WO2013076646A1 - A new diaza-benzofluoranthene derivative as drug - Google Patents
A new diaza-benzofluoranthene derivative as drug Download PDFInfo
- Publication number
- WO2013076646A1 WO2013076646A1 PCT/IB2012/056561 IB2012056561W WO2013076646A1 WO 2013076646 A1 WO2013076646 A1 WO 2013076646A1 IB 2012056561 W IB2012056561 W IB 2012056561W WO 2013076646 A1 WO2013076646 A1 WO 2013076646A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- disease
- cognitive impairment
- condition
- formula
- compound
- Prior art date
Links
- 239000003814 drug Substances 0.000 title abstract description 28
- 229940079593 drug Drugs 0.000 title description 22
- BTIVVMXJQAFZRV-UHFFFAOYSA-N 18,19-diazapentacyclo[10.7.1.02,11.03,8.016,20]icosa-1(20),2(11),3,5,7,9,12,14,16,18-decaene Chemical class N1=NC(C=2C3=CC=CC=C3C=CC=22)=C3C2=CC=CC3=C1 BTIVVMXJQAFZRV-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 150000003839 salts Chemical class 0.000 claims abstract description 53
- 238000000034 method Methods 0.000 claims abstract description 42
- 238000011282 treatment Methods 0.000 claims abstract description 36
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- 241000282414 Homo sapiens Species 0.000 claims abstract description 21
- 238000011321 prophylaxis Methods 0.000 claims abstract description 12
- 239000012453 solvate Substances 0.000 claims abstract description 11
- 239000004480 active ingredient Substances 0.000 claims abstract description 10
- 239000000126 substance Substances 0.000 claims abstract description 10
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 9
- 230000000626 neurodegenerative effect Effects 0.000 claims abstract description 9
- 230000000926 neurological effect Effects 0.000 claims abstract description 9
- 208000020016 psychiatric disease Diseases 0.000 claims abstract description 9
- 239000003085 diluting agent Substances 0.000 claims abstract description 8
- 239000003937 drug carrier Substances 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 208000010877 cognitive disease Diseases 0.000 claims description 59
- 208000028698 Cognitive impairment Diseases 0.000 claims description 52
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 34
- 201000010099 disease Diseases 0.000 claims description 24
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 17
- 208000018737 Parkinson disease Diseases 0.000 claims description 12
- 230000006735 deficit Effects 0.000 claims description 10
- 208000035475 disorder Diseases 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 208000024827 Alzheimer disease Diseases 0.000 claims description 7
- 201000006474 Brain Ischemia Diseases 0.000 claims description 7
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 7
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 claims description 7
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 claims description 7
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 claims description 7
- 201000011240 Frontotemporal dementia Diseases 0.000 claims description 7
- 208000031886 HIV Infections Diseases 0.000 claims description 7
- 206010019196 Head injury Diseases 0.000 claims description 7
- 208000023105 Huntington disease Diseases 0.000 claims description 7
- 208000002193 Pain Diseases 0.000 claims description 7
- 208000000609 Pick Disease of the Brain Diseases 0.000 claims description 7
- 208000006011 Stroke Diseases 0.000 claims description 7
- 206010008118 cerebral infarction Diseases 0.000 claims description 7
- 206010015037 epilepsy Diseases 0.000 claims description 7
- 208000013403 hyperactivity Diseases 0.000 claims description 7
- 230000007074 memory dysfunction Effects 0.000 claims description 7
- 208000027061 mild cognitive impairment Diseases 0.000 claims description 7
- 230000036407 pain Effects 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 208000004296 neuralgia Diseases 0.000 claims description 6
- 208000021722 neuropathic pain Diseases 0.000 claims description 6
- 201000001119 neuropathy Diseases 0.000 claims description 6
- 230000007823 neuropathy Effects 0.000 claims description 6
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 6
- 206010003805 Autism Diseases 0.000 claims description 5
- 208000020706 Autistic disease Diseases 0.000 claims description 5
- 201000010374 Down Syndrome Diseases 0.000 claims description 5
- 206010016845 Foetal alcohol syndrome Diseases 0.000 claims description 5
- 206010065390 Inflammatory pain Diseases 0.000 claims description 5
- 102000029797 Prion Human genes 0.000 claims description 5
- 108091000054 Prion Proteins 0.000 claims description 5
- 201000003631 narcolepsy Diseases 0.000 claims description 5
- 201000000980 schizophrenia Diseases 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 229910015900 BF3 Inorganic materials 0.000 claims 4
- 239000000654 additive Substances 0.000 claims 4
- 230000000996 additive effect Effects 0.000 claims 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Substances FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims 4
- 239000003054 catalyst Substances 0.000 claims 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims 2
- ADCOVFLJGNWWNZ-UHFFFAOYSA-N antimony trioxide Chemical compound O=[Sb]O[Sb]=O ADCOVFLJGNWWNZ-UHFFFAOYSA-N 0.000 claims 2
- YKYOUMDCQGMQQO-UHFFFAOYSA-L cadmium dichloride Chemical compound Cl[Cd]Cl YKYOUMDCQGMQQO-UHFFFAOYSA-L 0.000 claims 2
- MXWVIHZQMUONMP-UHFFFAOYSA-N ethoxyboron Chemical compound [B]OCC MXWVIHZQMUONMP-UHFFFAOYSA-N 0.000 claims 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 claims 2
- 229910052725 zinc Inorganic materials 0.000 claims 2
- 239000011701 zinc Substances 0.000 claims 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims 2
- OXOBKZZXZVFOBB-INIZCTEOSA-N (2s)-2-benzhydrylpyrrolidine Chemical compound C1CCN[C@@H]1C(C=1C=CC=CC=1)C1=CC=CC=C1 OXOBKZZXZVFOBB-INIZCTEOSA-N 0.000 claims 1
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims 1
- 239000004411 aluminium Substances 0.000 claims 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 1
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- 239000000908 ammonium hydroxide Substances 0.000 claims 1
- 229910052788 barium Inorganic materials 0.000 claims 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims 1
- 229910052681 coesite Inorganic materials 0.000 claims 1
- 229910052906 cristobalite Inorganic materials 0.000 claims 1
- GDVKFRBCXAPAQJ-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O GDVKFRBCXAPAQJ-UHFFFAOYSA-A 0.000 claims 1
- WNVQCJNZEDLILP-UHFFFAOYSA-N dimethyl(oxo)tin Chemical compound C[Sn](C)=O WNVQCJNZEDLILP-UHFFFAOYSA-N 0.000 claims 1
- 229960001545 hydrotalcite Drugs 0.000 claims 1
- 229910001701 hydrotalcite Inorganic materials 0.000 claims 1
- LNOZJRCUHSPCDZ-UHFFFAOYSA-L iron(ii) acetate Chemical compound [Fe+2].CC([O-])=O.CC([O-])=O LNOZJRCUHSPCDZ-UHFFFAOYSA-L 0.000 claims 1
- 239000002077 nanosphere Substances 0.000 claims 1
- 229910052682 stishovite Inorganic materials 0.000 claims 1
- 229910052905 tridymite Inorganic materials 0.000 claims 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 claims 1
- GPTWCNIDKQZDFF-UHFFFAOYSA-H trizinc;diphosphate;hydrate Chemical compound O.[Zn+2].[Zn+2].[Zn+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GPTWCNIDKQZDFF-UHFFFAOYSA-H 0.000 claims 1
- PBYZMCDFOULPGH-UHFFFAOYSA-N tungstate Chemical compound [O-][W]([O-])(=O)=O PBYZMCDFOULPGH-UHFFFAOYSA-N 0.000 claims 1
- 229940102001 zinc bromide Drugs 0.000 claims 1
- XLOMVQKBTHCTTD-UHFFFAOYSA-N zinc oxide Inorganic materials [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims 1
- 239000011787 zinc oxide Substances 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 abstract description 8
- 208000012902 Nervous system disease Diseases 0.000 abstract description 5
- 208000025966 Neurological disease Diseases 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 241000124008 Mammalia Species 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 235000002639 sodium chloride Nutrition 0.000 description 51
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 22
- 230000000694 effects Effects 0.000 description 20
- 241001465754 Metazoa Species 0.000 description 17
- DDNCQMVWWZOMLN-IRLDBZIGSA-N Vinpocetine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OCC)N5C2=C1 DDNCQMVWWZOMLN-IRLDBZIGSA-N 0.000 description 17
- 229960000744 vinpocetine Drugs 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 14
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 14
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 14
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 14
- 229960002646 scopolamine Drugs 0.000 description 14
- 241000700159 Rattus Species 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 description 12
- 229960002726 vincamine Drugs 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- -1 glutamic Chemical group 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 230000001965 increasing effect Effects 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 210000004556 brain Anatomy 0.000 description 9
- 230000004060 metabolic process Effects 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 208000004454 Hyperalgesia Diseases 0.000 description 8
- 206010012601 diabetes mellitus Diseases 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000002599 functional magnetic resonance imaging Methods 0.000 description 6
- 230000013016 learning Effects 0.000 description 6
- 108010088694 phosphoserine aminotransferase Proteins 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000002503 metabolic effect Effects 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- VKTOXAGUZWAECL-OALUTQOASA-N eburnamenine Natural products C1=CC=C2C(CCN3CCC4)=C5[C@H]3[C@]4(CC)C=CN5C2=C1 VKTOXAGUZWAECL-OALUTQOASA-N 0.000 description 4
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthene Chemical compound C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 230000001771 impaired effect Effects 0.000 description 4
- 210000001853 liver microsome Anatomy 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 210000002442 prefrontal cortex Anatomy 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 125000003831 tetrazolyl group Chemical group 0.000 description 4
- VKTOXAGUZWAECL-UHFFFAOYSA-N trans-eburnamenine Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)C=CN5C2=C1 VKTOXAGUZWAECL-UHFFFAOYSA-N 0.000 description 4
- 239000004381 Choline salt Substances 0.000 description 3
- HONLKDDLTAZVQV-NZSAHSFTSA-N Eburnamine Chemical group C1=CC=C2C(CCN3CCC4)=C5[C@H]3[C@@]4(CC)C[C@@H](O)N5C2=C1 HONLKDDLTAZVQV-NZSAHSFTSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 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 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 208000035154 Hyperesthesia Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000000540 analysis of variance Methods 0.000 description 3
- 230000003070 anti-hyperalgesia Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 235000019417 choline salt Nutrition 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 229960004132 diethyl ether Drugs 0.000 description 3
- VKTOXAGUZWAECL-RBUKOAKNSA-N eburnamenine Chemical class C1=CC=C2C(CCN3CCC4)=C5[C@H]3[C@@]4(CC)C=CN5C2=C1 VKTOXAGUZWAECL-RBUKOAKNSA-N 0.000 description 3
- 229940093499 ethyl acetate Drugs 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000006386 memory function Effects 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 238000002203 pretreatment Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 238000010159 Duncan test Methods 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 238000011785 NMRI mouse Methods 0.000 description 2
- 241000009328 Perro Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 241000863486 Vinca minor Species 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- 235000012216 bentonite Nutrition 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000036983 biotransformation Effects 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 230000001149 cognitive effect Effects 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000010437 gem Substances 0.000 description 2
- 230000000004 hemodynamic effect Effects 0.000 description 2
- 210000001320 hippocampus Anatomy 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 150000003248 quinolines Chemical class 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 238000009491 slugging Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
- KKAJSJJFBSOMGS-UHFFFAOYSA-N 3,6-diamino-10-methylacridinium chloride Chemical compound [Cl-].C1=C(N)C=C2[N+](C)=C(C=C(N)C=C3)C3=CC2=C1 KKAJSJJFBSOMGS-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-M 3-carboxynaphthalen-2-olate Chemical compound C1=CC=C2C=C(C([O-])=O)C(O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000208327 Apocynaceae Species 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 101001117089 Drosophila melanogaster Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1 Proteins 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000237858 Gastropoda Species 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 1
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 206010057040 Temperature intolerance Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 238000010162 Tukey test Methods 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 208000012886 Vertigo Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940090805 clavulanate Drugs 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- ACYGYJFTZSAZKR-UHFFFAOYSA-J dicalcium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Ca+2].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O ACYGYJFTZSAZKR-UHFFFAOYSA-J 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 229950000206 estolate Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 229940052303 ethers for general anesthesia Drugs 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000008543 heat sensitivity Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 150000002680 magnesium Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000007427 paired t-test Methods 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 238000011302 passive avoidance test Methods 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- QPMDWIOUHQWKHV-ODZAUARKSA-M potassium;(z)-4-hydroxy-4-oxobut-2-enoate Chemical compound [K+].OC(=O)\C=C/C([O-])=O QPMDWIOUHQWKHV-ODZAUARKSA-M 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229950002757 teoclate Drugs 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 238000002560 therapeutic procedure 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
- 230000000699 topical effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 231100000889 vertigo Toxicity 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000008979 vitamin B4 Nutrition 0.000 description 1
- 239000011579 vitamin B4 Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
- 230000002034 xenobiotic effect Effects 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
Definitions
- the field of this invention relates to a new diaza-benzofluoranthene derivative, a novel pharmaceutically applicable compound of formula (I), 16-tetrazolyl-eburnamenine.
- the field of this invention also relates to the pharmaceutically acceptable salts, hydrates and solvates of the compound of formula (I), and the hydrates and solvates of the pharmaceutically acceptable salts of formula (I).
- the field of this invention also relates to pharmaceutical compositions containing compound of formula (I), to preparation processes and new intermediate compounds thereof.
- the field of this invention also relates to the use of the compound of formula (I) in relieving, treating or preventing a variety of neurological, neurodegenerative and psychiatric diseases such as Alzheimer's disease, Parkinson's disease, Attention deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age Related Memory Dysfunction, Down Syndrome, Epilepsy, Stroke, Autism, Cerebral Ischemia, Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt-Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease, Substance Induced Cognitive Impairment, Narcolepsy, and Neuropathy of various origin, including, but not limited to Diabetic Neuropathy, as well as for the treatment of Pain (in particular Neuropathic Pain and Inflammatory Pain) and painful conditions.
- Pain in particular Neuropathic Pain and Inflammatory Pain
- painful conditions
- the eburnamine-vincamine alkaloids occur in the Apocynaceae plant family. Many eburnamine structures are pharmacologically active and exert diverse effects in the living body, the range expanding from antitumor activity through circulatory effects to cerebroprotection and on.
- Vincamine was first isolated from the leaves of Vinca minor in 1950 (Trudy nauchno- issledovatelnogo instituta lekatstvennych rajtenij. Moscow 1950;10:29-33). Studies ⁇ Compt Rend Soc Biol 1954;148: 1082-1086; Ann Pharm Fr 1955;13:328-333) demonstrated the beneficial effect of vincamine on circulation by decreasing arterial blood pressure, cardiac output, and heart rate. Subjective complaints of patients (dizziness, headache, vertigo) improved after vincamine administration and this was explained by supposing that vincamine dilated the cerebral vessels (Ther Hung 1965;13:3-6). Fischhof et al. (Neuropsychobiology 1996;34:29-35) reported on their study on the therapeutic effect of vincamine in the treatment of primary degenerative and vascular dementia.
- Vincamine is readily absorbed after oral administration in man (t max appr. 90 min) and its elimination half-life is approximately 2 hr. Vincamine undergoes largely to metabolism, only 6-7% of the parent compound is eliminated unchanged with urine. The main route of metabolism of vincamine is ester cleavage (Eur J Drug Metab Pharmacokin 1985;10:89- 103).
- vinpocetine ethylapovincaminate
- Vinpocetine has been used now for decades for prevention and treatment of cerebrovascular diseases predisposing to development of dementia. Animal experiments have demonstrated a beneficial effect of vinpocetine on memory and learning deficits induced by scopolamine and hypoxia (Pharmacology, Biochemistry and Behaviour 1986;24: 1123-1128; Pharmacology, Biochemistry and Behaviour 1987;26: 183-186.). Vinpocetine has also been claimed to enhance memory function in young healthy volunteers (Drug Development and Research 1988;14:191-193)
- Vinpocetine is also known of its hemodynamic effect, especially increasing cerebral blood flow in brain. Probably an improved microvascular circulation could be a favourable effect in diabetic peripheral neuropathy (DPN).
- DPN diabetic peripheral neuropathy
- DPN is the most common complication associated with diabetes and may affect the nervous system throughout the human body. Vinpocetine can selectively improve the blood flow in ischemic peripheral nerves through multiple actions, thus ameliorating the clinical symptoms of DPN fundamentally (Chinese Journal of New Drugs, 2009;18: 1415-1418).
- Vinpocetine is readily absorbed after oral administration in man, and subject of first pass metabolism.
- the main route of metabolism in man - similarly to vincamine - is the ester hydrolysis (Eur J Clin Pharmacol 1987;33:185-189).
- 16-tetrazolyl-eburnamenine contains an acidic moiety (tetrazolyl ring) beside the basic nitrogen of the eburnamenine skeleton.
- the 16- tetrazolyl-eburnamenine was effective in a mouse cognitive impairment model and caused an increased hemodynamic response in the prefrontal cortex and the ventral hypothalamic area of the brain. 16-tetrazolyl-eburnamenine had a superior effect compared with vinpocetine in diabetic neuropathic pain model in mice.
- 16-Tetrazolyl-eburnamenine has high metabolic stability. This feature could lead to a stable and optimal human oral bioavailability as a therapeutic advantage.
- the present invention relates to a new 16-tetrazolyl-eburnamenine of formula (I)
- the invention also relates to the pharmaceutical compositions containing the compound of formula (I) or hydrates or solvates thereof as active ingredient.
- the present invention in another aspect of the present invention are the synthesis of compounds of formula (I), and the chemical and pharmaceutical manufacture of medicaments containing these compounds, as well as the methods of treatment with these compounds, which means administering to a mammal to be treated - including human - effective amount/amounts of compounds of formula (I) of the present invention as such or as medicament.
- the present invention also relates to the pharmaceutical compositions comprising a therapeutically effective amount of compound of formula (I) or pharmaceutically acceptable salts thereof as active ingredient.
- a pharmaceutical composition comprising a therapeutically effective amount of compound of formula (I) or salt thereof and one or more pharmaceutically acceptable carrier and/or diluent.
- the present invention also relates to the process for manufacturing of the pharmaceutical compositions by mixing a therapeutically effective amount of a compound of formula (I) as active ingredient and a pharmaceutically acceptable carrier and/or diluent.
- a method for the treatment of neurological, neurodegenerative and psychiatric disease or condition comprising the step of administering to human, in need of such treatment and/or prophylaxis a pharmaceutical composition comprising a therapeutically effective amount of compound of formula (I) or pharmaceutically acceptable salts thereof alone or together with at least one and a pharmaceutically acceptable carrier and/or diluent.
- the said treatment and/or prophylaxis methods are used for the treatment of neurological, neurodegenerative and psychiatric disease or condition as Alzheimer's disease, Parkinson's disease, Attention deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age Related Memory Dysfunction, Down Syndrome, Epilepsy, Stroke, Autism, Cerebral Ischemia, Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt-Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease, Substance Induced Cognitive Impairment, Narcolepsy, and Neuropathy of various origin, including, but not limited to Diabetic Neuropathy, as well as for the treatment of Pain (in particular Neuropathic Pain and Inflammatory Pain) and painful conditions.
- Pain in particular Neuropathic Pain and Inflammatory Pain
- the present invention provides an industrially applicable process for the preparation of compound of formula (I).
- DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new 16-tetrazolyl-eburnamenine of formula (I)
- the salts of the present invention are pharmaceutically acceptable salts.
- Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compound of this invention.
- Salts of the compounds of the present invention may comprise acid addition salts.
- the salts are formed from pharmaceutically acceptable inorganic and organic acids.
- suitable acid salts include maleic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumic, acetic, propionic, succinic, glycolic, formic, lactic, aleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methansulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonic, hydroxynaphthoic, hydroiodic, malic, teroic, tannic, and the like.
- the salts of the present invention are pharmaceutically acceptable salts.
- Salts encompassed within the term "pharmaceutically acceptable salts" refer to nontoxic salts of the compound of this invention.
- Salts of the compound of the present invention may comprise base addition salts, as well, because of the acidic character of the tetrazolyl group.
- Salts derived from appropriate bases include alkali metal (e.g. sodium, potassium, lithium), alkaline earth metal (e.g. magnesium) salts.
- Physiologically acceptable salts of a compound with a tetrazolyl group include the anion of said compound in
- Preferred salts include sodium, calcium, potassium, lithium, magnesium.
- salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, a
- salts which are not pharmaceutically acceptable, may be useful in the preparation of the compound of this invention and these should be considered to form a further aspect of the invention.
- These salts such as oxalic or trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compound of the invention and their pharmaceutically acceptable salts.
- the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
- the novel compound of formula (I) may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being affected. Also in the description of the synthetic methods described below, it is understood that all proposed reaction conditions, including solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be conditions standard for that reaction, which should be readily recognized by one skilled in art.
- One skilled in art of organic synthesis understands that the functionality present on various portions of the edict molecule must be compatible with formula (I) falling into a given class may be compatible with some of the reaction conditions required in some of the methods described.
- 16-Tetrazolyl-eburnamenine of formula (I) of the invention can be prepared according to the following scheme shown below.
- the compound of formula (I) may be prepared by the reaction sequence presented on Scheme 1. Briefly, amide formation from the corresponding acid (J. Med. Chem. 51, 2008, 479-486; Chinese Journal of Natural Medicines 9, 2011; 51-57), can be followed by a demutation with POCI 3 yielding the corresponding nitrile. Reactions of the nitrile with sodium azide can provide the desired tetrazole formula (I).
- the invention further provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) or pharmaceutically acceptable salt thereof and one or more carriers and/or diluents in the pharmaceutical arts (also referred to as excipients).
- the excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).
- a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) the compound of formula (I) or salt thereof with at least one excipient.
- 16-tetrazolyl-eburnamenine, its salts and hydrate and solvate modifications can also be processed as a cyclodextrin complex or a solid dispersion form.
- compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose.
- a unit may contain a therapeutically effective dose of the compound of formula (I) or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose.
- Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
- such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.
- compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
- oral including buccal or sublingual
- rectal nasal
- topical including buccal, sublingual, or transdermal
- vaginal or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
- parenteral including subcutaneous, intramuscular, intravenous, or intradermal
- compositions When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or nonaqueous liquids; edible foams or whips; oil-in-water liquid emulsions or water-in-oil liquid emulsions.
- the compound or salt thereof of the invention or the pharmaceutical composition of the invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a "quick-dissolve" medicine.
- the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
- an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
- Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.
- Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin or non-gelatinous sheaths.
- Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation.
- a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested.
- suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
- Suitable binders include starch, gelatin, natural sugars, such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
- Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
- Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
- Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
- a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
- a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone
- a solution retardant such as paraffin
- a resorption accelerator such as a quaternary salt
- an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
- the powder mixture can be granulated by wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
- a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials
- the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
- the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets.
- the compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
- a clear opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or polymeric material, and a polish coating of wax can be provided.
- Dyestuffs can be added to these coatings to distinguish different dosages.
- Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient.
- Syrups can be prepared by dissolving the compound or salt thereof of the invention in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
- Suspensions can be formulated by dispersing the compound or salt of the invention in a non-toxic vehicle.
- Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.
- dosage unit formulations for oral administration can be microencapsulated.
- the formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.
- tablets and capsules are preferred for delivery of the pharmaceutical composition.
- 16-tetrazolyl-eburnamine and salts, hydrates, solvates thereof provides excellent possibility for transdermal use, as well, e.g. in forms of gels, creams, ointments, pastes or patches.
- treatment includes prophylaxis and refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject.
- Prophylaxis or prevention or delay of disease onset is typically accomplished by administering a drug in the same or similar manner as one would do to a patient with the developed disease or condition.
- the present invention provides a method of treatment of a human, suffering from a variety of neurological, neurodegenerative and psychiatric diseases such as Alzheimer's disease, Parkinson's disease, Attention deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age Related Memory Dysfunction, Down Syndrome, Epilepsy, Stroke, Autism, Cerebral Ischemia, Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt- Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease, Substance Induced Cognitive Impairment, Narcolepsy, and Neuropathy of various origin, including, but not limited to Diabetic Neuropathy, as well as for the treatment of Pain (in particular Neuropathic Pain and Inflammatory Pain) and painful conditions.
- Pain in particular Neuropathic Pain and Inflammatory Pain
- Such treatment comprises the step of administering a therapeutically effective amount of the compound of formula (I) or salt thereof to a human, in need of such treatment.
- Treatment can also comprise the step of administering a therapeutically effective amount of a pharmaceutical composition containing the compound of formula (I) or salt thereof to a human in need of such treatment.
- the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
- therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
- therapeutically effective amounts of the compound of formula (I), as well as salts thereof may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.
- the precise therapeutically effective amount of the compound or salt thereof of the invention will depend on a number of factors, including, but not limited to, the age and weight of the subject (patient) being treated, the precise disorder requiring treatment and its severity, the nature of the pharmaceutical formulation/composition, and route of administration, and will ultimately be at the discretion of the attending physician or veterinarian.
- the compound of formula (I) or salt thereof will be given for the treatment in the range of about 0.1 to 100 mg/kg body weight of recipient (patient, mammal) per day and more usually in the range of 0.1 to 10 mg/kg body weight per day.
- Acceptable daily dosages may be from about 1 to about 1000 mg/day, and preferably from about 1 to about 100 mg/day.
- This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub- doses per day such that the total daily dose is the same.
- An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se. Similar dosages should be appropriate for treatment, including prophylaxis, of the other conditions referred herein for treatment. In general, determination of appropriate dosing can be readily arrived at by one skilled in medicine or the pharmacy art.
- the two-trial place recognition test is based on the spontaneous inclination of rodents to explore a novel environment in a Y-maze ⁇ Brain Res 1992;588: 132-139).
- the learning task was carried out in a transparent plastic Y-maze (40 cm length, 12 cm width and 30 cm height). Numerous visual cues were placed around the arms and were kept constant during the experiment. The test consisted of two trials (Tl and T2) separated by intertrial intervals of 30 min. Mice were placed in the starting arm of the maze at the beginning of each trial. In Tl one of the symmetric arms of the maze were closed (it will be novel in T2) and the animals were allowed to explore the maze for 5 min (acquisition phase). In T2 mice had free access to all three arms for 2 min (retrieval phase). The time spent in each arm (novel and familiar) was measured separately by stopwatches.
- mice are able to discriminate between novel and familiar arms of a Y-maze, while post-acquisition injection of scopolamine impairs the place recognition memory and the improving effect of a compound can be investigated.
- 1 mg/kg dose of scopolamine was injected intraperitoneally.
- the protective effect of 16-tetrazolyl-eburnamine formula (I) was tested at oral doses of 10, 20 and 40 mg/kg given 60 min prior to the acquisition trial in a volume of 10 ml/kg.
- DI discrimination index
- Thermal hyperalgesia is a symptom of diabetic neuropathy (DN) in humans. Although only a subpopulation in DN patients shows this symptom, it is present more frequently in DN, than in other types of neuropathy ⁇ Diabetes Care 2000;23:510-517).
- DN diabetic neuropathy
- To model thermal hyperalgesia in animals we used diabetic mice and measured heat sensitivity by determining the temperature threshold that evokes withdrawal of the tail in an increasing temperature water bath (Eur J Pharmacol. 2007;564 (l-3):80-87). We tested if 16-tetrazolyl- eburnamenine formula (I) could reverse this thermal hyperalgesia.
- 16-tetrazolyl-eburnamenine formula (I) or the vehicle (2% ascorbic acid in saline) was administered orally, by gavage with treatment volume of 10 ml/kg.
- ThT thermal threshold
- mice were held in the palm of the hand with cotton-knitted gloves. About two thirds of the tail was immersed into the increasing temperature water bath generated by a SensoStress EXP-PL-1 device (Experimetria Ltd., Hungary). The initial temperature was set as 40 °C and was increased by 24 °C/min. At the point when the tail was withdrawn, the measurement was interrupted by a foot-switch, and the withdrawal temperature was then recorded. The cut-off temperature was considered as 50 °C.
- the poor quality EPIP pictures are fitted to these anatomical scans to localize the activity changes.
- the pretreatment time with 16-tetrazolyl-eburnamenine of formula (I) was 1 hour. Only one experiment with a double drug administration (pretreatment i.p. and provocation drug i.v.) was performed with each animal. Following 1000 sec control scanning period drugs were administered i.v. through a remote-operated pre-inserted cannula. Passive avoidance learning in scopolamine-treated rats
- the aim of the experiments was to investigate the effects of acute 16-tetrazolyl-eburnamenine of formula (I) treatment on attention and memory function of adult rats in passive avoidance learning.
- the memory function was impaired by scopolamine pre- treatment.
- Passive avoidance test was performed in an apparatus consisted of two compartments: one light and one dark (22 cm long, 20 cm wide and 25 cm high each) connected by a guillotine door.
- rats were put into in the dark compartment.
- habituation animals were put into the light compartment and allowed to enter the dark one where they stayed another 3 min (acquisition trial 1).
- animals were placed in the light compartment and the guillotine door was opened (acquisition trial 2). After being allowed to stay in the dark compartment for 3 min rats were replaced to the light compartment again. Latency to entering the dark was registered (acquisition trial 3).
- Enzyme catalyzed biotransformation (metabolism) of drugs can severely affect plasma levels and so determine drug amount available for pharmacological effect.
- the major place of drug metabolism in humans is the liver and in case of most drugs it is mainly mediated by cytochrome P450 enzymes.
- the most basic tool for determination of metabolic fate is incubation of drugs with a fraction of liver called microsomes which is rich in xenobiotic metabolizing CYPs, flavine monooxygenases (FMOs) and in several non-specific hydrolases.
- FMOs flavine monooxygenases
- metabolism of drugs can be characterized by the intrinsic clearance of parent drug which reflects the rate of drug removal by biotransformation.
- Figure 1 shows the time course of the anti-hyperalgesic effect of 16-tetrazolyl-eburnamenine. Shown are mean and SEM of thermal threshold data of diabetic mice treated with vehicle, 5 mg/kg and 10 mg/kg p.o. doses of 16-tetrazolyl-eburnamenine formula (I).
- Figure 2 shows the dose dependent anti-hyperalgesic effect of 16-tetrazolyl-eburnamenine formula (I) compared to vinpocetine in model of diabetic neuropathy in mice;
- Figure 3 shows the BOLD effect of 16-tetrazolyl-eburnamenine formula (I) in rat brain.
- Figure 4 shows the effect of 16-tetrazolyl-eburnamenine formula (I) pretreatment on the scopolamine (1 mg/kg, i.v.) evoked BOLD response decrease in prefrontal cortex.
- the compound of formula (I) can be prepared in accordance with the general knowledge of one skilled in the art and/or using methods set forth in the Example and/or Intermediate sections that follow. Solvents, temperatures, pressures, and other reaction conditions can readily be selected by one of ordinary skill in the art. Starting materials are commercially available and/or readily prepared by one skilled in the art.
- thermal threshold (ThT) was measured before, and 60, 120, and 180 min after administration of 16-tetrazolyl-eburnamenine formula (I).
- Anti-hyperalgesic effect was characterized by calculating percentage reversal of thermal hyperalgesia from group mean values, at the time of maximum effect (Tmax) according to the following formula:
- ThT is the mean thermal threshold value of the group in °C
- 16-tetrazolyl-eburnamenine formula (I) produced a dose dependent and, at the higher dose, statistically significant reversal of thermal hyperalgesia. Maximal effects were observed 120 min post-dose as 34, and 85% reversal of hyperalgesia for the 5 and 10 mg/kg dose, respectively. It can be concluded that these results support possible utility of 16-tetrazolyl-eburnamenine formula (I) in diabetic neuropathy.
- Figure 2. shows effect of 16-tetrazolyl-eburnamenine formula (I) compared to vinpocetine.
- the 5 and 10 mg/kg doses of 16-tetrazolyl-eburnamenine formula (I) produced 34% and 85% reversal of hyperalgesia, while the same doses of vinpocetine produced 49% and 57% reversal, respectively.
- the effect was not further increased (57%).
- 16-tetrazolyl-eburnamenine formula (I) caused clear BOLD increase in the area of cortex, thalamus and hippocampus (see Figure 3.). Increased BOLD marks increased function of the parts of the brain.
- scopolamine was used as a provocation drug.
- the intravenously administered scopolamine decreased the BOLD responses in the prefrontal cortex, but it had no visible effect in the hippocampus.
- One hour pretreatment with 16-tetrazolyl-eburnamenine formula (I) prevented inhibitory effect of scopolamine in the prefrontal cortex.
- Step through latency (STL) time of experimental animals was measured 1, 4 and 11 days after receiving electric shock during the learning trial.
- the effect of treatments with 16-tetrazolyl- eburnamenine formula (I) resulted in significant changes in this parameter revealed.
- the next table shows Intrinsic clearance (Cli nt ) of 16-tetrazolyl-eburnamenine of formula (I) in a pools of human, dog, rat and mouse liver microsomes.
- the 16-tetrazolyl-eburnamenine formula (I) is a low metabolic clearance compound in human, dog and rat liver microsomes; consumption of 16-tetrazolyl-eburnamenine formula (I) was not observed without NADPH; therefore extrahepatic (non CYP/FMO mediated metabolism) is not expected either. In mouse liver microsomes high metabolic clearance was obtained.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Neurology (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a new 16-tetrazolyl-eburnamenine of formula (I) or pharmaceutically acceptable salt thereof and/or hydrates and/or solvates thereof. The invention also relates to the pharmaceutical compositions containing the compound of formula (I) or hydrates or solvates thereof as active ingredient. The invention also relates to the synthesis of compounds of formula (I), and the chemical and pharmaceutical manufacture of medicaments containing these compounds, as well as the methods of treatment of mammals - including human - with these compounds. There is still further provided methods for the treatment of neurological, neurodegenerative and psychiatric diseases or conditions as well as comprising the step of administering to human, in need of such treatment and/or prophylaxis a pharmaceutical composition comprising a therapeutically effective amount of compound of formula (I) or pharmaceutically acceptable salts thereof alone or together with at least one and a pharmaceutically acceptable carrier and/or diluent.
Description
A new diaza-benzofluoranthene derivative as drug
FIELD OF THE INVENTION
The field of this invention relates to a new diaza-benzofluoranthene derivative, a novel pharmaceutically applicable compound of formula (I), 16-tetrazolyl-eburnamenine.
The field of this invention also relates to the pharmaceutically acceptable salts, hydrates and solvates of the compound of formula (I), and the hydrates and solvates of the pharmaceutically acceptable salts of formula (I).
The field of this invention also relates to pharmaceutical compositions containing compound of formula (I), to preparation processes and new intermediate compounds thereof.
The field of this invention also relates to the use of the compound of formula (I) in relieving, treating or preventing a variety of neurological, neurodegenerative and psychiatric diseases such as Alzheimer's disease, Parkinson's disease, Attention deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age Related Memory Dysfunction, Down Syndrome, Epilepsy, Stroke, Autism, Cerebral Ischemia, Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt-Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease, Substance Induced Cognitive Impairment, Narcolepsy, and Neuropathy of various origin, including, but not limited to Diabetic Neuropathy, as well as for the treatment of Pain (in particular Neuropathic Pain and Inflammatory Pain) and painful conditions.
BACKGROUND OF THE INVENTION
The eburnamine-vincamine alkaloids occur in the Apocynaceae plant family. Many eburnamine structures are pharmacologically active and exert diverse effects in the living body, the range expanding from antitumor activity through circulatory effects to cerebroprotection and on.
Vincamine Vinpocetine
Vincamine was first isolated from the leaves of Vinca minor in 1950 (Trudy nauchno- issledovatelnogo instituta lekatstvennych rajtenij. Moscow 1950;10:29-33). Studies {Compt Rend Soc Biol 1954;148: 1082-1086; Ann Pharm Fr 1955;13:328-333) demonstrated the beneficial effect of vincamine on circulation by decreasing arterial blood pressure, cardiac output, and heart rate. Subjective complaints of patients (dizziness, headache, vertigo) improved after vincamine administration and this was explained by supposing that vincamine dilated the cerebral vessels (Ther Hung 1965;13:3-6). Fischhof et al. (Neuropsychobiology 1996;34:29-35) reported on their study on the therapeutic effect of vincamine in the treatment of primary degenerative and vascular dementia.
Vincamine is readily absorbed after oral administration in man (tmax appr. 90 min) and its elimination half-life is approximately 2 hr. Vincamine undergoes largely to metabolism, only 6-7% of the parent compound is eliminated unchanged with urine. The main route of metabolism of vincamine is ester cleavage (Eur J Drug Metab Pharmacokin 1985;10:89- 103).
The most extensively studied compound with eburnamine structure is vinpocetine (ethylapovincaminate), a derivative of the Vinca minor alkaloid vincamine. Vinpocetine has been used now for decades for prevention and treatment of cerebrovascular diseases
predisposing to development of dementia. Animal experiments have demonstrated a beneficial effect of vinpocetine on memory and learning deficits induced by scopolamine and hypoxia (Pharmacology, Biochemistry and Behaviour 1986;24: 1123-1128; Pharmacology, Biochemistry and Behaviour 1987;26: 183-186.). Vinpocetine has also been claimed to enhance memory function in young healthy volunteers (Drug Development and Research 1988;14:191-193)
A series of publications reveals that the effects of vinpocetine are primarily connected to the inhibition of voltage dependent Na+ and Ca2+ channels, the interaction with the glutamate receptors and the inhibition of PDE1 leading to the increase of cAMP and especially cGMP (Eur J Pharmacol 1996;314:69-73, Brain Res Bull 2000;53:245-254, Med Res Rev 2005;53:737-757).
Vinpocetine is also known of its hemodynamic effect, especially increasing cerebral blood flow in brain. Probably an improved microvascular circulation could be a favourable effect in diabetic peripheral neuropathy (DPN).
DPN is the most common complication associated with diabetes and may affect the nervous system throughout the human body. Vinpocetine can selectively improve the blood flow in ischemic peripheral nerves through multiple actions, thus ameliorating the clinical symptoms of DPN fundamentally (Chinese Journal of New Drugs, 2009;18: 1415-1418).
Vinpocetine is readily absorbed after oral administration in man, and subject of first pass metabolism. The main route of metabolism in man - similarly to vincamine - is the ester hydrolysis (Eur J Clin Pharmacol 1987;33:185-189). These results revealed that improving the pharmacokinetic profile beside keeping the pharmacodynamic profile of the above mentioned eburnamine derivatives would be advantageous, and such compounds would be needed in the art.
Therefore we prepared differently substituted eburnamenine derivatives on the C16 atom of the skeleton (phylogenetic ring numbering refers to Experientia, 1965;21:508). The prepared compounds were investigated in terms of physicochemical, ADME (Absorption Distribution Metabolism Excretion) and pharmacodynamic profile. During these trials we noticed surprisingly that the compound formed with the exchange of the metabolically liable ester
group to a tetrazolyl moiety on the eburnamenine skeleton, the compound of formula (I), 16- tetrazolyl-eburnamine has some superior biological effects.
In contrast to vinpocetine and vincamine, 16-tetrazolyl-eburnamenine contains an acidic moiety (tetrazolyl ring) beside the basic nitrogen of the eburnamenine skeleton. The 16- tetrazolyl-eburnamenine was effective in a mouse cognitive impairment model and caused an increased hemodynamic response in the prefrontal cortex and the ventral hypothalamic area of the brain. 16-tetrazolyl-eburnamenine had a superior effect compared with vinpocetine in diabetic neuropathic pain model in mice.
16-Tetrazolyl-eburnamenine has high metabolic stability. This feature could lead to a stable and optimal human oral bioavailability as a therapeutic advantage.
SUMMARY OF THE INVENTION
In one aspect the present invention relates to a new 16-tetrazolyl-eburnamenine of formula (I)
(I) or pharmaceutically acceptable salt thereof and/or hydrates and/or solvates thereof.
In another aspect the invention also relates to the pharmaceutical compositions containing the compound of formula (I) or hydrates or solvates thereof as active ingredient.
In another aspect of the present invention are the synthesis of compounds of formula (I), and the chemical and pharmaceutical manufacture of medicaments containing these compounds, as well as the methods of treatment with these compounds, which means administering to a mammal to be treated - including human - effective amount/amounts of compounds of formula (I) of the present invention as such or as medicament.
In another aspect the present invention also relates to the pharmaceutical compositions comprising a therapeutically effective amount of compound of formula (I) or pharmaceutically acceptable salts thereof as active ingredient. Further, there is provided a pharmaceutical composition comprising a therapeutically effective amount of compound of formula (I) or salt thereof and one or more pharmaceutically acceptable carrier and/or diluent.
In another aspect the present invention also relates to the process for manufacturing of the pharmaceutical compositions by mixing a therapeutically effective amount of a compound of formula (I) as active ingredient and a pharmaceutically acceptable carrier and/or diluent.
In another aspect there is still further provided a method for the treatment of neurological, neurodegenerative and psychiatric disease or condition as well as comprising the step of administering to human, in need of such treatment and/or prophylaxis a pharmaceutical composition comprising a therapeutically effective amount of compound of formula (I) or pharmaceutically acceptable salts thereof alone or together with at least one and a pharmaceutically acceptable carrier and/or diluent. Particularly, the said treatment and/or prophylaxis methods are used for the treatment of neurological, neurodegenerative and psychiatric disease or condition as Alzheimer's disease, Parkinson's disease, Attention deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age Related Memory Dysfunction, Down Syndrome, Epilepsy, Stroke, Autism, Cerebral Ischemia, Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt-Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease, Substance Induced Cognitive Impairment, Narcolepsy, and Neuropathy of various origin, including, but not limited to Diabetic Neuropathy, as well as for the treatment of Pain (in particular Neuropathic Pain and Inflammatory Pain) and painful conditions.
Furthermore, in another embodiment the present invention provides an industrially applicable process for the preparation of compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new 16-tetrazolyl-eburnamenine of formula (I)
(I) or pharmaceutically acceptable salt thereof and/or hydrates and/or solvates thereof.
It will be understood by those skilled in the art that the compound of the present invention may also be utilized in the form of a pharmaceutically acceptable salt thereof.
Both organic and inorganic acids can be used for the formation of pharmaceutically acceptable acid addition salts of formula (I).
Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compound of this invention. Salts of the compounds of the present invention may comprise acid addition salts. In general, the salts are formed from pharmaceutically acceptable inorganic and organic acids. More specific examples of suitable acid salts include maleic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumic, acetic, propionic, succinic, glycolic, formic, lactic, aleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methansulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonic, hydroxynaphthoic, hydroiodic, malic, teroic, tannic, and the like.
Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to nontoxic salts of the compound of this invention. Salts of the compound of the present invention may comprise base addition salts, as well, because of the acidic character of the
tetrazolyl group. Salts derived from appropriate bases include alkali metal (e.g. sodium, potassium, lithium), alkaline earth metal (e.g. magnesium) salts. Physiologically acceptable salts of a compound with a tetrazolyl group include the anion of said compound in
combination with a suitable cation such as Na+, K+, Li+ and Mg2+. Preferred salts include sodium, calcium, potassium, lithium, magnesium.
Other representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, valerate and choline salts.
Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of the compound of this invention and these should be considered to form a further aspect of the invention. These salts, such as oxalic or trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compound of the invention and their pharmaceutically acceptable salts.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The novel compound of formula (I) may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being affected. Also in the description of the synthetic methods described below, it is understood that all proposed reaction conditions, including solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be conditions standard for that reaction, which should be readily recognized by one skilled in art. One skilled in art of organic synthesis understands that the functionality present on various portions of the edict
molecule must be compatible with formula (I) falling into a given class may be compatible with some of the reaction conditions required in some of the methods described.
16-Tetrazolyl-eburnamenine of formula (I) of the invention can be prepared according to the following scheme shown below.
According to the invention the compound of formula (I) may be prepared by the reaction sequence presented on Scheme 1. Briefly, amide formation from the corresponding acid (J. Med. Chem. 51, 2008, 479-486; Chinese Journal of Natural Medicines 9, 2011; 51-57), can be followed by a dehidratation with POCI3 yielding the corresponding nitrile. Reactions of the nitrile with sodium azide can provide the desired tetrazole formula (I).
Scheme 1.
The invention further provides a pharmaceutical composition comprising a compound of formula (I) or pharmaceutically acceptable salt thereof and one or more carriers and/or diluents in the pharmaceutical arts (also referred to as excipients). The excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).
In accordance with another aspect of the invention there is provided a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) the compound
of formula (I) or salt thereof with at least one excipient. 16-tetrazolyl-eburnamenine, its salts and hydrate and solvate modifications can also be processed as a cyclodextrin complex or a solid dispersion form.
Pharmaceutical compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose. Such a unit may contain a therapeutically effective dose of the compound of formula (I) or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.
Pharmaceutical compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the excipient(s).
When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or nonaqueous liquids; edible foams or whips; oil-in-water liquid emulsions or water-in-oil liquid emulsions. The compound or salt thereof of the invention or the pharmaceutical composition of the invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a "quick-dissolve" medicine.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.
Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin or non-gelatinous sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different dosages. Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient. Syrups can be prepared by dissolving the
compound or salt thereof of the invention in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound or salt of the invention in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.
Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.
In the present invention, tablets and capsules are preferred for delivery of the pharmaceutical composition. However, 16-tetrazolyl-eburnamine and salts, hydrates, solvates thereof provides excellent possibility for transdermal use, as well, e.g. in forms of gels, creams, ointments, pastes or patches.
As used herein, the term "treatment" includes prophylaxis and refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject. Prophylaxis (or prevention or delay of disease onset) is typically accomplished by administering a drug in the same or similar manner as one would do to a patient with the developed disease or condition.
The present invention provides a method of treatment of a human, suffering from a variety of neurological, neurodegenerative and psychiatric diseases such as Alzheimer's disease, Parkinson's disease, Attention deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age Related Memory Dysfunction, Down Syndrome, Epilepsy, Stroke, Autism, Cerebral Ischemia, Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt- Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease, Substance Induced Cognitive Impairment, Narcolepsy, and Neuropathy of various origin, including, but not limited to Diabetic Neuropathy, as well as for the treatment of Pain (in particular Neuropathic Pain and Inflammatory Pain) and painful conditions. Such treatment comprises the step of
administering a therapeutically effective amount of the compound of formula (I) or salt thereof to a human, in need of such treatment. Treatment can also comprise the step of administering a therapeutically effective amount of a pharmaceutical composition containing the compound of formula (I) or salt thereof to a human in need of such treatment. As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
The term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, therapeutically effective amounts of the compound of formula (I), as well as salts thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.
The precise therapeutically effective amount of the compound or salt thereof of the invention will depend on a number of factors, including, but not limited to, the age and weight of the subject (patient) being treated, the precise disorder requiring treatment and its severity, the nature of the pharmaceutical formulation/composition, and route of administration, and will ultimately be at the discretion of the attending physician or veterinarian. Typically, the compound of formula (I) or salt thereof will be given for the treatment in the range of about 0.1 to 100 mg/kg body weight of recipient (patient, mammal) per day and more usually in the range of 0.1 to 10 mg/kg body weight per day. Acceptable daily dosages may be from about 1 to about 1000 mg/day, and preferably from about 1 to about 100 mg/day. This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub- doses per day such that the total daily dose is the same. An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se. Similar dosages should be appropriate for treatment, including prophylaxis, of the other conditions referred herein for treatment. In general, determination of appropriate dosing can be readily arrived at by one skilled in medicine or the pharmacy art.
ASSAY METHODS:
Mouse cognitive impairment model
Method: The two-trial place recognition test is based on the spontaneous inclination of rodents to explore a novel environment in a Y-maze {Brain Res 1992;588: 132-139).
Male NMRI mice (Toxicoop, Hungary) weighing 22-25 g were used (n=15/groups).
The learning task was carried out in a transparent plastic Y-maze (40 cm length, 12 cm width and 30 cm height). Numerous visual cues were placed around the arms and were kept constant during the experiment. The test consisted of two trials (Tl and T2) separated by intertrial intervals of 30 min. Mice were placed in the starting arm of the maze at the beginning of each trial. In Tl one of the symmetric arms of the maze were closed (it will be novel in T2) and the animals were allowed to explore the maze for 5 min (acquisition phase). In T2 mice had free access to all three arms for 2 min (retrieval phase). The time spent in each arm (novel and familiar) was measured separately by stopwatches. Following 30 min inter-trial delay mice are able to discriminate between novel and familiar arms of a Y-maze, while post-acquisition injection of scopolamine impairs the place recognition memory and the improving effect of a compound can be investigated. Immediately after Tl, 1 mg/kg dose of scopolamine was injected intraperitoneally. The protective effect of 16-tetrazolyl-eburnamine formula (I) was tested at oral doses of 10, 20 and 40 mg/kg given 60 min prior to the acquisition trial in a volume of 10 ml/kg.
Differences between exploration times spent in familiar and novel arms for each group were evaluated by paired t test. A discrimination index (DI) was calculated for each animal, expressed by the ratio DI=TN-TF /TN+TF (TN meaning the time spent in the novel and TF in the familiar arm). DI values were calculated for each group. One-way analysis of variance (ANOVA) followed by post hoc Duncan test was used for statistical comparison.
Diabetic neuropathy model
Thermal hyperalgesia is a symptom of diabetic neuropathy (DN) in humans. Although only a subpopulation in DN patients shows this symptom, it is present more frequently in DN, than in other types of neuropathy {Diabetes Care 2000;23:510-517). To model thermal
hyperalgesia in animals we used diabetic mice and measured heat sensitivity by determining the temperature threshold that evokes withdrawal of the tail in an increasing temperature water bath (Eur J Pharmacol. 2007;564 (l-3):80-87). We tested if 16-tetrazolyl- eburnamenine formula (I) could reverse this thermal hyperalgesia.
Method: To induce diabetes mellitus, 200 mg/kg dose of streptozotocin was intraperitoneally injected into NMRI mice (Toxicoop, Hungary) weighing 25-3 lg. Blood glucose (BG) levels were checked 14-16 days after the STZ-challenge via AccuChek Active Glucose test stripes (Hoffmann-La Roche Ltd., Switzerland). Blood was taken from the retroorbital plexus, under halothane anaesthesia. Animals with BG level over 18 mM/liter were considered as diabetic and only these were included the experiments. Mice with BG<18 mM/liter were excluded, and also those which had mechanical tail-hurt or body weights below 20 g.
16-tetrazolyl-eburnamenine formula (I) or the vehicle (2% ascorbic acid in saline) was administered orally, by gavage with treatment volume of 10 ml/kg.
For measurement of thermal threshold (ThT) diabetic mice were held in the palm of the hand with cotton-knitted gloves. About two thirds of the tail was immersed into the increasing temperature water bath generated by a SensoStress EXP-PL-1 device (Experimetria Ltd., Hungary). The initial temperature was set as 40 °C and was increased by 24 °C/min. At the point when the tail was withdrawn, the measurement was interrupted by a foot-switch, and the withdrawal temperature was then recorded. The cut-off temperature was considered as 50 °C. fMRI study in rat
Preclinical phMRI studies have increasing importance in drug research. The best way to directly observe the effect of compounds in the brain seems to be an fMRI study. One of the fMRI methods, the BOLD (blood oxygen level dependent functional fMRI technique), uses the endogen contrast agent, deoxi-hemoglobin (Proc. Natl. Acad. Sci. USA 1990;87:9868- 9872). Several papers study the effect of various pharmacological agents on rat brain using BOLD fMRI (Nuroimage 2011;58:885-894; Psychopharmacology 2011;217:549-557). Further advantage of the method, that it gives possibility for the translation between human and animal data, the results of the animal studies with new drug candidates can compare to the results of human studies with launched drugs.
Therefore our cognitive improving compounds were tested in small animal MRI system. 16- tetrazolyl-eburnamine formula (I) was also tested in a provocation model. Its effect was tested on BOLD decrease caused by frequently used cognitive disturbing agent scopolamine.
Method: Male Wistar rats weighing 240-260 g anaesthetized with isoflurane were used in the experiments. Radio frequency (RF) pulses were transmitted using a volume coil. A receive- only phased array rat brain coil was placed on the dorsal surface of the rat's head. MR images were acquired using:
Anatomical images (gems, TR=200ms, TE=3,83ms (min), flip angle=45°, averages=3, dummy scans=4, data matrix= 192x192, FOV: same like functional Fov acquired both before and after the functional EPIP sequences. The poor quality EPIP pictures are fitted to these anatomical scans to localize the activity changes.
BOLD contrast images were received with EPIP (gradient echo, TR=3000ms, TE=10,0ms, flip angle=90°, shots:3, triple reference scan, averages=l, dummy scans=4, data matrix=64x64, FOV: orientated Axial90, 35x35mm, 6 interleaved slices, thickness 1mm, gap 0,2mm).
After 10 minutes control period drugs were administered i.p. Only one experiment with a single drug administration was performed with each animal.
Provocation protocol (differences): Anatomical images (gems, TR=200ms, TE=3,83ms (min), flip angle=45°, averages=3, dummy scans=4, data matrix= 192x192, FOV: same like functional Fov acquired both before and after the functional EPIP sequences. The poor quality EPIP pictures are fitted to these anatomical scans to localize the activity changes.
Bold contrast images were received with EPIP (gradient echo, TR=3000ms, TE=10,0ms, flip angle=90°, shots:3, triple reference scan, averages=l, dummy scans=4, data matrix=64x64, FOV: orientated coronal, 35x35mm, 9 interleaved slices, thickness 1mm, gap 0,2mm).
The pretreatment time with 16-tetrazolyl-eburnamenine of formula (I) was 1 hour. Only one experiment with a double drug administration (pretreatment i.p. and provocation drug i.v.) was performed with each animal. Following 1000 sec control scanning period drugs were administered i.v. through a remote-operated pre-inserted cannula.
Passive avoidance learning in scopolamine-treated rats
The aim of the experiments was to investigate the effects of acute 16-tetrazolyl-eburnamenine of formula (I) treatment on attention and memory function of adult rats in passive avoidance learning. In the applied rat model the memory function was impaired by scopolamine pre- treatment.
Method: Passive avoidance test was performed in an apparatus consisted of two compartments: one light and one dark (22 cm long, 20 cm wide and 25 cm high each) connected by a guillotine door. On the first training day rats were put into in the dark compartment. Following 3 min habituation animals were put into the light compartment and allowed to enter the dark one where they stayed another 3 min (acquisition trial 1). On the second day animals were placed in the light compartment and the guillotine door was opened (acquisition trial 2). After being allowed to stay in the dark compartment for 3 min rats were replaced to the light compartment again. Latency to entering the dark was registered (acquisition trial 3). During the 3rd trial immediately after entering the dark compartment the guillotine door was closed, and simultaneously an electrical shock (1.0 mA for 3 sec) was delivered to the animal via the metal grid floor, followed by 3 min stay in the dark. The retention trial was performed 24 h and repeated also 4 days and 10 days after the electric shock. At that time animals were put into the light compartment and the guillotine door was opened. The time taken to enter the dark compartment was recorded as step through latency (STL). A maximum latency of 300 sec was accepted.
Animals were treated on the second day, 40 minutes before the learning trial (electric shock) with scopolamine and 30 minutes before the trial with 16-tetrazolyl-eburnamenine of formula (I)-
Metabolism study
Enzyme catalyzed biotransformation (metabolism) of drugs can severely affect plasma levels and so determine drug amount available for pharmacological effect. The major place of drug metabolism in humans is the liver and in case of most drugs it is mainly mediated by cytochrome P450 enzymes. The most basic tool for determination of metabolic fate is
incubation of drugs with a fraction of liver called microsomes which is rich in xenobiotic metabolizing CYPs, flavine monooxygenases (FMOs) and in several non-specific hydrolases. In microsomal systems, at low drug substrate concentrations, metabolism of drugs can be characterized by the intrinsic clearance of parent drug which reflects the rate of drug removal by biotransformation.
Method: The 16-tetrazolyl-eburnamenine formula (I) at 1 μΜ nominal concentration was incubated up to 20 minutes with human (0.5 mg/ml; Lot.No.: 1010425; pool of 50; mixed gender; XenoTech, USA), dog (0.5 mg/ml; Lot.No.: 0810143; beagle, male; pool of 11; XenoTech, USA), rat (0.5 mg/ml; Lot.No.: 1010126 pool of 200; wistar, male; XenoTech, USA) or mouse (0.5 mg/ml; Lot.No.: 1110071; pool of 1002; CD-I, male; XenoTech, USA) liver microsomes in the presence of NADPH or without it. The amount of unchanged test compound was measured by HPLC. Intrinsic clearance (Clint) was calculated from the rate of compound consumption according to the following equations: Clint = Vmax / KM or if [S] « KM CL;nt = V / [S] where Vmax = maximal rate of enzyme reaction; KM = affinity constant of a substrate; [S] = substrate concentration; V = actual rate of enzyme reaction under first order conditions.
The present invention now will be described by way of illustration, but not limitation, according to its preferred embodiments, with particular reference to the attached figures, in which:
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the time course of the anti-hyperalgesic effect of 16-tetrazolyl-eburnamenine. Shown are mean and SEM of thermal threshold data of diabetic mice treated with vehicle, 5 mg/kg and 10 mg/kg p.o. doses of 16-tetrazolyl-eburnamenine formula (I).
Figure 2 shows the dose dependent anti-hyperalgesic effect of 16-tetrazolyl-eburnamenine formula (I) compared to vinpocetine in model of diabetic neuropathy in mice;
Figure 3 shows the BOLD effect of 16-tetrazolyl-eburnamenine formula (I) in rat brain.
Figure 4 shows the effect of 16-tetrazolyl-eburnamenine formula (I) pretreatment on the scopolamine (1 mg/kg, i.v.) evoked BOLD response decrease in prefrontal cortex.
EXAMPLES
The invention is further defined in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative examples set forth herein below, but rather defined by the claims appended hereto.
In general, the compound of formula (I) can be prepared in accordance with the general knowledge of one skilled in the art and/or using methods set forth in the Example and/or Intermediate sections that follow. Solvents, temperatures, pressures, and other reaction conditions can readily be selected by one of ordinary skill in the art. Starting materials are commercially available and/or readily prepared by one skilled in the art.
Example 1
(3aS,l lbS)-3a-Ethyl-l,2,3,3a,10,l lb-hexahydro-1 lH-5a,l la-diaza-benzorcdlfluoranthene-5- carboxylic acid
A mixture of 20 g (57.0 mmol) of (3aS,l lbS)-3a-ethyl-l,2,3,3a,10,l lb-hexahydro-11H- 5a, 1 la-diaza-benzo[cd]fluoranthene-5-carboxylic acid ethyl ester and 3.0 g (75.0 mmol) of sodium hydroxide in 120 mL of ethanol was re fluxed for 5 h. The reaction mixture was cooled, concentrated in vacuo and the residue was dissolved in 200 mL of water. The solution was acidified with 12 mL of acetic acide. The precipitated product was filtered off, washed with water and dried to yield 17.0 g (92.4 %) of the title compound. Mp: 257-259 °C. MS (EI) 323.1 (MH+).
Example 2
(3aS,l lbS)-3a-Ethyl-l,2,3,3a,10,l lb-hexahydro-1 lH-5a,l la-diaza-benzo[cdlfluoranthene-5- carboxylic acid amide
A mixture of 12.0 g (37.2 mmol) of (3aS,l lbS)-3a-ethyl-l,2,3,3a,10,l lb-hexahydro-11H- 5a,l la-diaza-benzo[cd]fluoranthene-5-carboxylic acid, 13.1 mL (179.5 mmol) of thionyl chloride, 0.5 mL of N,N-dimethylformamide in 170 mL of chloroform was refluxed for 4 h. The reaction mixture was cooled to 20 °C, poured into a mixture of 134 mL of 25 % ammonia solution and 350 g of ice, and then stirred for 2h. The organic layer was separated and the water phase was extracted with 200 mL of chloroform. The combined organic layers were washed with water, dried over anhydrous sodium sulfate and concentrated to yield 11.9 g (99%) of the title compound. The crude product was used in the next step. MS (EI) 322.1 (MH+).
Example 3
(3aS,l lbS)-3a-Ethyl-l,2,3,3a,10,l lb-hexahydro-1 lH-5a,l la-diaza-benzorcd1fluoranthene-5- carbonitrile
A mixture of 11.9 g (37.0 mmol) of (3aS,l lbS)-3a-ethyl-l,2,3,3a,10,l lb-hexahydro-11H- 5a, 1 la-diaza-benzo[cd]fluoranthene-5-carboxylic acid amide, 25.0 mL (268 mmol) of phosphorus oxychloride and 200 mL of chloroform was refluxed for 8h. The reaction mixture was cooled to 20 °C, poured into 1000 g of ice and neutralised with 40 % sodium hydroxide solution. The organic layer was separated and the water phase was extracted with 500 mL of chloroform. The combined organic layers were washed with water and saturated sodium carbonate solution, dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from a 1 : 1 mixture of 2-propanol and water to yield 9.9 g (88.2 %) of the title compound. Mp.: 129-130 °C. MS (EI) 304.2 (MH+).
Example 4
(3aS ,1 lbS -3a-Ethyl-5-(tetrazol-5-ylVL2,3.3a,10 ,1 lb-hexahydro-1 lH-5a,l la-diaza- benzo[cdlfluoranthene
16-tetrazolyl-eburnamenine
A mixture of 9.0 g (29.6 mmol) of (3aS,l lbS)-3a-ethyl-l,2,3,3a,10,l lb-hexahydro-11H- 5a,l la-diaza-benzo[cd]fluoranthene-5-carbonitrile, 9.64 g (148 mmol) of sodium azide and 7.95 g (148 mmol) of ammonium chloride in 150 mL of N,N-dimethylformamide was stirred at 110 °C for 3.5 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015- 0.040 mm) as adsorbent (Merck) and dioxane : methanol : 25 % ammonia solution = 5 : 1 : 1 as eluent to yield after acidification with acetic acid 9.6 lg (93.40 %) of the title compound. MS (EI) 347.3 (MH+).
Example 5
(3 aS .11 bS -3 a-Ethyl-5 -(tetrazol-5 -vO- 1.2.3.3 a.10.11 b-hexahydro- 1 lH-5a.l la-diaza- benzorcdlfluoranthene hydrochloride
16-tetrazolyl-eburnamenine hydrochloride
2.0 g (5.8 mmol) of 16-tetrazolyl-eburnamenine (IUPAC name: (3aS,l lbS)-3a-Ethyl-5- (tetrazol-5-yl)-l,2,3,3a,10,l lb-hexahydro-1 lH-5a,l la-diaza-benzo[cd]fluoranthene) was suspended in 20 mL ethylacetate. 10 mL of 20 % HC1 in ethylacetate was added dropwise. The resulting mixture was stirred overnight. The participated product was filtered and washed with ethylacetate and then dried to yield 2.18 g (98.0 %). MS (EI) 347.3 (MH+)
Example 6
(3aS.l lbS -3a-Ethyl-5-(tetrazol-5-ylV1.2.3.3a.l0.1 lb-hexahydro-1 lH-5a.l la-diaza- benzorcdlfluoranthene choline salt
16-tetrazolyl-eburnamenine choline salt
To a suspension of 0.5 g (1.44 mmol) of 16-tetrazolyl-eburnamenine (IUPAC name: (3aS,l lbS)-3a-Ethyl-5-(tetrazol-5-yl)-l,2,3,3a,10,l lb-hexahydro-1 lH-5a,l la-diaza- benzo[cd]fluoranthene) and 10 mL of ethanol 1.36 ml of 46 % cholin hydroxide solution (1.46 mmol) was added. The resulting solution was concentrated in vacuo and the residue was treated with diethyl ether. The precipitated product was filtered and dried to yield 0.6 g (92.5 %) of the title compound as an amorphous solid. MS (EI) 347.3 (MH ).
Example 7
(3 aS .11 bSV3 a-Ethyl-5 -(tetrazol-5 -νΠ- 1.2.3.3 a.10.11 b-hexahydro- 1 lH-5a.l la-diaza- benzorcdlfluoranthene potassium salt
16-tetrazolyl-eburnamenine potassium salt
To a suspension of 28.2299 g (81.49 mmol) of 16-tetrazolyl-eburnamenine (IUPAC name: (3aS,l lbS)-3a-Ethyl-5-(tetrazol-5-yl)-l,2,3,3a,10,l 1 b-hexahydro- 1 lH-5a,l la-diaza- benzo[cd]fluoranthene) and 640 mL of deionised water 9.144 g (81.49 mmol) of potassium tert-butoxide was added. The resulting solution was lyophilized to yield 29.87 g (95.3 %) of the title compound as an amorphous solid. MS (EI) 347.3 (MH ).
Example 8
(3aS.l lbS -3a-Ethyl-5-(tetrazol-5-ylV1.2.3.3a.l0.11 b-hexahydro- 1 lH-5a.l la-diaza- benzorcdlfluoranthene sodium salt
16-tetrazolyl-eburnamenine sodium salt
1.0 g (2.9 mmol) of 16-tetrazolyl-eburnamenine (IUPAC name: (3aS,l lbS)-3a-Ethyl-5- (tetrazol-5-yl)-l,2,3,3a,10,l 1 b-hexahydro- 1 lH-5a,l la-diaza-benzo[cd]fluoranthene) was suspended in 10 mL ethanol. 15 mL of 2.2 M NaOEt in ethanol was added dropwise. The resulting mixture was stirred for 1 hour and then it was diluted with THF : diethylether = 1 :10 (10 mL). The participated product was filtered and washed with THF : diethylether = 1 : 10 and then dried to yield 1.02 g (96.0 %). MS (EI) 347.3 (MH+)
Example 9
Mouse cognitive impairment model results
In the place recognition test vehicle-treated control mice could discriminate between the novel and the familiar arm in the recognition trial after an intertrial delay of 30 min, while scopolamine caused a clear discrimination deficit (Table). 16-Tetrazolyl-eburnamenine formula (I) dose-dependently and significantly improved the impairment in the place recognition, the highest dose (40 mg/kg) produced practically a complete reversal. The
discrimination index values (DI) significantly differed from DI measured in the impaired group as the next table shows.
+++ p < 0.001 compared to non-impaired control,
* p < 0. 05, ** p < 0. 01 compared to impaired control (ANOVA followed by Duncan test)
Example 10
Mouse Diabetic Neuropathy model results
16-tetrazolyl-eburnamenine formula (I) at the doses of 5 and 10 mg/kg was administered in the period of 2-4 weeks after the STZ-challenge, when expressed hyperalgesia was present. Mean and S.E.M. of tail withdrawal thresholds of animals involved in the study was 45.5 °C + 0.28 before STZ administration and 43.1+ 0.18 °C before administration of test compound. On test day thermal threshold (ThT) was measured before, and 60, 120, and 180 min after administration of 16-tetrazolyl-eburnamenine formula (I).
Anti-hyperalgesic effect was characterized by calculating percentage reversal of thermal hyperalgesia from group mean values, at the time of maximum effect (Tmax) according to the following formula:
ThT Drue, Tmax " ThT Vehicle, Tmax
REVERSAL (%) = x 100
mean ThTorug and Vehicle, Tpre-STZ " ThT Vehicle, Tmax
(ThT is the mean thermal threshold value of the group in °C)
Significance of differences between groups at each time point was analyzed by 2-way ANOVA followed by Tukey HSD test, comparing the ThTs for the drug-treated groups and the parallel vehicle-treated group using Statistica 5.0 software.
It can be seen in Figure 1. that 16-tetrazolyl-eburnamenine formula (I) produced a dose dependent and, at the higher dose, statistically significant reversal of thermal hyperalgesia. Maximal effects were observed 120 min post-dose as 34, and 85% reversal of hyperalgesia for the 5 and 10 mg/kg dose, respectively. It can be concluded that these results support possible utility of 16-tetrazolyl-eburnamenine formula (I) in diabetic neuropathy.
Figure 2. shows effect of 16-tetrazolyl-eburnamenine formula (I) compared to vinpocetine. The 5 and 10 mg/kg doses of 16-tetrazolyl-eburnamenine formula (I) produced 34% and 85% reversal of hyperalgesia, while the same doses of vinpocetine produced 49% and 57% reversal, respectively. When 20 mg/kg dose of vinpocetine was administered to mice, the effect was not further increased (57%). These results clearly show efficacy of 16-tetrazolyl- eburnamenine formula (I) over vinpocetine.
Example 11
fMRI study results
Administration of 16-tetrazolyl-eburnamenine formula (I) caused clear BOLD increase in the area of cortex, thalamus and hippocampus (see Figure 3.). Increased BOLD marks increased function of the parts of the brain.
Provocation model
In the study scopolamine was used as a provocation drug. The intravenously administered scopolamine decreased the BOLD responses in the prefrontal cortex, but it had no visible effect in the hippocampus. One hour pretreatment with 16-tetrazolyl-eburnamenine formula (I) prevented inhibitory effect of scopolamine in the prefrontal cortex.
Example 12
Passive avoidance
Step through latency (STL) time of experimental animals was measured 1, 4 and 11 days after receiving electric shock during the learning trial. The effect of treatments with 16-tetrazolyl- eburnamenine formula (I) resulted in significant changes in this parameter revealed.
Electric shock significantly increased the STL as compared to that found before shock in control rats. Scopolamine pre-treatment resulted in a short latency, comparable to the latency time during the last trial, which was significantly shorter compared to controls. 16-tetrazolyl- eburnamenine formula (I) induced significant elevation of STL after scopolamine pre- treatment.
Example 13
Metabolism study results
The next table shows Intrinsic clearance (Clint) of 16-tetrazolyl-eburnamenine of formula (I) in a pools of human, dog, rat and mouse liver microsomes.
The 16-tetrazolyl-eburnamenine formula (I) is a low metabolic clearance compound in human, dog and rat liver microsomes; consumption of 16-tetrazolyl-eburnamenine formula (I) was not observed without NADPH; therefore extrahepatic (non CYP/FMO mediated metabolism) is not expected either. In mouse liver microsomes high metabolic clearance was obtained.
The results indicate that the human oral bioavailability of 16-tetrazolyl-eburnamenine formula (I) may not be limited by intense metabolic hepatic extraction.
Claims
1. A compound of formula (I)
(I)
or a pharmaceutically acceptable salt thereof or a hydrate or a solvate of the compound of formula (I), or a hydrate or a solvate of a pharmaceutically acceptable salt of formula (I).
A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier and/or diluent.
A process for the manufacturing pharmaceutical composition having a therapeutically effective amount of a compound according to claim 1 as active ingredient and a pharmaceutically acceptable carrier and/or diluent.
A method for treatment and/or prophylaxis of a neurological and/or neurodegenerative and/or psychiatric disease or condition comprising the step of administering a human in need of such treatment and/or prophylaxis a therapeutically-effective amount of a compound in accordance with claim 1.
A method for treatment and/or prophylaxis of a neurological and/or neurodegenerative and/or psychiatric disease or condition comprising the step of administering a human in need of such treatment and/or prophylaxis a pharmaceutical composition according to claim 2 containing a therapeutically-effective amount of a compound in accordance with claim 1.
A method for treatment according to claim 5, wherein said disease or condition is selected from Alzheimer's disease, Parkinson's disease, Attention deficit and Hyperactivity
Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age Related Memory Dysfunction, Down Syndrome, Epilepsy, Stroke, Autism, Cerebral Ischemia, Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt- Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease, Substance Induced Cognitive Impairment, Narcolepsy, and Neuropathy of various origin, including, but not limited to Diabetic Neuropathy, as well as for the treatment of Pain (in particular Neuropathic Pain and Inflammatory Pain) and painful conditions.
7. A method according to claim 6 wherein said disease or condition is Alzheimer's disease.
8. A method according to claim 6 wherein said disease or condition is Mild Cognitive Impairment.
9. A method according to claim 6 wherein said disease or condition is Attention deficit and Hyperactivity Disorder.
10. A method according to claim 6 wherein said disease or condition is Age Related Memory Dysfunction.
11. A method according to claim 6 wherein said disease or condition is Substance Induced Cognitive Impairment.
12. A method according to claim 6 wherein said disease or condition is Epilepsy.
13. A method according to claim 6 wherein said disease or condition is selected from Stroke, Cerebral Ischemia.
14. A method according to claim 6 wherein said disease or condition is selected from Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt-
Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease.
15. A method according to claim 6 wherein said disease or condition is Pain.
16. The use of a compound according to claim 1 for the treatment and/or prophylaxis of a neurological and/or neurodegenerative and/or psychiatric disease or condition.
17. The use of a pharmaceutical composition according to claim 2 for the treatment and/or prophylaxis of a neurological and/or neurodegenerative and/or psychiatric disease or condition.
18. The use according to claim 16 and 17, wherein said disease or condition is selected from Alzheimer's disease, Parkinson's disease, Attention deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age Related Memory Dysfunction, Down Syndrome, Epilepsy, Stroke, Autism, Cerebral Ischemia, Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt- Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease, Substance Induced Cognitive Impairment, Narcolepsy, and Neuropathy of various origin, including, but not limited to Diabetic Neuropathy, as well as for the treatment of Pain (in particular Neuropathic Pain and Inflammatory Pain) and painful conditions.
19. The use according to claim 18 wherein said disease or condition is Alzheimer's disease.
20. The use according to claim 18 wherein said disease or condition is Mild Cognitive Impairment.
21. The use according to claim 18 wherein said disease or condition is Attention deficit and Hyperactivity Disorder.
22. The use according to claim 18 wherein said disease or condition is Age Related Memory Dysfunction.
23. The use according to claim 18 wherein said disease or condition is Substance Induced Cognitive Impairment.
24. The use according to claim 18 wherein said disease or condition is Epilepsy.
25. The use according to claim 18 wherein said disease or condition is selected from Stroke, Cerebral Ischemia.
26. The use according to claim 18 wherein said disease or condition is selected from Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt- Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease.
27. The use according to claim 18 wherein said disease or condition is Pain.
28. A process for the preparation of compound of formula (I) according to claim 1 comprising a) reacting the compound of formula (IV)
(IV) with thionyl chloride and ammonium hydroxide
b) reacting the obtained compound of formula (III)
wherein the meaning of M is H, Na, Si(R)3, Sn(R)3, A1(R)2 and
wherein R represents Ci_6 straight or branched alkyl group,
to yield the compound of formula (I).
29. The process according to claim 28, wherein said additive or catalyst is selected from the group consisting of the compounds of ammonium chloride, triethylammonium chloride, acetic acid, aluminium trichloride, ethoxy boron trifluoride of empirical formula BF3*OEt, zinc bromide, cadmium chloride, trimethylaluminium, zinc sulphide- nanosphere, iron(III) chloride-silicium dioxide the compound of formula FeCl3-Si02, antimony trioxide, barium wolframate, nano-zinc oxide, zinc/aluminium hydrotalcite, zinc
phosphate hydrate of empirical formula Znio(P04)60H, iron(II) acetate, tetra-n- butylammonium fluoride, and dimethyl tin oxide.
30. A process for the preparation of compound of formula (I) in accordance with claim 28 comprising reacting the compound of formula (II)
(I I) with M-N3 in the presence of additive or catalyst,
wherein the meaning of M is H, Na, Si(R)3, Sn(R)3, A1(R)2
wherein R represents Ci_4 straight or branched alkyl,
to yield the compound of formula (I).
31. The process according to claim 30, wherein said additive or catalyst is selected from the group consisting of the compounds of ammonium chloride, triethylammonium chloride, acetic acid, aluminium trichloride, ethoxy boron trifluoride of empirical formula BF3*OEt.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU1100641A HU230482B1 (en) | 2011-11-22 | 2011-11-22 | A new diaza-benzofluoranthene derivate as drug |
HUP1100641 | 2011-11-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2013076646A1 true WO2013076646A1 (en) | 2013-05-30 |
Family
ID=89990509
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2012/056561 WO2013076646A1 (en) | 2011-11-22 | 2012-11-20 | A new diaza-benzofluoranthene derivative as drug |
Country Status (2)
Country | Link |
---|---|
HU (1) | HU230482B1 (en) |
WO (1) | WO2013076646A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103926337A (en) * | 2014-03-01 | 2014-07-16 | 江苏斯威森生物医药工程研究中心有限公司 | HPLC method for measuring vinpocetine content |
WO2016124129A1 (en) * | 2015-02-04 | 2016-08-11 | 南京明德新药研发股份有限公司 | Diaza-benzofluoranthrene compounds |
WO2018024225A1 (en) * | 2016-08-04 | 2018-02-08 | 哈药集团技术中心 | Salt and crystal of diaza-benzofluorane compound |
WO2018069312A1 (en) * | 2016-10-11 | 2018-04-19 | Deutsches Zentrum Für Neurodegenerative Erkrankungen E. V. (Dzne) | Treatment of synucleinopathies |
CN114762688A (en) * | 2021-01-13 | 2022-07-19 | 南京宁丹新药技术有限公司 | Application of composition containing cilostazol in cerebrovascular diseases |
WO2023216533A1 (en) * | 2022-05-09 | 2023-11-16 | 南京中医药大学 | Indole alkaloid, and preparation method therefor and use thereof |
-
2011
- 2011-11-22 HU HU1100641A patent/HU230482B1/en unknown
-
2012
- 2012-11-20 WO PCT/IB2012/056561 patent/WO2013076646A1/en active Application Filing
Non-Patent Citations (25)
Title |
---|
ANN PHARM FR, vol. 13, 1955, pages 328 - 333 |
BRAIN RES BULL, vol. 53, 2000, pages 245 - 254 |
BRAIN RES, vol. 588, 1992, pages 132 - 139 |
CHINESE JOURNAL OF NATURAL MEDICINES, vol. 9, 2011, pages 51 - 57 |
CHINESE JOURNAL OF NEW DRUGS, vol. 18, 2009, pages 1415 - 1418 |
COMPT REND SOC BIOL, vol. 148, 1954, pages 1082 - 1086 |
DENOBLE ET AL: "Vinpocetine enhances retrieval of a step-through passive avoidance response in rats", PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, ELSEVIER, US, vol. 26, no. 1, 1 January 1987 (1987-01-01), pages 183 - 186, XP023808098, ISSN: 0091-3057, [retrieved on 19870101], DOI: 10.1016/0091-3057(87)90552-1 * |
DENOBLE V J ET AL: "Vinpocetine: Nootropic effects on scopolamine-induced and hypoxia-induced retrieval deficits of a step-through passive avoidance response in rats", PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, ELSEVIER, US, vol. 24, no. 4, 1 April 1986 (1986-04-01), pages 1123 - 1128, XP025539133, ISSN: 0091-3057, [retrieved on 19860401], DOI: 10.1016/0091-3057(86)90465-X * |
DIABETES CARE, vol. 23, 2000, pages 510 - 517 |
DRUG DEVELOPMENT AND RESEARCH, vol. 14, 1988, pages 191 - 193 |
EUR J CLIN PHARMACOL, vol. 33, 1987, pages 185 - 189 |
EUR J DRUG METAB PHARMACOKIN, vol. 10, 1985, pages 89 - 103 |
EUR J PHARMACOL, vol. 314, 1996, pages 69 - 73 |
EUR J PHARMACOL., vol. 564, no. 1-3, 2007, pages 80 - 87 |
EXPERIENTIA, vol. 21, 1965, pages 508 |
FISCHHOF ET AL., NEUROPSYCHOBIOLOGY, vol. 34, 1996, pages 29 - 35 |
J. MED. CHEM., vol. 51, 2008, pages 479 - 486 |
MED RES REV, vol. 53, 2005, pages 737 - 757 |
MOSCOW, vol. 10, 1950, pages 29 - 33 |
NUROIMAGE, vol. 58, 2011, pages 885 - 894 |
PHARMACOLOGY, BIOCHEMISTRY AND BEHAVIOUR, vol. 24, 1986, pages 1123 - 1128 |
PHARMACOLOGY, BIOCHEMISTRY AND BEHAVIOUR, vol. 26, 1987, pages 183 - 186 |
PROC. NATL. ACAD. SCI. USA, vol. 87, 1990, pages 9868 - 9872 |
PSYCHOPHARMACOLOGY, vol. 217, 2011, pages 549 - 557 |
THER HUNG, vol. 13, 1965, pages 3 - 6 |
Cited By (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103926337A (en) * | 2014-03-01 | 2014-07-16 | 江苏斯威森生物医药工程研究中心有限公司 | HPLC method for measuring vinpocetine content |
RU2697513C2 (en) * | 2015-02-04 | 2019-08-15 | Харбин Фармасьютикал Груп Ко., Лтд. Дженерал Фармасьютикал Фэктори | Diazabenzofluoranthrene compounds |
WO2016124129A1 (en) * | 2015-02-04 | 2016-08-11 | 南京明德新药研发股份有限公司 | Diaza-benzofluoranthrene compounds |
KR20170109671A (en) * | 2015-02-04 | 2017-09-29 | 하얼빈 파마슈티컬 그룹 컴퍼니.,리미티드. 제너럴 파마슈티컬 팩토리 | Diazabenzofluoranthene compound |
CN107614498A (en) * | 2015-02-04 | 2018-01-19 | 哈药集团制药总厂 | Diaza benzofluoranthrene class compound |
JP2018506582A (en) * | 2015-02-04 | 2018-03-08 | ▲は▼薬集団製薬総廠Harbin Pharmaceutical Group Co., Ltd. General Pharmaceutical Factory | Diaza-benzofluoranthene compounds |
TWI706950B (en) * | 2015-02-04 | 2020-10-11 | 哈藥集團技術中心 | Diaza-benzofluoranthene compound |
US10017507B2 (en) | 2015-02-04 | 2018-07-10 | Harbin Pharmaceutical Group Co., Ltd. General Pharmaceutical Factory | Diaza-benzofluoranthrene compounds |
AU2016214802B2 (en) * | 2015-02-04 | 2018-08-30 | Harbin Pharmaceutical Group Co., Ltd. General Pharmaceutical Factory | Diaza-benzofluoranthrene compounds |
CN107614498B (en) * | 2015-02-04 | 2020-06-05 | 哈药集团制药总厂 | Diaza-benzofluoranthenes |
RU2697513C9 (en) * | 2015-02-04 | 2019-12-19 | Харбин Фармасьютикал Груп Ко., Лтд. Дженерал Фармасьютикал Фэктори | Diazabenzofluoranthrene compounds |
KR101998011B1 (en) * | 2015-02-04 | 2019-07-08 | 하얼빈 파마슈티컬 그룹 컴퍼니.,리미티드. 제너럴 파마슈티컬 팩토리 | diaza-benzofluoranthene compound |
EP3495361B1 (en) * | 2016-08-04 | 2020-10-28 | Harbin Pharmaceutical Group Co., Ltd. General Pharmaceutical Factory | Salt and crystal of diaza-benzofluorane compound |
RU2762189C2 (en) * | 2016-08-04 | 2021-12-16 | Харбин Фармасьютикал Груп Ко., Лтд. Дженерал Фармасьютикал Фэктори | Salts and crystalline forms of diazabenzofluoranthene compounds |
KR20190035854A (en) * | 2016-08-04 | 2019-04-03 | 하얼빈 파마슈티컬 그룹 컴퍼니.,리미티드. 제너럴 파마슈티컬 팩토리 | Salts and crystals of diazabenzofluorane compounds |
AU2017306606B2 (en) * | 2016-08-04 | 2020-04-30 | Harbin Pharmaceutical Group Co., Ltd. General Pharmaceutical Factory | Salts and crystal forms of diaza-benzofluoranthrene compounds |
CN109563090A (en) * | 2016-08-04 | 2019-04-02 | 哈药集团制药总厂 | Diaza-benzofluoranthrene class compound salt form and crystal form |
AU2017306606A8 (en) * | 2016-08-04 | 2019-12-05 | Harbin Pharmaceutical Group Co., Ltd. General Pharmaceutical Factory | Salts and crystal forms of diaza-benzofluoranthrene compounds |
WO2018024225A1 (en) * | 2016-08-04 | 2018-02-08 | 哈药集团技术中心 | Salt and crystal of diaza-benzofluorane compound |
KR102275415B1 (en) | 2016-08-04 | 2021-07-09 | 하얼빈 파마슈티컬 그룹 컴퍼니.,리미티드. 제너럴 파마슈티컬 팩토리 | Salts and crystals of diaza-benzofluoran compounds |
CN109563090B (en) * | 2016-08-04 | 2021-02-23 | 哈药集团制药总厂 | Salt forms and crystal forms of diaza-benzofluoranthenes |
US10918628B2 (en) | 2016-10-11 | 2021-02-16 | Deutsches Zentrum Für Neurodegenerative Erkrankungen E. V. (Dzne) | Treatment of synucleinopathies |
WO2018069312A1 (en) * | 2016-10-11 | 2018-04-19 | Deutsches Zentrum Für Neurodegenerative Erkrankungen E. V. (Dzne) | Treatment of synucleinopathies |
EP4112053A1 (en) * | 2016-10-11 | 2023-01-04 | Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE) | Treatment of synucleinopathies |
CN114762688A (en) * | 2021-01-13 | 2022-07-19 | 南京宁丹新药技术有限公司 | Application of composition containing cilostazol in cerebrovascular diseases |
WO2023216533A1 (en) * | 2022-05-09 | 2023-11-16 | 南京中医药大学 | Indole alkaloid, and preparation method therefor and use thereof |
Also Published As
Publication number | Publication date |
---|---|
HUP1100641A2 (en) | 2013-06-28 |
HU230482B1 (en) | 2016-07-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2656699B2 (en) | Substituted benzylaminoquinuclidine | |
WO2013076646A1 (en) | A new diaza-benzofluoranthene derivative as drug | |
DE60132710T2 (en) | 3-SUBSTITUTED CHINUCLIDINES AND THEIR USE AS NICOTINE AGONISTS | |
US6476041B1 (en) | 1,4 substituted piperidinyl NMDA/NR2B antagonists | |
CA3213029A1 (en) | Parp inhibitor containing piperazine structure, preparation method therefor and pharmaceutical use thereof | |
CN106905322B (en) | Pyrrolopyrimidine penta azacyclo derivative and its application | |
US20240166610A1 (en) | Substituted pyridazine phenol derivatives | |
EP2982674B1 (en) | Pyridinylpyrazoloquinoline compound | |
PT2139892E (en) | Substituted pyrimidodiazepines useful as plk1 inhibitors | |
EP3700895B1 (en) | Polycyclic amides as muscarinic m1 receptor positive allosteric modulators | |
DE60317684T4 (en) | SUBSTITUTED 2,4-DIHYDROPYRROLOc3,4BUCHINOLINE-9-ON DERIVATIVES SUITABLE AS PHOSPHODIESTERASE INHIBITORS | |
WO2008128431A1 (en) | L-stepholidine (l-spd) derivatives, preparation method and usage thereof | |
DE60307102T2 (en) | 3-SUBSTITUTED CHINUCLIDINE AND ITS USE | |
US11267810B2 (en) | Aminopyrimidine compound and composition comprising same and use thereof | |
JP2000128879A (en) | 1,3,8-triazaspiro[4.5]decanone compound as orl1-receptor agonist | |
US6635652B1 (en) | Azaindolizinone derivatives and cerebral function improvers containing the same as the active ingredient | |
DE69814563T2 (en) | Pyrrolo- (3,2-b) pyridines and their use as 5-HT1F agonists | |
US8378112B2 (en) | Glycyrrhetinic acid derivative and use thereof | |
WO2023196517A1 (en) | Cdk9 inhibitors | |
EP4310080A1 (en) | Polymorphic forms of compound and preparation method therefor and application thereof | |
WO2019096113A1 (en) | Deuterium-substituted boron-containing compound, and pharmaceutical composition and use | |
EP3472155B1 (en) | Deuterated compounds for treating pain | |
US20230192625A1 (en) | Substituted benzimidazole compound and composition comprising same | |
US20050261342A1 (en) | Metabolites of (+)-(2S,3S)-3(2-methoxy-5- trifluoromethoxybenzylamino)-2-phenyl-piperidine | |
US12065441B2 (en) | Pyrazolopyrimidine derivative, use thereof and pharmaceutical composition |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12813978 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 12813978 Country of ref document: EP Kind code of ref document: A1 |