US3360435A - Treatment of depressed states - Google Patents
Treatment of depressed states Download PDFInfo
- Publication number
- US3360435A US3360435A US457837A US45783765A US3360435A US 3360435 A US3360435 A US 3360435A US 457837 A US457837 A US 457837A US 45783765 A US45783765 A US 45783765A US 3360435 A US3360435 A US 3360435A
- Authority
- US
- United States
- Prior art keywords
- phenylindene
- dimethylaminoethyl
- hydrochloride
- reserpine
- ethyl
- 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
Links
- 208000020401 Depressive disease Diseases 0.000 title 1
- 238000000034 method Methods 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 11
- 230000001430 anti-depressive effect Effects 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 230000000994 depressogenic effect Effects 0.000 claims description 5
- 230000037396 body weight Effects 0.000 claims description 4
- KAQPNQMPHIRKJJ-UHFFFAOYSA-N n,n-dimethyl-2-(1-phenylinden-1-yl)ethanamine Chemical compound C1=CC2=CC=CC=C2C1(CCN(C)C)C1=CC=CC=C1 KAQPNQMPHIRKJJ-UHFFFAOYSA-N 0.000 claims description 2
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 16
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 13
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 13
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 13
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 13
- 229960003147 reserpine Drugs 0.000 description 13
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000000935 antidepressant agent Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 229940005513 antidepressants Drugs 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- ILASZRLOZFHWOJ-UHFFFAOYSA-N 3-phenyl-1h-indene Chemical compound C12=CC=CC=C2CC=C1C1=CC=CC=C1 ILASZRLOZFHWOJ-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- -1 2-dimethylaminoethyl halide Chemical class 0.000 description 5
- 206010015995 Eyelid ptosis Diseases 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- HUGLAQUJRPXQOX-UHFFFAOYSA-N n-methyl-2-(1-phenylinden-1-yl)ethanamine Chemical compound C1=CC2=CC=CC=C2C1(CCNC)C1=CC=CC=C1 HUGLAQUJRPXQOX-UHFFFAOYSA-N 0.000 description 5
- 201000003004 ptosis Diseases 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 230000000144 pharmacologic effect Effects 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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000000891 anti-reserpine Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000003368 psychostimulant agent Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 229940025084 amphetamine Drugs 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229960002887 deanol Drugs 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 230000017858 demethylation Effects 0.000 description 2
- 238000010520 demethylation reaction Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 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
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- VYKJMAKWRQRTHX-UHFFFAOYSA-N 1-phenyl-1H-indene hydrochloride Chemical compound Cl.C1(=CC=CC=C1)C1C=CC2=CC=CC=C12 VYKJMAKWRQRTHX-UHFFFAOYSA-N 0.000 description 1
- PXORBAGTGTXORO-UHFFFAOYSA-N 1-phenyl-1h-indene Chemical compound C1=CC2=CC=CC=C2C1C1=CC=CC=C1 PXORBAGTGTXORO-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010021113 Hypothermia Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 206010027646 Miosis Diseases 0.000 description 1
- 208000006550 Mydriasis Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 206010039424 Salivary hypersecretion Diseases 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
- 229920002253 Tannate Polymers 0.000 description 1
- XLUXHEZIGIDTCC-UHFFFAOYSA-N acetonitrile;ethyl acetate Chemical compound CC#N.CCOC(C)=O XLUXHEZIGIDTCC-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000036626 alertness Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003874 central nervous system depressant Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000002635 electroconvulsive therapy Methods 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- ZQDWYQDJDCIFKC-UHFFFAOYSA-N methanesulfonic acid;phosphoric acid Chemical compound CS(O)(=O)=O.OP(O)(O)=O ZQDWYQDJDCIFKC-UHFFFAOYSA-N 0.000 description 1
- 230000003547 miosis Effects 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- ZTCKJGNZNKVHOJ-UHFFFAOYSA-N n,n-dimethyl-2-(1-phenylinden-1-yl)ethanamine;hydrochloride Chemical compound Cl.C1=CC2=CC=CC=C2C1(CCN(C)C)C1=CC=CC=C1 ZTCKJGNZNKVHOJ-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- PCQXINPAZOWYGC-UHFFFAOYSA-N n-methyl-2-(1-phenylinden-1-yl)ethanamine;hydrochloride Chemical compound Cl.C1=CC2=CC=CC=C2C1(CCNC)C1=CC=CC=C1 PCQXINPAZOWYGC-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000026451 salivation Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HWEXKRHYVOGVDA-UHFFFAOYSA-M sodium;3-trimethylsilylpropane-1-sulfonate Chemical compound [Na+].C[Si](C)(C)CCCS([O-])(=O)=O HWEXKRHYVOGVDA-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
- F16B—DEVICES FOR FASTENING OR SECURING CONSTRUCTIONAL ELEMENTS OR MACHINE PARTS TOGETHER, e.g. NAILS, BOLTS, CIRCLIPS, CLAMPS, CLIPS OR WEDGES; JOINTS OR JOINTING
- F16B12/00—Jointing of furniture or the like, e.g. hidden from exterior
- F16B12/44—Leg joints; Corner joints
- F16B12/48—Non-metal leg connections
Definitions
- reserpine antagonism tests The measurement of antidepressant effects in the laboratory is accomplished by means of a group of tests referred to generally as reserpine antagonism tests.
- One of the effects of reserpine on which its pharmacologic use is based is its ability to induce a depressed state.
- concomitant pharmacologic or physiologic effects are exerted, including hypothermia, ptosis, and miosis.
- Antidepressant drugs such as imipramine and amitriptyline have the capacity to prevent these physiological effects.
- a predetermined dose of test compound is administered orally to each mouse of several groups of test mice.
- reserpine 2.0 mg./kg.
- ptosis is measured by placing each mouse on a platform away from light and estimating the extent of closure of the palpebral fissure.
- Ptosis is significant if the opening is not greater than 50% of normal.
- the reserpine effect is significantly modified if the palpebral opening is greater than 50% of normal.
- the reduction of rectal temperature following reserpine is used as a parameter. Reserpine alone produces a significant reduction of rectal temperature in mice. Antidepresant drugs will prevent this effect.
- Antidepressant drugs can be distinguished from psychostimulan-t drugs such as amphetamine by reversing the order of administration in the above test. That is, by administering reserpine first followed by the test drug, the extent of reversal of reserpine effect can be determined.
- Psychostimulants characteristically have the ability to reverse the reserpine effects, while the antidepressants do not. That is, the antidepressants will prevent but not reverse the reserpiue effects in mice.
- the above tests are conducted according to accepted pharmacological technique, by administering various doses of drug-s to groups of test animals and then conexhibits an ED value of 10 mg./-kg., while I-(Z-dimethylaminoethyl) l-phenylindene hydrochloride exhibits ED value for the prevention of reserpine ptosis in mice administration of I-(Z-dimethylaminoethyl) l-phenylindene hydrochloride elicits a truly outstanding antireserpine effect in animals characterizing the material as an antidepressant agent.
- PREPARATION 1-(2-dimethylaminoethyl) l-phenylindene is prepared from 3-phenylindene by alkylation thereof with a 2-dimethylaminoethyl halide such as the bromide, chloride or iodide or other alkylating agent capable of introducing the Z-dime-thylaminoethyl group.
- a 2-dimethylaminoethyl halide such as the bromide, chloride or iodide or other alkylating agent capable of introducing the Z-dime-thylaminoethyl group.
- alkylating agent is a reactive ester of Z-dimethylaminoethanol such as the ester with p-toluenesulfonic acid.
- the alkylation of 3-phenylindene with a Z-dimethylaminoethyl halide or other reactive ester of Z-dimethylaminoethanol is conducted on an alkali metal salt of3- phenylindene.
- the intermediate alkali metal salt is prepared by reaction of 3-phenylindene with a strong base such as sodium amide, sodium hydride, lithium amide, butyl lithium, sodium triphenylmethyl, or others.
- the alkali metal salt of 3-phenylindene is preferably prepared in situ and allowed to react with the Z-dimethylaminoethyl halide without isolation. For this reason, the alkali metal base employed for salt formation may be looked upon simply as a condensing agent for the reaction between 3-phenylindene and Z-dimethylarninoethyl halide.
- the mixture may contain dialkylated products as well.
- This mixture of products can be separated by conventional methods, including distillation and fractional crystallization of acid addition salts thereof from appropriate solvents and solvent mixtures.
- the individal pure products can then be unequivocally identified by interpretation of their nuclear magnetic resonance spectra.
- Compound I is one of the active agents used in the antidepressant process of the present invention.
- Compound II is substantially inactive.
- Compound II may exist as an isomer or mixture of isomers where the double bond is in either the 1,2-position or in the 2,3-position, as is indicated by the dotted line and double headed arrow in the above formula.
- PROCEDURE 3-phenylindene 76.8 g., is dissolved in 150 ml. of ether and treated with 0.4 mole of freshly prepared butyl lithium solution while protected from atmospheric moisture by dry nitrogen gas. A temperature of 20-30" C. is maintained during the addition of the butyl lithium solution, after which the solution is refluxed for /2 hour.
- the reaction mixture is then diluted with 200 ml. of ether and added to a solution of 0.5 mole of fl-dimethylaminoethyl chloride in 100 ml. of ether.
- a further reflux period of 2 hours is then commenced, after which the reaction mixture is allowed to cool and then extracted with 200 ml. of 6N-hydrochloric acid.
- the aqueous layer is separated, basified, and extracted with ether.
- the ether extracts are dried, the solvent removed by distillation, and the residue distilled in vacuo, B.P. l54163/0.2 mm., 11 1.5906,
- the pure free base 1-(Z-dimethylaminoethyl)-1-phenylindene may be obtained by treatment of the pure hydrochloride salt having the physical constants listed above with a solution of a strong alkali such as aqueous sodium hydroxide.
- the pure free base obtained in this fashion has the following properties:
- Any desired pharmaceutically acceptable acid addition salt may be obtained by direct neutralization of the free base with the appropriate acid. Purification of the free base to the extent referred to above is not necessary for this purpose. If a crude form of the base is employed, care should be taken to characterize the salt formed therefrom, for instance, by nuclear magnetic resonance studies, as having the structure of Compound I.
- Pharmaceutically acceptable acid addition salts are those in which the anion does not contribute significant toxicity to the salt in the dosages thereof employed in accordance with the present invention.
- suitable salts are the acetate, propionate, butyrate, pamoate, tannate, mucate, citrate, malate, tosylate, mesylate phosphate, nitrate, sulfate, hydrobromide, hydroiodide, hydrochloride, etc.
- the hydrochloride salt described above is soluble in water at room temperature to the extent of by weight. It is also soluble in ethanol and in warm isopropanel from which it crystallizes on cooling. It is stable in aqueous solution.
- the 1-[2-(methylamino)ethyl] 1 phenylindene may be prepared from Compound I by demethylation with alkyl haloformate followed by hydrolysis and decarboxylation as shown in the following equation:
- the demethylation step proceeds best at temperatures of from to 150 C.
- the 1-[2-(methylamino)ethyl]-l-phenyl indene may be prepared by reacting the l-phenyl indene salt with a N-(2-haloethyl)-N-rnethyl carbamic acid ester of the formula where X and R are as above defined to produce Compound III directly as above shown.
- the further steps of hydrolysis and decarboxylation are as in the above equation and in the procedure following.
- the benzene layer is then dried over potassium carbonate, the drying agent removed, and the solvent evaporated in vacuo.
- the residual 1-[2-(N-carbethoxy-N-methyl) aminoethyl1-1-phenylindene is then refluxed for 10 hours with a solution of 6 g. of potassium hydroxide in 25 ml. of aqueous ethanol.
- the reaction mixture is cooled, diluted with benzene, and extracted with three 5 ml. portions of water.
- the mixture is dried over potassium carbonate, and the product recovered from the extract by evaporation as before.
- the residue is dissolved in ether and treated with hydrogen chloride, resulting in precipitation of the desired product.
- This material is recrystallized first from an ethylacetate-acetonitrile mixture, and then from acetone, M.P. 176-178 C.
- Infrared absorption maxima are observed at the following wave lengths: 3030; 2930; 2760; 2428; 1588; 8; 790, 769, 754, 732 and 699 cmf
- DOSAGE Toxicity studies were conducted in mice of the Swiss- W ebster strain weighing 18 to 25 g. and treated orally with 10 mL/kg. of body weight of an aqueous solution 75 containing varying doses of 1-(Z-dimethylaminoethyl)-1- phenyl-l-indene hydrochloride at a pH of 4.0-5.5 by intubation. The animals were observed for signs of side effects and the number of deaths occurring within 24 hours was recorded. Dose response curves Were prepared.
- the dose eliciting detectable side effect in 50% of the animals was found to be 14 mg./kg. and the dose resulting in death of 50% of the animals (LD was found to be 84 mg./ kg.
- Side effects observed included hype activity, increased respiratory depth, and ataxia.
- the intraperitonea l LD in the mouse is 52.5 mg./kg.
- the oral LD in the rat is 385 mg./kg.
- the intravenous LD in the dog is estimated to be about 30 mg./kg.
- the effective antidepressant dosage range for l-(2-dimethylaminoethyl) 1 phenylindene hydrochloride and l- [2- (methylamino) ethyl] -1-phenylindene hydrochloride in the process of the present invention is from about 0.1 mg. to about 5 mg./kg. of body weight of the animal being treated.
- no side effects such as mydriasis, lack of salivation, or other side effects which are frequently manifested by the secondary pharmacologic properties of prior antidepressant drugs are observed.
- Dosage according to the present invention may be by either the oral or parenteral routes. In the ordinary case, the oral route is preferred as a matter of convenience, but occasionally when this method of dosage cannot be accomplished due to idiosyncrasy, parenteral administration is satisfactory and preferred.
- Solution for injection A sterile aqueous solution having a concentration of 25 mg./m1. of l-(2-dimethylaminoethyl)-1-phenylindene hydrochloride is prepared by dissolving 25 g. of the substance in 9 l. of water for injection, U.S.P., adjusting to pH 5.5 with dilute aqueous sodium hydroxide, and dilution to 10 1. This solution is then filtered sparkling clear and filled into 2 ml. glass ampoules and sealed. The ampoules are then sterilized by heating.
- Capsules-A dry blend of 5.0 g. of 1-(2-dimethylaminoethyl)-1-phenylindene hydrochloride, 19.8 g. of lactose, and 0.2 g. of magnesium stearate is prepared. This mixture is then employed to fill No. 2 hard gelatin capsules, each with 250 mg. of the blend.
- the process of eliciting an antidepressant effect in a host subject to a depressed condition which comprises administering to said host a dose of from 0.1 to 5 rug/kg. of body weight of said host of a compound selected from the group consisting of l-(2-dimethylaminoethyl)-1-phenylindene, 1-[2-(methyla1mino)ethyl]-1- pbenylidene and the pharmaceutically acceptable acid addition salts thereof.
Landscapes
- Health & Medical Sciences (AREA)
- General Engineering & Computer Science (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Mechanical Engineering (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US457837A US3360435A (en) | 1964-09-15 | 1965-05-21 | Treatment of depressed states |
GB28248/65A GB1041989A (en) | 1964-09-15 | 1965-07-02 | A process of preparing 1-(2-dimethylaminoethyl)-1-phenylindene and 1-[2-(methylamino) ethyl]-1-phenylindene |
IL23869A IL23869A (en) | 1964-09-15 | 1965-07-02 | 1 -) 2 - Dimethylaminoethyl (- 1 - phenylindene and 1 -] 2 -) methyl - amino (ethyl [- 1 - phenylindene |
ES0315465A ES315465A1 (es) | 1964-09-15 | 1965-07-17 | Un procedimiento para preparar compuestos con propiedades estimulantes del sistema nervioso. |
SE9813/65A SE322770B (de) | 1964-09-15 | 1965-07-26 | |
DE19651543216 DE1543216B1 (de) | 1964-09-15 | 1965-07-27 | Verfahren zur Herstellung von 1-(2'-Dimethylaminoaethyl)-1-phenylinden und 1-(2'-Methylaminoaethyl)-1-phenylinden |
BR171638/65A BR6571638D0 (pt) | 1964-09-15 | 1965-07-28 | Um processo para preparar 1-(2-dimetil-amino-etil) 1-fenil indeno e 1-(2-metil amino eti1)-1-fenil-indeno |
CH1068665A CH463486A (de) | 1964-09-15 | 1965-07-29 | Verfahren zur Herstellung von 1-(2-Dimethyl-aminoäthyl)-1-phenylinden |
CH1114968A CH473760A (de) | 1964-09-15 | 1965-07-29 | Verfahren zur Herstellung von 1-(2-Methylaminoäthyl)-1-phenylinden |
AT707165A AT267511B (de) | 1965-05-21 | 1965-07-30 | Verfahren zur Herstellung neuer 1-Phenyl-1-(2'-aminoäthyl)-indene und ihrer Salze |
BE667739D BE667739A (de) | 1964-09-15 | 1965-07-30 | |
NL6509895A NL6509895A (de) | 1964-09-15 | 1965-07-30 | |
FR26747A FR4646M (de) | 1964-09-15 | 1965-07-30 | |
FR26746A FR1482826A (fr) | 1964-09-15 | 1965-07-30 | Procédé de préparation des composés du groupe comprenant le 1-(2-diméthylaminoéthyl)-1-phénylindène, le 1-[2-(méthylamino)-éthyl]-1-phénylindène et leurs sels d'addition d'acides |
SE08871/68A SE332171B (de) | 1964-09-15 | 1968-06-28 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US39767364A | 1964-09-15 | 1964-09-15 | |
US457837A US3360435A (en) | 1964-09-15 | 1965-05-21 | Treatment of depressed states |
Publications (1)
Publication Number | Publication Date |
---|---|
US3360435A true US3360435A (en) | 1967-12-26 |
Family
ID=27015954
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US457837A Expired - Lifetime US3360435A (en) | 1964-09-15 | 1965-05-21 | Treatment of depressed states |
Country Status (11)
Country | Link |
---|---|
US (1) | US3360435A (de) |
BE (1) | BE667739A (de) |
BR (1) | BR6571638D0 (de) |
CH (2) | CH463486A (de) |
DE (1) | DE1543216B1 (de) |
ES (1) | ES315465A1 (de) |
FR (2) | FR1482826A (de) |
GB (1) | GB1041989A (de) |
IL (1) | IL23869A (de) |
NL (1) | NL6509895A (de) |
SE (2) | SE322770B (de) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE371190B (de) * | 1972-03-24 | 1974-11-11 | Kabi Ab |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB959704A (en) * | 1961-08-31 | 1964-06-03 | Smith Kline French Lab | New indene derivatives and method of preparing the same |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2798888A (en) * | 1952-08-12 | 1957-07-09 | Ciba Pharm Prod Inc | Indene and indane compounds and their production |
-
1965
- 1965-05-21 US US457837A patent/US3360435A/en not_active Expired - Lifetime
- 1965-07-02 GB GB28248/65A patent/GB1041989A/en not_active Expired
- 1965-07-02 IL IL23869A patent/IL23869A/en unknown
- 1965-07-17 ES ES0315465A patent/ES315465A1/es not_active Expired
- 1965-07-26 SE SE9813/65A patent/SE322770B/xx unknown
- 1965-07-27 DE DE19651543216 patent/DE1543216B1/de active Pending
- 1965-07-28 BR BR171638/65A patent/BR6571638D0/pt unknown
- 1965-07-29 CH CH1068665A patent/CH463486A/de unknown
- 1965-07-29 CH CH1114968A patent/CH473760A/de not_active IP Right Cessation
- 1965-07-30 BE BE667739D patent/BE667739A/xx unknown
- 1965-07-30 FR FR26746A patent/FR1482826A/fr not_active Expired
- 1965-07-30 FR FR26747A patent/FR4646M/fr not_active Expired
- 1965-07-30 NL NL6509895A patent/NL6509895A/xx unknown
-
1968
- 1968-06-28 SE SE08871/68A patent/SE332171B/xx unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB959704A (en) * | 1961-08-31 | 1964-06-03 | Smith Kline French Lab | New indene derivatives and method of preparing the same |
Also Published As
Publication number | Publication date |
---|---|
BE667739A (de) | 1966-01-31 |
DE1543216B1 (de) | 1972-11-09 |
SE332171B (de) | 1971-02-01 |
SE322770B (de) | 1970-04-20 |
FR1482826A (fr) | 1967-06-02 |
IL23869A (en) | 1970-09-17 |
CH463486A (de) | 1968-10-15 |
FR4646M (de) | 1966-12-05 |
CH473760A (de) | 1969-06-15 |
NL6509895A (de) | 1966-03-16 |
BR6571638D0 (pt) | 1973-08-14 |
ES315465A1 (es) | 1966-06-01 |
GB1041989A (en) | 1966-09-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Halliwell et al. | A comparison of imipramine, chlorpromazine and related drugs in various tests involving autonomic functions and antagonism of reserpine | |
KR101536023B1 (ko) | 조합된 sert, 5-ht3 및 5-ht1a 활성을 가진 화합물의 치료 용도 | |
Hussain et al. | Prodrug approaches to enhancement of physicochemical properties of drugs IV: novel epinephrine prodrug | |
US3534055A (en) | Certain substituted 1-amino-1,2,3,4-tetrahydro naphthalenes and pharmaceutically acceptable salts thereof | |
JPH0114231B2 (de) | ||
JPH0224821B2 (de) | ||
JPH0317046A (ja) | アリールオキシフエニルプロピルアミン、その製造方法及びその使用方法 | |
EP0539470B1 (de) | Neuromuskuläre blocker | |
JPH0134226B2 (de) | ||
US3360435A (en) | Treatment of depressed states | |
US7361655B2 (en) | Pharmaceutically effective compounds | |
US4285943A (en) | Novel pharmaceutical compositions incorporating an aryltrifluoroethanol | |
US3816433A (en) | 4-fluoro-ypsilon-(4-methylpiperidino)-butyrophenone and its pharmaceutically acceptable salts | |
IE46171B1 (en) | N-(1'-allyl-2'-pyrrolidylmethyl)-2,3-dimethoxy-5-sulphamoylbenzamide and derivatives | |
US3794651A (en) | 1-(omega-(4-phenylpiperazinyl)alkyl)-2-methylbenzimidazoles | |
US3928603A (en) | New derivatives of alpha-methyl benzylamine in treating inflammation | |
JP2010529124A (ja) | 新規方法 | |
US3150139A (en) | Nu-methylpiperazinocyclohexanol derivatives | |
US3629418A (en) | Process for producing an anti-depressant effect with piperazine quinolines | |
US3457354A (en) | Treatment of hypertension with 2-hydroxy (or amino) - 4,5 - dihydroxyphenethylamine derivatives | |
US3037982A (en) | Phenylpiperazinylalkyl propionanilides | |
US3496186A (en) | 2-aminomethyl benzofuran derivatives | |
US3367832A (en) | Treating pain with 2, 2-diphenyl-4-(2-piperidyl)-1, 3-dioxolane | |
US3523954A (en) | Novel alpha-amino-substituted (3,4-methylenedioxy - phenyl) - alkanones and salts thereof | |
US3761509A (en) | N,n{40 -alkylenebis (4-substituted-benzamides) |