USRE42327E1 - Medicinal compositions improving brain function and method for improving brain function - Google Patents
Medicinal compositions improving brain function and method for improving brain function Download PDFInfo
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- USRE42327E1 USRE42327E1 US12/683,813 US68381304A USRE42327E US RE42327 E1 USRE42327 E1 US RE42327E1 US 68381304 A US68381304 A US 68381304A US RE42327 E USRE42327 E US RE42327E
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- ingredient
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- pharmaceutical composition
- ethoxy
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- 238000000034 method Methods 0.000 title claims abstract description 16
- 239000000203 mixture Substances 0.000 title description 2
- 230000003925 brain function Effects 0.000 title 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 150000005215 alkyl ethers Chemical class 0.000 claims abstract description 18
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 239000004615 ingredient Substances 0.000 claims description 26
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 229960001685 tacrine Drugs 0.000 claims description 11
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 claims description 11
- 229960003530 donepezil Drugs 0.000 claims description 10
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- HQNACSFBDBYLJP-UHFFFAOYSA-N 1-[3-[2-(1-benzothiophen-5-yl)ethoxy]propyl]azetidin-3-ol Chemical compound C1C(O)CN1CCCOCCC1=CC=C(SC=C2)C2=C1 HQNACSFBDBYLJP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002393 azetidinyl group Chemical group 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- RLUCYBFCLXANSO-BTJKTKAUSA-N 1-[3-[2-(1-benzothiophen-5-yl)ethoxy]propyl]azetidin-3-ol;(z)-but-2-enedioic acid Chemical compound OC(=O)\C=C/C(O)=O.C1C(O)CN1CCCOCCC1=CC=C(SC=C2)C2=C1 RLUCYBFCLXANSO-BTJKTKAUSA-N 0.000 claims 3
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 abstract description 23
- 229960004373 acetylcholine Drugs 0.000 abstract description 23
- 230000002490 cerebral effect Effects 0.000 abstract description 20
- 108090000371 Esterases Proteins 0.000 abstract description 15
- 230000002401 inhibitory effect Effects 0.000 abstract description 15
- 230000000141 anti-hypoxic effect Effects 0.000 abstract description 13
- 210000002569 neuron Anatomy 0.000 abstract description 9
- 230000006870 function Effects 0.000 abstract description 6
- 230000016273 neuron death Effects 0.000 abstract description 6
- 230000004064 dysfunction Effects 0.000 abstract description 5
- 206010008190 Cerebrovascular accident Diseases 0.000 abstract description 4
- 206010039966 Senile dementia Diseases 0.000 abstract description 4
- 208000006011 Stroke Diseases 0.000 abstract description 4
- 208000013677 cerebrovascular dementia Diseases 0.000 abstract description 4
- 230000000302 ischemic effect Effects 0.000 abstract description 4
- 230000003902 lesion Effects 0.000 abstract description 4
- 206010027175 memory impairment Diseases 0.000 abstract description 4
- 230000002265 prevention Effects 0.000 abstract description 2
- -1 methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy Chemical group 0.000 description 116
- 125000003277 amino group Chemical group 0.000 description 14
- 125000003545 alkoxy group Chemical group 0.000 description 10
- BKMCUGFGPQNYHG-RSAXXLAASA-N (1r)-1-(1-benzothiophen-5-yl)-2-[2-(diethylamino)ethoxy]ethanol;hydrochloride Chemical compound Cl.CCN(CC)CCOC[C@H](O)C1=CC=C2SC=CC2=C1 BKMCUGFGPQNYHG-RSAXXLAASA-N 0.000 description 8
- 125000003342 alkenyl group Chemical group 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 125000004414 alkyl thio group Chemical group 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 0 [1*]C([2*])COCN([3*])[4*] Chemical compound [1*]C([2*])COCN([3*])[4*] 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- NSGDYZCDUPSTQT-UHFFFAOYSA-N N-[5-bromo-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxopyridin-3-yl]cycloheptanecarboxamide Chemical compound Cc1c(Br)cn(Cc2ccc(F)cc2)c(=O)c1NC(=O)C1CCCCCC1 NSGDYZCDUPSTQT-UHFFFAOYSA-N 0.000 description 4
- 125000003302 alkenyloxy group Chemical group 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 4
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 230000000324 neuroprotective effect Effects 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 125000005530 alkylenedioxy group Chemical group 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 2
- YLUSMKAJIQOXPV-UHFFFAOYSA-N 2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-amine Chemical compound C1CCCC2=C1N=C1CCCC1=C2N YLUSMKAJIQOXPV-UHFFFAOYSA-N 0.000 description 2
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 2
- YJFGQHCDMAPJFY-UHFFFAOYSA-N 2-[3-[2-(1-benzothiophen-5-yl)ethoxy]propyl-methylamino]ethanol Chemical compound OCCN(C)CCCOCCC1=CC=C2SC=CC2=C1 YJFGQHCDMAPJFY-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- HPOIPOPJGBKXIR-UHFFFAOYSA-N 3,6-dimethoxy-10-methyl-galantham-1-ene Natural products O1C(C(=CC=2)OC)=C3C=2CN(C)CCC23C1CC(OC)C=C2 HPOIPOPJGBKXIR-UHFFFAOYSA-N 0.000 description 2
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 2
- LPCKPBWOSNVCEL-UHFFFAOYSA-N Chlidanthine Natural products O1C(C(=CC=2)O)=C3C=2CN(C)CCC23C1CC(OC)C=C2 LPCKPBWOSNVCEL-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
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- 125000001118 alkylidene group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000003435 aroyl group Chemical group 0.000 description 2
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 229960003980 galantamine Drugs 0.000 description 2
- BGLNUNCBNALFOZ-WMLDXEAASA-N galanthamine Natural products COc1ccc2CCCC[C@@]34C=CCC[C@@H]3Oc1c24 BGLNUNCBNALFOZ-WMLDXEAASA-N 0.000 description 2
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 2
- 239000008246 gaseous mixture Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000006038 hexenyl group Chemical group 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- JGPMMRGNQUBGND-UHFFFAOYSA-N idebenone Chemical compound COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O JGPMMRGNQUBGND-UHFFFAOYSA-N 0.000 description 2
- 229960004135 idebenone Drugs 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229960005490 ipidacrine Drugs 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- IYVSXSLYJLAZAT-NOLJZWGESA-N lycoramine Natural products CN1CC[C@@]23CC[C@H](O)C[C@@H]2Oc4cccc(C1)c34 IYVSXSLYJLAZAT-NOLJZWGESA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
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- 125000001424 substituent group Chemical group 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
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- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 2
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- LXFQSRIDYRFTJW-UHFFFAOYSA-N 2,4,6-trimethylbenzenesulfonic acid Chemical compound CC1=CC(C)=C(S(O)(=O)=O)C(C)=C1 LXFQSRIDYRFTJW-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- 125000006032 3-methyl-3-butenyl group Chemical group 0.000 description 1
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-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- This invention relates to a pharmaceutical composition for improving the cerebral function which contains an alkyl ether derivative and a compound having acetylcholine esterase inhibiting activity, and to a method using an alkyl ether derivative in combination with a compound having acetylcholine esterase inhibiting activity for the purpose of. improving the cerebral function.
- drugs for symptomatic treatment of this memory impairment for example, compounds having an acetylcholine esterase inhibiting activity such as Tacrine, Donepezil, and the like are used.
- the anti-hypoxic activity is used for evaluating the neuroprotective activity in-vitro, and it is reported that, in the in-vivo experiments, too, compounds having a neuroprotective activity show the same effect as above [Ann. N. Y. Acad. Sci., Vol. 890, Pages 406-420, 1999]. Further, it has been reported that the anti-hypoxic activity is shown by compounds activating the in-brain acetylcholine neurons and by Tacrine (1,2,3,4-tetrahydro-9-acridinamine hydrochloride) showing an acetylcholine esterase inhibiting activity [Jpn. J. Pharmacol., Vol. 62, Pages 81-86, 1993].
- a work for studying the in-vivo anti-hypoxic activity can be regarded as a method for evaluating the compounds having one of the neuroprotective effect and the in-brain acetylcholine neurons activating effect or both of these effects.
- the 1,2-ethanediol derivatives or salts thereof described in JP 3-232830A and JP 4-95070A are compounds useful as a cerebral function-improving agent, and particularly (R)-1- ⁇ benzo[b]thiophen-5-yl ⁇ -2-[2-(N,N-diethylamino ⁇ ethoxy]ethanol hydrochloride (hereinafter, referred to as T-588) is a preferable compound. It has been reported that T-588 has an anti-hypoxic activity and an anti-amnestic activity, and promotes the release of in-brain acetylcholine (SOCIETY FOR NEUROSCIENCE, Abstracts, Vol. 21, Page 947, 1995).
- T-588 exhibits a protecting effect on the neuronal death caused by amyloid-beta-protein (SOCIETY FOR NEUROSCIENCE, Abstracts, Vol. 24, Part 1, Page 228, 1998) and that T-588 exhibits an increasing effect on the action of nerve growth factor (WO96/12717).
- SOCIETY FOR NEUROSCIENCE NEUROSCIENCE, Abstracts, Vol. 24, Part 1, Page 228, 1998)
- T-588 exhibits an increasing effect on the action of nerve growth factor (WO96/12717).
- WO96/12717 nerve growth factor
- acetylcholine esterase inhibiting drugs such as Tacrine, Donepezil, Galanthamine, and the like are commercially available as cerebral function-improving drugs including Alzheimer's disease-curing drug, these drugs have problems in the point of side-reactions because some of them have a hepatic toxicity and some others have a side reaction accompanied by activation of acetylcholine neurons other than central nervous system.
- acetylcholine esterase inhibiting drugs for example, a combination of a brain circulation metabolism improver such as Idebenone and an acetylcholine esterase inhibitor (JP 10-259126A) or a combination of a compound having a nerve growth factor-like activity (SR57746A) and an acetylcholine esterase inhibitor (WO99/25363), etc. are being attempted.
- a brain circulation metabolism improver such as Idebenone and an acetylcholine esterase inhibitor
- SR57746A nerve growth factor-like activity
- WO99/25363 acetylcholine esterase inhibitor
- R 1 represents a substituted or unsubstituted heterocyclic group
- R 2 represents a hydrogen atom or a hydroxyl group
- R 3 and R 4 which may be the same or different, each represents a substituted or unsubstituted alkyl, or R 3 and R 4 , taken together with the nitrogen atom to which they are linked, form a substituted or unsubstituted cyclic amino group
- m represents an integer of 1 to 5
- n represents an integer of 1 to 6; or a salt thereof, including T-588.
- Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom
- alkyl group means a straight chain or branched chain C 1-12 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like
- lower alkyl group means a straight chain or branched chain C 1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like
- alkoxy group means a straight or branched chain C 1-12 alkyloxy group such as methoxy, ethoxy, propoxy, isoprop
- the heterocyclic group of R 1 may be substituted with at least one residue selected from halogen atom, optionally substituted amino, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, ar-lower alkylthio, ar-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino groups, or optionally protected amino group, optionally protected hydroxyl group, nitro group, heterocyclic group, oxo group, lower alkylenedioxy group and the like.
- halogen atom optionally substituted amino, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkyl
- the amino groups of R 3 and R 4 and the cyclic amino group which R 3 and R 4 form in conjunction with the nitrogen atom to which R 3 and R 4 are linked may be substituted with at least one group selected from halogen atom, optionally substituted amino group, lower alkyl group, aryl group, ar-lower alkyl group, ar-lower alkenyl group, aroyl group, ar-lower alkenoyl group, heterocyclic group and the like.
- R 1 , R 3 , R 4 and the cyclic amino group which R 3 and R 4 form in conjunction with the nitrogen atom to which R 3 and R 4 and linked may further be substituted with at least one group selected from halogen atom, optionally protected hydroxyl group, optionally protected carboxyl group, optionally protected amino group, lower alkyl group, lower alkoxy group, lower acyl group, cycloalkyl group, ar-lower alkyl group and the like.
- the protecting group for carboxyl group includes all the residues which can conventionally be used as a protecting group for carboxyl group, of which examples include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, 1,1-dimethylpropyl, butyl, tert-butyl and the like; aryl groups such as phenyl, naphthyl and the like; ar-lower alkyl groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl and the like; acyl-lower alkyl groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl and the like; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl, 2-
- the protecting group for hydroxyl group include all the residues which can conventionally be used for protection of hydroxyl group, of which examples include acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)-ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-a
- the protecting group for amino group include all the residues which can conventionally be used as a protecting group for amino groups, of which examples include acyl groups such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di- and tri-)chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthal
- salts of the compounds of general formula [1] conventionally known salts formed at the position of basic group such as amino groups and the like and acidic group such as hydroxyl group, carboxyl group and the like can be referred to.
- the salts formed at the position of basic group for example, salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; salts formed with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, malic acid, tartaric acid, aspartic acid and the like; and salts formed with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like can be referred to.
- salts formed at the position of acidic group for example, salts formed with an alkali metal such as sodium, potassium and the like; salts formed with an alkaline earth metal such as calcium, magnesium and the like; ammonium salts, salts formed with a nitrogen-containing organic base such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-beta-phenethylamine, 1-ephenamine, N,N′-dibenzylethylenediamine and the like; etc.
- an alkali metal such as sodium, potassium and the like
- salts formed with an alkaline earth metal such as calcium, magnesium and the like
- ammonium salts, salts formed with a nitrogen-containing organic base such as trimethylamine, triethylamine, tributyl
- alkyl ether derivatives of general formula [I] or salts thereof have isomers such as optical isomer, geometrical isomer, tautomer, etc.
- the present invention involves all those isomers, and further involves hydrates, solvates and all the crystalline forms.
- alkyl ether derivative or salt thereof used as the ingredient (A) compounds represented by general formula [1] in which the substituents are selected from the following combinations are preferable.
- R 1 is a benzothienyl or benzofuranyl group which may be substituted with a group selected from halogen atoms, alkyl groups and phenyl group
- R 2 is a hydroxyl group
- R 3 is an alkyl group
- R 4 is an alkyl group which may be substituted with an alkoxy-substituted phenyl group or R 3 and R 4 , taken in conjunction with a nitrogen atom to which R 3 and R 4 are linked, form a pyrrolidine ring, piperidine ring, piperazine ring or a morpholine ring
- m is 1
- n is 2.
- R 1 is a benzothienyl or benzofuranyl group which may be substituted with a group selected from halogen atom, alkyl group optionally substituted with hydroxyl group, alkoxy group, carboxyl group, aminocarbonyl group, hydroxyl group, alkylthio group, phenyl group and pyridyl group;
- R 2 is a hydrogen atom;
- R 3 is an alkyl group which may be substituted with a group selected from phenyl group optionally substituted with halogen atom, alkoxy group or nitro group, optionally protected hydroxyl group, alkylamino group and alkynyl group;
- R 4 is an alkyl group which may be substituted with a phenyl group;
- a specific example of such a compound is 2-[[3-(2-benzo[b]thiophen-5-ylethoxy)propyl](methyl)amino]-1-ethanol.
- R 1 is a benzothienyl or benzofuranyl group which may be substituted with a group selected from halogen atom, alkyl group and phenyl group
- R 2 is a hydrogen atom
- R 3 or R 4 is an alkyl group which may be substituted with hydroxyl group, optionally protected amino group and alkylamino group, or R 3 and R 4 represent an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring or a morpholine ring which is formed by R 3 and R 4 together with the nitrogen atom to which R 3 and R 4 are linked
- m is 1
- n is 2 to 3.
- alkyl ether derivatives of general formula [1] or salts thereof can be produced according to the method described in JP 3-47158A, JP 3-232830A, JP 4-95070A, WO99/31056, WO00/76957, PCT/JP02/10827, etc.
- ingredient (B) As the compound having an acetylcholine esterase inhibiting activity used in this invention as ingredient (B), for example, the following can be referred to:
- a pharmaceutical preparation such as tablet, capsule, powder, granule, fine granule, pill, suspension, emulsion, solution, syrup, injection, eye drop and the like can be formed in the usual manner by appropriately using pharmaceutically acceptable assistants such as excipient, carrier, diluent, stabilizer and the like.
- the pharmaceutical preparation thus formed can be administered orally or non-orally.
- the proportions of the ingredients (A) and (B) may be selected appropriately, the amount of ingredient (B) is 0.0005-1 part by weight per 1 part by weight of ingredient (A).
- the amounts of ingredients (A) and (B) vary depending on the combination thereof, for example, the amount of ingredient (B) (the compound having an acetylcholine esterase inhibitory activity) may be an amount at which a reaction of the peripheral nervous symptom (predominantly, the reaction caused by the parasympathetic nervous system such as diarrhoea, lacrimmation, salivation, etc.) does not appear significantly.
- the amount of ingredient (B) may be an amount at which a reaction of the peripheral nervous symptom (predominantly, the reaction caused by the parasympathetic nervous system such as diarrhoea, lacrimmation, salivation, etc.) does not appear significantly.
- the amount is about 0.05 mg to 10 mg per day in the case of Donepezil, about 1 mg to 120 mg per day in the case of Zanapezil, about 5 mg to 200 mg per day in the case of Tacrine, about 10 mg to 300 mg per day in the case of Ipidacrine, and about 0.5 mg to 20 mg per day in the case of Rivastigmine.
- ingredient (A) varies depending on the kind of ingredient (B), namely the compound having an acetylcholine esterase inhibitory activity, it is 0.01 to 500 mg per day.
- Test compounds A1, A2, A3, B1 and B2 were put to use after dissolution in distilled water.
- Test compounds C1 and C2 were put to use after suspending them in 0.5% solution of methylcellulose.
- test was carried out according to the method described in Japanese Journal of Pharmacology, Vol. 62, Page 81, 1993.
- mice To one group (6-10 animals) of ddY male mice having an age of 4-5 weeks was orally administered a test compound dissolved in distilled water or suspended in 0.5% methyl cellulose solution. Thirty minutes after the administration, the mice were introduced into a glass container at a volume of 300 mL, and a gaseous mixture composed of 4% of oxygen and 96% of nitrogen was passed though the glass container at a flow rate of 5 L/minute. The period of time from the start of passing the gaseous mixture to the death of the mice was measured. To the control group, distilled water was administered orally.
- the anti-hypoxic activity of each test compound was calculated according to the following formula: (Survival time of mouse in the test compound ⁇ administered group/Survival time of mouse in the control group) ⁇ 100% The results are shown in Tables 1-3.
- Anti-hypoxic activity can synergistically be improved by combining the alkyl ether derivative of general formula [1] or a salt thereof with a compound having an acetylcholine esterase inhibitory activity. Accordingly, the combination of this invention is useful as a method for improving the cerebral function.
- a pharmaceutical composition containing the compound according to the combination of this invention is useful for treatment and prevention of dysfunction of cerebral acetylcholine neurons in the sequela of cerebrovascular dementia, senile dementia, Alzheimer's disease and ischemic cerebral lesion and in the cerebral apoplexy or the memory impairment caused by selective neuronal death.
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US20090093453A1 (en) | 2006-04-26 | 2009-04-09 | Toyama Chemical Co., Ltd | Neurogenesis inducer or neuropathy therapeutic agent comprising alkyl ether derivative or salt thereof |
US20090209512A1 (en) | 2006-04-26 | 2009-08-20 | Toyama Chemical Co., Ltd. | Neurogenesis inducer or neuropathy therapeutic agent comprising alkyl ether derivative or salt thereof |
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