US3870715A - Substituted amino ethyl meta benzoic acid esters - Google Patents
Substituted amino ethyl meta benzoic acid esters Download PDFInfo
- Publication number
- US3870715A US3870715A US347287A US34728773A US3870715A US 3870715 A US3870715 A US 3870715A US 347287 A US347287 A US 347287A US 34728773 A US34728773 A US 34728773A US 3870715 A US3870715 A US 3870715A
- Authority
- US
- United States
- Prior art keywords
- benzoic acid
- ethyl
- compound
- methyl ester
- equiv
- 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.)
- Expired - Lifetime
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- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 title abstract description 4
- 150000001558 benzoic acid derivatives Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- -1 m-(2-(N-methylpiperazino)ethyl)benzoic acid methyl ester Chemical compound 0.000 claims description 48
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- IGJQEMHBYKNIQR-UHFFFAOYSA-N methyl 3-[2-[benzyl(methyl)amino]ethyl]benzoate Chemical compound COC(=O)C1=CC=CC(CCN(C)CC=2C=CC=CC=2)=C1 IGJQEMHBYKNIQR-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- RAPYMZCCHMPKNZ-UHFFFAOYSA-N ethyl 3-[2-(2-phenylethylamino)ethyl]benzoate Chemical compound C(C)OC(C1=CC(=CC=C1)CCNCCC1=CC=CC=C1)=O RAPYMZCCHMPKNZ-UHFFFAOYSA-N 0.000 claims description 3
- OOBSNJQWJKDVEO-UHFFFAOYSA-N methyl 3-(2-piperidin-1-ylethyl)benzoate Chemical compound COC(C1=CC(=CC=C1)CCN1CCCCC1)=O OOBSNJQWJKDVEO-UHFFFAOYSA-N 0.000 claims description 3
- 150000004702 methyl esters Chemical class 0.000 claims description 3
- BLTBMJSBRKZMFR-UHFFFAOYSA-N methyl 3-[2-(3-phenylpropylamino)ethyl]benzoate Chemical compound COC(C1=CC(=CC=C1)CCNCCCC1=CC=CC=C1)=O BLTBMJSBRKZMFR-UHFFFAOYSA-N 0.000 claims description 2
- OULCHRYMGAELDV-UHFFFAOYSA-N methyl 3-[2-[benzyl(2-methoxyethyl)amino]ethyl]benzoate Chemical compound COC(C1=CC(=CC=C1)CCN(CCOC)CC1=CC=CC=C1)=O OULCHRYMGAELDV-UHFFFAOYSA-N 0.000 claims description 2
- NUXOLRUSEITVEC-UHFFFAOYSA-N propyl 3-[2-(2-phenylethylamino)ethyl]benzoate Chemical compound C(CC)OC(C1=CC(=CC=C1)CCNCCC1=CC=CC=C1)=O NUXOLRUSEITVEC-UHFFFAOYSA-N 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 abstract description 15
- 230000032050 esterification Effects 0.000 abstract description 13
- 150000003839 salts Chemical class 0.000 abstract description 12
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 9
- 230000007062 hydrolysis Effects 0.000 abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003795 chemical substances by application Substances 0.000 abstract description 6
- 230000002048 spasmolytic effect Effects 0.000 abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 35
- 238000000034 method Methods 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000000203 mixture Substances 0.000 description 16
- 238000009835 boiling Methods 0.000 description 15
- 238000002844 melting Methods 0.000 description 13
- 230000008018 melting Effects 0.000 description 13
- 239000007858 starting material Substances 0.000 description 13
- 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 11
- 238000010992 reflux Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 125000003710 aryl alkyl group Chemical group 0.000 description 8
- 229920002261 Corn starch Polymers 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 7
- 125000002877 alkyl aryl group Chemical group 0.000 description 7
- 239000008120 corn starch Substances 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 150000003254 radicals Chemical group 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 235000010233 benzoic acid Nutrition 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- WRCSFUANACAWCW-UHFFFAOYSA-N 1-(2-chloroethyl)-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(CCCl)=C1 WRCSFUANACAWCW-UHFFFAOYSA-N 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- HLBBSWSJLPLPRU-UHFFFAOYSA-N methyl 3-[2-[benzyl(methyl)amino]ethyl]benzoate;hydrochloride Chemical compound [Cl-].COC(=O)C1=CC=CC(CC[NH+](C)CC=2C=CC=CC=2)=C1 HLBBSWSJLPLPRU-UHFFFAOYSA-N 0.000 description 4
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000002775 capsule Substances 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
- 239000003937 drug carrier Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000002452 interceptive effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- YDKIPCCKZKQMDT-UHFFFAOYSA-N 2-[3-(trifluoromethyl)phenyl]ethanol Chemical compound OCCC1=CC=CC(C(F)(F)F)=C1 YDKIPCCKZKQMDT-UHFFFAOYSA-N 0.000 description 2
- DEXWRQGUDRTZSX-UHFFFAOYSA-N 4-[2-[3-(trifluoromethyl)phenyl]ethyl]morpholine Chemical compound FC(F)(F)C1=CC=CC(CCN2CCOCC2)=C1 DEXWRQGUDRTZSX-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 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
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 150000001559 benzoic acids Chemical class 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000007963 capsule composition Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- HVAAHUDGWQAAOJ-UHFFFAOYSA-N n-benzylethanamine Chemical compound CCNCC1=CC=CC=C1 HVAAHUDGWQAAOJ-UHFFFAOYSA-N 0.000 description 2
- QOGWLMDFIDRFDL-UHFFFAOYSA-N n-methyl-2-[3-(trifluoromethyl)phenyl]ethanamine Chemical compound CNCCC1=CC=CC(C(F)(F)F)=C1 QOGWLMDFIDRFDL-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 229940117803 phenethylamine Drugs 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000002787 reinforcement Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- ABXGMGUHGLQMAW-UHFFFAOYSA-N 1-[3-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=CC(C(F)(F)F)=C1 ABXGMGUHGLQMAW-UHFFFAOYSA-N 0.000 description 1
- NNMBNYHMJRJUBC-UHFFFAOYSA-N 1-bromo-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(Br)=C1 NNMBNYHMJRJUBC-UHFFFAOYSA-N 0.000 description 1
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- XNIOWJUQPMKCIJ-UHFFFAOYSA-N 2-(benzylamino)ethanol Chemical compound OCCNCC1=CC=CC=C1 XNIOWJUQPMKCIJ-UHFFFAOYSA-N 0.000 description 1
- UVPCIEMOLVZPCV-UHFFFAOYSA-N 2-(diethylaminomethyl)benzoic acid Chemical compound CCN(CC)CC1=CC=CC=C1C(O)=O UVPCIEMOLVZPCV-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- NNWUEBIEOFQMSS-UHFFFAOYSA-N 2-Methylpiperidine Chemical compound CC1CCCCN1 NNWUEBIEOFQMSS-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- MNNZINNZIQVULG-UHFFFAOYSA-N 2-chloroethylbenzene Chemical compound ClCCC1=CC=CC=C1 MNNZINNZIQVULG-UHFFFAOYSA-N 0.000 description 1
- RGHPCLZJAFCTIK-UHFFFAOYSA-N 2-methylpyrrolidine Chemical compound CC1CCCN1 RGHPCLZJAFCTIK-UHFFFAOYSA-N 0.000 description 1
- XHKGPMUOGBWYPC-UHFFFAOYSA-N 2-phenyl-n-(trifluoromethyl)ethanamine Chemical compound FC(F)(F)NCCC1=CC=CC=C1 XHKGPMUOGBWYPC-UHFFFAOYSA-N 0.000 description 1
- PVZQUECKYKDDED-UHFFFAOYSA-N 3-(2-azaniumylethyl)benzoate Chemical compound NCCC1=CC=CC(C(O)=O)=C1 PVZQUECKYKDDED-UHFFFAOYSA-N 0.000 description 1
- JEGMWWXJUXDNJN-UHFFFAOYSA-N 3-methylpiperidine Chemical compound CC1CCCNC1 JEGMWWXJUXDNJN-UHFFFAOYSA-N 0.000 description 1
- KYINPWAJIVTFBW-UHFFFAOYSA-N 3-methylpyrrolidine Chemical compound CC1CCNC1 KYINPWAJIVTFBW-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
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- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 1
- 231100000229 OECD 452 Chronic Toxicity Study Toxicity 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- WSWOKFODOPIESP-UHFFFAOYSA-M [Br-].FC(F)(F)C1=CC=CC([Mg+])=C1 Chemical compound [Br-].FC(F)(F)C1=CC=CC([Mg+])=C1 WSWOKFODOPIESP-UHFFFAOYSA-M 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 1
- 229910001626 barium chloride Inorganic materials 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- PWZFXELTLAQOKC-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide;tetrahydrate Chemical compound O.O.O.O.[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O PWZFXELTLAQOKC-UHFFFAOYSA-A 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 125000005283 haloketone group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 125000003717 m-cresyl group Chemical group [H]C1=C([H])C(O*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000036244 malformation Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000036997 mental performance Effects 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- VSCNWJMUKRBDCF-UHFFFAOYSA-N methyl 3-[2-(benzylamino)ethyl]benzoate Chemical compound COC(=O)C1=CC=CC(CCNCC=2C=CC=CC=2)=C1 VSCNWJMUKRBDCF-UHFFFAOYSA-N 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- BHKFRWOEIYJBLN-UHFFFAOYSA-N n-benzyl-2-methoxyethanamine Chemical compound COCCNCC1=CC=CC=C1 BHKFRWOEIYJBLN-UHFFFAOYSA-N 0.000 description 1
- OUMBFMLKPJUWDQ-UHFFFAOYSA-N n-benzylpropan-1-amine Chemical compound CCCNCC1=CC=CC=C1 OUMBFMLKPJUWDQ-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003506 spasmogen Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000004308 thiabendazole Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000005023 xylyl group Chemical group 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
- C07D295/14—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
Definitions
- M-aminoethyl benzoic acid is described in Chemical Abstracts 52, 6404.
- Para-aminoethyl benzoic acid and its ethyl ester is disclosed in Chemical Abstracts 25, 2194.
- Diethylaminomethylbenzoic acid and its ethyl ester is shown in Beilstein XIV, 488.
- Various p-(aminoalkyl)benzoic acids and esters are disclosed in Chemical Abstracts 38, 732.
- the present invention relates to a series of substituted aminoethyl'meta benzoic acid esters and their salts which compounds are useful as spasmolytics, psychotherapeutic agents and agents facilitating learning.
- the compounds of the present invention have the general structural formula COOR:
- R is hydrogen, hydroxy, lower alkoxy or lower alkyl
- R is hydrogen or lower alkyl
- R;, is lower alkyl, aralkyl or lower alkyl aryl
- R taken independently is hydrogen, lower alkyl, aralkyl, lower alkyl aryl, hydroxy lower alkyl and lower alkoxy lower alkyl
- R taken independently is lower alkyl, aralkyl, lower alkyl aryl or lower alkoxy lower alkyl
- R and R taken together with the adjacent nitrogen atom form a saturated five or six membered heterocyclic ring which may contain one additional hetero atom selected from the group consisting of O- and -NR where R., is hy drogen or lower alkyl and the pharmaceutically acceptable acid addition salts thereof.
- alkyl is meant to include straight or branched chain hydrocarbon radicals such as methyl, ethyl, n-propyl, T-butyl, hexyl, heptyl, and the like.
- alkoxy is meant to include a radical group wherein an alkyl moiety is bonded to an oxygen atom through an ether linkage, the valence of the radical being derived from said oxygen atom. Suitable examples of alkoxy groups include methoxy, ethoxy, butoxy and the like.
- aralkyl is meant to include radical groups such as phenyl lower alkyl, especially radical groups such as benzyl, phenylethyl and the like.
- Lower alkyl aryl is meant to encompass groups such as lower alkyl phenyl,
- lower alkoxy lower alkyl is meant to include radical groups such as methoxy methyl, methoxy ethyl, ethoxy methyl, ethoxy ethyl, and the like.
- suitable heterocyclic radical groups obtained when R., and R are taken together with the adjacent nitrogen atom include morpholino, piperidino, piperazino and N-lower alkyl piperazino.
- the compounds of formula I form acid addition salts with a variety of inorganic and organic acids.
- Suitable inorganic acids for this purpose include the hydrohalic acids such as hydrochloric and hydrobromic acids, sulfuric acid, phosphoric acid, sulfamic acid and the like.
- Suitable organic acids for this purpose include tartaric acid, citric acid, maleic acid, hexonic acid, and the like.
- Compounds of formula I in the form of acid addition salts with pharmaceutically unacceptable acids can be converted to acid addition salts with pharmaceutically acceptable acids by ion exchange procedures known in the art.
- R is hydrogen or lower alkoxy, preferably methoxy
- R is hydrogen
- R is lower alkyl
- R is hydrogen or lower alkyl
- R is lower alkyl
- aralkyl preferably benzyl or parachloro benzyl or lower alkoxy lower alkyl, preferably methoxy ethyl.
- Exemplary of compounds of the present invention are the following: m-[2-(benzylmethylamino)-ethyl]benzoic acid methyl ester m-[2-(benzylmethylamino)-ethyl]benzoic acid ethyl ester m-[2-morpholino-ethyl)-benzoic acid methyl ester m-[2-(N-methylpiperazino)ethyl]benzoic acid methyl ester m-(2-piperidinoethyl)-benzoic acid methyl ester m-[Z-(benzylethylamino)-ethyl]benzoic acid methyl ester m-[2-(N-benzyl-N-(2-methoxyethyl)amino)- ethyl]benzoic acid methyl ester m-(Z-diethylaminoethyl)-benzoic acid methyl ester m-[(2-methyl)(2-is
- the esterification is conductedin the presence of a strong acid, preferably a mineral acid, most preferably, concentrated sulfuric acid or an organic acid such as an aryl or alkyl sulfonic acid, e.g., tuluenesulfonic acid or methyl sulfonic acid at a temperature in the range of from about 40C to the reflux temperature of the reaction medium.
- a strong acid preferably a mineral acid, most preferably, concentrated sulfuric acid or an organic acid such as an aryl or alkyl sulfonic acid, e.g., tuluenesulfonic acid or methyl sulfonic acid
- condensation reagents instead of acids in the esterification reaction. Suitable condensation reagents include the carbodiimides, most perferably dicyclocarbodiimide. Conditions for this reaction embodiment are known per se in the art.
- esters of formula I from the acids of formula II.
- activated derivatives of the carboxyl moiety such as an acid halide, i.e., acid chloride; acid anhydride or acid imidazole can be utilized in the esterification reaction with alcohols of formula 111.
- activated derivatives can be prepared from the benzoic acids of formula II by procedures well known in the art.
- methyl and phenyl esters falling within the scope of formula I can be prepared by reacting the benzoic acids of formula II with diazomethyl or diazophenyl, respectively, under the conventional conditions for this procedure.
- the benzoic acid compounds of formula ll are derived from correspondingly substituted trifluoromethyl compounds of the formula lll CFJ
- R R R and R are as above by hydrolysis in the presence of a strong mineral acid such as sulfuric acid or hydrofluoric acid or a combination of these two acids or a combination of one or both of the above and another acid such as phosphoric acid, hydrochloric acid, alkyl-sulfonic acid (preferably methyl sulfonic acid or aryl sulfonic acid, preferably toluene sulfonic acid).
- This hydrolysis reaction may be conducted at a temperature in the range of from about C. to the reflux temperature of the reaction mixture, most preferably at about the reflux temperature of the reaction mixture.
- R R and R are hydrogen
- the product compounds may be converted to corresponding compounds of the present invention by esterifying as above and then reacting the primary amine ester compound under conventional conditions with the appropriate R and/or R derivative, such as for example, the halide derivative to alkylate the amine.
- Suitable halide derivatives for this purpose include benzyl chloride, methyl iodide and the like.
- alkylation may be accomplished using the desired aldehyde of a R, and/or R compound, such as formaldehyde, benzaldehyde, etc. followed by reduction in a manner known per se.
- Suitable amines falling within the scope of formula V and thus finding use in the present invention are the following: piperazine, N-methylpiperazine, pyrrolidine, 2-methylpyrrolidine, 3- methylpyrrolidine, piperidine, 2-methylpiperidine, 3- methylpiperidine, 4-methylpiperidine, morpholine, dibeta-hydroxyethylamine, betahydroxyethylmethylamine, betahydroxyethyl-benzylamine, benzyllower alkylamino, preferably benzyl-methyl-amine, benzyl-ethyl-amine and benzyl-propylamine and dibenzylamine; wherein the benzyl group may be substituted in any of the above with a non-interfering group in the 2, 3, 4 or alpha position.
- Suitable non-interfering groups include lower alkyl, preferably, methyl, lower alkoxy, preferably methoxy, halogen, preferably chloro, nitro, sulfates, phen
- the aforesaid Grignard reagent can be reacted with ethyleneimine or a substituted homolog and the resultant primary amine can be alkylated as described hereinbefore to produce desired compounds of formula IV or, if desired, alkylation can be delayed until after hydrolysis of the trifluoromethyl group and esterification.
- m-trifluoromethylacetophenone can be halogenated on the carbon adjacent to the keto group.
- the resulting haloketone can be reacted with an amine of formula V above and the resultant aminoketone reduced with a chemical reducing agent, such as a metal hydride, i.e., sodium hydride or a complex metal hydride, i.e., lithium aluminum hydride or sodium borohydride to yield the desired compounds of formula IV wherein R, is hydroxy.
- a chemical reducing agent such as a metal hydride, i.e., sodium hydride or a complex metal hydride, i.e., lithium aluminum hydride or sodium borohydride
- the benzoic acid ester derivatives of the present invention can be conveniently prepared by a sequence of reactions as outlined above. These compounds are made readily accessible by such reaction sequences due to the relative inertness of the trifluoromethyl group which does not interfere with preparation of the Grignard reagents.
- noninterfering groups include lower alkyl, halogen, hydroxy, lower alkoxy, nitro, sulfate and the like.
- compounds of formula I may contain asymmetric carbon atoms in the ethylene sidechain depending on secondary substitution or asymmetric centers in other places. Racemie mixtures as well as the optical enantiomers of such compounds are to be considered within the scope of this invention. Racemate pairs can be separated by conventional resolution procedures, such as, for example, fractional crystallization of diastcreomer salts formed with an optically active acid, i.c., tartaric acid, camphorsulfonic acid and the like. Chromatographic procedures for effecting such resolution are also known in the art.
- the compounds of formula I of the present invention are useful in facilitating certain parameters of intellectual performance in the experimental animal and in man, such as, for example, the enhancement of learning and memory. Additionally, the compounds of formula I are useful as cholinergic and spasmolytic agents. These compounds can be administered for prolonged periods of time without producing undesirable side effects as determined by standard pharmacological evalnation.
- the spasmolytic activity of the instant compounds can be demonstrated by the effect on the isolated ileum stimulated by such spasmogens as acetyl chloine, barium chloride and histamine.
- spasmogens as acetyl chloine, barium chloride and histamine.
- papaverine as a standard, the following table demonstrates the comparable activity found as a result of this test.
- the compounds of this invention not only exhibit the various activities hereinbefore described but moreover are of low toxicity and exhibit few undesirable side effects.
- a preferred species of the invention m-[2-(benzylmethylamino)-ethyl]-benzoic acid methyl ester was found to have an oral LD of about 500-700 mg/kg in mice.
- the compounds of formula I When utilized to enhance mental performance in higher mammals, the compounds of formula I may be administered in oral dosages in the range of from about 0.01 to about 4 mg/kg. preferably in the range of from about 0.01 to about 2 mg/kg, most preferably from about 0.05 to about l.2 mg/kg. Parenteral dosages of about to 100 times these levels are preferred in laboratory test animals.
- the desired compounds of this invention are employed in the described uses in the form of nontoxic acid addition salts and may be administered to mammalians as pure compounds. It is advisable, however, to first combine one or more of the novel compounds with a suitable pharmaceutical carrier to attain a more satisfactory size to dosage relationship.
- compositions which are liquid or solid may be used, the preferred liquid carrier being water in a pharmaceutically acceptable emulsion, suspension or solution. Flavoring materials may be included in the solutions as desired.
- Solid pharmaceutical carriers such as starch, sugar, talc, mannitol and the like may be used to, form powders.
- the powders may be given directly or incorporated in tablet, capsule or suppository preparations.
- EXAMPLE 1 A total of g. of N-benzyl-N-methyl-3- trifluoromethyl-phenethylamine hydrochloride was dissolved in 40 g. of concentrated sulfuric acid and the resultant solution was heated on a water bath for 3 hours. The reaction mixture was then cooled and combined with 50 ml. of methyl alcohol. This solution was refluxed for 3 hours at which time most of the excess methyl alcohol was removed by distillation. The residual mixture was cooled and poured slowly into 200 ml. of cold water. The acid aqueous solution was carefully made alkaline and extracted with ether. The ether extract was dried and anhydrous hydrochloric acid/ether was added.
- the hydrochloride salt was converted to the free base by addition of alkali hydroxide to the aqueous solution of the salt.
- the base was extracted with ether and the ether removed in vacuo.
- the free benzoic acid derivative was obtained by hydrolysis of the hydrochloride salt of the ester with hydrochloric acid and after recrystallization there was obtained crude m-[2-(benzyl-methylamino)- ethyl]benzoic acid.
- the starting material may be prepared as follows:
- EXAMPLE 2 In analogy to the procedure of Example 1, hydrolysis of Nbenzyl-N-methyl-3-trifluoromethylphenethylamine with sulfuric acid, followed by esterification with ethyl alcohol yielded m-[Z-(benzylmethylamino)-ethyl]benzoic acid ethyl ester. M.p. 1 l5l 17C.
- the starting material may be prepared as follows:
- the starting material may be prepared as follows:
- chloroform solution was briefly washed with water, bicarbonate solution and water. It was dried and distilled to yield 110 g. (90%) of a-methyl-3-trifluoromethylphenethyl chloride boiling at 103l05C/25 mm.
- the starting material may be prepared as follows:
- the starting material may be prepared as follows:
- Example 1 3- trifluoromethyl-phenethylchloride was reacted with morpholine to produce 3-trifluoromethyl-phenethyl morpholine in 84% yield, the pre-base product boiling at C/0.3 mm.
- EXAMPLE 8 In analogy to the procedure of Example 1 m-(Z-piperidinoethyl)-benzoic acid methyl ester was prepared by the sulfuric acid hydrolysis and esterification with methyl alcohol of 3-trifluoromethylphenethylpiperidine.
- EXAMPLE 12 In analogy to the procedure of Example 1 concentrated sulfuric acid hydrolysis of N-benzyl-N-ethyl-3- 5 trifluoromethylphenethylamine followed by esterification with methyl alcohol yielded m-[Z-(benzyle- EXAMPLE 9 thylamino)-ethyl]benzoic acid methyl ester. A mixture of 4 grams of m-[2-(benzylmethylamino)- ethyl]-benzoic acid methyl ester, 10 g. of npropylalcohol and 4 g. of concentrated sulfuric acid 10 was heated to reflux temperature.
- the starting material may be prepared as follows: was rendered alkaline with sodium hydroxide. Utilizing the procedure of Example 1 3-trifluorome- The free base was extracted with ether and the exthylphenethyl chloride was reacted with N-methylpiptract dried over potassium carbonate and distilled.
- the starting material may be prepared as follows:
- the starting material may be prepared as follows:
- EXAMPLE 17 Tablet Formulation A prehydrolyzed food grade corn starch. Any similar prehydrolyzed corn starch may be used.
- the mixture was granulated to a heavy paste with water and the moist mass was passed through a N o. 12 screen. It was then dried overnight at F.
- the dried granules were passed through a No. 16 screen and transferred to a suitable mixer.
- the calcium stearate was added and mixed until uniform.
- the mixture was compressed at a tablet weight of 410 mg. using tablet punches having a diameter of approximately inch. (Tablets may be either flat or biconvex and may be scored if desired.)
- EXAMPLE 19 Capsule Formulation Per Capsule m-l2-(Benzylmethylamino)-ethyllhenzoic acid 1. m-[2-(Benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride was mixed with lactose and corn starch in a suitable mixer.
- the mixture was filled into No. 4 hard shell gelatin capsules on a Parke Davis capsulating machine.
- the starting material may be prepared as follows:
- EXAMPLE 22 In analogy to the procedure of Example 1, 3 trifluoromethylphenethyl pyrrolidine was hydrolyzed, esterified with methyl alcohol, and converted to the hydrochloride to yield m-(2-pyrro1idinoethy1)-benzoic acid methyl ester hydrochloride melting at 188-189C.
- the starting material may be prepared inanalogy to the method of Example 1 wherein 3-trifluoromethy1- phenethyl chloride was reacted with pyrrolidine to produce 3-trifluoromethy1phenethyl pyrrolidine in 51% yield as a liquid boiling at l17C./30 mm.
- the starting material may be prepared as follows:
- EXAMPLE 24 In analogy to the procedure of Example 1, N-methyl- N-Z-hydroxy ethyl-B-hydroxy-a-methyl-3-trifluoromethylphenethylamine was hydrolyzed with concentrated sulfuric acid and esterified with methyl alcohol followed by conversion to the hydrochloride to yield m-2- (N-methyI-N-Z-hydroxyethyl)amino-B-hydroxy-amethyl-benzoic acid, methyl ester hydrochloride, melting at 206207C.
- EXAMPLE 25 A total of 3.0 g. of m-2-cyclohexylaminoethylbenzoic acid methyl ester hydrochloride was added to 20 ml. of methanol and there was thereafter added 1.15
- the starting material may be prepared as follows:
- R is hydrogen, hydroxy, lower alkoxy or lower alkyl; R is hydrogen or lower alkyl; R is lower alkyl, aralkyl or lower alkyl aryl; R taken independently is hydrogen, lower alkyl, aralkyl, lower alkyl aryl, hydroxy lower alkyl and lower alkoxy lower alkyl; R taken independently is lower alkyl, aralkyl, lower alkyl aryl or lower alkoxy lower alkyl; and R and R taken together with the adjacent nitrogen atom form a saturated five or six membered heterocyclic ring which may contain one additional hetero atom selected from the group consisting of O and NR where R is hydrogen or lower alkyl and the optical antipodes and the pharmaceutically acceptable acid addition salts thereof.
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Abstract
A series of substituted amino ethyl meta benzoic acid esters and their salts are useful as spasmolytics, psychotherapeutic agents and agents facilitating learning. These compounds may conveniently be prepared by hydrolysis of suitably substituted trifluoromethyl derivatives followed by esterification with a desired alcohol.
Description
United States Patent Hansl Mar. 11, 1975 I SUBSTITUTED AMINO ETl-IYL META [58] Field of Search 260/247.2 B, 471 R, 293.81. BENZOIC ACID ESTERS 260/293.82, 326.47, 326.5, 268 R [76] Inventor: Nikolaus R. Hansl, 196 La Vereda Rd., Santa Barbara, Calif. 93108 [56] References CM FOREIGN PATENTS OR APPLICATIONS [22] Flled: 1973 32-5564 7/1957 Japan 260/47] R 21 APPL 347 2 7 1,074,052 5/1956 Germany 260/471 R 631,855 6/1936 Germany 260/471 R Related U.S. Application Data [63] Continuation-impart of Ser. No. 233,339, March 9, Primary Examiner-Lorraine A. Weinberger 1972, abandoned, which is a continuation-in-part of Assistan/ Examiner-Paul ,1. Killos Ser. No. 745,352, July 17, 1968, and a continuationin-part of Ser. No. 85,283, Oct. 29, 1970, Pat. No. 57 ABSTRACT A series of substituted amino ethyl meta benzoic acid [52] U 5 Cl 260,247 2 B 260/247 260/247 2 R esters and their salts are useful as spasmolytics. psychotherapeutic agents and agents facilitating learning.
260/268 R, 260/293.81, 260/293.82, 260/326.47, 260/326.5, 260/471 R, 260/518 A, 260/518 R, 260/519, 260/570.5,
Int. Cl C07d 87/36 These compounds may conveniently be prepared by hydrolysis of suitably substituted trifluoromethyl derivatives followed by esterification with a desired alcohol.
19 Claims, N0 Drawings SUBSTITUTED AMINO ETI-IYL META BENZOIC ACID ESTERS RELATED APPLICATIONS This application is a continuation-in-part of copending US. Patent Application Ser. No. 233,339, filed Mar. 9, 1972, now abandoned which is a continuationin-part of copending US. Patent Application Ser. No. 745,352, filed July 17, 1968, titled AMINOALKYL- BENZOIC ACID DERIVATIVES and Ser. No. 85,283, filed Oct. 29, 1970, now U.S. Pat. 3,792,048 titled AMlNO-ALKYL-BENZOIC ACID DERIVA- TIVES.
BACKGROUND OF THE INVENTION M-aminoethyl benzoic acid is described in Chemical Abstracts 52, 6404. Para-aminoethyl benzoic acid and its ethyl ester is disclosed in Chemical Abstracts 25, 2194. Diethylaminomethylbenzoic acid and its ethyl ester is shown in Beilstein XIV, 488. Various p-(aminoalkyl)benzoic acids and esters are disclosed in Chemical Abstracts 38, 732.
BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a series of substituted aminoethyl'meta benzoic acid esters and their salts which compounds are useful as spasmolytics, psychotherapeutic agents and agents facilitating learning. The compounds of the present invention have the general structural formula COOR:
H H R4 l l -N I l R1 R2 R I wherein R, is hydrogen, hydroxy, lower alkoxy or lower alkyl; R is hydrogen or lower alkyl; R;, is lower alkyl, aralkyl or lower alkyl aryl; R taken independently is hydrogen, lower alkyl, aralkyl, lower alkyl aryl, hydroxy lower alkyl and lower alkoxy lower alkyl; R taken independently is lower alkyl, aralkyl, lower alkyl aryl or lower alkoxy lower alkyl; and R and R taken together with the adjacent nitrogen atom form a saturated five or six membered heterocyclic ring which may contain one additional hetero atom selected from the group consisting of O- and -NR where R., is hy drogen or lower alkyl and the pharmaceutically acceptable acid addition salts thereof.
As used herein the term lower" includes radical groups containing from 1 to 7 carbon atoms. The term alkyl" is meant to include straight or branched chain hydrocarbon radicals such as methyl, ethyl, n-propyl, T-butyl, hexyl, heptyl, and the like. The term alkoxy is meant to include a radical group wherein an alkyl moiety is bonded to an oxygen atom through an ether linkage, the valence of the radical being derived from said oxygen atom. Suitable examples of alkoxy groups include methoxy, ethoxy, butoxy and the like. The term aralkyl" is meant to include radical groups such as phenyl lower alkyl, especially radical groups such as benzyl, phenylethyl and the like. Lower alkyl aryl is meant to encompass groups such as lower alkyl phenyl,
particularly tolyl, xylyl and the like. The term lower alkoxy lower alkyl" is meant to include radical groups such as methoxy methyl, methoxy ethyl, ethoxy methyl, ethoxy ethyl, and the like. Examples of suitable heterocyclic radical groups obtained when R., and R are taken together with the adjacent nitrogen atom include morpholino, piperidino, piperazino and N-lower alkyl piperazino.
The compounds of formula I form acid addition salts with a variety of inorganic and organic acids. Suitable inorganic acids for this purpose include the hydrohalic acids such as hydrochloric and hydrobromic acids, sulfuric acid, phosphoric acid, sulfamic acid and the like. Suitable organic acids for this purpose include tartaric acid, citric acid, maleic acid, hexonic acid, and the like. Compounds of formula I in the form of acid addition salts with pharmaceutically unacceptable acids can be converted to acid addition salts with pharmaceutically acceptable acids by ion exchange procedures known in the art.
Preferred compounds of formula I of the present invention are obtained when R, is hydrogen or lower alkoxy, preferably methoxy, R is hydrogen, R is lower alkyl, R is hydrogen or lower alkyl and R is lower alkyl, aralkyl, preferably benzyl or parachloro benzyl or lower alkoxy lower alkyl, preferably methoxy ethyl.
Exemplary of compounds of the present invention are the following: m-[2-(benzylmethylamino)-ethyl]benzoic acid methyl ester m-[2-(benzylmethylamino)-ethyl]benzoic acid ethyl ester m-[2-morpholino-ethyl)-benzoic acid methyl ester m-[2-(N-methylpiperazino)ethyl]benzoic acid methyl ester m-(2-piperidinoethyl)-benzoic acid methyl ester m-[Z-(benzylethylamino)-ethyl]benzoic acid methyl ester m-[2-(N-benzyl-N-(2-methoxyethyl)amino)- ethyl]benzoic acid methyl ester m-(Z-diethylaminoethyl)-benzoic acid methyl ester m-[(2-methyl)(2-isopropylamino)-ethyl]benzoic acid methyl ester m-[Z-(methylisopropylamino)-ethyl]benzoic acid methyl ester m-[2-(benzylmethylamino)-ethyl]-benzoic acid nacid where R R R and R are as above with alcohols of the formula R OH where R;, is as above. The esterification is conductedin the presence of a strong acid, preferably a mineral acid, most preferably, concentrated sulfuric acid or an organic acid such as an aryl or alkyl sulfonic acid, e.g., tuluenesulfonic acid or methyl sulfonic acid at a temperature in the range of from about 40C to the reflux temperature of the reaction medium. Excess amounts of the alcohol may be employed to serve as the solvent medium if desired. It is also possible to employ condensation reagents instead of acids in the esterification reaction. Suitable condensation reagents include the carbodiimides, most perferably dicyclocarbodiimide. Conditions for this reaction embodiment are known per se in the art.
It is also within the scope of the present invention to employ alternate procedures for the preparation of the esters of formula I from the acids of formula II. For example, activated derivatives of the carboxyl moiety such as an acid halide, i.e., acid chloride; acid anhydride or acid imidazole can be utilized in the esterification reaction with alcohols of formula 111. These activated derivatives can be prepared from the benzoic acids of formula II by procedures well known in the art.
Additionally, the methyl and phenyl esters falling within the scope of formula I can be prepared by reacting the benzoic acids of formula II with diazomethyl or diazophenyl, respectively, under the conventional conditions for this procedure.
The benzoic acid compounds of formula ll are derived from correspondingly substituted trifluoromethyl compounds of the formula lll CFJ
where R R R and R are as above by hydrolysis in the presence of a strong mineral acid such as sulfuric acid or hydrofluoric acid or a combination of these two acids or a combination of one or both of the above and another acid such as phosphoric acid, hydrochloric acid, alkyl-sulfonic acid (preferably methyl sulfonic acid or aryl sulfonic acid, preferably toluene sulfonic acid). This hydrolysis reaction may be conducted at a temperature in the range of from about C. to the reflux temperature of the reaction mixture, most preferably at about the reflux temperature of the reaction mixture.
Compounds of formula II wherein R R and R are hydrogen may be obtained from the corresponding mcyanomethylbenzoic acids by catalytic reduction using H and Raney nickel in the manner described by Takegi ct 11]., Chemical Abstracts 52, 6403(g). The product compounds may be converted to corresponding compounds of the present invention by esterifying as above and then reacting the primary amine ester compound under conventional conditions with the appropriate R and/or R derivative, such as for example, the halide derivative to alkylate the amine. Suitable halide derivatives for this purpose include benzyl chloride, methyl iodide and the like. Alternatively, alkylation may be accomplished using the desired aldehyde of a R, and/or R compound, such as formaldehyde, benzaldehyde, etc. followed by reduction in a manner known per se.
Compounds of formula N, where not already available in the art can be obtained starting from a mtrifluoromethylphenyl-magnesium Grignard reagent by reaction with an appropriate alkylene or substituted alkylene oxide, i.e., ethylene oxide, propylene oxide and the like, followed by halogenation of the resulting alcohol and then by reaction of the halide derivative with an amine of the formula where R, and R are as above.
Examples of suitable amines falling within the scope of formula V and thus finding use in the present invention are the following: piperazine, N-methylpiperazine, pyrrolidine, 2-methylpyrrolidine, 3- methylpyrrolidine, piperidine, 2-methylpiperidine, 3- methylpiperidine, 4-methylpiperidine, morpholine, dibeta-hydroxyethylamine, betahydroxyethylmethylamine, betahydroxyethyl-benzylamine, benzyllower alkylamino, preferably benzyl-methyl-amine, benzyl-ethyl-amine and benzyl-propylamine and dibenzylamine; wherein the benzyl group may be substituted in any of the above with a non-interfering group in the 2, 3, 4 or alpha position. Suitable non-interfering groups include lower alkyl, preferably, methyl, lower alkoxy, preferably methoxy, halogen, preferably chloro, nitro, sulfates, phenyl and the like.
In an alternative to the above procedure, the aforesaid Grignard reagent can be reacted with ethyleneimine or a substituted homolog and the resultant primary amine can be alkylated as described hereinbefore to produce desired compounds of formula IV or, if desired, alkylation can be delayed until after hydrolysis of the trifluoromethyl group and esterification.
In another variant m-trifluoromethylacetophenone can be halogenated on the carbon adjacent to the keto group. The resulting haloketone can be reacted with an amine of formula V above and the resultant aminoketone reduced with a chemical reducing agent, such as a metal hydride, i.e., sodium hydride or a complex metal hydride, i.e., lithium aluminum hydride or sodium borohydride to yield the desired compounds of formula IV wherein R, is hydroxy.
The benzoic acid ester derivatives of the present invention can be conveniently prepared by a sequence of reactions as outlined above. These compounds are made readily accessible by such reaction sequences due to the relative inertness of the trifluoromethyl group which does not interfere with preparation of the Grignard reagents.
The preceding reactions can be illustrated by the following reaction schemes: m-CF -C H -B Mg -+mCF;,C H MgBr ni-oia-unr -ii isiumfill:
O OH;
The above reaction schemes are for purpose of illustration; it is within the skill of the art to utilize different sequences of the above reaction or to apply them to related compounds.
It is also within the scope of the present invention to prepare compounds of formula I bearing additional non-interfering groups on the aromatic ring. Such noninterfering groups include lower alkyl, halogen, hydroxy, lower alkoxy, nitro, sulfate and the like. Furthermore, compounds of formula I may contain asymmetric carbon atoms in the ethylene sidechain depending on secondary substitution or asymmetric centers in other places. Racemie mixtures as well as the optical enantiomers of such compounds are to be considered within the scope of this invention. Racemate pairs can be separated by conventional resolution procedures, such as, for example, fractional crystallization of diastcreomer salts formed with an optically active acid, i.c., tartaric acid, camphorsulfonic acid and the like. Chromatographic procedures for effecting such resolution are also known in the art.
The compounds of formula I of the present invention are useful in facilitating certain parameters of intellectual performance in the experimental animal and in man, such as, for example, the enhancement of learning and memory. Additionally, the compounds of formula I are useful as cholinergic and spasmolytic agents. These compounds can be administered for prolonged periods of time without producing undesirable side effects as determined by standard pharmacological evalnation.
The spasmolytic activity of the instant compounds can be demonstrated by the effect on the isolated ileum stimulated by such spasmogens as acetyl chloine, barium chloride and histamine. Using papaverine as a standard, the following table demonstrates the comparable activity found as a result of this test.
Spasmolytic Activity in the Isolated Rabbit ileum Both acquisition and memory retention appear improved in the experimental animal after treatment with the compounds of this invention. Standard avoidance response tests using negative reinforcement (electric shock) as well as maze tests using positive reinforcement (water reward) were conducted using rats as the experimental animal. Using m-[2-(benzylmethylamino )-ethyl]-benzoic acid methyl ester as the test compound, it was found that a compound of this structure facilitates the rats acquisition and increases subsequent retention.
The compounds of this invention not only exhibit the various activities hereinbefore described but moreover are of low toxicity and exhibit few undesirable side effects. For example, a preferred species of the invention m-[2-(benzylmethylamino)-ethyl]-benzoic acid methyl ester was found to have an oral LD of about 500-700 mg/kg in mice.
Reproduction studies have been carried out through two offspring generations and no evidence of malformation has been found after treatment with compounds of this invention. Additionally, pathological examination of brains, livers, and other organs of rats at termination of chronic toxicity studies revealed no evidence of pathological changes due to drug action. Tolerance studies have been carried out in the dog and monkey where the compounds of formula I were found well tolerated in doses as high as 50 mg/kg.
When utilized to enhance mental performance in higher mammals, the compounds of formula I may be administered in oral dosages in the range of from about 0.01 to about 4 mg/kg. preferably in the range of from about 0.01 to about 2 mg/kg, most preferably from about 0.05 to about l.2 mg/kg. Parenteral dosages of about to 100 times these levels are preferred in laboratory test animals.
The desired compounds of this invention are employed in the described uses in the form of nontoxic acid addition salts and may be administered to mammalians as pure compounds. It is advisable, however, to first combine one or more of the novel compounds with a suitable pharmaceutical carrier to attain a more satisfactory size to dosage relationship.
Pharmaceutical carriers which are liquid or solid may be used, the preferred liquid carrier being water in a pharmaceutically acceptable emulsion, suspension or solution. Flavoring materials may be included in the solutions as desired.
Solid pharmaceutical carriers such as starch, sugar, talc, mannitol and the like may be used to, form powders. The powders may be given directly or incorporated in tablet, capsule or suppository preparations.
EXAMPLE 1 A total of g. of N-benzyl-N-methyl-3- trifluoromethyl-phenethylamine hydrochloride was dissolved in 40 g. of concentrated sulfuric acid and the resultant solution was heated on a water bath for 3 hours. The reaction mixture was then cooled and combined with 50 ml. of methyl alcohol. This solution was refluxed for 3 hours at which time most of the excess methyl alcohol was removed by distillation. The residual mixture was cooled and poured slowly into 200 ml. of cold water. The acid aqueous solution was carefully made alkaline and extracted with ether. The ether extract was dried and anhydrous hydrochloric acid/ether was added. The crude hydrochloride salt precipitated and was recrystallized from methyl alcohol/ether and then from isoamyl alcohol/ether mixtures. A total of l 1.2 g. of white crystalline material consisting of m-[2- (benzylmethylamino)-ethyl]-benzoic acid methyl ester hydrochloride was obtained melting at l50-l5lC.
The hydrochloride salt was converted to the free base by addition of alkali hydroxide to the aqueous solution of the salt. The base was extracted with ether and the ether removed in vacuo.
Neut. Equiv., 283
Analysis:
Found:
The free benzoic acid derivative was obtained by hydrolysis of the hydrochloride salt of the ester with hydrochloric acid and after recrystallization there was obtained crude m-[2-(benzyl-methylamino)- ethyl]benzoic acid.
The starting material may be prepared as follows:
To a refluxing and vigorously stirred solution of the Grignard reagent prepared from 100 g. (0.444 moles) of m-trifluoromethylbromobenzene and 12 g. (0.5 moles) of magnesium in 400 ml. of anhydrous ether there was added an ether solution of 40 g. (0.89 mole) of ethylene oxide. Reflux was maintained by the exothermic reaction and continued after the addition was completed for four additional hours. The reaction mixture, after cooling, was decomposed by pouring into iced, diluted hydrochloric acid. The ether layer was separated, washed briefly, dried and distilled. The residue yielded 59 g. (65%)of 3-trifluoromethyl phenethyl alcohol, b.p. 7376C/0.4 mm.
To a refluxing mixture of g. (0.8 mole) of thionyl chloride in 300 ml. of chloroform and 0.5 g. of pyridine there was added dropwise with vigorous stirring l35 g. (0.71 mole) of 3-trifluoromethyl phenethyl alcohol. After the addition was completed reflux was continued for 2 hours. Excess thionyl chloride and hydrochloric acid was removed in vacuo. The chloroform solution was briefly washed with water, bicarbonate solution, and then water again. The organic layer was dried and distilled. Yield g. (95%) of 3-trifluoromethylphenethyl-chloride boiling at 98-l00 C/25 mm.
A mixture of 20 g. (0.1 mole) of 3-trifluoromethylphenethyl-chloride and 25 g. (0.2 mole) of benzylmethylamine was heated for 12 hours at l00C. Upon cooling, the reaction mixture was acidified with aqueous hydrochloric acid and extracted with ether. The ether soluble portion was cooled, made alkaline with alkali hydroxide and the liberated base extracted with ether. The ether extract was dried and distilled to yield N-benzyl-N-methyl-3-trifluoromethyl-phenethyl-amine as a colorless liquid. The yield was 24 g. (82%), b.p. l091l0C/0.3 mm.
Analysis: Calculated for C H F N: Neut. Equiv. 293 Found: Neut. Equiv. 204
EXAMPLE 2 In analogy to the procedure of Example 1, hydrolysis of Nbenzyl-N-methyl-3-trifluoromethylphenethylamine with sulfuric acid, followed by esterification with ethyl alcohol yielded m-[Z-(benzylmethylamino)-ethyl]benzoic acid ethyl ester. M.p. 1 l5l 17C.
Analysis: Calculated for C H NO Neut. Equiv. 297 Found: Neut. Equiv. 301
EXAMPLE 3 In analogous fashion to Example 1 N,N-diethyl-3- trifluoromethyl-phenethylamine was hydrolyzed with sulfuric acid followed by esterification with methyl alcohol to yield m-[Z-diethylamino)-ethyl]benzoic acid methyl ester. Conversion to the hydrochloride salt as above yielded product melting at l 16C.
Calculated for C H NO Neut. Equiv. 27l
Analysis:
Found: Neut. Equiv. 270
was
Analysis: Calculated for c H F Nz Neut. Equiv., 245 Found: Neut. Equiv., 242
EXAMPLE 4 Analysis: Calculated for C H ClNo Neut. Equiv., 304 Found: Neut. Equiv., 307
Conversion of the free base to the hydrochloride salt in the manner described in Example 1 yielded product melting at 228C.
The starting material may be prepared as follows:
A total of 8 g. (0.038 mole) of 3-trifluoromethylphenethylchloride and 6 g. (0.038 mole) of N-(pchlorophenyl)N-methylamine in 20 ml. of isopropyl alcohol containing 6 g. (0.043 mole) of potassium carbonate were reacted at 100C. for 14 hours. The reaction mixture was worked up in the manner analogous to that in Example 1. After distillation 4.7 g. (37.7%) of the free base of N-(p-chlorobenzyl)-N-methyl-3- trifluoromethyl-phenethylamine was obtained boiling at l32-l34C/0.5'mm.
Calculated for C,,H,,CIF;,N: Neut. Equiv., 328
Analysis:
Found: Neut. Equiv., 324
EXAMPLE Calculated for C ,,H NO Neut. Equiv., 234
Analysis:
Found: Neut. Equiv., 236
The starting material may be prepared as follows:
3-Trifluoromethyl-phenylmagnesium bromide and propylene oxide were reacted in analogous manner to that described in Example 1. The liquid a-methyl-3-trifluoromethyl-phenethyl alcohol obtained in 50% yield had a boiling point of 80C/1 mm.
To a refluxing mixture of 77.3 g. (0.65 mole) of thionyl chloride in 350 ml. of chloroform and 0.5 g. of pyridine there was added dropwise with vigorous stirring 120.4 g. (0.589 mole) of a-methyl-3-trifluoromethylphenethyl alcohol. After the addition was completed reflux was continued for 2 hours. Excess thionyl chloride and hydrochloric acid were removed in vacuo. The
chloroform solution was briefly washed with water, bicarbonate solution and water. It was dried and distilled to yield 110 g. (90%) of a-methyl-3-trifluoromethylphenethyl chloride boiling at 103l05C/25 mm.
EXAMPLE 6 By analogy to the procedures of Example 1 m-[(2- methyl)(2-benzylmethylamino)-ethyl]benzoic acid methyl ester was prepared by sulfuric acid hydrolysis and methanol esterification of N-benzyl-N-methyl-amethyl-3-trifluoromethyl phenethylamine.
The starting material may be prepared as follows:
By a procedure analogous to Example 1 a-methyl-3- trifluoromethyl-phenethylchloride was reacted with benzylmethylamine to yield N-benzyl-N-methylamethyl-3-trifluoromethyl phenethylamine boiling at ll5C/0.5 mm.
Analysis: Calculated for C H F N: Neut. Equiv., 307 Found: Neut. Equiv., 307
EXAMPLE 7 In analogy to the procedure of Example 1 3- trifluoromethyl-phenethyl-morpholine was hydrolyzed in sulfuric acid and esterified with methyl alcohol to produce m-(2-morpholinoethyl)-benzoic acid methyl ester. m.p. 207208C. (acetone).
Analysis: Calculated for C H NO Neut. Equiv., 249 Found: Neut. Equiv., 250
The starting material may be prepared as follows:
According to the procedure of Example 1 3- trifluoromethyl-phenethylchloride was reacted with morpholine to produce 3-trifluoromethyl-phenethyl morpholine in 84% yield, the pre-base product boiling at C/0.3 mm.
Analysis: Calculated for C H F N: Neut. Equiv., 247 Found: Neut. Equiv., 249
EXAMPLE 8 In analogy to the procedure of Example 1 m-(Z-piperidinoethyl)-benzoic acid methyl ester was prepared by the sulfuric acid hydrolysis and esterification with methyl alcohol of 3-trifluoromethylphenethylpiperidine.
Analysis: Calculated for C H NO Neut. Equiv., 247 Found: Neut. Equiv.. 25 1 Analysis: Calculated for C H F N: Neut. Equiv., 257 Found: Neut. Equiv., 260
EXAMPLE 12 In analogy to the procedure of Example 1 concentrated sulfuric acid hydrolysis of N-benzyl-N-ethyl-3- 5 trifluoromethylphenethylamine followed by esterification with methyl alcohol yielded m-[Z-(benzyle- EXAMPLE 9 thylamino)-ethyl]benzoic acid methyl ester. A mixture of 4 grams of m-[2-(benzylmethylamino)- ethyl]-benzoic acid methyl ester, 10 g. of npropylalcohol and 4 g. of concentrated sulfuric acid 10 was heated to reflux temperature. Workup in the nor- Analysls' Calculated for EfESj; 523:3: 33; mal manner yielded m-[2-(benzylmethylamino)- ethyl]benzoic acid n-propyl ester which when converted to the hydrochloride salt had a melting point of M.p. 125127C. (acetone). 108C. The starting material may be prepared as follows:
By the procedure described in Example 1 N'benzyl- N-ethyl-3-trifluoromethyl-phenethylamine was prei pared by the reaction between 3-trifluoromethyl- Analysls' Calculated for fiSg; phenethylchloride and benzylethylamine.
U EXAMPLE 13 Analogous to the procedure of Example 1 N-benzyl- N-(2-methoxyethyl)-3-trifluoromethyl- EXAMPLE l0 phenethylamine was hydrolyzed in concentrated sulfu- Reaction of 5 grams (0.0163 mole) of m-[2- ric acid followed by esterification with methyl alcohol (benzylmcthylamino)-ethyl]benzoic acid and 6 g. of to yield m-[2-(N-benzyl-N-(2-meth0xyethyl)amino)- thionyl chloride yielded the corresponding'crudeacid ethy1]benzoic acid methyl ester. chloride which was then further reacted without purification with 74 g. (1 mole) of t-butyl alcohol at reflux. Upon removal of the excess alcohol the free base of m- [2-(benzylmethylamino)-ethyl]benzoic acid t-butyl Analy Calculate? fifig; ester is obtained. Conversion to the hydrochloride in the previously described manner followed by recrystallization of the hydrochloride salt from acetone ether Th arting material may be prepared as follows: yielded the pure hydrochloride salt melting at 196C. A total 0f 10 g- H1016) 0f riflu0r me hylphenethylchloride was reacted with 16 g. (0.1 mole) of 2-methoxyethylbenzylamine for 12 hours at 110C. The reaction mixture was worked up in the manner de- I scribed in Example 1 and after distillation 7.9 g ws; #33:; 53353;; i833 40 (46.5%) of the free base of N-benzy|-N-(2 methoxyethyl)-3-trifluoromethyl-phenethylamine was obtained boiling at 120C/0.3 mm. EXAMPLE 11 By analogy to the procedure of Example 1 3- trifluoromethylphenethyl-N-methylpiperazine was hy- Analysis" Calculated gl lfil gl E233: drolyzed in concentrated sulfuric acid and esterified with methyl alcohol to yield m-[2-(N-methylpiperazino)-ethyl]benzoic acid methyl ester. M.P. 229-230C. EXAMPLE 14 In a manner analogous to Example 1 N-benzyl-N- methyl-B-methoxy-Sl-trifluoromethyl-phenethylamine was hydrolyzed with concentrated sulfuric acid fol- Amlys'sz Calculated for Q3 523:1; 52. lowed by esterification with methyl alcohol. The solution of-the product ester in acid of methanol was poured into an excess of ice cold water and the mixture The starting material may be prepared as follows: was rendered alkaline with sodium hydroxide. Utilizing the procedure of Example 1 3-trifluorome- The free base was extracted with ether and the exthylphenethyl chloride was reacted with N-methylpiptract dried over potassium carbonate and distilled. Diserazine to give N-methyl-N-(3-trifluoromethyl)- 6O tillation yielded m-[l-methoxy-Z-(benzylmephenethylpiperazine in 68% yield boiling at thylamino)-ethyl]benzoic acid methyl ester boiling at 89-90C/0.3 mm. l50C/0.3 mm.
Non! liquiv.. 313
Neut. Equiv., 272
Analysis:
Neut. Equiv., 275
Cnlculutcd for C H Fa I Found:
Analysis: Calculated l'or C H NO Found: Ncul Equiv., 3l6
The starting material may be prepared as follows:
In analogy to the procedure of Example 1 a mixture of 14 g. (0.05 mole) of ,B-methoxy-3-trifluoromethylphenethyl bromide and 13 g. (0.1 mole) of benzylmethylamine was reacted at 100C. for three hours. Distillation yielded N-benzyl-N-methyl-B-methoxy-3- trifluoromethyl-phenethylamine boiling at lOC/0.2 mm.
Analysis: Calculated for C l-l F NOz Neut. Equiv., 323 Found: Neut. Equiv., 325
EXAMPLE 15 In analogous manner to the procedure of Example 1 hydrolysis of N-benzyl-B-methoxy-3-trifluoromethyl phenethylamine with concentrated sulfuric acid followed by esterification with methyl alcohol yielded m- [l-methoxy-2-(benzylamino )-ethyl]benzoic acid methyl ester. Conversion to the hydrochloride salt yielded material melting at 243C.
Calculated for C H NO Neut. Equiv., 299
Analysis:
Found: Neut. Equiv., 302
The starting material may be prepared as follows:
In analogous fashion to the procedure of Example 1 a mixture of 25 g. (0.09 mole) of ,B-methoxy-3-trifluoromethylphenethyl bromide was reacted with 19 g. (0.18 mole) of benzylamine at 100C. for 3 hours. Distillation yielded N-benzylB-methoxy-3;trifluoromethylphenethylamine boiling at l37C/0.3 mm.
1. Mix the m-[2-(benzylmethylamino)ethyl]benzoic acid methyl ester hydrochloride, lactose and corn starch in a suitable mixing container and add the starch paste slowly to achieve a heavy, moist mass.
2. Pass this moist mass through a No. mesh screen (or similar suitable coarse screen).
3. Place the moist granules on drying pans and dry at 1 10F.
4. Pass the dried granules through a No. 16 mesh screen, place in a suitable mixing container and add the talcum, magnesium stearate, and second portion of corn starch.
5. Mix well and compress into tablets on either a single or multiple tabletting machine to an individual tablet weight of 200 mgs. An 11/32 inch standard concave scored punch is suitable, yielding tablets with a thickness of approximately 3.35 mm.
EXAMPLE 17 Tablet Formulation A prehydrolyzed food grade corn starch. Any similar prehydrolyzed corn starch may be used.
Procedure:
1. m-[2-(benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride, lactose, corn starch, and Amijel BOll were blended in a suitable mixer.
2. The mixture was granulated to a heavy paste with water and the moist mass was passed through a N o. 12 screen. It was then dried overnight at F.
3. The dried granules were passed through a No. 16 screen and transferred to a suitable mixer. The calcium stearate was added and mixed until uniform.
4. The mixture was compressed at a tablet weight of 410 mg. using tablet punches having a diameter of approximately inch. (Tablets may be either flat or biconvex and may be scored if desired.)
EXAMPLE l8 Capsule Formulation Per Capsule m-[2-(Benzylmethylamino)-ethyllbenzoic acid methyl ester hydrochloride 5 mg.
Lactose 178 mg. Corn Starch 37 mg. Tale 5 mg.
Total Weight 225 mg.
Procedure:
EXAMPLE 19 Capsule Formulation Per Capsule m-l2-(Benzylmethylamino)-ethyllhenzoic acid 1. m-[2-(Benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride was mixed with lactose and corn starch in a suitable mixer.
2. The mixture was further blended by passing through a Fitzpatrick Comminuting Machine with a No. 1A screen with knives forward. '7
3. The blended powder was returned to the mixer, the talc added and blended thoroughly.
4. The mixture was filled into No. 4 hard shell gelatin capsules on a Parke Davis capsulating machine.
EXAMPLE 20 Analogous to the procedure of Example 9, m-[2- (benzylamino)-ethyl]-benzoic acid methyl ester was transesterified with benzyl alcohol in the presence of concentrated sulfuric acid. After workup in the usual manner and conversion to the hydrochloride salt, the product m-[2-(benzylamino)-ethyl]benzoic acid benzyl ester hydrochloride was obtained, m.p. 153155C.
EXAMPLE 21 By analogy to the procedure of Example 1 N-methyl- 3-trifluoromethyl phenethylamine was hydrolyzed and then esterified with m-cresol followed by conversion to the hydrochloride to yield m-[2-(methy1amino)- ethyllbenzoic acid, m-cresyl ester hydrochloride melting at 162C.
Analysis: Calculated for C H NO Neut. Equiv., 269 Found: Neut. Equiv., 272
The starting material may be prepared as follows:
In analogy to the procedure of Example 1, trifluoromethylphenethyl chloride was reacted with anhydrous monomethylamine in methanol in a pressure bottle for four hours at 1 C. Isolation in the usual manner yielded N-methyl-3-trifluoromethylphenethylamine boiling at 94-96C/40 mm.
Calculated for C H F N: Neut. Equiv., 203
Analysis:
Found: Neut. Equiv., 197
Conversion to the hydrochloride in the usual manner yielded the salt melting at l46-147C.
EXAMPLE 22 In analogy to the procedure of Example 1, 3 trifluoromethylphenethyl pyrrolidine was hydrolyzed, esterified with methyl alcohol, and converted to the hydrochloride to yield m-(2-pyrro1idinoethy1)-benzoic acid methyl ester hydrochloride melting at 188-189C.
Analysis: Calculated for C H NO Neut. Equiv., 223 Found: Neut. Equiv., 223
The starting material may be prepared inanalogy to the method of Example 1 wherein 3-trifluoromethy1- phenethyl chloride was reacted with pyrrolidine to produce 3-trifluoromethy1phenethyl pyrrolidine in 51% yield as a liquid boiling at l17C./30 mm.
Analysis: Calculated for C H F Nz Neut. Equiv., 243 Found: Neut. Equiv., 244
EXAMPLE 23 In analogy to the procedure of Example 1, 3- trifluoromethylphenethyl-p-toluidene was hydrolyzed with concentrated sulfuric acid and esterified with methyl alcohol followed by conversion to the hydrochloride to yield m-2-(p-toluidinoethyl)-benzoic acid methyl ester hydrochloride, melting at 156157C.
Analysis: Calculated for C H NO N. 4.58 Found: N. 4.45
The starting material may be prepared as follows:
B-Trifluoromethylphenethyl chloride and p-toluidine were reacted in analogy to the procedure in Example 1 to yield 3-trifluoromethylphenethyl-p-toluidine boiling at l47C./1.8 mm.
Analysis: Calculated for C H F Nz N. 4.45 I Found: N. 4.25.
Conversion to the hydrochloride in the usual manner yielded the corresponding hydrochloride salt melting at 162-l63C.
EXAMPLE 24 In analogy to the procedure of Example 1, N-methyl- N-Z-hydroxy ethyl-B-hydroxy-a-methyl-3-trifluoromethylphenethylamine was hydrolyzed with concentrated sulfuric acid and esterified with methyl alcohol followed by conversion to the hydrochloride to yield m-2- (N-methyI-N-Z-hydroxyethyl)amino-B-hydroxy-amethyl-benzoic acid, methyl ester hydrochloride, melting at 206207C.
Analysis: Calculated for C,.,H ,NO .HCl: N. 4.62 Found: N. 4.37
Calculated for CI: 11.3 Found: 1 1.1
EXAMPLE 25 A total of 3.0 g. of m-2-cyclohexylaminoethylbenzoic acid methyl ester hydrochloride was added to 20 ml. of methanol and there was thereafter added 1.15
Analysis: Calculated for C H NO Neut. Equiv., 331 Found: Neut. Equiv., 331
The starting material may be prepared as follows:
In analogy to the procedure of Example 1, 3-trifiuoromethylphenethyl chloride was reacted with cyclohexylamine to yield 3-trifluoromethylphenethyl cyclohexylamine boiling at ll6C./l.1 mm.
Analysis: Calculated for C, H F;,N: Neut. Equiv., 271 Found: Neut. Equiv., 270
Hydrolysis of 3-trifluoromethylphenethyl cyclohexylamine in analogy to the procedure of Example 1 with concentrated sulfuric acid followed by esterification with methyl alcohol and conversion to the hydrochloride yielded m-(2-cyclohexylamino)-ethyl benzoic acid methyl ester hydrochloride, melting at 2l0-2l 1C.
Analysis: Calculated for C H NO Neut. Equiv., 261 Found: Neut. Equiv., 262
I claim: 1. A compound of the formula 1|; H R. -t N R1 2 Rs wherein R is hydrogen, hydroxy, lower alkoxy or lower alkyl; R is hydrogen or lower alkyl; R is lower alkyl, aralkyl or lower alkyl aryl; R taken independently is hydrogen, lower alkyl, aralkyl, lower alkyl aryl, hydroxy lower alkyl and lower alkoxy lower alkyl; R taken independently is lower alkyl, aralkyl, lower alkyl aryl or lower alkoxy lower alkyl; and R and R taken together with the adjacent nitrogen atom form a saturated five or six membered heterocyclic ring which may contain one additional hetero atom selected from the group consisting of O and NR where R is hydrogen or lower alkyl and the optical antipodes and the pharmaceutically acceptable acid addition salts thereof.
2. The compound of claim 1 wherein R and R both are hydrogen and R is lower alkyl.
3. The compound of claim 2 which is m-[2- (benzylmethylamino)-ethyl]benzoic acid methyl ester.
4. The compound of claim 2 which is m-[2- (benzylmethylamino)-ethyl]benzoic acid ethyl ester.
5. The compound of claim 2 which is m-[2- morpholino-ethyl)-benzoic]acid methyl ester.
6. The compound of claim 2 which is m-[2-(N- methylpiperazino)ethyl]benzoic acid methyl ester.
7. The compound of claim 2 which is m-(2-piperidinoethyl)-benzoic acid methyl ester.
8. The compound of claim 2 which is m-[2-(benzylethylamino)-ethyl]benzoic acid methyl ester.
9. The compound of claim 2 which is m-(2- diethylaminoethyl)-benzoic acid methyl ester.
10. The compound of claim 2 which is m-[Z- (methylisopropylamino)-ethyl]benzoic acid methyl ester.
11. The compound of claim 2 which is m-[2- (bentylmethylamino)-ethyl]benzoic acidn-propyl ester.
12. The compound of claim 2 which is m-[2- (benzylmethylamino)-ethyl]benzoic acid t-butyl ester.
13. The compound of claim 2 which is m-[Z-(N- benzyl-N-(Z-methoxyethyl)amino)-ethyl]benzoic acid methyl ester.
14. The compound of claim 1 wherein R is hydrogen and R and R are lower alkyl.
15. The compound of claim 14 which is m-[(2- methyl)(2-isopropylamino)-ethyllbenzoic acid methyl ester.
16. The compound of claim 14 which is m-[(2- methyl)(2-benzylmethylamino)-ethyl]benzoic acid methyl ester.
17. The compound of claim 1 wherein R is lower alkoxy, R is hydrogen and R is lower alkyl.
18. The compound of claim 17 which is m-[lmethoxy-2-(benzylmethylamino)ethyl]benzoic acid methyl ester.
19. The compound of claim 17 which is m-[lmethoxy-2-(benzylamino)-ethyl]benzoic acid methyl ester.
Claims (19)
1. A COMPOUND OF THE FORMULA
1. A compound of the formula
2. The compound of claim 1 wherein R1 and R2 both are hydrogen and R3 is lower alkyl.
3. The compound of claim 2 which is m-(2-(benzylmethylamino)-ethyl)benzoic acid methyl ester.
4. The compound of claim 2 which is m-(2-(benzylmethylamino)-ethyl)benzoic acid ethyl ester.
5. The compound of claim 2 which is m-(2-morpholino-ethyl)-benzoic)acid methyl ester.
6. The compound of claim 2 which is m-(2-(N-methylpiperazino)ethyl)benzoic acid methyl ester.
7. The compound of claim 2 which is m-(2-piperidinoethyl)-benzoic acid methyl ester.
8. The compound of claim 2 which is m-(2-(benzylethylamino)-ethyl)benzoic acid methyl ester.
9. The compound of claim 2 which is m-(2-diethylaminoethyl)-benzoic acid methyl ester.
10. The compound of claim 2 which is m-(2-(methylisopropylamino)-ethyl)benzoic acid methyl ester.
11. The compound of claim 2 which is m-(2-(benzylmethylamino)-ethyl)-benzoic acid n-propyl ester.
12. The compound of claim 2 which is m-(2-(benzylmethylamino)-ethyl)benzoic acid t-butyl ester.
13. The compound of claim 2 which is m-(2-(N-benzyl-N-(2-methoxyethyl)amino)-ethyl)benzoic acid methyl ester.
14. The compound of claim 1 wherein R1 is hydrogen and R2 and R3 are lower alkyl.
15. The compound of claim 14 which is m-((2-methyl)(2-isopropylamino)-ethyl)benzoic acid methyl ester.
16. The compound of claim 14 which is m-((2-methyl)(2-benzylmethylamino)-ethyl)benzoic acid methyl ester.
17. The compound of claim 1 wherein R1 is lower alkoxy, R2 is hydrogen and R3 is lower alkyl.
18. The compound of claim 17 which is m-(1-methoxy-2-(benzylmethylamino)ethyl)benzoic acid methyl ester.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US347287A US3870715A (en) | 1972-03-09 | 1973-04-02 | Substituted amino ethyl meta benzoic acid esters |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US23333972A | 1972-03-09 | 1972-03-09 | |
US347287A US3870715A (en) | 1972-03-09 | 1973-04-02 | Substituted amino ethyl meta benzoic acid esters |
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Publication Number | Publication Date |
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US3870715A true US3870715A (en) | 1975-03-11 |
Family
ID=26926826
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Application Number | Title | Priority Date | Filing Date |
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US347287A Expired - Lifetime US3870715A (en) | 1972-03-09 | 1973-04-02 | Substituted amino ethyl meta benzoic acid esters |
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Country | Link |
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US (1) | US3870715A (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4182775A (en) * | 1976-09-04 | 1980-01-08 | Hoechst Aktiengesellschaft | Benzoic acids and process for their preparation |
US4654371A (en) * | 1978-06-28 | 1987-03-31 | Beecham Group P.L.C. | Secondary amines, their preparation and use in pharmaceutical compositions |
US4690931A (en) * | 1982-10-13 | 1987-09-01 | Synthelabo | Therapeutically useful 1-phenyl-2-piperidinoalkanol derivatives |
US4754047A (en) * | 1979-08-16 | 1988-06-28 | American Cyanamid Company | Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and/or improving the efficiency of feed utilization thereby |
US4845127A (en) * | 1978-07-03 | 1989-07-04 | Eli Lilly And Company | Phenethanolamines, compositions containing the same and method for effecting weight control |
EP2389187A4 (en) * | 2009-01-20 | 2013-12-04 | Los Angeles Biomed Res Inst | SORBIC AND BENZOIC ACID AND DERIVATIVES THEREOF FOR ENHANCING THE ACTIVITY OF A NEUROPHARMACEUTICAL PRODUCT |
US10098861B1 (en) | 2017-10-24 | 2018-10-16 | Syneurx International (Taiwan) Corp. | Pharmaceutical composition comprising sodium benzoate compound and clozapine, and uses thereof |
US10336679B2 (en) | 2016-10-24 | 2019-07-02 | Syneurx International (Taiwan) Corp. | Polymorphic forms of sodium benzoate and uses thereof |
US11369579B2 (en) | 2016-10-24 | 2022-06-28 | Syneurx International (Taiwan) Corp. | Polymorphic forms of sodium benzoate and uses thereof |
US11731928B2 (en) | 2016-06-13 | 2023-08-22 | Syneurx International (Taiwan) Corp. | Co-crystals of sodium benzoate and uses thereof |
US11739046B2 (en) | 2016-06-13 | 2023-08-29 | Syneurx International (Taiwan) Corp. | Co-crystals of lithium benzoate and uses thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE631855C (en) * | 1934-07-26 | 1936-06-29 | I G Farbenindustrie Akt Ges | Process for the preparation of N- (aminoalkyl) -anthranilic acid alkyl esters |
DE1074052B (en) * | 1960-01-28 | Zyma S A Nyon Waadt (Schweiz) | Process for the preparation of the locally active m - (2 diethylamino ethoxy) benzoic acid ethyl ester |
-
1973
- 1973-04-02 US US347287A patent/US3870715A/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1074052B (en) * | 1960-01-28 | Zyma S A Nyon Waadt (Schweiz) | Process for the preparation of the locally active m - (2 diethylamino ethoxy) benzoic acid ethyl ester | |
DE631855C (en) * | 1934-07-26 | 1936-06-29 | I G Farbenindustrie Akt Ges | Process for the preparation of N- (aminoalkyl) -anthranilic acid alkyl esters |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4182775A (en) * | 1976-09-04 | 1980-01-08 | Hoechst Aktiengesellschaft | Benzoic acids and process for their preparation |
US4654371A (en) * | 1978-06-28 | 1987-03-31 | Beecham Group P.L.C. | Secondary amines, their preparation and use in pharmaceutical compositions |
US4753962A (en) * | 1978-06-28 | 1988-06-28 | Beecham Group P.L.C. | Secondary amines, their preparation and use in pharmaceutical compositions |
US4845127A (en) * | 1978-07-03 | 1989-07-04 | Eli Lilly And Company | Phenethanolamines, compositions containing the same and method for effecting weight control |
US4754047A (en) * | 1979-08-16 | 1988-06-28 | American Cyanamid Company | Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and/or improving the efficiency of feed utilization thereby |
US4690931A (en) * | 1982-10-13 | 1987-09-01 | Synthelabo | Therapeutically useful 1-phenyl-2-piperidinoalkanol derivatives |
US9675604B2 (en) | 2009-01-20 | 2017-06-13 | Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center | Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical |
US9649304B2 (en) | 2009-01-20 | 2017-05-16 | Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center | Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical |
EP2389187A4 (en) * | 2009-01-20 | 2013-12-04 | Los Angeles Biomed Res Inst | SORBIC AND BENZOIC ACID AND DERIVATIVES THEREOF FOR ENHANCING THE ACTIVITY OF A NEUROPHARMACEUTICAL PRODUCT |
US10039730B2 (en) | 2009-01-20 | 2018-08-07 | Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center | Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical |
US10149845B2 (en) | 2009-01-20 | 2018-12-11 | Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center | Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical |
US11529342B2 (en) | 2009-01-20 | 2022-12-20 | Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center | Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical |
US11731928B2 (en) | 2016-06-13 | 2023-08-22 | Syneurx International (Taiwan) Corp. | Co-crystals of sodium benzoate and uses thereof |
US11739046B2 (en) | 2016-06-13 | 2023-08-29 | Syneurx International (Taiwan) Corp. | Co-crystals of lithium benzoate and uses thereof |
US10336679B2 (en) | 2016-10-24 | 2019-07-02 | Syneurx International (Taiwan) Corp. | Polymorphic forms of sodium benzoate and uses thereof |
US11369579B2 (en) | 2016-10-24 | 2022-06-28 | Syneurx International (Taiwan) Corp. | Polymorphic forms of sodium benzoate and uses thereof |
US10098861B1 (en) | 2017-10-24 | 2018-10-16 | Syneurx International (Taiwan) Corp. | Pharmaceutical composition comprising sodium benzoate compound and clozapine, and uses thereof |
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