of reacting a phenoxy ethanone of formula VIA vherein y, z, n nd p have the definitions given in claim 1° and x is a blocked phenolic group vith a triaryl (lover alkyl) phosphonium bromide under the conditions of the vittig's reaction to produce an ethylenic derivative of formula IXxAP 0 0 0 1 8 8 vherein z, y, n and p have the definitions given in claim 1’R is a lover alkyl radical and X is blocked-phenolic group and submitting this latter to hydrogenolysis in the presence of a metallic catalyst to produce an α-alkyl ethoxy derivative of formula ΙλR »» vherein Z, 7, n and p have the definitions given in claim 1”X is a hydroxy and R is a lover alkyl radical vhich may vhen desired, be alkylated or acylated under the above-defined conditions.
- 18*- A process for producing a compound of formula I according to any of the claims 1 to 3*, vhich comprises the steps of reacting a substituted aryl aldehyde of formula X (Z)_ - Ar - CHO (X) vherein Z and p are defined as given in claim 1* and X is a blocked phenolic group vith a triaryl (phenoxy methyl) phosphonium salt under the conditions of the Vittlg's reaction to produce an ethylenic compound of the formula XII (7)„ - Ar' - 0 - CH - CH - Ar - Z (XII)X^ vherein Z, Ar, Ar', X, Ί, n and p have the definitions given in claim 1’- hydrogenating the latter by means of hydrogen in the presence of a metallic catalyst into a compound of formula I (Y)„ - Ar' - 0 - CH2 CH2 - Ar - (Z)p (I) »»- 57 vherein the substituents Z, Ar, Ar', 7, n, p and X have the definitions given in claim 1®
- 19*- A process for producing a compound of formula I according to claims 1 to 3* vherein a substituted benzaldehyde of formula XACHO vherein Z and p have the definitions given in claim 1* and X is a blocked phenol is reacted vith a triaryl (phenoxy methyl) phosphonium salt under the conditions of the Vitting's reaction to produce an ethylenic derivative of formula XIACH - CH OH vherein Z, 7, n and p have the definitions given in claim 1* and X is a blocked phenolic group vhich is further hydrogenated into a compound of formula IA by means of hydrogen in the presence of a metallic catalyst.AP 0 0 0 1 8 8
- 20*- A process for producing a compound of formula I according to claims 1 to 3’ vhich comprises the steps of blocking the reactive functions of a hydroxy aryl alkanol of formula XIII (Z)PAr \CHCHOH (XIII)X .Γ- *- 58 vherein Z, Ar, R and Rx have the definitions given in claim 1° and X is a free hydroxyl by means of an easily-split reagent, then reacting the thusblocked derivative vith a phenolic derivative of formula XIVOBAr' (XIV) vherein Y, n and Ar' have the definitions given in claim 1* to produce an aryloxy ethyl arylidenic derivative of formula XVR R,I I (Z)B - Ar - CB - CB - 0 - Ar' - (Υ). (XV)X vherein Z, Y, Ar, Ar', n and p have the definitions given in claim 1°R and Rx, the same or different each other, are a hydrogen or a lover alkyl radical and X is a blocked phenolic group and make free the hydroxy function by means of an alkaline agent to produce a compound of formula I
- 21*- A process for producing a compound of formula I accordint to any of claims 1 to 3· vhich comprises the steps of blocking the reacting functions of a (hydroxy phenyl) ethanol of formula XIIx (Z)pCB - CBOH (XIIA) vherein Z and p are defined as given in claim 1* X is a hydroxy s- 59 R and R: are a hydrogen or a lover alkyl by means of a reagent vhich is easily split, contacting the thusblocked derivative vith a phenol of formula XIIIAHO vherein Y and n have the definitions given in claim 1° to produce a phenylethoxy phenyle of formula XIVA vherein Ζ, Y, n and p have the definitions given in claim 1°R and Rx are hydrogen or a lover alkyl and X is a blocked phenolic group and making free the hydroxyl function by means of an alkaline agent, to produce a compound of formula IA
- 22*- As intermediate compounds, the ethylenic derivatives of formulaAP 0 0 0 1 8 8RC-CH vherein Y, Ζ, X, R, n and p have the definitions given in claim 1®
- 23*- As intermediate compounds, the ethylenic derivatives of formula *» vherein Z, Y, X, n ana p are defined as given in claim 1’
- 24·- The pharmaceutical composition vhich containg as active ingredient at least one compound of formula ICH, - CH, - 0 (Z)p - Ar^ ^Ar'-(Y)n (I)X vherein Z, Ar, Ar', Y, X, n and p have the definitions given in claim 1’ according to any of claims 1 to 11® in admixture or conjunction vith an inert, non-toxic, pharmaceutically-acceptable carrier or vehicle.
- 25*_ A pharmaceutical composition according to claim 24° vherein the carrier or vehicle is one of those vhich are appropriate for the administration through parenteral, digestive, rectal, permucous or percutaneous vays.
- 26*- A pharmaceutical composition according to any of claims 24 and 25’ vherein the content of active ingredient ranges from 1 to 200 mg per unit dosage.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR898913607A FR2653119B1 (en) | 1989-10-18 | 1989-10-18 | NOVEL ARYLOXY ALCOYL BENZENES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
CA002028031A CA2028031A1 (en) | 1989-10-18 | 1990-10-19 | Aryloxy alcoyl benzens, process for the preparation thereof and pharmaceutical compositions comprizing them |
Publications (2)
Publication Number | Publication Date |
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AP9000223A0 AP9000223A0 (en) | 1991-01-31 |
AP188A true AP188A (en) | 1992-05-01 |
Family
ID=25674347
Family Applications (1)
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---|---|---|---|
APAP/P/1990/000223A AP188A (en) | 1989-10-18 | 1990-10-18 | Novel aryloxy alcohol benzenes, processes for their preparation as well as the pharmaceutical compositions containing them. |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP0428423A3 (en) |
JP (1) | JPH03255043A (en) |
AP (1) | AP188A (en) |
AU (1) | AU650429B2 (en) |
CA (1) | CA2028031A1 (en) |
FR (1) | FR2653119B1 (en) |
HU (1) | HU212938B (en) |
OA (1) | OA09465A (en) |
PT (1) | PT95624A (en) |
RU (1) | RU2042659C1 (en) |
ZA (1) | ZA908355B (en) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5191108A (en) * | 1987-10-01 | 1993-03-02 | Hoffmann-La Roche Inc. | Catechol carboxylic acids |
DE3903988A1 (en) * | 1989-02-10 | 1990-08-30 | Basf Ag | OXIDIZED DIPHENYLHETEROALKANES, THEIR PREPARATION AND USE |
US4937371A (en) * | 1989-02-21 | 1990-06-26 | Hoffmann-La Roche Inc. | Dihydroxynaphthalene derivatives |
AU5016793A (en) * | 1992-08-20 | 1994-03-15 | Cytomed, Inc | Dual functional anti-inflammatory and immunosuppressive agents |
JPH07179402A (en) * | 1993-10-20 | 1995-07-18 | Ishihara Sangyo Kaisha Ltd | Substituted benzene derivative, its production and pest-controlling agent containing the same |
EP0920306A2 (en) | 1996-07-12 | 1999-06-09 | Leukosite, Inc. | Chemokine receptor antagonists and methods of use therefor |
SE9801992D0 (en) | 1998-06-04 | 1998-06-04 | Astra Ab | New 3-aryl-2-hydroxypropionic acid derivative I |
MA26634A1 (en) | 1998-06-04 | 2004-12-20 | Astra Ab | NOVEL 3-ARYL PROPIONIC ACID DERIVATIVES AND THE LIKE |
TWI262185B (en) * | 1999-10-01 | 2006-09-21 | Eisai Co Ltd | Carboxylic acid derivatives having anti-hyperglycemia and anti-hyperlipemia action, and pharmaceutical composition containing the derivatives |
CA2464770C (en) * | 2001-11-21 | 2011-08-16 | Sterix Limited | Compound |
KR20080086523A (en) | 2006-01-25 | 2008-09-25 | 웰스태트 테러퓨틱스 코포레이션 | Compounds for the treatment of metabolic disorders |
FR2917084B1 (en) * | 2007-06-05 | 2009-07-17 | Galderma Res & Dev | NOVEL 3-PHENYL PROPANOIC ACID DERIVATIVES OF PPAR-TYPE RECEPTORS, THEIR METHOD OF PREPARATION AND THEIR USE IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS |
FR2984730A1 (en) * | 2011-12-22 | 2013-06-28 | Diverchim | NEW ANTI-AGE AND DEPIGMENTING COSMETIC COMPOSITIONS |
CN106986789B (en) | 2016-01-20 | 2019-07-16 | 中国人民解放军军事医学科学院生物医学分析中心 | Hydroquinone compound and preparation method thereof and the application in antitumor or immunological regulation |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3674521D1 (en) * | 1985-08-29 | 1990-10-31 | Hoechst Ag | 6-PHENOXYMETHYL-4-HYDROXYTETRAHYDROPYRAN-2-ONE, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AS MEDICINAL PRODUCTS, PHARMACEUTICAL PREPARATIONS AND INTERMEDIATE PRODUCTS. |
NZ226371A (en) * | 1987-10-01 | 1992-12-23 | Hoffmann La Roche | Phenyl carboxylic acid ether derivatives and pharmaceutical compositions |
WO1990012006A1 (en) * | 1989-04-07 | 1990-10-18 | Pfizer Inc. | Substituted 1-[3-(heteroarylmethoxy)phenyl]alkanols and related compounds in the treatment of asthma, arthritis and related diseases |
-
1989
- 1989-10-18 FR FR898913607A patent/FR2653119B1/en not_active Expired - Fee Related
-
1990
- 1990-10-17 EP EP19900402920 patent/EP0428423A3/en not_active Withdrawn
- 1990-10-18 AP APAP/P/1990/000223A patent/AP188A/en active
- 1990-10-18 HU HU906498A patent/HU212938B/en not_active IP Right Cessation
- 1990-10-18 JP JP2280554A patent/JPH03255043A/en active Pending
- 1990-10-18 RU SU904831747A patent/RU2042659C1/en active
- 1990-10-18 ZA ZA908355A patent/ZA908355B/en unknown
- 1990-10-18 PT PT95624A patent/PT95624A/en not_active Application Discontinuation
- 1990-10-18 OA OA59871A patent/OA09465A/en unknown
- 1990-10-19 CA CA002028031A patent/CA2028031A1/en not_active Abandoned
- 1990-10-22 AU AU64869/90A patent/AU650429B2/en not_active Ceased
Non-Patent Citations (1)
Title |
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NONE * |
Also Published As
Publication number | Publication date |
---|---|
PT95624A (en) | 1991-09-13 |
AU6486990A (en) | 1992-06-11 |
HUT57175A (en) | 1991-11-28 |
CA2028031A1 (en) | 1992-04-20 |
JPH03255043A (en) | 1991-11-13 |
FR2653119B1 (en) | 1994-08-05 |
OA09465A (en) | 1992-11-15 |
EP0428423A3 (en) | 1992-09-02 |
RU2042659C1 (en) | 1995-08-27 |
EP0428423A2 (en) | 1991-05-22 |
AU650429B2 (en) | 1994-06-23 |
AP9000223A0 (en) | 1991-01-31 |
HU212938B (en) | 1996-12-30 |
HU906498D0 (en) | 1991-04-29 |
ZA908355B (en) | 1991-08-28 |
FR2653119A1 (en) | 1991-04-19 |
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