ZA200403970B - Aminoindane derivatives as serotonin and norepinephrine uptake inhibitors. - Google Patents
Aminoindane derivatives as serotonin and norepinephrine uptake inhibitors. Download PDFInfo
- Publication number
- ZA200403970B ZA200403970B ZA200403970A ZA200403970A ZA200403970B ZA 200403970 B ZA200403970 B ZA 200403970B ZA 200403970 A ZA200403970 A ZA 200403970A ZA 200403970 A ZA200403970 A ZA 200403970A ZA 200403970 B ZA200403970 B ZA 200403970B
- Authority
- ZA
- South Africa
- Prior art keywords
- indan
- benzo
- dioxol
- amine
- cis
- Prior art date
Links
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 title description 6
- XJEVHMGJSYVQBQ-UHFFFAOYSA-N 2,3-dihydro-1h-inden-1-amine Chemical class C1=CC=C2C(N)CCC2=C1 XJEVHMGJSYVQBQ-UHFFFAOYSA-N 0.000 title description 3
- 229940076279 serotonin Drugs 0.000 title description 3
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 title description 2
- 239000003772 serotonin uptake inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- -1 aminoindane compound Chemical class 0.000 claims description 10
- PTPIVPHHADFGNX-HZPDHXFCSA-N (1r,3r)-3-(1,3-benzodioxol-5-yl)-n,n-dimethyl-2,3-dihydro-1h-inden-1-amine Chemical compound C1=C2OCOC2=CC([C@H]2C[C@H](C3=CC=CC=C32)N(C)C)=C1 PTPIVPHHADFGNX-HZPDHXFCSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- PTPIVPHHADFGNX-JKSUJKDBSA-N (1r,3s)-3-(1,3-benzodioxol-5-yl)-n,n-dimethyl-2,3-dihydro-1h-inden-1-amine Chemical compound C1=C2OCOC2=CC([C@@H]2C[C@H](C3=CC=CC=C32)N(C)C)=C1 PTPIVPHHADFGNX-JKSUJKDBSA-N 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- DKUHNBODNFGGHX-DLBZAZTESA-N (1r,3s)-3-(1,3-benzodioxol-5-yl)-n-ethyl-n-methyl-2,3-dihydro-1h-inden-1-amine Chemical compound C1=C2OCOC2=CC([C@@H]2C[C@H](C3=CC=CC=C32)N(C)CC)=C1 DKUHNBODNFGGHX-DLBZAZTESA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- JCUKVVMMQXBTLU-JKSUJKDBSA-N (1r,3s)-3-(1,3-benzodioxol-5-yl)-n-ethyl-2,3-dihydro-1h-inden-1-amine Chemical compound C1=C2OCOC2=CC([C@@H]2C[C@H](C3=CC=CC=C32)NCC)=C1 JCUKVVMMQXBTLU-JKSUJKDBSA-N 0.000 claims 1
- RWNKETJYTFOCDU-LSDHHAIUSA-N (1r,3s)-3-(1,3-benzodioxol-5-yl)-n-methyl-2,3-dihydro-1h-inden-1-amine Chemical compound C1=C2OCOC2=CC([C@@H]2C[C@H](C3=CC=CC=C32)NC)=C1 RWNKETJYTFOCDU-LSDHHAIUSA-N 0.000 claims 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000012131 assay buffer Substances 0.000 description 6
- 208000019901 Anxiety disease Diseases 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
- 230000012154 norepinephrine uptake Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- RWNKETJYTFOCDU-HUUCEWRRSA-N (1r,3r)-3-(1,3-benzodioxol-5-yl)-n-methyl-2,3-dihydro-1h-inden-1-amine Chemical compound C1=C2OCOC2=CC([C@H]2C[C@H](C3=CC=CC=C32)NC)=C1 RWNKETJYTFOCDU-HUUCEWRRSA-N 0.000 description 4
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 4
- 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 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 208000019022 Mood disease Diseases 0.000 description 4
- 206010041250 Social phobia Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 230000002152 alkylating effect Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000003607 modifier Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 208000019906 panic disease Diseases 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- FTISNRLQEWYJLS-CZUORRHYSA-N (1r,3r)-3-(6-chloro-1,3-benzodioxol-5-yl)-n,n-dimethyl-2,3-dihydro-1h-inden-1-amine Chemical compound C1=C(Cl)C([C@@H]2C[C@H](C3=CC=CC=C32)N(C)C)=CC2=C1OCO2 FTISNRLQEWYJLS-CZUORRHYSA-N 0.000 description 3
- HYSDYHSKDCPDMN-IUODEOHRSA-N (1r,3r)-3-(6-chloro-1,3-benzodioxol-5-yl)-n-methyl-2,3-dihydro-1h-inden-1-amine Chemical compound C1=C(Cl)C([C@@H]2C[C@H](C3=CC=CC=C32)NC)=CC2=C1OCO2 HYSDYHSKDCPDMN-IUODEOHRSA-N 0.000 description 3
- BEJRILPUQMZOAL-DLBZAZTESA-N (1r,3s)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-n,n-dimethyl-2,3-dihydro-1h-inden-1-amine Chemical compound O1CCOC2=CC([C@@H]3C[C@H](C4=CC=CC=C43)N(C)C)=CC=C21 BEJRILPUQMZOAL-DLBZAZTESA-N 0.000 description 3
- XQWWILDNIXNWIZ-LEWJYISDSA-N (1r,3s)-n,n-dimethyl-3-naphthalen-2-yl-2,3-dihydro-1h-inden-1-amine Chemical compound C1=CC=CC2=CC([C@@H]3C[C@H](C4=CC=CC=C43)N(C)C)=CC=C21 XQWWILDNIXNWIZ-LEWJYISDSA-N 0.000 description 3
- YXZFHLBCAHVVHH-CJNGLKHVSA-N 2-[(1s,3s)-3-(1,3-benzodioxol-5-yl)-2,3-dihydro-1h-inden-1-yl]ethanamine Chemical compound C1=C2OCOC2=CC([C@@H]2C[C@H](C3=CC=CC=C32)CCN)=C1 YXZFHLBCAHVVHH-CJNGLKHVSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- DNAVCFRHPHWYGY-WFASDCNBSA-N [(1r,3s)-3-(1,3-benzodioxol-5-yl)-2,3-dihydro-1h-inden-1-yl]methanamine Chemical compound C1=C2OCOC2=CC([C@@H]2C[C@H](C3=CC=CC=C32)CN)=C1 DNAVCFRHPHWYGY-WFASDCNBSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229960002866 duloxetine Drugs 0.000 description 3
- 150000002118 epoxides Chemical class 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 2
- HRZLHGQTQDQMRZ-UHFFFAOYSA-N 3-(1,3-benzodioxol-5-yl)-2,3-dihydroinden-1-one Chemical compound C1=C2OCOC2=CC(C2CC(C3=CC=CC=C32)=O)=C1 HRZLHGQTQDQMRZ-UHFFFAOYSA-N 0.000 description 2
- NOIIUHRQUVNIDD-UHFFFAOYSA-N 3-[[oxo(pyridin-4-yl)methyl]hydrazo]-N-(phenylmethyl)propanamide Chemical compound C=1C=CC=CC=1CNC(=O)CCNNC(=O)C1=CC=NC=C1 NOIIUHRQUVNIDD-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 2
- 206010033664 Panic attack Diseases 0.000 description 2
- 206010034912 Phobia Diseases 0.000 description 2
- 229920002873 Polyethylenimine Polymers 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 229960004424 carbon dioxide Drugs 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 229960001653 citalopram Drugs 0.000 description 2
- 230000002301 combined effect Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 210000005080 cortical synaptosome Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000003365 glass fiber Substances 0.000 description 2
- 239000008103 glucose Substances 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
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229960003057 nialamide Drugs 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 208000028173 post-traumatic stress disease Diseases 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002287 radioligand Substances 0.000 description 2
- 238000005932 reductive alkylation reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000000697 serotonin reuptake Effects 0.000 description 2
- 230000013275 serotonin uptake Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 201000001716 specific phobia Diseases 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000004808 supercritical fluid chromatography Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 230000001960 triggered effect Effects 0.000 description 2
- 229960004688 venlafaxine Drugs 0.000 description 2
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- GBCASTISUOURFZ-ZWKOTPCHSA-N (1r,3s)-3-(1,3-benzodioxol-5-yl)-n,n-diethyl-2,3-dihydro-1h-inden-1-amine Chemical compound C1=C2OCOC2=CC([C@@H]2C[C@H](C3=CC=CC=C32)N(CC)CC)=C1 GBCASTISUOURFZ-ZWKOTPCHSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- ZQPBOYASBNAXOZ-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)acetonitrile Chemical compound N#CCC1=CC=C2OCOC2=C1 ZQPBOYASBNAXOZ-UHFFFAOYSA-N 0.000 description 1
- NHWQMJMIYICNBP-UHFFFAOYSA-N 2-chlorobenzonitrile Chemical compound ClC1=CC=CC=C1C#N NHWQMJMIYICNBP-UHFFFAOYSA-N 0.000 description 1
- FKHYYOUFMJBLAF-UHFFFAOYSA-N 3-(3,3-dimethyl-1-phenyl-2-benzothiophen-1-yl)-n-methylpropan-1-amine Chemical compound S1C(C)(C)C2=CC=CC=C2C1(CCCNC)C1=CC=CC=C1 FKHYYOUFMJBLAF-UHFFFAOYSA-N 0.000 description 1
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 1
- NUTPROPWGPYRSU-UHFFFAOYSA-N 5-(3-chloro-2,3-dihydro-1h-inden-1-yl)-1,3-benzodioxole Chemical compound C1=C2OCOC2=CC(C2CC(C3=CC=CC=C32)Cl)=C1 NUTPROPWGPYRSU-UHFFFAOYSA-N 0.000 description 1
- SKTFQHRVFFOHTQ-UHFFFAOYSA-N 8-bromo-1,3-dimethyl-7h-purine-2,6-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC(Br)=N2 SKTFQHRVFFOHTQ-UHFFFAOYSA-N 0.000 description 1
- 208000017194 Affective disease Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 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
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N Theophylline Natural products O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N benzocyclopentane Natural products C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000000105 evaporative light scattering detection Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N monoethanolamine hydrochloride Natural products NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 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
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229950002139 talsupram Drugs 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
-
- 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
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
- C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
- C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Aminoindane derivatives as serotonin and norepinephrine uptake inhibitors : The invention provides novel aminoindane derivatives which are useful in the treatment of affective disorders, such as depression and anxiety disorders. ‘ 5
The combined effect of serotonin reuptake inhibition and norepinephrine uptake inhibition on depression is explored in clinical studies of compounds such as
Duloxetine (Wong DT : Duloxetine (LY-248686): an inhibitor of serotonin and noradrenaline uptake and an antidepressant drug candidate Expert Opinion on
Investigational Drugs (1998) 7 10 1691-1699) and Venlafaxine (Khan-A; Fabre-LF;
Rudolph-R: Venlafaxine in depressed outpatients Psychopharmacology Bulletin (1991) 27, 141-144).
The present invention provides novel compounds which posses the combined effect of serotonin reuptake inhibition and norepinephrine uptake inhibition for the treatment of affective disorders, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and © angoraphobia.
The present invention relates to compounds having the formula I
R? R!
RE © a R14 N
Cy
RIS x
R16 ® he u I wherein
X is -O-, -S- or -CR'R’-; .
Y is -CR°R’-, -CR*R’-CR’R’- or -CR*~CR"-; or X and Y together form a group -
CR*=CR’-, or -CR*=CR’-CR°R’-; and '
Uis -O-, -S- or CR°R'}; or
Xis-O-, -S- or -CR*R’-; and
Y and U together form a group CR®=CR’-, -CR®=CR’-CR'’R., or —~CR°R’-CR'*=CR""-; ~ orX and Y and U together form -CR*=CR’-CR®*=CR’-; ’
R! and R? are independently selected from hydrogen, C;.¢-alkyl, Cy.¢-alkenyl, Cy.4- alkynyl, Cs.g-cycloalkyl, or R! and R? to gether with the nitrogen, to which they are attached, form a 3-7-membered saturated ring optionally containing one further heteroatom;
R", RY R" and R'® are each independently selected from hydrogen, halogen, cyano, nitro, Cy.g-alkyl, Cz ¢-alkenyl, C,.¢-alkynyl, and Cs g-cycloalkyl;
Ris hydrogen, halogen, C;¢-alkyl or cyano;
RY, R>, RC R, R% R’ R!° and R!! are each independently selected from hydrogen and
Cius-alkyl, . or an acid addition salt thereof: .
© WO 03/055873 PCT/DK02/00873
The invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable acid addition salt thereof and at least one . pharmaceutically acceptable carrier or diluent. ) 5 The invention further provides the use of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of affective disorders, such as depression and anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and angoraphobia.
The invention also provides a method for the treatment of an affective disorder as mentioned above in a living animal body, including a human, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof.
According to one specific embodiment of the invention, X and U is selected from -O- and -S- and Y is -CR°R’- or -CR'R’-CR®R’-,
According to another specific embodiment of the invention, X and Y and U together form ~CR*=CR’>-CR*=CR’-.
Preferred compounds according to the invention are:
Trans-(3-Benzo[ 1,3]dioxol-5-yl-indan-1-yl)dimethylamine,
Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine, , Trans-(3-Benzo[ 1,3]dioxol-5-yl-indan-1-yl)diethylamine,
Cis-(3-Benzo| 1,3]dioxol-5-yl-indan-1-yl)diethylamine, ‘ 30 Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)ethylamine,
Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)ethylamine,
Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)methylamine,
Cis-(3-Benzo[ 1,3]dioxol-5-yl-indan-1-yl)methylamine,
(+)-trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine, (-)-trans-(3-Benzo[ 1,3]dioxol-5-yl-indan-1-yl)dimethylamine, (+)-cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine, ’ (-)-cis-(3-Benzo[ 1,3]dioxol-5-yl-indan-1-yl)dimethylamine, Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-ethyl-methyl-amine, !
Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-ethyl-methyl-amine,
Cis-[3+(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-indan-1-yl}-dimethyl-amine,
Trans-[3-(2,3-Dihydro-benzo[ 1,4]dioxin-6-yl)-indan-1-yl]-dimethyl-amine,
Cis-Dimethyl-(3-naphthalen-2-yl-indan-1-yl)-amine,
Trans-Dimethyl-(3-naphthalen-2-yl-indan-1-yl)-amine,
Cis-[3-(6-Chloro-benzo[1,3]dioxol-5-yl)-indan-1-y1]-dimethyl-amine,
Trans-[3-(6-Chloro-benzo[ 1,3]dioxol-5-yl)-indan-1-yl]-dimethyl-amine,
Cis-[3-(6-Chloro-benzo[ 1,3]dioxol-5-yl)-indan-1-yl]-methyl-amine,
Trans-[3-(6-Chloro-benzo[ 1,3]dioxol-5-yl)-indan-1-yl]-methyl-amine,
Cis-Enantiomer-1-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-methyl-amine and
Cis-Enantiomer-2-(3-Benzo[ 1,3]dioxol-5-yl-indan-1-yl)-methyl-amine or acid addition salts thereof.
As used herein halogen means fluoro, chloro, bromo or iodo. © The term Cy alkyl refers to a branched or unbranched alkyl group having from one to ~~ six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.
Similarly, C, alkenyl and C, alkynyl, respectively, designate such groups having from two to six carbon atoms including one double bond and triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl
The term C;.5 cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and , cyclooctyl.
R! and R? may together with the nitrogen atom to which they are attached form a 3-7 membered ring optionally containing one further heteroatom, such as aziridinyl, h azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. 5 Exemplary of organic acid addition salts according to the invention are those formed with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline.
Exemplary of inorganic acid addition salts according to the invention are those formed with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. The acid addition salts of the invention are preferably pharmaceutically acceptable salts formed with non-toxic acids.
The compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. The solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
Some of the compounds of the present invention contain chiral centres and such compounds exist in the form of isomers (e.g. enantiomers or diastereomers). The invention includes all such isomers and any mixtures thereof including racemic mixtures.
Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, . and liberating the optically active amine compound by treatment with a base. Racemic compounds of the present invention can thus be resolved into their optical antipodes, ! 30 e.g., by fractional crystallisation of d- or 1- (tartrates, mandelates or camphorsulphonate) salts for example. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix.
The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives or by enzymatic resolvation.
Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet and S. ’
Wilen in “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, New
York (1981).
Optically active compounds can also be prepared from optically active starting matenals.
The compounds of the invention may be prepared by: 1) Alkylating an amine of formula III with an alkylating reagent of formula IT:
R13
R14 L (I 15 RZ R'
ES RIS I SR SE Ce
U H iy (1m) wherein R, R'-R%, R"*® XY and U are as previously defined, and L is a leaving group such as halogen, mesylate or tosylate; 2) Reductive alkylation of an indane ketone of formula IV with an amine of formula HI:
R13
R14 O
Cr
R15 2 1 ‘ X, a JR
R16 Y
U H
(Iv) ny wherein R, R!- R? , R316 X,Y and U are as previously defined, 3) Opening an epoxide of formula V with an amine of formula III:
R13
RY 0) (oh
RIS X R’ R'
R16 he N u H wherein R, R!- R* R*'® XY and U are as previously defined.
The alkylation according to method 1) is conveniently performed in an organic solvent such as an alcohol or ketone with a suitable boiling point, preferably in the presence of an organic or inorganic base (potassium carbonate, diisopropylethylamine or triethylamine) at reflux temperature. Alternatively, the alkylation can be performed ' 15 ata fixed temperature, which is different from the boiling point, in one of the above- mentioned solvents or in dimethyl formamide (DMF), dimethylsulfoxide (DMSO) or ' N-methylpyrrolidin-2-one (NMP), preferably in the presence of a base such as those mentioned above. The alkylating derivatives of formula II have been described in the literature (e.g. Bogeso, K.P. J. Med. Chem. 26, 1983, 935-947; Bogeso, K.P. et al. J.
Med. Chem. 28, 1985, 1817-1828; Sommer, M.B. et al. J. Org. Chem. 55, 1990,
4822-4827 and references cited therein) and the amines of formula IH are commercially available.
The reductive alkylation according to method 2) is performed by standard literature methods. The reaction can be performed in one step under standard reductive ' amination conditions using e.g. sodium cyanoborohydride or in two steps, e.g. by condensation of amines of formula III with a reagent of formula IV followed by reduction of the resulting imine with sodium cyanoborohydride or sodium borohydride. The ketones of formula IV can be prepared as described in the literature (e.g. Bogesg, K.P. J. Med. Chem. 26, 1983, 935-947; Begese, K.P. ef al. J. Med.
Chem. 28, 1985, 1817-1828; Sommer, M.B. et al. J. Org. Chem. 55, 1990, 4822-4827 and references cited therein).
The epoxide opening according to method 3) is conveniently performed in an organic : solvent such as a suitably boiling alcohol or ketone using an excess of an amine of formula IIT at reflux temperature.
Epoxides of formula IV can be prepared by methods described in the literature (e.g.
Ghosh, A.K. et al. Synthesis 5; 1997; 541-544; Palmer, M.J. et al.;
J.Chem.Soc.Perkin Trans.1,2002, 416 - 427).
The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. For example: Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are , compatible with the active ingredients.
Solutions for injections may be prepared by dissolving the active ingredient and ‘ possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to desired volume, sterilising the solution and filling it in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
The pharmaceutical compositions of this invention or those which are manufactured in accordance with this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.
Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg. The total daily dose is usually in the range of about 0.05 - 500 mg, and most preferably about 0.1 to 50 mg of the active compound of the invention.
Experimental
The compounds of the invention exemplified in the following have been characterized using the following methods:
Melting points were determined on a Biichi B-540 apparatus and are uncorrected.
Mass spectra were obtained on a Quattro MS-MS system from VG Biotech, Fisons © Instruments. Analytical LC-MS data were obtained on a PE Sciex API 150EX TT instrument equipped with IonSpray source and Shimadzu LC-8A/SLC-10A LC system. The LC conditions (50 X 4.6 mm YMC ODS-A with 5 pm particle size) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (90:10:0.05) to water/acetonitrile/trifluoroacetic acid (10:90:0.03) in 7 min at 2 mL/min. Purity was determined by integration of the UV trace (254 nm). The retention times R, are expressed in minutes. Preparative LC-MS-separation was performed on the same , instrument. The LC conditions (50 X 20 mm YMC ODS-A with 5 pm particle size) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (80:20:0.05) to : 30 water/acetonitrile/trifluoroacetic acid (5:95:0.03) in 7 min at 22.7 mL/min. Fraction collection was performed by split-flow MS detection. 'H NMR spectra were recorded at 250.13 MHz on a Bruker AC 250 or at 500.13 MHz on a Bruker DRX 500. Deuterated chloroform (99.8% D) or dimethylsulfoxide
(99.9% D) were used as solvents. TMS was used as internal reference standard.
Chemical shifts are expressed as ppm values. The following abbreviations are used for multiplicity of NMR signals: s=singlet, d=doublet, t=triplet, qg=quartet, qv=quintet, h=heptet, dd=double doublet, dt=double triplet, dg=double quartet, tt=triplet of triplets, m= multiplet, b=broad. NMR signals corresponding to acidic protons are to } some extent omitted. Content of water in crystalline compounds was determined by
Kar] Fischer titration. For column chromatography, silica gel of type Kieselgel 60, 40- 60 mesh ASTM was used. For ion-exchange chromatography, the following material was used: SCX-columns (1 g) from Varian Mega Bond Elut®, Chrompack cat. No. 220776. Prior to use, the SCX-columns were pre-conditioned with 10% solution of acetic acid in methanol (3 mL).
Preparation of intermediates
A. Alkylating reagents 3-Amino-1-(benzo[l1,3] dioxol-5-yl)-1-cyano-1H-indene-2-carboxylic acid methyl ester
A mixture of 2-chlorobenzonitrile (12.3 g) and benzo[1,3]dioxol-5-yl-acetonitrile (10 g) in dimethylformamide (25 mL) was added with stirring and cooling in an ice bath to potassium terz-butoxide (20.1 g) dissolved in dimethylformamide (50 mL) at such a rate that the temperature did not exceed 25 °C. After stirring for 0.5 h, methyl chloroacetate (11.1 g) was added in 10 min. After being stirred for 24h at rt, the mixture was poured into a mixture of 0.1 M HCI (200 mL), heptane (30 mL) and . toluene (15 mL). Stirring for 1 h, filtration and washing with water (2 x 50 mL), toluene (2 x 10 mL) and heptane (2 x 25 mL) afforded 79% of 3-Amino-1- . benzo[1,3]dioxol-5-yl-1-cyano-1 H-indene-2-carboxylic acid methyl ester.
3-(Benzo[l,3] dioxol-5-yl)-indan-1-one
A mixture of 3-amino-1-benzo[1,3]dioxol-5-yl-1-cyano-1H-indene-2-carboxylic acid ) methyl ester (10 g) and acetic acid (30 mL) were heated to 100 °C; 60% aqueous sulfuric acid (20 mL) was added with stirring during 30 min. The mixture was heated to 110 °C for 6 h, cooled to rt, extracted with toluene (50+10 mL), washed with water (3 x 100 mL), extracted with 0.1 M aqueous sodium hydroxide (100 + 20 mL), acidified with concentrated hydrochloric acid, extracted with toluene (25 + 10 mL), and filtrated through activated carbon. Removal of the toluene gave 80% of 1- (benzo[1,3]dioxol-5-yl1)-3-oxo-indan-1-carboxylic acid. The acid was subsequently decarboxylated by heating to 100 °C in N-methylpyrrolidone (15 mL) for 1 h. After cooling, the solution was poured into water (40 mL) with efficient stirring. Filtration, washing with water (5 x 20 mL), dissolution in ethyl acetate (40 mL), filtration through activated carbon and removal of the ethyl acetate gave 80% of 3- (benzo[1,3]dioxol-5-yl)-indan-1-one.
Cis-3-(benzo[1,3] dioxol-5-yl)-indan-1-ol
Sodium borohydride (1.5 g) was added in portions with stirring at 10-15 °C to a solution of 3-(benzo[1,3]dioxol-5-yl)-indan-1-one (10 g) in a mixture of ethanol (75 mL) and dimethoxyethane (75 mL). The mixture was stirred at rt for 1 h and then evaporated in vacuo. The resulting oil was treated with water and diethyl ether, and ~~ the organic phase was separated and washed with water and 0.1 N HCI, dried (MgS04) and evaporated in vacuo to give cis-3-(benzo[1,3]dioxol-5-yl)-indan-1-ol as a brown oil (10 g). 5-(3-Chloro-indan-1-yl)-benzo[1, 3] dioxole
Thionyl chloride (7 mL) was added with stirring and cooling at 15 °C to a solution of , cis-3-(benzo[ 1,3]dioxol-5-yl)-indan-1-ol (10 g) in dichloromethane (300 mL). The mixture was stirred at rt for 40 min. The mixture was washed twice with water, dried . 30 (MgSO04) and evaporated in vacuo to give a quantitative yield of 5-(3-chloroindan-1- yDbenzo[1,3]dioxole as an oil, which was used in the next step without further purification.
Preparation of the compounds of the invention
Example 1 : trans-(3-Benzo[l,3]dioxol-5-yl-indan-1-yl)dimethylamine (1) and cis-(3- ‘
Benzo[ 1,3] dioxol-5-yl-indan-1-yl)dimethylamine (2)
A mixture of 5-(3-chloroindan-1-y1)-benzo{1,3]dioxole (11 g) and 70 mL of 33% dimethylamine in ethanol was Kept at 100 °C in a steel autoclave for 16h. The mixture was cooled and evaporated in vacuo. The residue was dissolved in diethylether and washed with water and 2 N NaOH. The organic phase was dried (magnesium sulphate) evaporated in vacuo and the residue was purified by flash chromatography on silicagel using a gradient-eluent: 1) ethyl acetate/heptane (80:20) and 2) ethyl acetate/ethanol/triethylamine (90:10:4) to give the crude products as clear oils.
Trans-(3-Benzo[l,3]dioxol-5-yi-indan-1-yl)dimethylamine (1)
The slow-eluting compound is the trans isomer (3 g).
HNMR (CDCl): 1.95-2.05 (m, 1H); 2.30 (s, 6H); 2.60-2.70 (m, 1H); 4.40 (m, 2H); 5.90 (s, 2H), 6.55 (m, 1H); 6.65 (m, 1H), 6.70 (m, 1H), 6.95 (m, 1H), 7.25 (m, 1H), 7.45 (mm, 1H). The compound could be converted to the fumarate salt from ethyl acetate/ethanol as a white crystalline compound.
Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine (2)
The fast-eluting compound is the cis isomer (1 g). "H NMR (CDCl): 1.95-2.05 (m, 1H); 2.30 (s, 6H); 2.60-2.70 (m, 1H); 4.10 (m, 1H); 4.45 (m, 1H), 5.90 (s, 2H); 6.55 (m, 1H); 6.65 (m, 1H), 6.70 (m, 1H), 6.95 (m, 1H), 7.25 (m, 1H), 7.45 (m, 1H). The compound could be converted to the fumarate salt from ethyl acetate/ethanol as a white crystalline compound. i
The following compounds 3-14 were prepared analogously, HPLC-retention time and purity are described in table 1.: ’
Trans-(3-Benzo[ 1,3] dioxol-5-yl-indan-1-yl)diethylamine(3)
Cis-(3-Benzo[1,3] dioxol-5-yl-indan-1-yl)diethylamine(4)
Trans-(3-Benzo[ 1,3] dioxol-5-yl-indan-1-yl)ethylamine (5)
Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)ethylamine (6) . Trans-(3-Benzo[ 1,3] dioxol-5-yl-indan-1-yl)methylamine (7)
Cis-(3-Benzo[ 1,3] dioxol-5-yl-indan-1-yl) methylamine (8) Trans-(3-Benzo[l,3]dioxol-5-yl-indan-1-yl)-ethyl-methyl-amime (13)
Cis-(3-Benzo[ 1,3] dioxol-5-yl-indan-1-yl)-ethyl-methyl-amine (14)
Cis-[3-(2,3-Dihydro-benzo[ 1,4] dioxin-6-yl)-indan-1-yl] -dimethyl-amine (15)
Trans-[3-(2,3-Dihydro-benzo[1,4] dioxin-6-yl)-indan-1-yl] -dimethyl-amine (16)
Cis-Dimethyl-(3-naphthalen-2-yl-indan-1-yl)-amine (17) Trans-Dimethyl-(3-naphthalen-2-yl-indan-1-yl)-amine (18)
Cis-[3-(6-Chloro-benzo[1,3] dioxol-5-yl)-indan-1-yl] -dimethyl-amine (19)
Trans-[3-(6-Chloro-benzo[ 1,3] dioxol-5-yl)-indan-1-yl]-dimethyl-amine (20)
Cis-[3-(6-Chloro-benzo[ 1,3] dioxol-5-yl)-indan-1-yl]-methyl-amine (21)
Trans-[3-(6-Chloro-benzo[ 1,3] dioxol-5-yl)-indan-1-yl]-methyl-amine (22)
Compound Retention time Purity % (UV) Purity % (min) (ELSD) 1 1.88 85.18 99.12 2 1.9 93.92 99.26 3- 183 -- ~~ --- 9925 99.72 — - - eee 4 1.87 95.85 99.69 5 1.58 100 95.80 6 1.73 86.91 99.74 7 1.79 94.36 99.59 8 1.86 95.34 99.70 13 1.83 78.3 98.1 14 1.89 81.8 93.3 15 1.73 78.1 99.8 16 1.68 84.7 92.7 17 2.10 92.5 99.8 \ 18 2.10 92.8 99.9 19 2.08 75.1 97.7 1.89 96.4 99.7 ) 21 2.08 81.8 96.3 22 2.00 86.8 97.1 23 1.83 82.4 99.1 24 1.87 77.3 98.5
Table 1
Example 2 (H)-trans-(3-Benzo[l,3]dioxol-5-yl-indan-1-yl)dimethylamine (9) and (-)-trans-(3- Benzo[l,3]dioxol-5-yl-indan-1-yl)dimethylamine (10)
Compound 1, trans-(3-Benzo[ 1,3]dioxol-5-yl-indan-1-yl)dimethylamine, was subjected to resolution by chiral HPLC using a Gilson SF3 supercritical fluid chromatography system equipped with chiralcelOD columns (4.6 mm x 25 cm for analytical and 10 mm x 25 cm for preparative runs). The particle size in the columns was 10 um. A solution of compound 1, trans-(3-benzo[1,3]dioxol-5-yl-indan-1- yl)dimethylamine, (1 g) in methanol (1 mL1) was injected in 40 pL portions on a preparative column. The column was eluted with carbondioxide — modifier (75:25).
The modifier was 2-propanol with diethylamine (0.5%) and trifluoracetic acid (0.5%).
The flow was 18.9 ml/min at 20 Mpa. Fraction collection was triggered by UV- detection (210 nM). The fractions containing the separate products were pooled and evaporated in vacuo which gave the enantiomers 9 and 10. (H)-trans-(3-Benzo[ 1,3] dioxol-5-yl-indan-1-yl)dimethylamine (9): o. = +14.0 (conc. = 1% in Methanol) oo ] ] oo (-)-trans-(3-Benzof 1, 3] dioxol-5-yl-indan-1 )dimethylamine (10): a =-14.7 (conc. = 1% in Methanol)
Example 3 (+)-cis-(3-Benzo[ 1,3] dioxol-5-yl-indan-1-yl)dimethylamine (11) and (-)-cis-(3-
Benzo[1,3] dioxol-5-yl-indan-1-yl)dimethylamine (12)
Compound 2, cis-(3-benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine, was subjected to resolution by chiral HPLC using a Gilson SF3 supercritical fluid chromatography ’ system equipped with chiralcelOD columns (4.6 mm x 25 cm for analytical and 10 mm Xx 25 cm for preparative runs). The particle size in the columns was 10 pm. A solution of compound 2, cis-(3-benzo[1,3]dioxol-5-yl-indan-1-yl)dimethylamine, (1
8) in methanol (1 mL) was injected in 40 pL portions on a preparative column. The column was eluted with carbondioxide — modifier (75:25). The modifier was 2- * propanol] with diethylamine (0.5%) and trifluoracetic acid (0.5%). The flow was 18.9 ml/min at 20 Mpa. Fraction collection was triggered by UV-detection (210 nM). The fractions containing the separate products were pooled and evaporated in vacuo which gave the enantiomers 11 and 12. (*)-cis-(3-Benzo[ 1,3] dioxol-5-yl-indan-1-yl)dimethylamine (11): o. = +3.3 (conc. = 1% in Methanol) 12. (-)-cis-(3-Benzo[1,3] dioxol-5-yl-indan-1-yl)dimethylamine (12): o. = -4.4 (conc. = 1% in Methanol)
The following compounds were prepared analogously: (+)-Cis-(3-Benzo[ 1,3] dioxol-5-yl-indan-1-yl)-methyl-amine (23) (-)-Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-methyl-amine (24)
Pharmacological testing
The compounds of the invention were tested in well- recognised and reliable tests.
The tests were as follows:
Measurements of ["H]noradrenaline uptake into rat cortical synaptosomes.
Fresh cortex from male Wistar rats (125-225 g) are homogenized in 0.32 M sucrose supplemented with 1mM nialamid with a glass/teflon homogenizer. The homogenate is centrifuged at 600 x g for 10 min at 4 °C. The pellet is discarded and the supematant is centrifuged at 20.000 x g for 55 min. The final pellet is homogenized (20 sec) in this assay buffer (6 mg original tissue/mL = 4 mg/well). Test compounds (or buffer) and 10 . nM [*H]-noradrenaline are added to deep 96 well plates and shaken briefly. Composition of assay buffer: 123 mM NaCl, 4.82 mM KCl, 0.973 mM CaCl,, 1.12 mM MgSO, ¢ 30 12.66 mM Na;HPOq, 2.97 mM NaH,POy, 0.162 mM EDTA, 10 mM glucose and 1 mM ascorbic acid. Buffer is oxygenated with 95% 0,/5% CO, for 10 min at 37 °C and pH is adjusted 7.4. The incubation is started by adding tissue to a final assay volume of 1 my].
After 15 min incubation with radioligand at 37 °C, samples are filtered directly on
Unifilter GF/C glass fiber filters (soaked for 1 hour in 0.1% polyethylenimine) under vacuum and immediately washed with 3 x 1 mL assay buffer. Non-specific uptake is determined using talsupram (10 uM final concentration). Duloxetine is included as . reference in all experiments as dose-response curve. 5 .
Measurements of [’H]-5-HT uptake into rat cortical synaptosomes.
Whole brains from male Wistar rats (125-225 g), excluding cerebellum, are homogenized in 0.32 M sucrose supplemented with 1mM nialamid with a glass/teflon homogenizer. The homogenate is centrifuged at 600 x g for 10 min at 4 °C. The pellet is discarded and the supernatant is centrifuged at 20.000 x g for 55 min. The final pellet is homogenized (20 sec) in this assay buffer (0.5 mg original tissue/well). Test compounds (or buffer) and 10 nM [°H]-5-HT are added to 96 well plates and shaken briefly.
Composition of assay buffer: 123 mM NaCl, 4.82 mM KCl, 0.973 mM CaCl, 1.12 mM
MgSOs, 12.66 mM Na,HPO,, 2.97 mM NaH,;PO,, 0.162 mM EDTA, 10 mM glucose and 1 mM ascorbic acid. Buffer is oxygenated with 95% 0,/5% CO, for 10 min at 37 °C and pH is adjusted 7.4. The incubation is started by adding tissue to a final assay volume of 0.2 mL. After 15 min incubation with radioligand at 37 °C, samples are filtered directly on Unifilter GF/C glass fiber filters (soaked for 1 hour in 0.1% polyethylenimine) under vacuum and immediately washed with 3 x 0.2 ml assay buffer.
Non-specific uptake is determined using citalopram (10 pM final concentration).
Citalopram is included as reference in all experiments as dose-response curve.
Results of the experiments shoved that the compounds of the invention showed that the compounds all inhibit the norepinephrine and serotonine uptake with ICso below 200 nM. ’
Claims (4)
- Claims:- 1. An aminoindane compound having the formula I r 2 1 ’ re RK AR R14 N Pa RP X \ R16 ) Y U I wherein X is -O-, -S- or -CR*R’-; Y is -CR°R’-, -CR°R’-CR®R’- or -CR®<CR’-; or X and Y together form a group - CR*=CR’-, or -CR*=CR’-CR°R’-, and Uis-O-, -S- or CR'R";15. . . or X is -O-, -S- or -CR*R’-; and Y and U together form a group CR®=CR’-, -CR®=CR’-CR!’R}!-, or-CR°R’-CR'*=CR''-; or X and Y and U together form —-CR*=CR’-CR*=CR’-; R! and R? are independently selected from hydrogen, C,.¢-alkyl, C,¢-alkenyl, C;5- * 25 alkynyl, Cs g-cycloalkyl, or R! and R? together with the nitrogen, to which they are attached, form a 3-7 membered ring optionally containing one further heteroatom;RB, R'™ R" and R® are each independently selected from hydrogen, halogen, cyano, nitro, Cy¢-alkyl, C, ¢-alkenyl, Cy ¢-alkynyl, and Cj.g-cycloalkyi; R is hydrogen, C;.s-alkyl or cyano; X R*, RRS, R’, R%, R%, R'® and R"! are each independently selected form hydrogen and Ci-alkyl; or an acid addition salt thereof,
- 2. A compound according to claim 1 wherein X and U is selected from -O- and -S- and Y is -CR°R’- or -CR*R’-CR*R’-.
- 3. A compound according to claim 1 wherein X and Y and U together form —CR*=CR’-CR®=CR’-.
- 4. A compound according to claim 1 which is Trans-(3-Benzo[ 1,3]dioxol-5-yl-indan-1-yl)-dimethyl-amine, Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-dimethyl-amine, . Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-y1)-diethyl-amine, ~~ Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-diethyl-amine, Co ) Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-ethyl-amine, Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-ethyl-amine, Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-methyl-amine, Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-methyl-amine, (+)-trans-(3-Benzo[ 1,3]dioxol-5-yl-indan-1-yl)-dimethyl-amine, (-)-trans-(3-Benzol[ 1,3]dioxol-5-yl-indan-1-y1)-dimethyl-amine, (+)-cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-dimethyl-amine, \ (-)-cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-dimethyl-amine, Trans-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-ethyl-methyl-amine, ’ Cis-(3-Benzo[1,3]dioxol-5-yl-indan-1-yl)-ethyl-methyl-amine, Cis-[3-(2,3-Dihydro-benzo[ 1,4]dioxin-6-yl)-indan-1-yl]-dimethyl-amine,
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DKPA200101939 | 2001-12-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200403970B true ZA200403970B (en) | 2005-08-22 |
Family
ID=33547528
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200403970A ZA200403970B (en) | 2001-12-21 | 2004-05-21 | Aminoindane derivatives as serotonin and norepinephrine uptake inhibitors. |
Country Status (8)
Country | Link |
---|---|
KR (1) | KR20040075904A (en) |
AR (1) | AR037936A1 (en) |
BR (1) | BR0214987A (en) |
EA (1) | EA007655B1 (en) |
IS (1) | IS7282A (en) |
PL (1) | PL369525A1 (en) |
UA (1) | UA76266C2 (en) |
ZA (1) | ZA200403970B (en) |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8628644D0 (en) * | 1986-12-01 | 1987-01-07 | Lunbeck A S H | Intermediates |
DK286990D0 (en) * | 1990-12-04 | 1990-12-04 | Lundbeck & Co As H | indan derivatives |
DK55192D0 (en) * | 1992-04-28 | 1992-04-28 | Lundbeck & Co As H | 1-piperazino-1,2-dihydroindene derivatives |
GB9315600D0 (en) * | 1993-07-28 | 1993-09-08 | Smithkline Beecham Plc | Compounds |
GB9315566D0 (en) * | 1993-07-28 | 1993-09-08 | Smithkline Beecham Plc | Medicaments |
CA2180841C (en) * | 1994-01-10 | 2007-03-27 | Sasson Cohen | 1-aminoindan derivatives and compositions thereof |
WO1998055447A1 (en) * | 1997-06-05 | 1998-12-10 | Venantius Limited | 3-aminoindane derivatives, process for their preparation and pharmaceutical compositions containing them |
WO1999035119A1 (en) * | 1998-01-09 | 1999-07-15 | Pharm-Eco Laboratories, Inc. | Synthesis of 3-aryl-1-indanamines |
-
2002
- 2002-05-21 IS IS7282A patent/IS7282A/en unknown
- 2002-12-18 BR BR0214987-7A patent/BR0214987A/en not_active IP Right Cessation
- 2002-12-18 UA UA20040705315A patent/UA76266C2/en unknown
- 2002-12-18 PL PL02369525A patent/PL369525A1/en not_active Application Discontinuation
- 2002-12-18 KR KR10-2004-7009905A patent/KR20040075904A/en not_active Application Discontinuation
- 2002-12-18 EA EA200400846A patent/EA007655B1/en not_active IP Right Cessation
- 2002-12-19 AR ARP020105023A patent/AR037936A1/en not_active Application Discontinuation
-
2004
- 2004-05-21 ZA ZA200403970A patent/ZA200403970B/en unknown
Also Published As
Publication number | Publication date |
---|---|
PL369525A1 (en) | 2005-05-02 |
BR0214987A (en) | 2004-12-14 |
AR037936A1 (en) | 2004-12-22 |
UA76266C2 (en) | 2006-07-17 |
EA200400846A1 (en) | 2004-12-30 |
KR20040075904A (en) | 2004-08-30 |
IS7282A (en) | 2004-05-21 |
EA007655B1 (en) | 2006-12-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20080119547A1 (en) | Aminoindane Derivatives As Serotonin And Norepinephrine Uptake Inhibitors | |
EP1149087B1 (en) | Piperidine, tetrahydropyridine and piperazine derivatives, their preparation and use | |
JP4091648B2 (en) | 2- (1H-Indolylsulfanyl) -benzylamine derivative | |
US6476035B1 (en) | Indole and 2,3-dihydroindole derivatives, their preparation and use | |
KR100325964B1 (en) | Bicyclic Aromatic Compounds as Therapeutic Agents | |
CZ256090A3 (en) | Derivative in position of 8-substituted 2-aminotetralin, processes of its preparation, pharmaceutical composition containing thereof and its use | |
AU778674B2 (en) | New morpholinobenzamide salts | |
ZA200403970B (en) | Aminoindane derivatives as serotonin and norepinephrine uptake inhibitors. | |
US20030050306A1 (en) | Novel heteroaryl derivatives, their preparation and use | |
JP2001302599A (en) | New heterocyclopalkylbenzocyclobutane, heteroarylbenzocyclobutane compound, method for producing the same and medicinal composition containing the same | |
US6331544B1 (en) | Indane or dihydroindole derivatives | |
US6436940B2 (en) | Indane or dihydroindole derivatives | |
GB2247887A (en) | N-(1,2,3,4-Tetrahydronaphthalen-2-yl)azetidine derivatives | |
MXPA02006591A (en) | Novel heteroaryl derivatives, their preparation and use |