EP0712388A1 - Utilisation de phenols et de derives de phenols comme medicaments a effet reducteur du facteur i de coagulation - Google Patents
Utilisation de phenols et de derives de phenols comme medicaments a effet reducteur du facteur i de coagulationInfo
- Publication number
- EP0712388A1 EP0712388A1 EP94926836A EP94926836A EP0712388A1 EP 0712388 A1 EP0712388 A1 EP 0712388A1 EP 94926836 A EP94926836 A EP 94926836A EP 94926836 A EP94926836 A EP 94926836A EP 0712388 A1 EP0712388 A1 EP 0712388A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- hydroxy
- alkyloxy
- substituted
- omega
- 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.)
- Withdrawn
Links
- 150000002989 phenols Chemical class 0.000 title claims abstract description 27
- 239000003814 drug Substances 0.000 title claims abstract description 12
- 230000000694 effects Effects 0.000 title claims abstract description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 title claims description 10
- -1 C1-C4-alkyl urethane Chemical compound 0.000 claims abstract description 53
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 16
- 125000001424 substituent group Chemical group 0.000 claims abstract description 12
- LBKPGNUOUPTQKA-UHFFFAOYSA-N ethyl n-phenylcarbamate Chemical group CCOC(=O)NC1=CC=CC=C1 LBKPGNUOUPTQKA-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 7
- 239000005711 Benzoic acid Substances 0.000 claims abstract description 6
- 235000010233 benzoic acid Nutrition 0.000 claims abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 5
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims abstract description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 4
- 150000003014 phosphoric acid esters Chemical class 0.000 claims abstract description 4
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 150000002148 esters Chemical class 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 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 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 3
- 208000029078 coronary artery disease Diseases 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 2
- 125000006295 amino methylene group Chemical group [H]N(*)C([H])([H])* 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 230000002490 cerebral effect Effects 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 20
- 102000008946 Fibrinogen Human genes 0.000 description 16
- 108010049003 Fibrinogen Proteins 0.000 description 16
- 229940012952 fibrinogen Drugs 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 241000779819 Syncarpia glomulifera Species 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000001739 pinus spp. Substances 0.000 description 6
- 229940036248 turpentine Drugs 0.000 description 6
- 239000012071 phase Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 4
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- 235000005513 chalcones Nutrition 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 150000001789 chalcones Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- OQSNPMDWFJMKLH-UHFFFAOYSA-N 3-(4-chlorophenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one Chemical compound C1=CC(O)=CC=C1C(=O)C=CC1=CC=C(Cl)C=C1 OQSNPMDWFJMKLH-UHFFFAOYSA-N 0.000 description 2
- GOUHYARYYWKXHS-UHFFFAOYSA-N 4-formylbenzoic acid Chemical compound OC(=O)C1=CC=C(C=O)C=C1 GOUHYARYYWKXHS-UHFFFAOYSA-N 0.000 description 2
- 229940073735 4-hydroxy acetophenone Drugs 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010051124 Hyperfibrinogenaemia Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 2
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- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 229960000516 bezafibrate Drugs 0.000 description 2
- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 description 2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
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Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
- C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
- C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/73—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
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- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
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- 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
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- 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
- C07C235/56—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 atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/11—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton
- C07C255/13—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/56—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
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- C07—ORGANIC CHEMISTRY
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- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
- C07C39/15—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings with all hydroxy groups on non-condensed rings, e.g. phenylphenol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
- C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
- C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/88—Unsaturated compounds containing keto groups containing halogen
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
Definitions
- the present invention relates to the new use of phenols and phenol derivatives for the production of medicaments with a fibrinogen-lowering effect.
- the invention also relates to new phenols and phenol derivatives, processes for their preparation and medicaments which contain these compounds.
- the invention relates to the use of phenols and phenol derivatives of the general formula I.
- R denotes hydrogen or one to three substituents which are selected independently of one another from the series halogen, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, cyano or trifluoromethyl,
- X is in the meta or para position to B and means the following groups:
- omega-hydroxy-C2-Cg-alkyloxy group substituted or unsubstituted phenyl urethane, phosphoric acid ester, aliphatic carboxylic acid ester group or, optionally substituted, benzoic acid ester grouping,
- R denotes one to three substituents which are identical or different independently of one another and are located in any position on the benzene ring in relation to the substituent B.
- halogen means fluorine, chlorine, bromine and iodine, with chlorine being preferred.
- C ..- C 4 alkyl or alkoxy includes a straight chain or branched alkyl radical with 1-4 C atoms, methyl and isopropyl being preferred.
- unbranched alkylene chains with 2-6 C atoms are preferred, it being possible for one of the saturated C atoms to be replaced by an oxygen atom or by one of the groups NH,> CO or> CH-OH.
- two adjacent saturated C atoms can also be replaced together by a group CONH- or -NHCO-.
- the oxygen atom is preferably para to the phenoxy oxygen of group X.
- these groups are preferably in the alpha position to one of the two benzene rings.
- the substituent X is in the meta or para position to the substituent B.
- Ci-C ⁇ -alkyloxy for the substituent X means a straight-chain or branched alkyloxy chain, preferably methoxy, ethoxy and n-butyloxy.
- the following alkoxy groups, which are substituted at the terminal C atom by a hydroxyl, halogen or cyano group, are particularly preferred: a) omega-hydroxy-C 2 -C 6 -alkyloxy, b) omega-halogen-C 2 - Cg-alkyloxy and c) omega-cyano-C "-Cg-alkyloxy or / and carry one or two methyl groups on the C atom adjacent to the ether oxygen.
- Omega-hydroxy-C 2 -Cg-alkyloxy preferably means 2-hydroxy-ethoxy, 4-hydroxy-butoxy, 3-hydroxy-2-propoxy or 3-hydroxy-2-methyl-2-propoxy.
- Omega-halogen-C 2 -Cg-alkyloxy preferably means omega-chloro-C 2 -Cg-alkyloxy, and here in particular 2-chloro-ethoxy- and 4-chloro-butoxy.
- Omega-cyano-C ⁇ -C6-alkyloxy preferably means cyanomethyloxy and 5-cyano-pentyloxy. If the group X comprises a C. .. C 4 -alkyl urethane group, the alkyl group may be straight-chain or branched.
- Methyl, ethyl and t-butyl urethane are preferred.
- the phenyl radical in phenyl urethane can be unsubstituted or substituted by halogen, preferably chlorine, in the 3- or 4-position.
- the substituent X comprises a benzoic acid ester radical
- the phenyl radical is optionally substituted one or more times, preferably with halogen, methoxy or methyl.
- Suitable aliphatic carboxylic ester residues are preferably those of acetic acid, propionic acid or n- or iso-butyric acid. If X is the benzoyloxy radical, this can optionally be substituted in the meta or para position, preferably by halogen.
- radicals R are 4- or 3-chloro, 4-fluoro, 4 or 3-trifluoromethyl, 4-methyl, 4-methoxy, 4-cyano, 2,4di-chloro and 2-methoxy-5-chloro.
- Preferred radicals X are in the para position to B and are hydroxy, carboxymethoxy, 1-carboxyethoxy, 1-carboxypropyloxy, 3-carboxypropyloxy, 2-hydroxyethoxy, 3-hydroxypropyl-2- oxy, 3-hydroxy-2-methyl-propyl-2-oxy, propyl-2-oxy and the rest -0-C (CH 3 ) 2 -CH 2 -0-C0- (CH 2 ) 2 -C00H.
- R is 4-chloro, 4-trifluoromethyl or 4Cyano
- X is in the para position to B.
- Particularly preferred compounds of the general formula I are those in which R is 4-chlorine, X is in the para position to B and 1-carboxyethoxy and B represents trimethylene, trimethylene carbonyl or pentamethylene carbonyl.
- the present invention also relates to new phenols and phenol derivatives falling under the formula.
- B is the group -CONHCH 2 CH 2 -
- R is the chlorine atom in the para position
- X in the para position is the hydroxyl group, carboxymethoxy, 1-carboxypropyloxy or the p-chlorobenzoyloxy radical
- R is hydrogen and X in the para position is the hydroxyl group, while B is the group CONHCH 2 CH 2 -,
- R is the chlorine atom in the para position
- B represents the trimethylene group
- X represents the hydroxy group in the para position
- X in the para position of the 1-carboxyethoxy radical and R in the para position is the chlorine atom, while B is the methylene, carbonyl or aminomethylene group,
- X in the para position is the 3-hydroxypropyl-2-oxy radical
- R in the para position is the chlorine atom
- B is the group> CHOH.
- Other works describe their use as a starting material or as a reaction component.
- the compounds of the formula I are highly effective substances which reduce the fibrinogen concentration in the blood, which is particularly important for the treatment of cardiovascular diseases such as peripheral arterial occlusive disease, coronary heart disease and cerebral circulatory disorders Meaning is.
- the most important rheological factors of the microcirculation are the fibrinogen-dependent parameters plasma viscosity and erythrocyte aggregation.
- High concentrations of fibrinogen (and other protein fractions) lead to an enormous increase in plasma viscosity and erythrocyte aggregation.
- a therapeutic reduction in plasma fibrinogen levels means a significant improvement in blood flow properties and thus an increase in microcirculation with improved oxygen release.
- the compounds of the formula I have a pronounced fibrinogen-lowering action which is superior to that of the bezafibrate described as fibrinogen-lowering (Cook et al., TIPS Reviews 11 (1990), 450).
- fibrinogen antagonists are substances which are able to prevent the binding of fibrinogen to a GP Ilb-Illa receptor located on the platelets, while the compounds of the general formula I the concentration of fibrinogen in the blood Reduce.
- R 0 "
- R has the meaning given above.
- Suitable reactive derivatives are the acid halides, in particular the acid chlorides, or else acid imidazolides.
- suitable acid-binding agents are alkali metal hydroxides (reaction under Schotten-Baumann conditions) or organic bases such as pyridine (see, for example, DE-AS 2 149 070) or triethylamine.
- Such phenoxyalkyl carboxylic acids are described, for example, according to DE-AS 2 149 070 by reacting the phenols (Ia) with alpha-haloacetic acid esters or alpha-halogenopropionic acid esters in inert solvents such as butanone-2 and in the presence of acid acceptors such as powdered potassium carbonate.
- the ethyl esters of bromo or chlorocarboxylic acids are preferably used as the halocarboxylic acid esters.
- the resulting oxycarboxylic acid esters are then saponified to give the carboxylic acids by heating with an alcoholic alkali metal hydroxide solution.
- condensation is preferably carried out in an aqueous alkaline medium, e.g. in the presence of aqueous sodium hydroxide solution.
- condensation may also be preferred in the presence of mineral acid, e.g. aqueous-alcoholic hydrochloric acid.
- the reduction of the chalcones Ib .. or Ib 2 to the trimethylene compounds Id according to the invention preferably takes place in two stages: First, the chalcones become the dihydrochalkones of the general formula Ic. or Ic 2 reduced,
- Alk is the C ⁇ AIk Irest and Phe is unsubstituted or substituted phenyl.
- the compounds of general formula I prepared if they are acidic or basic in nature, can be converted into physiologically tolerable salts, and in the case of carboxylic acids their conversion into esters with physiologically acceptable alcohols is possible.
- Pharmacologically acceptable inorganic or organic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, methylglucamine, morpholine or ethanolamine are suitable for the formation of salts from carboxylic acids of the general formula I.
- Suitable acids for forming salts on bases of the general formula I are, for example, hydrochloric acid, sulfuric acid, acetic acid, citric acid, maleic acid, fumaric acid and tartaric acid.
- esters of these carboxylic acids with lower monohydric alcohols such as methanol or ethanol
- polyhydric alcohols such as glycerol
- alcohols are also included which carry other functional groups, such as e.g. Ethanolamine.
- the pure enantiomers can be prepared from the racemates of the compounds of the general formula I obtained by racemate resolution (via salt formation with optically active bases). Pure enantiomers can also be obtained by using optically active starting materials in the synthesis.
- the substances of the general formula I are mixed with suitable pharmaceutical carriers, flavoring, flavoring and coloring agents and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, e.g. in olive oil, suspended or dissolved.
- the substances of the general formula I and their salts can be administered enterally or parenterally in liquid or solid form.
- Water is preferably used as the injection medium, which contains the additives, such as stabilizers, solubilizers or buffers, which are customary for injection solutions.
- additives are e.g. B. tartrate and citrate buffers, complexing agents (such as ethylenediaminetetraacetic acid and their non-toxic salts) and high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation.
- Solid carriers are e.g. B.
- Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.
- the dosage can depend on various factors such as the mode of administration, species, age or individual condition.
- the compounds of the formula I are usually applied in amounts of 1.5 to 15 mg, preferably 5-10 mg per day and per kg of body weight. It is preferred to distribute the daily dose over two applications, two tablets with an active ingredient content of 85 to 200 mg each being administered for each application. The tablets can also be retarded, so that only one tablet with 100-1000 mg of active ingredient has to be given per day.
- Sprague-Dawley rats (breeder: IFFA-CREDO, France) take 500 ⁇ l blood from the tail vein and use the CLAUSS method with a 2-channel coaguiometer (Biomatik 2000 Coagulometer, Sarstedt) the basal plasma fibrinogen concentration is determined. The animals then receive 50 mg / kg of the test substance p.o. (Standard dosage) in 1% tylose solution. Two hours after application of the test substance, an i.m. injection of 0.05 ml turpentine is placed in a hind limb. A further two hours after application of terpentine, the test substance is again p.o. administered, as well as after 24 and 48 hours.
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Abstract
L'invention concerne l'utilisation de phénols et de dérivés de phénols de la formule générale développée (I) pour préparer des médicaments à effet réducteur du facteur I de coagulation. L'invention concerne en outre de nouveaux phénols et dérivés de phénols, leurs procédés de préparation et des médicaments qui contiennent ce composé. Dans la formule (I), R désigne hydrogène ou un à trois substituants sélectionnés indépendamment les uns des autres dans la série halogène, alkyle C1-C4, alcoxy C1-C4, hydroxy, cyano ou trifluorométhyl, B symbolise une chaîne alkylène saturée ou non saturée, ayant jusqu'à six atomes de C, non substituée ou éventuellement substituée en position quelconque par un ou deux groupe(s) méthyle, un des atomes de C saturés pouvant être remplacé par un atome d'oxygène ou par un des groupes >NH, >C=O ou >CH-OH, et deux atomes de C saturés adjacents pouvant également être remplacés conjointement par un groupe -CONH- ou -NHCO, et X est en position méta ou para par rapport à B et désigne les groupes suivants: un groupe hydroxy ou un groupe alkyluréthane C1-C4 dérivé du précédent ou un groupe phényluréthane substitué ou non substitué, un groupe alkyloxy C1-C6, omega-hydroxy-alkyloxy C2-C6, omega-halogène-alcoxy C2-C6 ou omega-cyano-alkyloxy C1-C6 non ramifié ou substitué par un ou deux groupes méthyle en position quelconque, un groupement alkyluréthane C1-C4, un groupement phényluréthane, un groupement ester d'acide phosphorique, un groupement ester d'acide carboxylique aliphatique substitués ou non substitués, ou bien un groupement benzoate éventuellement substitué dérivés du groupe omega-hydroxy-alkyloxy C2-C6, un groupe aminocarbonyle-alkyloxy C1-C6 ou un groupe N-hydroxy-aminocarbonyle-alkyloxy C1-C6, carboxyméthoxy, 1-carboxy-éthoxy, 1-carboxy-propyloxy ou 3-carboxy-propyloxy, le reste -O-C-(CH3)2-CH2-O-CO-(CH2)2-COOH, le reste benzoyloxy qui est éventuellement substitué.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4327365A DE4327365A1 (de) | 1993-08-14 | 1993-08-14 | Verwendung von Phenolen und Phenolderivaten als Arzneimittel mit fibrinogensenkender Wirkung |
DE4327365 | 1993-08-14 | ||
PCT/EP1994/002709 WO1995005358A1 (fr) | 1993-08-14 | 1994-08-13 | Utilisation de phenols et de derives de phenols comme medicaments a effet reducteur du facteur i de coagulation |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0712388A1 true EP0712388A1 (fr) | 1996-05-22 |
Family
ID=6495210
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP94926836A Withdrawn EP0712388A1 (fr) | 1993-08-14 | 1994-08-13 | Utilisation de phenols et de derives de phenols comme medicaments a effet reducteur du facteur i de coagulation |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0712388A1 (fr) |
JP (1) | JPH09501670A (fr) |
AU (1) | AU7653394A (fr) |
CA (1) | CA2169187A1 (fr) |
DE (1) | DE4327365A1 (fr) |
WO (1) | WO1995005358A1 (fr) |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5550292A (en) * | 1993-08-30 | 1996-08-27 | Otsuka Pharmaceutical Co., Ltd. | Benzylamine derivatives |
FR2713637B1 (fr) * | 1993-12-15 | 1996-01-05 | Cird Galderma | Nouveaux composés bi-aromatiques dérivés d'amide, compositions pharmaceutiques et cosmétiques les contenant et utilisations. |
US5883294A (en) * | 1997-06-18 | 1999-03-16 | The Regeants Of The University Of California | Selective thyroid hormone analogs |
EP0947511A1 (fr) * | 1998-03-30 | 1999-10-06 | F. Hoffmann-La Roche Ag | Dérivés de l'acide phénoxyacétique et de phénoxyméthyltétrazole ayant une activité antitumorale |
EP1206442A4 (fr) * | 1999-08-24 | 2004-12-29 | Univ Virginia Commonwealth | Modificateurs allosteriques chiraux substitues d'hemoglobine |
WO2001051454A1 (fr) * | 2000-01-13 | 2001-07-19 | Emisphere Technologies, Inc. | Composes et compositions permettant d"administrer des principes actifs |
US7569724B2 (en) | 2000-09-29 | 2009-08-04 | Topotarget Uk Limited | Carbamic acid compounds comprising an amide linkage as HDAC inhibitors |
GB0023983D0 (en) * | 2000-09-29 | 2000-11-15 | Prolifix Ltd | Therapeutic compounds |
FR2841784B1 (fr) | 2002-07-08 | 2007-03-02 | Composition a base de derives de 1,3-diphenylprop-2en-1-one substitues, preparation et utilisations | |
FR2841900B1 (fr) | 2002-07-08 | 2007-03-02 | Genfit S A | Nouveaux derives de 1,3-diphenylprop-2-en-1-one substitues, preparation et utilisations |
ES2328819T3 (es) | 2003-04-07 | 2009-11-18 | Pharmacyclics, Inc. | Hidroxamatos como agentes terapeuticos. |
BRPI0506718A (pt) | 2004-01-08 | 2007-05-02 | Genfit | compostos, processo de preparação dos mesmos, e, composição farmacêutica ou cosmética |
FR2864956B1 (fr) * | 2004-01-08 | 2006-04-28 | Genfit S A | Compose derive de 1,3-diphenylprop-2-en-1-one, preparation et utilisations |
FR2875805B1 (fr) * | 2004-09-27 | 2006-12-29 | Genfit S A | Composes derives de n-(benzyl) phenylacetamide substitues, preparation et utilisations |
US7737164B2 (en) | 2006-05-18 | 2010-06-15 | Wisconsin Alumni Research Foundation | Cyanopyridine antibacterial agents |
FR2902789A1 (fr) * | 2006-06-21 | 2007-12-28 | Genfit Sa | Derives de 1,3-diphenylpropane substitues, preparations et utilisations |
AU2007340129B2 (en) | 2006-12-26 | 2012-02-02 | Pharmacyclics Llc | Method of using histone deacetylase inhibitors and monitoring biomarkers in combination therapy |
KR101483805B1 (ko) | 2007-01-30 | 2015-01-16 | 파마시클릭스, 인코포레이티드 | 히스톤 데아세틸라제 억제제에 대한 암 내성을 확인하는 방법 |
US8603521B2 (en) | 2009-04-17 | 2013-12-10 | Pharmacyclics, Inc. | Formulations of histone deacetylase inhibitor and uses thereof |
ES2627820T3 (es) | 2011-09-13 | 2017-07-31 | Pharmacyclics, Inc. | Formulaciones de inhibidor de histona desacetilasa en combinación con bendamustina y usos de las mismas |
WO2015017812A1 (fr) | 2013-08-02 | 2015-02-05 | Pharmacyclics, Inc. | Méthodes permettant de traiter des tumeurs solides |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2149070C3 (de) * | 1971-10-01 | 1978-03-23 | Boehringer Mannheim Gmbh, 6800 Mannheim | Phenoxyalkylcarbonsäurederivate und deren Salze, Verfahren zu deren Herstellung und Arzneimittel |
DE2432560A1 (de) * | 1974-07-06 | 1976-01-22 | Boehringer Mannheim Gmbh | Neue phenoxyalkylcarbonsaeurederivate und verfahren zur herstellung derselben |
JPS518228A (ja) * | 1974-07-10 | 1976-01-23 | Takeda Chemical Industries Ltd | Chikanfuenokishikarubonsanruino seizoho |
GB1499508A (en) * | 1974-12-06 | 1978-02-01 | Ici Ltd | 3,3,3-trifluoropropionic acid derivatives |
GB1563195A (en) * | 1975-08-20 | 1980-03-19 | Sori Soc Rech Ind | Derivating of phenoxy-alkylcarboxylic acids |
DE2541342A1 (de) * | 1975-09-17 | 1977-03-31 | Boehringer Mannheim Gmbh | Neue phenoxyalkylcarbonsaeuren und verfahren zur herstellung derselben |
CH630879A5 (de) * | 1977-08-29 | 1982-07-15 | Siegfried Ag | Verfahren zur herstellung lipidsenkender alkylenglykolderivate. |
EP0002408A1 (fr) * | 1977-11-26 | 1979-06-13 | SOCIETE DE RECHERCHES INDUSTRIELLES S.O.R.I. Société anonyme dite: | Nouveaux composés phénoxy-alcanols substitués, leur procédé de préparation et leur application en thérapeutique |
CA2020888A1 (fr) * | 1989-07-27 | 1991-01-28 | Philippe Guerry | Derives d'aminoalkoxybenzene substitues |
-
1993
- 1993-08-14 DE DE4327365A patent/DE4327365A1/de not_active Withdrawn
-
1994
- 1994-08-13 JP JP7506754A patent/JPH09501670A/ja active Pending
- 1994-08-13 WO PCT/EP1994/002709 patent/WO1995005358A1/fr not_active Application Discontinuation
- 1994-08-13 AU AU76533/94A patent/AU7653394A/en not_active Abandoned
- 1994-08-13 CA CA002169187A patent/CA2169187A1/fr not_active Abandoned
- 1994-08-13 EP EP94926836A patent/EP0712388A1/fr not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO9505358A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1995005358A1 (fr) | 1995-02-23 |
CA2169187A1 (fr) | 1995-02-23 |
AU7653394A (en) | 1995-03-14 |
JPH09501670A (ja) | 1997-02-18 |
DE4327365A1 (de) | 1995-02-16 |
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