IL42472A - Dialkylaminoalkyl esters of 6-methoxy-2-naphthylpropionic acid and salts thereof and their preparation - Google Patents
Dialkylaminoalkyl esters of 6-methoxy-2-naphthylpropionic acid and salts thereof and their preparationInfo
- Publication number
- IL42472A IL42472A IL42472A IL4247273A IL42472A IL 42472 A IL42472 A IL 42472A IL 42472 A IL42472 A IL 42472A IL 4247273 A IL4247273 A IL 4247273A IL 42472 A IL42472 A IL 42472A
- Authority
- IL
- Israel
- Prior art keywords
- methoxy
- naphthyl
- naphthy1
- propionate
- compound
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims description 10
- CMWTZPSULFXXJA-UHFFFAOYSA-N 2-(6-methoxy-2-naphthalenyl)propanoic acid Chemical compound C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 title description 6
- 238000002360 preparation method Methods 0.000 title description 2
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 title 1
- -1 propionyl halide Chemical class 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 33
- CMWTZPSULFXXJA-UHFFFAOYSA-M 2-(6-methoxynaphthalen-2-yl)propanoate Chemical compound C1=C(C(C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-M 0.000 claims description 21
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 18
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 235000019260 propionic acid Nutrition 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 150000004820 halides Chemical class 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- 239000011976 maleic acid Substances 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 claims description 3
- 125000006413 ring segment Chemical group 0.000 claims description 3
- 150000002689 maleic acids Chemical class 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- WFKLHNXTOWCYSM-UHFFFAOYSA-N 2-(6-methoxynaphthalen-2-yl)propanoyl 2-(6-methoxynaphthalen-2-yl)propanoate Chemical compound C1=C(OC)C=CC2=CC(C(C)C(=O)OC(=O)C(C)C3=CC4=CC=C(C=C4C=C3)OC)=CC=C21 WFKLHNXTOWCYSM-UHFFFAOYSA-N 0.000 claims 4
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims 3
- PIIXFZVFKNOFFG-UHFFFAOYSA-N 2-(6-methoxynaphthalen-2-yl)propanoic acid;hydrochloride Chemical compound Cl.C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 PIIXFZVFKNOFFG-UHFFFAOYSA-N 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 229940095574 propionic acid Drugs 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000008064 anhydrides Chemical class 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UJPKMTDFFUTLGM-UHFFFAOYSA-N 1-aminoethanol Chemical compound CC(N)O UJPKMTDFFUTLGM-UHFFFAOYSA-N 0.000 description 1
- KEVKXUZQHIMSCM-UHFFFAOYSA-N 1-pyrrolidin-1-ylethanol Chemical compound CC(O)N1CCCC1 KEVKXUZQHIMSCM-UHFFFAOYSA-N 0.000 description 1
- KKFDCBRMNNSAAW-UHFFFAOYSA-N 2-(morpholin-4-yl)ethanol Chemical compound OCCN1CCOCC1 KKFDCBRMNNSAAW-UHFFFAOYSA-N 0.000 description 1
- UWKDZWSATBBGBN-UHFFFAOYSA-N 2-[ethyl(methyl)amino]ethanol Chemical compound CCN(C)CCO UWKDZWSATBBGBN-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- VKCNNDPZFOVURD-UHFFFAOYSA-N 2-naphthalen-1-ylpropanoic acid Chemical compound C1=CC=C2C(C(C(O)=O)C)=CC=CC2=C1 VKCNNDPZFOVURD-UHFFFAOYSA-N 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010010254 Concussion Diseases 0.000 description 1
- 208000034693 Laceration Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 239000012972 dimethylethanolamine Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000027950 fever generation Effects 0.000 description 1
- 239000011440 grout Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012430 organic reaction media Substances 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
- C07D233/08—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms
- C07D233/12—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D233/14—Radicals substituted by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
42472/2 Blalkylaminoalkyl esters of 6-raethoxy-2« naphthylpropionic acid and salts thoreof and thoir preparation SYNTEX CORPORATION C. 40617 42472/2 % This invention relates to dialkylaininoalkyl esters of 2-(6-methoxy-2-naphthy1) ropionic acid and the pharmaceutically acceptable salts thereof. \ The compounds of the present invention are represented by the following structural formula: wherein R and R° are independently lower alkyl or 2 3 together R and R and the nitrogen atom to which they are attached form a saturated heterocyclic ring having from 3 through 6 ring atoms; and n is an integer from 2 through 4, inclusive, and the pharmaceutically acceptable salts thereof.
The structural formula above is intended to include the d, the 1, and the d, 1 isomers thereof. The compounds of this invention have been named as the dialkylaminoalky1 ester of a particular 2- ( 6-methoxy-2-naphthyl) propionic acid, for example, β-Ν,Ν-dimethylaminoethyl d 2- ( 6-methoxy-2 -naphthy1) propionic acid. It is intended. that the designation "d", "1" or "dl" refer to the optical isomerism of the propionic acid precursor, and not necessarily the optical isomerism of the resultant di- · alkylaminoalkylester. Thus, with respect to the aforementioned compound, for example, it should be understood that the resultant product is the β-Ν,Ν-dimeth laminoethyl ester of d 2- ( 6-methoxy-2 -naphthyl).propionic acid. 'Other compounds named in this specification should be subject, to the same interpretation.
As used in this specification, the term " lower, alkyl" "refers 42472/2 to both straight and branched chain alkyl groups having. a total of from 1-6 carbon atoms and thus includes primary, secondary and. tertiary alkyl groups. Typical lower alkyl groups include, for example, methyl, ethyl, n-propyl,^ isopropyl, n-butyl, t- butyl, n-hexyl, and the like. The term "saturated heterocyclic ring" refers to saturated heterocyclic rings containing at least- one nitrogen ring atom. Typical heterocyclic rings include, for example, pyrrolidinyl , morpholino, piperazin-l-yl , piperidinyl , and the like.
The presently preferred compounds of this invention are 2 3 where R and R are each either methyl or ethyl, and n is 2.
Thus, the presently preferred compounds are β-Ν,Ν-dimethylamino- ethyl d 2- ( 6-methoxy-2-naphthy1) -propionate and β- , N-diethy1- aminoethyl d 2- (6-methoxy-2-naphthyl) -propionate .
The compounds of this invention, as represented by Formula I above, can be prepared by reacting a 2 - ( 6-rnethoxy-2 -naphthy1) ■ propionic acid with, an acid halide, such as oxalyl chloride, to afford a 2- ( 6-methoxy-2-naphthy1) -propionyl halide, and reacting the halide derivative so produced with a hydroxyalky1amine , such as Ν,Ν-dimethylhydroxyethylamine or N, -diethylhydroxyethy lamine , 2 3 to afford the compounds of Formula. I where R and R are lower I alkyl, or with a N-hydroxyalky1-heterocyclic amine to afford the compounds of Formula I where R 2 and R3 and. the nitrogen atom to which they are attached form a heterocyclic ring.
The 2- (6-methoxy-2-naphthyl) propionic acids are known compounds which can be prepared, for example, according to the pro-I cedures shown by U.S. Patents Nos . 3,651,106; 3,652,683; 3,658,858; 3,658,863; 3,663,584; and other patents assigned to the assignee of this invention, which describe further processes for preparing these compounds. The d isomers of the acid compounds are particularly preferred.
The first step of this reaction sequence wherein a 2- (6-methoxy-2-naphthyl) propionic acid is reacted with the acid halide can be conveniently effected at temperatures in the range from about 15°C. to about 80°C. for about 1/2 to about 18 hours, using about 1 to about 2 moles of the acid halide per mole of the pro-pionic acid compound. Suitable acid halides include, for example, oxalyl chloride, thionyl chloride, phosphorus pentachloride, and the like. This reaction is generally conducted in an inert organic reaction medium for example, benzene, diethyl ether, toluene, and the like.
The halide derivative produced in the first step of the reaction, as described above, is reacted with the amine reactant to afford the compound of Formula I. This reaction is typically conducted at temperatures in the range from about 0°C. to about 50°C. for about 1/4 to about 18 hours, using a slight excess of the amine reactant. Since hydroxyalkylamines are liquid materials, by providing a greater excess thereof, the hydroxyalkylamine can be utilized as the medium in which the reaction can be conducted. However, the reaction can also be conducted in the presence of an inert solvent, such as, for example, acyclic or cyclic ethers, such as ethyl ether or tetrahydrofuran; halogenated hydrocarbons, such as chloroform and methylene dichloride and the like. Suitable hydroxyalkylamines include, for example, N,N-dimethy1-hydroxyethylamine , N,N-diethy1-hydroxyethylamine, N-methyl-N-ethyl-hydroxyethylamine, Ν,Ν-dipropyl-hydroxyethy1- amine, and the like. The product comp6und of Formula I is then separated from the reaction mixture by conventional procedures .
The compounds of this invention, as represented by Formula. I above, can also be prepared by converting 2- ( 6-methoxy-2-naphthyl) propionic acid to the corresponding acid anhydride, and then reacting the anhydride with a N,N-dialkyl-hydroxyalkylamine (or a N-hydroxyalkyl-hetero-cyclic amine) to afford the corresponding compound of Formula I. For example, the acid anhydride can be prepared by heating 2- (6-methoxy-2-naphthy1) propionic acid at reflux in the presence of an excess of acetic anhydride.
The reaction of the anhydride so produced with the amine compound is as set forth above, with benzene being a suitable inert solvent.
Pharmaceutically acceptable salts of the aforementioned esters can be prepared, according to procedures known in this art, by treating .the dialkylamirioalkyl ester with a pharmaceutically acceptable inorganic or organic acid, such as, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, citric acid, lactic acid, succinic acid, maleic acid, benzoic acid, and the like .
In certain of the process steps described herein, the respective intermediate products are preferably separated from the reaction mixture and purified prior to 'the use thereof as starting materials for the next step in the process. Such separation and purification can be effected by any suitable procedure. For example, typical separation procedures include filtration, extraction, and evaporation, and typical purification procedures include crystallization, and both thin-layer and column chromatography. Optimum separation and purification procedures can be obtained for any given step by routine experimentation. In other of the process steps, the product thereof can be retained in the reaction mixture and utilized, if desired, without actual separation and purification as the starting material for the next step in the reaction sequence .
The compounds of Formula I exhibit anti-inflammatory, analgesic, and anti-pyretic activities and are, accordingly, employed in the treatment of inflammation, pain and pyrexia in mammals. For example, inflammatory conditions of the muscular skeletal system, skeletal joints, and other tissues can be treated. Accordingly, these compounds are useful in the treatment of conditions characterized by inflammation such as rheumatism, concussion, laceration, arthritis, bone-fractures, posttraumatic conditions, and grout. The compounds of this invention can be utilized systemically (eg, orally) , or applied topically (eg, for the treatment of inflammation of the eye) .
DESCRIPTION OF SPECIFIC EMBODIMENTS The following specific description is given to enable those skilled in this art to more clearly understand and practice the present invention. It should not be considered as a limitation upon the scope of the invention but merely as being illustrative and representative thereof.
EXAMPLE I A slurry of 3.00 g. dl 2-(6-methoxy-2-naphthyl) -propionic acid and 9.6 ml. oxalyl chloride in 60 ml. benzene is held for 2 hours and then evaporated under vacuum.
The brown crystalline residue so obtained is dl 2- (6-methoxy-2-naphthyl) propiony1 chloride .
EXAMPLE II The residue from Example I is dissolved in 50 ml. of anhydrous ethyl ether with stirring, and treated with 3 ml. of dimethyl-ethanolamine which results in the immediate precipitation of a white crystalline solid. After the solution is stirred for 30 minutes, a portion of saturated aqueous sodium bicarbonate is added thereto, whereupon the crystalline material dissolves. The organic layer is washed several times with saturated aqueous sodium bicarbonate, water and, finally, saturated sodium chloride, dried over potassium carbonate, and evaporated under vacuum to yield β-Ν,Ν-dimethylaminoethyl dl 2-(6-methoxy-2-naphthyl) propionate .
EXAMPLE III A portion of the β-Ν,Ν-dimethylaminoethyl dl-2-(6-methoxy-2-naphthyl) propionate of Example II in ethyl ether is treated with a few drops of concentrated hydrochloric acid and an oily precipitate forms. The ethyl ether is decanted off and the oily residue dissolved in methylene dichloride, dried over molecular sieves, and evaporated under vacuum to yield a residue which crystallizes upon standing for a period of about 60 hours. The crystalline residue is triturated with ethyl ether and, after filtration, 370 mg. of a white crystalline mass is obtained.
This crystalline mass contains β-Ν,Ν-dimethylaminoethy1 dl 2- ( 6-methoxy-2-naphthyl) propionate · hydrochloride salt (m.pt .ca.119-122°C) .
The procedure of this Example is repeated except sulfuric acid, nitric acid, phosphoric acid, acetic acid, citric acid, lactic acid, succinic acid, maleic acid and benzoic acid are respectively substituted for the hydrochloric acid to form the corresponding pharmaceutically acceptable salts of β-Ν,Ν-dimethylaminoethy1 dl 2- ( 6-methoxy-2-naphthy1) propionate.
EXAMPLE IV Example II is repeated except: , -diethy1-hydroxyethylamine ; ,N-dipropy1-hydroxyethylamine ; Ν,Ν-dibuty1-hydroxyethylamine ; Ν,Ν-dimethy1-hydroxypropylamine N, N-diethy1-hydroxypropylamine ; N,N-dipropy1-hydroxypropylamine ; N, N-dibuty1-hydroxypropylamine ; , -dimethy1-hydroxybutylamine ; Ν,Ν-diethy1-hydroxybutylamine Ν,Ν-dipropyl-hydroxybutylamine ; N, N-dibuty1-hydroxybutylamine ; N-rnethy 1-N-ethyl-hydroxyethylamine ; N-methy 1-N-propy 1-hydroxyethylamine ; N-methy1-N-buty1-hydroxyethy lamine ; N-ethy1-N-propy1-hydroxyethy lamine ; N-ethy1-N-buty1-hydroxyethylamine ; N-propy1-N-buty1-hydroxyethy lamine ; ' '' N-methy l N-ethylrhydroxypropy lamine ; N-methy 1-N-propy1-hydroxypropylamine ; N-methy 1-N-buty1-hydroxypropylamine ; N-ethy1-N-propy 1-hydroxypropy lamine ; N-ethy 1-N-buty1-hydroxypropylamine ,· N-propy1-N-buty1-hydroxypropylamine ;.
N-methy 1-N-ethy1-hydroxybutyla ine ; N-methy1-N-propyl-hydroxybutylamine ; N-ethy1-N-propy1-hydroxybutylamine ; and N-ethy1-N-butyl-hydroxybuty lamine are respectively substituted for the N, -dimethy1-hydroxyethylamine of Example II, and d 2 - ( 6-methoxy-2-naphthyl) propionic acid is substituted for the dl 2- ( 6-rnethoxy-2-naphthyl) propionic acid of Example 1, to afford the following compounds: 2-(N,N-diethylamino) ethyl d 2- ( 6-methoxy-2-naphthyl) -propionate; 2- (Ν,Ν-dipropylamino) ethy 1 d 2- ( 6-methoxy-2-naphthy1) -propionate ; 2- (N,N-dibutylamino) ethyl d 2- ( 6-methoxy-2-naphthyl) -propionate; 3- (N, N-dimethylamino) ropyl d 2- ( 6-methoxy-2-naphthyl) propionate; hydrochloride salt, m.p. 145-146°C. 3- (Ν,Ν-diethylamino) ropyl d 2- ( 6'-methoxy-2-naphthy1) -propionate; 3- (Ν,Ν-dipropylamino) ropyl d 2- ( 6-methoxy-2-naphthy1) propionate; 3- (Ν,Ν-dibutylamino) propyl d 2- ( 6-methoxy-2-naphthyl) -propionate; 4- (Ν,Ν-dimethy lamino)butyl d 2- ( 6-methoxy-2-naphthy1) -propionate ; 4-(N,N-diethylamino)butyl d 2- ( 6-methoxy-2-naphthyl) -propionate ; 4- (Ν,Ν-dipropylamino) utyl d 2- ( 6-methoxy-2-naphthy 1) -propionate ; 4- (N,N-dibutylamino)butyl d 2- ( 6-methoxy-2-naphth 1) -propionate ; 2- (N-methyl-N-ethylamino) ethyl d 2- ( 6-methoxy-2-naphthy1) ropionate ; 2- (N-methyl-N-propylamino) ethyl d 2- ( 6-methoxy-2-naphthyl) propionate ; 2- (N-methyl-N-butylamino) ethyl d 2- ( 6-methoxy-2-naphthyl) propionate ; 2- (N-ethyl-N-propylamino) ethyl d 2- ( 6-methoxy-2-naphthyl) propionate ; 2- (N-ethyl-N-butylamino) ethyl d 2- ( 6-methoxy-2-naphthyl) propionate ; 2- (N-propyl-N-butylamino) ethyl d 2- ( 6-methoxy-2-naphthy1) propionate ; 3- (N-methyl-N-ethylamino) propyl d 2- ( 6-methoxy-2-naphthy1) propionate ; 42472/2 3- (N-methy1-N-propylumino) propyl d 2- ( 6-methoxy-2-naphthy1) propionate ; 3- (N-inethyl-N-butylamino) propyl d 2- ( 6-methoxy-2-naphthyl) propionate 3- (N- ethyl-N-propylamino) propyl d 2- ( 6-methoxy-2 -naphthy1) propionate ; 3- (N-ethy1-N-butylamino) propyl d 2 - ( 6-rnethoxy-2 -naphthy1) propionate ; 3- (N-propy1-N-butylamino) propyl d 2- ( 6-methoxy-2-naphthy1) propionate ; 4- (N-methy1-N-ethylamino) butyl d 2- (6-methoxy-2-naphthyl) propionate ; 4- (N-methy1-N-propylamino) butyl d 2- ( 6-methoxy-2-naphthyl) ropionate 4- (N-ethy1-N-propylamino) butyl d 2 - ( 6-methoxy-2 -naphthy1) ropionate and 4- (N-ethy1-N-butylamino) butyl d 2- ( 6-methoxy-2 -naphthyl) ropionate .
EXAMPLE V- Examp.les I and II are repeated, except d 2 - ( 6-methoxy- 2 -naphthyl) propionic acid is substituted for the dl 2-( 6-methoxy-2-naphthy1) ropionic acid of Example I. There is obtained β-Ν,Ν-dimethylaininoethyl d 2- ( 6-methoxy-2-naphthyl) propionate .
EXAMPLE VI Examples I and II are repeated except that 1-hydroxyethyl-pyrrolidine ; 4-hydroxyethylmorpholine ; and 1- - - hydroxyethy1-piperidine ; are respectively substituted for the dimethy1-ethanolainine of Example II, and d 2-(6-methoxy-2-naphthyl) propionic acid is subst tuted for the - . dl 2- (6-rnethoxy-2-naphthyl) propionic acid of Example I.
There is obtained: ■ 2- (pyrrolidin-l-yl) ethyl d 2 - ( 6-methoxy-2 -naphthy1) -propionate; hydrochloride salt, rn.p. 140-140.5°C. ' 2- (morpholino) ethyl d 2- (6-methoxy-2-naphthyl) proprionate ; and 2- (piperid-l-y 1) ethyl d 2- ( 6-methoxy-2 -naphthy1) -propionate, hydrochloride salt, m.p. 137-139°C.
■' EXAMPLE VII A solution of 50 g. of d 2- ( 6-methoxy-2-naphthy1) -propionic acid in 250 ml. of acetic anhydride is heated under reflux for one hour. Evaporation under vacuum gives bis [2- (6-methoxy-2-naphthy1) propionic] anhydride.. The anhydride so produced in 200 ml. benzene is added to 20 g. of Ν,Ν-dietbyl-hydroxyetbylamine, and the mixture held overnight at room temperature. The mixture is washed first with sodium bicarbonate solution and then with water, and the. solvent removed under vacuum to afford 2-(N,N-diethylamino) ethyl d 2- ( 6-methoxy-2 -naphthyl) -propionate .
EXAMPLE VIII 23 G. of 2-(N,N-diethylamino) ethyl d 2- ( 6-methoxy-2-naphthyl) propionate of Example VII above in 250 ml. ether is mixed with 9 g. of maleic acid in 250 ml. ether. Impurities are removed by washing the precipated product with ether. Drying under vacuum gives 2- (Ν,Ν-diethylamino) ethyl d 2- (6-methoxy-2 -naphthyl) propionate *maleic acid salt.
EXAMPLE IX Example VII is repeated except N,N-dimethyl-hydroxy-ethylamine is substituted for the N,N-diethyl-hydroxyethyl-amine to afford 2- (Ν,Ν-dimethylamino) ethyl d 2- ( 6-methoxy-2-naphthyl) propionate.
While the present invention has been described with reference to specific embodiments thereof, it should be understood by those skilled in this art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications can be made to adapt a particular situation, material or composition of matter, process, process step or steps, or then-present objective to the spirit of this invention without departing from its essential teachings.
Claims (12)
1. A- rocess for preparing a ' compound represented by the formula: wherein R and R are independently lower alkyl or together R2 and R3 and the nitrogen atom to which they are attached form a saturated heterocyclic ring having from 3 through 6 ring atoms, and n is an integer from 2 x through 4, inclusive, and the pharmaceutically acceptable salts thereof; said process comprising converting a 2- ( 6-methoxy-2-naphthy1) -propionic acid to a 2- ( 6-methoxy-2 -naphthy1) propionyl halide or a 2 -( 6-methoxy-2-naphthy1) propionic anhydride, and reacting said 2- (6-methoxy-2 -naphthy1) propionyl halide or said 2- (6-methoxy-2 -naphthy1) propionic anhydride with a hydroxyalky1-amine or a N-hydroxyalkyl-heterocyclic amine to afford the corresponding compound of Formula I· bove, and, optionally, treating said compound of Formula I with an inorganic or organic acid to form a pharmaceutically acceptable salt thereof.
2. The process of Claim 1 wherein dl 2- (6-methoxy-2-naphth l) propionic acid is converted to a dl 2- ( 6-methoxy-2-naphthy1) propionyl halide or a dl 2 -( 6-methoxy-2 -naphthy1) -propionic anhydride ,. and said dl 2- (6-methoxy-2 -naphthy1) -propionyl halide or said dl 2- ( 6-methoxy-2-naphthy1) propionic anhydride is reacted with Ν,Ν-dimethyl-hydroxyethylamine to afford β-Ν,Ν-dimethylaminoethyl dl 2- ( 6-methoxy-2 -naphthyl) -
3. The process of Claim 2 wherein said β-Ν,Ν-dimethyl-aminoethyl- dl 2- ( 6-methoxy-2-naphthy1) propionate is treated with hydrochloric acid to form β-Ν,Ν-dimethylaminoethyl dl 2- (6-methoxy-2-naphthyl) propionate 'hydrochloric acid salt.
4. The process of Claim 1 wherein d 2- (6-methoxy-2-naphthyl) propionic acid is converted to a d 2- ( 6-methoxy-2-naphthyl) ropionyl halide or a d 2- (6-methoxy-2-naphthyl) -propionic anhydride, and said d 2- ( 6-methoxy-2-naphthyl) -propionyl halide or said d 2- (6-methoxy-2-naphthyl) propionic anhydride is reacted with Ν,Ν-diethyl-hydroxyethylamine to afford β-Ν,Ν-diethylaminoethyl d 2- ( 6-methoxy-2-naphthyl) -propionate .
5. The process of Claim 4 wherein said β-Ν,Ν-diethyl-aminoethyl d 2- ( 6-methoxy-2-naphthyl) ropionate is treated with maleic acid to form β-Ν,Ν-diethylaminoethyl d 2-(6-methoxy-2-naphthyl) propionate «maleic acid salt.
6. The process of Claim 1 wherein d 2- (6-methoxy-2-naphthyl) propionic acid is converted to a d 2- (6-methoxy-2-naphthyl) propionyl halide or a d 2- ( 6-methoxy-2-naphthyl) -propionic anhydride, and said d 2- ( 6-methoxy-2-naphthyl) -propionyl halide or said d 2- (6-methoxy-2-naphthyl) propionic anhydride is reacted with N,N-dimethyl-hydroxyethylamine to afford β-Ν,Ν-dimethylaminoethy1 d 2-(6-methoxy-2-naphth l) propionate .
7. A compound represented by the structural formula: yl 42472/2 t 2 3 or together R and R and the nitrogen atom to which j ■ they are attached form a saturated heterocyclic ring • having from 3 through 6 ring atoms, and n is an intege from 2 through 4, inclusive; and the pharmaceutically acceptable salts thereof.
8. ; The compound of Claim 7 wherein said compound is β-Ν,Ν-dimethylaminoethyl dl 2- ( 6-methoxy-2-naphthy 1) -propionate .
9. The compound of Claim 7 wherein said compound is β-Ν,Ν-dimeth laminoethyl dl 2- ( 6-methoxy-2-naphthyl) -propionate -hydrochloric acid salt.
10. The compound of Claim 7 wherein said compound is β-Ν,Ν-diethylaminoethy 1 d 2- ( 6-methoxy-2 -naphthylj -propionate.
11. The compound of Claim 7 wherein said compound is β Ν,Ν-diethylaminoethyl d 2- (6-m'ethoxy-2 -naphthy1) -propionate ' aleic acid salt. - -
12. The compound of Claim 7 wherein said compound is β-Ν,Ν-dimethylaminoethy 1 d 2- (6-methoxy-2 -naphthy1) -propionate.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26664072A | 1972-06-27 | 1972-06-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL42472A0 IL42472A0 (en) | 1973-08-29 |
| IL42472A true IL42472A (en) | 1977-01-31 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL42472A IL42472A (en) | 1972-06-27 | 1973-06-11 | Dialkylaminoalkyl esters of 6-methoxy-2-naphthylpropionic acid and salts thereof and their preparation |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5438097B2 (en) |
| AT (1) | AT323145B (en) |
| AU (1) | AU472375B2 (en) |
| BE (1) | BE801440A (en) |
| CA (1) | CA1012159A (en) |
| CH (1) | CH581605A5 (en) |
| DE (1) | DE2331665C2 (en) |
| ES (1) | ES416311A1 (en) |
| FR (1) | FR2190451B1 (en) |
| GB (1) | GB1377316A (en) |
| IL (1) | IL42472A (en) |
| NL (1) | NL175910C (en) |
| ZA (1) | ZA733992B (en) |
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| EP0289262A3 (en) * | 1987-04-27 | 1989-05-31 | Syntex Pharmaceuticals International Limited | Omega-quaternary ammonium alkyl esters and thioesters of acidic nonsteroidal antiinflammatory drugs |
| EP2054384A4 (en) * | 2006-08-15 | 2010-11-03 | Techfields Biochem Co Ltd | POSITIVELY-CHARGED WATER-SOLUBLE PRODRUGS CONTAINING ARYL- AND HETEROARYLPROPIONIC ACIDS AND HAVING A VERY HIGH SPEED OF SKIN PENETRATION |
| KR101366296B1 (en) * | 2012-03-07 | 2014-02-21 | 주식회사 포스코 | Constructing method For fireproof material |
| JP6290947B2 (en) * | 2016-02-05 | 2018-03-07 | テックフィールズ バイオケム カンパニー リミテッド | Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin permeability |
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| BE647400A (en) * | 1963-05-02 | 1964-10-30 | ||
| ZA701191B (en) * | 1969-03-24 | 1971-09-29 | Syntex Corp | 2-(6-substituted-2'-naphthyl)acetic acid esters and process for producing same |
-
1973
- 1973-06-11 IL IL42472A patent/IL42472A/en unknown
- 1973-06-11 CA CA173,695A patent/CA1012159A/en not_active Expired
- 1973-06-12 ZA ZA00733992A patent/ZA733992B/en unknown
- 1973-06-13 GB GB2814473A patent/GB1377316A/en not_active Expired
- 1973-06-14 AU AU56903/73A patent/AU472375B2/en not_active Expired
- 1973-06-15 AT AT528473A patent/AT323145B/en not_active IP Right Cessation
- 1973-06-22 DE DE2331665A patent/DE2331665C2/en not_active Expired
- 1973-06-26 FR FR7323264A patent/FR2190451B1/fr not_active Expired
- 1973-06-26 BE BE132718A patent/BE801440A/en not_active IP Right Cessation
- 1973-06-26 NL NLAANVRAGE7308876,A patent/NL175910C/en not_active IP Right Cessation
- 1973-06-26 ES ES416311A patent/ES416311A1/en not_active Expired
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Also Published As
| Publication number | Publication date |
|---|---|
| CH581605A5 (en) | 1976-11-15 |
| GB1377316A (en) | 1974-12-11 |
| NL7308876A (en) | 1974-01-02 |
| NL175910C (en) | 1985-01-16 |
| AU472375B2 (en) | 1976-05-20 |
| IL42472A0 (en) | 1973-08-29 |
| JPS5438097B2 (en) | 1979-11-19 |
| ZA733992B (en) | 1975-01-29 |
| JPS504053A (en) | 1975-01-16 |
| NL175910B (en) | 1984-08-16 |
| DE2331665C2 (en) | 1983-04-21 |
| CA1012159A (en) | 1977-06-14 |
| AT323145B (en) | 1975-06-25 |
| AU5690373A (en) | 1974-12-19 |
| DE2331665A1 (en) | 1974-01-17 |
| ES416311A1 (en) | 1976-05-16 |
| FR2190451B1 (en) | 1976-12-31 |
| BE801440A (en) | 1973-12-26 |
| FR2190451A1 (en) | 1974-02-01 |
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