WO1997030983A1 - Tetrahydro-n,n-dimethyl-2,2-diphenyl-3-feranemethanamine, its enantiomers, and their pharmaceutically acceptable acid addition salts - Google Patents
Tetrahydro-n,n-dimethyl-2,2-diphenyl-3-feranemethanamine, its enantiomers, and their pharmaceutically acceptable acid addition salts Download PDFInfo
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- WO1997030983A1 WO1997030983A1 PCT/GR1997/000007 GR9700007W WO9730983A1 WO 1997030983 A1 WO1997030983 A1 WO 1997030983A1 GR 9700007 W GR9700007 W GR 9700007W WO 9730983 A1 WO9730983 A1 WO 9730983A1
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- diphenyl
- tetrahydro
- dimethyl
- pharmaceutically acceptable
- enantiomers
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- 239000002253 acid Substances 0.000 title claims abstract description 13
- 150000003839 salts Chemical class 0.000 title claims abstract description 9
- 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 title claims description 7
- BOTHKNZTGGXFEQ-UHFFFAOYSA-N 1-(2,2-diphenyloxolan-3-yl)-n,n-dimethylmethanamine Chemical compound CN(C)CC1CCOC1(C=1C=CC=CC=1)C1=CC=CC=C1 BOTHKNZTGGXFEQ-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000001961 anticonvulsive agent Substances 0.000 claims abstract description 9
- 229960003965 antiepileptics Drugs 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 230000001777 nootropic effect Effects 0.000 claims abstract description 9
- 230000001773 anti-convulsant effect Effects 0.000 claims abstract description 8
- FSCZMMHEBXDNHK-UHFFFAOYSA-N 5-oxo-2,2-diphenyloxolane-3-carboxylic acid Chemical compound OC(=O)C1CC(=O)OC1(C=1C=CC=CC=1)C1=CC=CC=C1 FSCZMMHEBXDNHK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000001430 anti-depressive effect Effects 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 9
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- WSAIHHXILSVYIY-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-1,1-diphenylbutane-1,4-diol Chemical compound C=1C=CC=CC=1C(O)(C(CCO)CN(C)C)C1=CC=CC=C1 WSAIHHXILSVYIY-UHFFFAOYSA-N 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- ZJYBSROTYNQNFP-UHFFFAOYSA-N n,n-dimethyl-5-oxo-2,2-diphenyloxolane-3-carboxamide Chemical compound CN(C)C(=O)C1CC(=O)OC1(C=1C=CC=CC=1)C1=CC=CC=C1 ZJYBSROTYNQNFP-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 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 abstract description 2
- 239000000935 antidepressant agent Substances 0.000 abstract description 2
- 229940005513 antidepressants Drugs 0.000 abstract description 2
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 4
- MAUMSNABMVEOGP-UHFFFAOYSA-N (methyl-$l^{2}-azanyl)methane Chemical compound C[N]C MAUMSNABMVEOGP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000003556 anti-epileptic effect Effects 0.000 description 2
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 2
- 230000019771 cognition Effects 0.000 description 2
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000000457 gamma-lactone group Chemical group 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N Acetylene Chemical compound C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 230000003109 amnesic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- -1 dimethylamino ethyl Chemical group 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000012048 forced swim test Methods 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 230000000848 glutamatergic effect Effects 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Definitions
- the present invention relates to a new and original molecule with anticonvulsant, antidepressive and nootropic activity, and to a process for its preparation.
- the antiepileptics currently used have a negative effect on memory and cognition. None of them exhibit simultaneously anticonvulsant, antidepressant and nootropic activity. According to this invention such a molecule has been found.
- the present invention consists in the molecule : tetrahydro-N,N-dimethyl-2, 2-diphenyl-3-furanemethan- amine (Formula 7 on Scheme 1) , its enantiomers, and their pharmaceutically acceptable acid addition salts.
- the compound of the invention may be prepared according to the following reaction steps (as shown on Scheme 1) : tetrahydro-2,2-diphenyl-5-oxofuran-3-carboxylic acid (2) is converted into its carbonyl chloride (3) with thienyl chloride, the carbonyl chloride (3) is reacted with dimethylamine so as to give tetrahydro-N, N-dimethyl-2, 2-diphenyl-5- oxo-3-furanecarboxamide (4), the latter is reduced with LiAlH* so as to give 2- (dimethylamino ethyl) -1, 1-diphenyl-l, -butanediol (5) , the latter is cyclized in acid medium so as to give tetrahydro-N,N-dimethyl-2, 2-diphenyl-3-furanemethan- amine (7) , which may be salified by a pharmaceutically acceptable acid and/or separated into its enantiomers.
- the starting tetrahydro-2, 2-diphenyl-5-oxofuran-3- carboxylic acid (2) may be prepared by reacting benzophenone (1) with succinic anhydride in the presence of zinc chloride and triethylamine.
- the preparation of the acid addition salts of the compound of the invention and the separation of the enantiomers may be carried out by methods known in the art.
- AE37 tetrahydro-N,N-dimethyl-2, 2-diphenyl- 3-furanemethanamine, hydrochloride
- AE37 tetrahydro-N,N-dimethyl-2, 2-diphenyl- 3-furanemethanamine, hydrochloride
- AE37 tetrahydro-N,N-dimethyl-2, 2-diphenyl- 3-furanemethanamine, hydrochloride
- Binding studies showed a strong displacement of [ 3 H] DIOXO and [ 3 H]QNB by AE37 (with IC50 of 0.28 or 0.48 ⁇ M respectively) . These data demonstrated a very significative agonistic action (partial agonism) on the muscarinic receptors. This action could, on the basis of recent theoretical works, indirectly stimulate the glutamatergic neuromediation in the brain (via cholinergic of ⁇ -glycinergic mechanism) . In good agreement with the above-mentioned pharmacological and biochemical results, AE37 exhibited strong nootropic action in the passive avoidance (step- down) test on mice, from 0,3 to 30 mg/kg p.o. (p.o.
- mice appeared up to 300 mg/kg) .
- MES maximal electro-shock test
- AE37 also exhibited a strong antidepressive action in the forced swim test on mice.
- ⁇ -aminolactones (6 in the scheme 1), their Isomeric ⁇ -aminolactones and the tetrahydrofuran analogs of the latter exhibited weaker anticonvulsant action in the MES test of mice.
- the tetrahydrofuran analogs on the ⁇ -aminolactones exhibited a strong nootropic action in the passive avoidance (step-down) test on mice.
- AE37 could claim a special position in the therapeutic of epilepsy in a very original way. It combines anticonvulsant and nootropic action (antiepileptics have usually amnesic and cognition impairing action) .
- a further object of the present invention is a pharmaceutical composition which comprises tetrahydro-N,N-dimethyl-2, 2-diphenyl-3-furanemethan- amine, its enantiomer or their acid addition salt and a pharmaceutically acceptable carrier or diluent, and the use of said compounds for the preparation of pharmaceuticals with anticonvulsant, antidepressive and nootropic activity.
- the compounds of the invention may be administered at a dose of 1-100 mg/day, preferably 10-50 mg/day, usually by oral route.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention relates to tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanemethanamine and its pharmaceutically acceptable acid additon salts. The novel compound may be prepared from tetrahydro-2,2-diphenyl-5-oxofuran-3-carboxylic acid which is converted to the corresponding acid chloride and N,N-dimethyl-amide. The latter is reduced to an aminodiol which gives the final new molecule after cyclization under appropriate conditions. The compound of the invention has anticonvulsant antidepressant and nootropic activity, and may be used as a medicament.
Description
Tetrahydro-N,N-dimethyl-2, 2-diphenyl-3-furanemethan- amine,its enantiomers, and their pharmaceutically acceptable acid addition salts.
The present invention relates to a new and original molecule with anticonvulsant, antidepressive and nootropic activity, and to a process for its preparation. The antiepileptics currently used have a negative effect on memory and cognition. None of them exhibit simultaneously anticonvulsant, antidepressant and nootropic activity. According to this invention such a molecule has been found. The present invention consists in the molecule : tetrahydro-N,N-dimethyl-2, 2-diphenyl-3-furanemethan- amine (Formula 7 on Scheme 1) , its enantiomers, and their pharmaceutically acceptable acid addition salts. The compound of the invention may be prepared according to the following reaction steps (as shown on Scheme 1) : tetrahydro-2,2-diphenyl-5-oxofuran-3-carboxylic acid (2) is converted into its carbonyl chloride (3) with thienyl chloride, the carbonyl chloride (3) is reacted with dimethylamine so as to give tetrahydro-N, N-dimethyl-2, 2-diphenyl-5- oxo-3-furanecarboxamide (4), the latter is reduced with LiAlH* so as to give 2- (dimethylamino ethyl) -1, 1-diphenyl-l, -butanediol (5) , the latter is cyclized in acid medium so as to give tetrahydro-N,N-dimethyl-2, 2-diphenyl-3-furanemethan- amine (7) , which may be salified by a pharmaceutically acceptable acid and/or separated into its enantiomers. The starting tetrahydro-2, 2-diphenyl-5-oxofuran-3- carboxylic acid (2) may be prepared by reacting benzophenone (1) with succinic anhydride in the presence of zinc chloride and triethylamine. The preparation of the acid addition salts of the compound of the invention and the separation of the
enantiomers may be carried out by methods known in the art.
In the following Example, melting points were determined using a Buchi capillary apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer 883 spectrophotometer. ^-and 13C-NMR spectra were determined on a Bruker AC 200 spectrophotometer, at 200 MHz and 50 MHz respectively, using CDC13 as solvent and TMS as internal standard.
EXAMPLE
TETRAHYDRO-N,N-DIMETHYL-5-0X0-2, 2-DIPHENYL-3-FURANE- CARBOXAMIDE (4) A mixture of 7g (25 mmol) of acid (2) (Ar=C6H5) and 20 ml of thionyl chloride was heated at 60°C for 1 h. The excess thionyl chloride was removed in vacuo and the resulting solid chloride (3) [Mp: 146-148 °C (ether-n- pentane) IR(nujol) : v (C=0) 1770 cm-1 (acid chloride), v (C=0) 1775 cm-1 (γ-lactone) ] was dissolved in dry THF (50 ml) . To this solution cooled in an ice bath, a solution of 2.76g (60 mmol) of dimethylamine in 20 ml of dry THF was added dropwise with stirring. After the addition was complete, stirring was continued at ice bath temperature for 3h and the dimethylamine hydrochloride formed was filtered off and washed with THF. The filtrate was then evaporated to dryness under reduced pressure and the remaining crude solid, upon trituration with a mixture of ether-n-pentane yielded 6.5g (85%) of (4) . Mp: 133-134°C (ethanol-ether) , IR (nujol) : v(C=0) 1765 cm-1 (γ-lactone) , v(C=0) 1620 cm-1 (amide) ^H-NMR (CDC13) , 6 (ppm) : 2.48-2.62 (q.lH, A region, AMX, AM: 18 Hz, JAX: 9 Hz, furan 4-H) , 2.60 (s, 3H, CH3N) , 2.65 (s, 3H, CH3N) , 2.75-2.97 (d, 1H, M region, AMX, JAM: 18 Hz, JM^O HZ, furan 4-H) , 4.37-4.43
(d, 1H, X region, AMX, JA*:9 HZ, JMX:0 Hz, furan 3-H) , 7.35-7,60 (m, 10H, 2xC6H5) , Anal. (Cι9H19N03) : C,H,N. 2- (DIMETHYLAMINOMETHYL) -1, 1-DIPHENYL-1, 4-BUTANEDIOL (5) A solution of 3.8g (12.3 mmol) of amide (4) in 20 ml of dry THF was added dropwise with stirring to a suspension of 1.87g (49 mmol) of LiAlH4 in 30 ml of dry THF. The reaction mixture was refluxed for lOh and was then hydrolysed with water and 10% sodium hydroxide solution under ice-cooling. The inorganic precipitate was filtered off and washed with THF. The filtrate was then dried (Na2S04) and evaporated to dryness under vacuum to give 3.2g (87%) of aminodiol (5) Mp: 108- 110°C (ether-n-pentane) , IR (nujol) : v(OH) 3420-3160 cm"1, XH- MR (CDCls) δ(ppm) : 1.30-2.00 (dm, 2H, CH2CH2OH) ,2.10-2.50 (m, 2H, CH2N) , 2.21 (s, 6H, (CH3)2N), 2.62-2.91 (m, 1H, ethine H) , 3.50-3.72 (m, 2H, CH2OH) , 3.90-5.70 (br.s, 2H, 2XOH) , 7.15-7.52 (m, 10H, 2XC6H5) . Anal. (Cι9H25N02) : C,H,N.
TETRAHYDRO-N,N-DIMETHYL-2, 2-DIPHENYL-3-FURANEMETHAN- AMINE (7)
A mixture of 1.9g (6.4 mmol) of aminodiol (5) and 2.4g (12.8 mmol) of p-toluenesulfonic acid in 70 ml of dry benzene was refluxed for 5h with continuous removal of water via a Dean-Stark trap. After treatment of the reaction mixture with 100 ml 10% NaOH solution, the organic layer was separated and the aqueous phase extracted with ether. The combined organic phase was washed with water and evaporated to dryness. The residue was purified by column chromatography on neutral aluminum oxide using a mixture of n-hexane- ether 3:1 as eluent. After removal of the solvents
1.55g (87%) of product (7) were obtained. Mp: 87-90°C
(n-pentane) . :H-NMR (CDC13) δ (ppm) : 1.85-2.04 (m, 2H, furan 4-H) , 2.08-2.17 (m, 2H, CH2N) , 2.20
(s, 6H, (CH3)2N) , 3.02-3.18 (m, 1H, furan 3-H) , 3.76-3.90 (q, 1H, furan 5-H) . 4.15-4.27 (m, 1H, furan 5-H) , 7.07- 7.55 (m, 10H, 2XC6H5) .13C-NMR δ (ppm) : 29.91 (4-C), 44.42 (3-C), 45.87 [2X(CH3)2N], 61.08 (CH2N), 65.56 (5-C), 89.13 (2-C), 126.11, 126.30, 126.47, 126.79, 127.63,
128.16, (10 tertiary aromatic C) . 143.69 (quaternary aromatic C) , 146.41 (quaternary aromatic C) .
Hydrochloride Mp: 224-225°C (ethanol-ether) . Anal.
(C19H24C1N0) : C,H,C1,N. In the following, tetrahydro-N,N-dimethyl-2, 2-diphenyl- 3-furanemethanamine, hydrochloride is named "AE37". AE37, as the β-aminolactones (6 of the scheme 1) or the α-aminolactones and their tetrahydrofuran analogs, displayed anti-GABA ergic action, but in contrast, on the in vivo experiments with mice of rats, no antiglycinergic (A) activity was observed. Atropine precipitated the convulsions induced by AE37 when the latter was administered in very high (toxic) doses (up to 200 mg/kg, i.p) . Binding studies showed a strong displacement of [3 H] DIOXO and [3 H]QNB by AE37 (with IC50 of 0.28 or 0.48 μM respectively) . These data demonstrated a very significative agonistic action (partial agonism) on the muscarinic receptors. This action could, on the basis of recent theoretical works, indirectly stimulate the glutamatergic neuromediation in the brain (via cholinergic of β-glycinergic mechanism) . In good agreement with the above-mentioned pharmacological and biochemical results, AE37 exhibited strong nootropic action in the passive avoidance (step- down) test on mice, from 0,3 to 30 mg/kg p.o. (p.o. toxicity in mice appeared up to 300 mg/kg) . On the other hand, and in good agreement with an indirect B-glycinergic action of AE37 we found a strong anticonvulsant activity on the maximal electro-shock
test (MES) on mice with an (ED50) of 17,5 mg/kg (p.o.) 1 hour after AE37 and 15 mg/kg (p.o.) 4 hours after AE37 (therapeutic index ≡ 1/20) .
AE37 also exhibited a strong antidepressive action in the forced swim test on mice.
Finally, β-aminolactones (6 in the scheme 1), their Isomeric α-aminolactones and the tetrahydrofuran analogs of the latter exhibited weaker anticonvulsant action in the MES test of mice. However the tetrahydrofuran analogs on the α-aminolactones exhibited a strong nootropic action in the passive avoidance (step-down) test on mice. These pharmacological data indicate that AE37 could claim a special position in the therapeutic of epilepsy in a very original way. It combines anticonvulsant and nootropic action (antiepileptics have usually amnesic and cognition impairing action) . On the other hand the nootropic action of AE37 could constitute a good perspective for a use in the memory impairing or in the Alzheimer's disease. Consequently a further object of the present invention is a pharmaceutical composition which comprises tetrahydro-N,N-dimethyl-2, 2-diphenyl-3-furanemethan- amine, its enantiomer or their acid addition salt and a pharmaceutically acceptable carrier or diluent, and the use of said compounds for the preparation of pharmaceuticals with anticonvulsant, antidepressive and nootropic activity. The compounds of the invention may be administered at a dose of 1-100 mg/day, preferably 10-50 mg/day, usually by oral route.
CH2C'-2 2) r^O-HCI
Jones reageht
Ar = c9h5. R2N * (CH^Jj , Hydrochloride Mp = 224 - 225°C
Scheme 1
Claims
1. Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanemethane- amine, its enantiomers, and their pharmaceutically acceptable acid addition salts.
2. A compound of claim 1, characterized in that the acid addition salt is the hydrocloride.
3. A pharmaceutical composition, characterized in that it comprises a compound of claim 1 or 2 and a pharmaceutically acceptable carrier or diluent.
4. A process for the preparation of a compound of claim 1, characterized in that :
tetrahydro-2,2-diphenyl-5-oxofuran-3-carboxylic acid is converted into its carbonyl chloride with thionyl chloride,
the carbonyl chloride is reacted with dimethylamine so as to give tetrahydro-N, N-dimethyl-2, 2-diphenyl-5-oxo- 3-furanecarboxamide,
the latter is reduced with LiA1H4 so as to give 2- (dimethylaminomethyl)-1,1-diphenyl-1,4-butanediol, the latter is cyclized in acid medium so as to give tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanemethan- amine,
which may be salified by a pharmaceutically acceptable acid and/or separated into its enantiomers.
5. Use of the molecule : tetrahydro-N,N-dimethyl-2,2- diphenyl-3- furanemethanamine, its enantioners and their salts for the preparation of pharmaceuticals with anticonvulsant, antidepressive and nootropic activity.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU16140/97A AU1614097A (en) | 1996-02-21 | 1997-02-20 | Tetrahydro-n,n-dimethyl-2,2-diphenyl-3-feranemethanamine, its enantiomers, and their pharmaceutically acceptable acid addition salts |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GR960100061 | 1996-02-21 | ||
| GR96100061 | 1996-02-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997030983A1 true WO1997030983A1 (en) | 1997-08-28 |
Family
ID=10942335
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GR1997/000007 WO1997030983A1 (en) | 1996-02-21 | 1997-02-20 | Tetrahydro-n,n-dimethyl-2,2-diphenyl-3-feranemethanamine, its enantiomers, and their pharmaceutically acceptable acid addition salts |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU1614097A (en) |
| GR (1) | GR1002616B (en) |
| WO (1) | WO1997030983A1 (en) |
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| GR1003205B (en) * | 1998-11-16 | 1999-09-03 | Pharmaceutical use of two isomerous derivatives of tetrahydrofuranics:tetrahudro-n,n-dimethyl-5,5-diphenyl-3-furanomethanamine (ae14) and tetrahydro-n,n-dimethyl-2,2-diphenyl-3-furanomethanamine (ae37) | |
| GR990100386A (en) * | 1999-11-05 | 2001-07-31 | A OR B (MONO- OR DI-ALKYLAMINOMETHYL)-C-BUTYROLACTONES AND THEIR CORRESPONDING TETRAHYDROFURAN ANALOGUES AS NEW PROTOTYPE NOOTROPES, ANTI-ANOIC (ALZHEIMER'S DISEASE), ANTIPELIPUS AND NEUROPROTECTIVE DRUGS WITH A UNIQUE MEDICATION OF ... . | |
| GR1004208B (en) * | 2001-10-15 | 2003-04-04 | Αλεξανδρος Βαμβακιδης | Aminotetrahydrofuran derivatives, muscarinic/sigma/sodium channel ligands, with synergic sigma/muscarinic (neuroactivating) and sigma/sodium channel (neuroprotective) components, as prototypical activating - neuroprotectors and neuroregenerative drugs |
| FR2897535A1 (en) * | 2006-02-21 | 2007-08-24 | Alexandre Vamvakides | New sigma ligands such as (mono- or di-alkylaminoalkyl) gamma-butyrolactones, aminotetrahydrofurans and (1-adamantyl)benzenes alkylamines, useful e.g. in the preparation of pharmaceutical products of anti-cancerous activity |
| CN101646430A (en) * | 2007-01-17 | 2010-02-10 | 亚历山大·瓦姆瓦基德斯 | Novel sigma-receptor ligands with antiapoptotic and/or proapoptotic properties based on cellular biochemical mechanisms, and neuroprotective, anticancer, antimetastasis and anti(chronic) inflammatory effects |
| WO2010097641A1 (en) | 2009-02-26 | 2010-09-02 | Alexandre Vamvakides | SIGMA(σ) RECEPTORS LIGANDS WITH ANTI-APOPTOTIC AND/OR PRO-APOPTOTIC PROPERTIES, OVER CELLULAR MECHANISMS, EXHIBITING PROTOTYPICAL CYTOPROTECTIVE AND ALSO ANTICANCER ACTIVITY |
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Also Published As
| Publication number | Publication date |
|---|---|
| AU1614097A (en) | 1997-09-10 |
| GR1002616B (en) | 1997-02-20 |
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