JP5543958B2 - オリゴマー−アリールオキシ置換プロパンアミンコンジュゲート - Google Patents
オリゴマー−アリールオキシ置換プロパンアミンコンジュゲート Download PDFInfo
- Publication number
- JP5543958B2 JP5543958B2 JP2011504017A JP2011504017A JP5543958B2 JP 5543958 B2 JP5543958 B2 JP 5543958B2 JP 2011504017 A JP2011504017 A JP 2011504017A JP 2011504017 A JP2011504017 A JP 2011504017A JP 5543958 B2 JP5543958 B2 JP 5543958B2
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- Prior art keywords
- oligomer
- compound
- water
- aryloxy
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical class CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 title claims description 81
- 150000001875 compounds Chemical class 0.000 claims description 106
- 239000000203 mixture Substances 0.000 claims description 78
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 68
- 239000000178 monomer Substances 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 23
- 125000006850 spacer group Chemical group 0.000 claims description 22
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
- 125000001544 thienyl group Chemical group 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000004104 aryloxy group Chemical group 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 125000002541 furyl group Chemical group 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- 229920000233 poly(alkylene oxides) Polymers 0.000 claims description 6
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- 125000001475 halogen functional group Chemical group 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
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- 125000003277 amino group Chemical group 0.000 description 18
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- 239000000935 antidepressant agent Substances 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 229940005513 antidepressants Drugs 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
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- HPVHJPMLORARSR-UHFFFAOYSA-N 3-(dimethylamino)-1-thiophen-2-ylpropan-1-one;hydron;chloride Chemical compound Cl.CN(C)CCC(=O)C1=CC=CS1 HPVHJPMLORARSR-UHFFFAOYSA-N 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 10
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
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- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 7
- XWCNSHMHUZCRLN-UHFFFAOYSA-N 3-(dimethylamino)-1-thiophen-2-ylpropan-1-ol Chemical compound CN(C)CCC(O)C1=CC=CS1 XWCNSHMHUZCRLN-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
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- 125000006239 protecting group Chemical group 0.000 description 7
- 235000011121 sodium hydroxide Nutrition 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 6
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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- BLGXFZZNTVWLAY-UHFFFAOYSA-N beta-Yohimbin Natural products C1=CC=C2C(CCN3CC4CCC(O)C(C4CC33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-UHFFFAOYSA-N 0.000 description 5
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- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- SHPKCSFVQGSAJU-SEPHDYHBSA-L potassium fumarate Chemical compound [K+].[K+].[O-]C(=O)\C=C\C([O-])=O SHPKCSFVQGSAJU-SEPHDYHBSA-L 0.000 description 1
- 235000019295 potassium fumarate Nutrition 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- DOKHEARVIDLSFF-UHFFFAOYSA-N prop-1-en-1-ol Chemical compound CC=CO DOKHEARVIDLSFF-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000001671 psychotherapy Methods 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 230000037321 sleepiness Effects 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 230000005586 smoking cessation Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960005453 strychnine Drugs 0.000 description 1
- 229960000412 strychnine sulfate Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003463 sulfur Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 150000003555 thioacetals Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000035922 thirst Effects 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229960000949 yohimbine hydrochloride Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- 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
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/24—Antidepressants
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Description
本出願は、米国特許法第119条(e)に基づいて、2008年4月11日に出願された米国仮特許出願第61/123,929号の優先権の利益を主張するものであり、その開示全体を参照により本明細書に援用する。
式中、R1は、C5〜C7シクロアルキル、チエニル、ハロチエニル、(C1〜C4アルキル)チエニル、フラニル、ピリジルまたはチアゾリルであり、Arは、
であり、
R2およびR3は各々独立に、水素またはメチルであり、
各R4は独立に、ハロ、C1〜C4アルキル、C1〜C3アルコキシまたはトリフルオロメチルであり、
各R5は独立に、ハロ、C1〜C4アルキルまたはトリフルオロメチルであり、
mは、0、1または2であり、
nは、0または1であり、
Xは、スペーサー部分であり、
POLYは、水溶性非ペプチドオリゴマーである。
式中、R1は、C5〜C7シクロアルキル、チエニル、ハロチエニル、(C1〜C4アルキル)チエニル、フラニル、ピリジルまたはチアゾリルであり、Arは、
であり、
R2は、水素またはメチルであり、
各R4は独立に、ハロ、C1〜C4アルキル、C1〜C3アルコキシまたはトリフルオロメチルであり、
各R5は独立に、ハロ、C1〜C4アルキルまたはトリフルオロメチルであり、
mは、0、1または2であり、
nは、0または1であり、
Xは、スペーサー部分であり、
POLYは、水溶性非ペプチドオリゴマーである。
式中、Xは、スペーサー部分であり、
POLYは、水溶性非ペプチドオリゴマーである。
式中、Xは、スペーサー部分であり、
POLYは、水溶性非ペプチドオリゴマーである。
式中、R1は、C5〜C7シクロアルキル、チエニル、ハロチエニル、(C1〜C4アルキル)チエニル、フラニル、ピリジルまたはチアゾリルであり、Arは、
であり、
R2およびR3は各々独立に、水素またはメチルであり、
各R4は独立に、ハロ、C1〜C4アルキル、C1〜C3アルコキシまたはトリフルオロメチルであり、
各R5は独立に、ハロ、C1〜C4アルキルまたはトリフルオロメチルであり、
mは、0、1または2であり、
nは、0または1である。
また、例示としてのアリールオキシ置換プロパンアミン化合物は、(+)−(S)−N−メチル−3−(ナフタレン−1−イルオキシ)−3−(チオフェン−2−イル)プロパン−1−アミンも含む。
本発明の好ましい実施形態では、例えば以下が提供される:
(項目1)
安定したまたは分解可能な連結によって水溶性非ペプチドオリゴマーと共有結合的に結合されたアリールオキシ置換プロパンアミン残基を含む化合物。
(項目2)
以下の構造:
を有し、
式中、R 1 は、C 5 〜C 7 シクロアルキル、チエニル、ハロチエニル、(C 1 〜C 4 アルキル)チエニル、フラニル、ピリジルまたはチアゾリルであり、Arは、
であり、
R 2 およびR 3 は各々独立に、水素またはメチルであり、
各R 4 は独立に、ハロ、C 1 〜C 4 アルキル、C 1 〜C 3 アルコキシまたはトリフルオロメチルであり、
各R 5 は独立に、ハロ、C 1 〜C 4 アルキルまたはトリフルオロメチルであり、
mは、0、1または2であり、
nは、0または1であり、
Xは、スペーサー部分であり、
POLYは、水溶性非ペプチドオリゴマーである、項目1に記載の化合物。
(項目3)
構造:
を有し、
式中、R 1 は、C 5 〜C 7 シクロアルキル、チエニル、ハロチエニル、(C 1 〜C 4 アルキル)チエニル、フラニル、ピリジルまたはチアゾリルであり、Arは、
であり、
R 2 は、水素またはメチルであり、
各R 4 は独立に、ハロ、C 1 〜C 4 アルキル、C 1 〜C 3 アルコキシまたはトリフルオロメチルであり、
各R 5 は独立に、ハロ、C 1 〜C 4 アルキルまたはトリフルオロメチルであり、
mは、0、1または2であり、
nは、0または1であり、
Xは、スペーサー部分であり、
POLYは、水溶性非ペプチドオリゴマーである、項目1に記載の化合物。
(項目4)
構造:
を有し、
式中、Xは、スペーサー部分であり、
POLYは、水溶性非ペプチドオリゴマーである、項目1に記載の化合物。
(項目5)
構造:
を有し、
式中、Xは、スペーサー部分であり、
POLYは、水溶性非ペプチドオリゴマーである、項目1に記載の化合物。
(項目6)
前記アリールオキシ置換プロパンアミン残基が、式:
を有するアリールオキシ置換プロパンアミンの残基であり、
式中、R 1 は、C 5 〜C 7 シクロアルキル、チエニル、ハロチエニル、(C 1 〜C 4 アルキル)チエニル、フラニル、ピリジルまたはチアゾリルであり、Arは、
であり、
R 2 およびR 3 は各々独立に、水素またはメチルであり、
各R 4 は独立に、ハロ、C 1 〜C 4 アルキル、C 1 〜C 3 アルコキシまたはトリフルオロメチルであり、
各R 5 は独立に、ハロ、C 1 〜C 4 アルキルまたはトリフルオロメチルであり、
mは、0、1または2であり、
nは、0または1である、項目1に記載の化合物。
(項目7)
前記アリールオキシ置換プロパンアミン残基が、式:
を有するアリールオキシ置換プロパンアミンの残基である、項目1に記載の化合物。
(項目8)
前記水溶性非ペプチドオリゴマーがポリ(アルキレンオキシド)である、項目1〜7のいずれか一項に記載の化合物。
(項目9)
前記ポリ(アルキレンオキシド)がポリ(エチレンオキシド)である、項目8に記載の化合物。
(項目10)
水溶性非ペプチドオリゴマーが約1〜約30のモノマーで構成される、項目1〜9のいずれか一項に記載の化合物。
(項目11)
前記水溶性非ペプチドオリゴマーが約1〜約10のモノマーで構成される、項目10に記載の化合物。
(項目12)
前記ポリ(アルキレンオキシド)がアルコキシまたはヒドロキシエンドキャッピング部分を含む、項目8に記載の化合物。
(項目13)
単一の水溶性非ペプチドオリゴマーが前記アリールオキシ置換プロパンアミン残基に結合されている、項目1〜12のいずれか一項に記載の化合物。
(項目14)
2つ以上の水溶性非ペプチドオリゴマーが前記アリールオキシ置換プロパンアミン残基に結合されている、項目1〜13のいずれか一項に記載の化合物。
(項目15)
前記アリールオキシ置換プロパンアミン残基が、安定した連結によって共有結合的に結合されている、項目1〜14のいずれか一項に記載の化合物。
(項目16)
前記アリールオキシ置換プロパンアミン残基が、分解可能な連結によって共有結合的に結合されている、項目1〜15のいずれか一項に記載の化合物。
(項目17)
前記連結がエーテル連結である、項目1〜16のいずれか一項に記載の化合物。
(項目18)
前記連結がエステル連結である、項目1〜17のいずれか一項に記載の化合物。
(項目19)
安定したまたは分解可能な連結によって水溶性非ペプチドオリゴマーと共有結合的に結合されたアリールオキシ置換プロパンアミン残基を含む化合物と、任意に、薬学的に許容される賦形剤とを含む、組成物。
(項目20)
安定したまたは分解可能な連結によって水溶性非ペプチドオリゴマーと共有結合的に結合されたアリールオキシ置換プロパンアミン残基を含む化合物を含む組成物であって、前記化合物が剤形で存在する、組成物。
(項目21)
水溶性非ペプチドオリゴマーをアリールオキシ置換プロパンアミンに共有結合的に結合させることを含む、方法。
(項目22)
安定したまたは分解可能な連結によって水溶性非ペプチドオリゴマーと共有結合的に結合されたアリールオキシ置換プロパンアミン残基を含む化合物を、これを必要とする被検体に投与することを含む、治療方法。
式中、R1は、C5〜C7シクロアルキル、チエニル、ハロチエニル、(C1〜C4アルキル)チエニル、フラニル、ピリジルまたはチアゾリルであり、Arは、
であり、
R2およびR3は各々独立に、水素またはメチルであり、
各R4は独立に、ハロ、C1〜C4アルキル、C1〜C3アルコキシまたはトリフルオロメチルであり、
各R5は独立に、ハロ、C1〜C4アルキルまたはトリフルオロメチルであり、
mは、0、1または2であり、
nは、0または1である。
の構造を有する、化合物が得られる。
また、例示としてのアリールオキシ置換プロパンアミン化合物は、(+)−(S)−N−メチル−3−(ナフタレン−1−イルオキシ)−3−(チオフェン−2−イル)プロパン−1−アミン(デュロキセチン)も含む。
式中、R1は、C5〜C7シクロアルキル、チエニル、ハロチエニル、(C1〜C4アルキル)チエニル、フラニル、ピリジルまたはチアゾリルであり、Arは、
であり、
R2およびR3は各々独立に、水素またはメチルであり、
各R4は独立に、ハロ、C1〜C4アルキル、C1〜C3アルコキシまたはトリフルオロメチルであり、
各R5は独立に、ハロ、C1〜C4アルキルまたはトリフルオロメチルであり、
mは、0、1または2であり、
nは、0または1であり、
Xは、スペーサー部分であり、
POLYは、水溶性非ペプチドオリゴマーである。
式中、R1は、C5〜C7シクロアルキル、チエニル、ハロチエニル、(C1〜C4アルキル)チエニル、フラニル、ピリジルまたはチアゾリルであり、Arは、
であり、
R2は、水素またはメチルであり、
各R4は独立に、ハロ、C1〜C4アルキル、C1〜C3アルコキシまたはトリフルオロメチルであり、
各R5は独立に、ハロ、C1〜C4アルキルまたはトリフルオロメチルであり、
mは、0、1または2であり、
nは、0または1であり、
Xは、スペーサー部分であり、
POLYは、水溶性非ペプチドオリゴマーである。
式中、Xは、スペーサー部分であり、
POLYは、水溶性非ペプチドオリゴマーである。
式中、Xは、スペーサー部分であり、
POLYは、水溶性非ペプチドオリゴマーである。
イソシアネート(R−N=C=O)はヒドロキシル基またはアミノ基と反応して、それぞれ、カルバミン酸塩(RNH−C(O)−OR’)または尿素(RNH−C(O)−NHR’)連結を形成する。アルデヒド、ケトン、グリオキサール、ジオン、これらの水和物またはアルコールアダクト(すなわち、アルデヒド水和物、ヘミアセタール、アセタール、ケトン水和物、ヘミケタール、ケタール)を、好ましくはアミンと反応させた後、必要があれば得られるイミンを還元して、アミン連結を得る(還元アミン化)。
デュロキセチンおよび新規PEG−デュロキセチンコンジュゲート:
(S)−デュロキセチンの合成:
Claims (14)
- 安定したまたは分解可能な連結によって水溶性非ペプチドオリゴマーと共有結合的に結合されたアリールオキシ置換プロパンアミン残基を含む化合物であって、
ここで、前記化合物は、以下の構造:
を有し、
式中、R 1 は、C 5 〜C 7 シクロアルキル、チエニル、ハロチエニル、(C 1 〜C 4 アルキル)チエニル、フラニル、ピリジルまたはチアゾリルであり、Arは、
であり、
R 2 およびR 3 は各々独立に、水素またはメチルであり、
各R 4 は独立に、ハロ、C 1 〜C 4 アルキル、C 1 〜C 3 アルコキシまたはトリフルオロメチルであり、
各R 5 は独立に、ハロ、C 1 〜C 4 アルキルまたはトリフルオロメチルであり、
mは、0、1または2であり、
nは、0または1であり、
Xは、スペーサー部分であり、
POLYは、水溶性非ペプチドオリゴマーである、化合物。 - 構造:
を有する、請求項1に記載の化合物。 - 前記水溶性非ペプチドオリゴマーがポリ(アルキレンオキシド)である、請求項1〜2のいずれか一項に記載の化合物。
- 前記ポリ(アルキレンオキシド)がポリ(エチレンオキシド)である、請求項3に記載の化合物。
- 前記水溶性非ペプチドオリゴマーが1〜30のモノマーで構成される、請求項1〜4のいずれか一項に記載の化合物。
- 前記水溶性非ペプチドオリゴマーが1〜10のモノマーで構成される、請求項5に記載の化合物。
- 前記ポリ(アルキレンオキシド)がアルコキシまたはヒドロキシエンドキャッピング部分を含む、請求項3に記載の化合物。
- 前記アリールオキシ置換プロパンアミン残基が、安定した連結によって共有結合的に結合されている、請求項1〜7のいずれか一項に記載の化合物。
- 前記アリールオキシ置換プロパンアミン残基が、分解可能な連結によって共有結合的に結合されている、請求項1〜8のいずれか一項に記載の化合物。
- 前記連結がエーテル連結である、請求項1〜9のいずれか一項に記載の化合物。
- 前記連結がエステル連結である、請求項1〜10のいずれか一項に記載の化合物。
- 請求項1に記載の化合物と、任意に、薬学的に許容される賦形剤とを含む、組成物。
- 請求項1に記載の化合物を含む組成物であって、前記化合物が剤形で存在する、組成物。
- 請求項1に記載の化合物を含む、治療を必要とする被検体を治療するための組成物。
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