WO1993014113A1 - Peptides with tachykinin antagonist activity - Google Patents
Peptides with tachykinin antagonist activity Download PDFInfo
- Publication number
- WO1993014113A1 WO1993014113A1 PCT/JP1993/000002 JP9300002W WO9314113A1 WO 1993014113 A1 WO1993014113 A1 WO 1993014113A1 JP 9300002 W JP9300002 W JP 9300002W WO 9314113 A1 WO9314113 A1 WO 9314113A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- compound
- salt
- formula
- defined above
- Prior art date
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- 239000002462 tachykinin receptor antagonist Substances 0.000 title claims description 4
- 108090000765 processed proteins & peptides Proteins 0.000 title description 14
- 230000000694 effects Effects 0.000 title description 3
- 102000004196 processed proteins & peptides Human genes 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 120
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 102000003141 Tachykinin Human genes 0.000 claims abstract description 8
- 108060008037 tachykinin Proteins 0.000 claims abstract description 8
- 230000001404 mediated effect Effects 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 107
- 150000003839 salts Chemical class 0.000 claims description 88
- 238000006243 chemical reaction Methods 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 7
- 150000003973 alkyl amines Chemical class 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 6
- 125000004450 alkenylene group Chemical group 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 3
- 238000006683 Mannich reaction Methods 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 claims description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
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- -1 organic acid salt Chemical class 0.000 description 107
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- 102100024304 Protachykinin-1 Human genes 0.000 description 6
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- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-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
- 125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 125000004532 benzofuran-3-yl group Chemical group O1C=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004534 benzothien-2-yl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004197 benzothien-3-yl group Chemical group [H]C1=C(*)C2=C([H])C([H])=C([H])C([H])=C2S1 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- SEQPSPZFEZDRLX-UHFFFAOYSA-N benzyl 1h-indole-3-carboxylate Chemical compound C=1NC2=CC=CC=C2C=1C(=O)OCC1=CC=CC=C1 SEQPSPZFEZDRLX-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- DKVNPHBNOWQYFE-UHFFFAOYSA-N carbamodithioic acid Chemical compound NC(S)=S DKVNPHBNOWQYFE-UHFFFAOYSA-N 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 1
- 150000001845 chromium compounds Chemical class 0.000 description 1
- LRCIYVMVWAMTKX-UHFFFAOYSA-L chromium(ii) acetate Chemical compound [Cr+2].CC([O-])=O.CC([O-])=O LRCIYVMVWAMTKX-UHFFFAOYSA-L 0.000 description 1
- XBWRJSSJWDOUSJ-UHFFFAOYSA-L chromium(ii) chloride Chemical compound Cl[Cr]Cl XBWRJSSJWDOUSJ-UHFFFAOYSA-L 0.000 description 1
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- 108010086192 chymostatin Proteins 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000002592 cumenyl group Chemical group C1(=C(C=CC=C1)*)C(C)C 0.000 description 1
- RCJVRSBWZCNNQT-UHFFFAOYSA-N dichloridooxygen Chemical compound ClOCl RCJVRSBWZCNNQT-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- HBFXVTVOSLPOEY-UHFFFAOYSA-N ethoxyethane;2-propan-2-yloxypropane Chemical compound CCOCC.CC(C)OC(C)C HBFXVTVOSLPOEY-UHFFFAOYSA-N 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- WMYNMYVRWWCRPS-UHFFFAOYSA-N ethynoxyethane Chemical group CCOC#C WMYNMYVRWWCRPS-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 235000020932 food allergy Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 238000011597 hartley guinea pig Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 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 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 description 1
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 125000004246 indolin-2-yl group Chemical group [H]N1C(*)=C([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 description 1
- 239000004137 magnesium phosphate Substances 0.000 description 1
- 229910000157 magnesium phosphate Inorganic materials 0.000 description 1
- 229960002261 magnesium phosphate Drugs 0.000 description 1
- 235000010994 magnesium phosphates Nutrition 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
- 239000011565 manganese chloride Substances 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- IIZIDOVNRVNSCV-UHFFFAOYSA-N methyl 1-[2-(dimethylamino)ethyl]indole-3-carboxylate Chemical compound C1=CC=C2C(C(=O)OC)=CN(CCN(C)C)C2=C1 IIZIDOVNRVNSCV-UHFFFAOYSA-N 0.000 description 1
- CUTKAOYBTIKPLC-UHFFFAOYSA-N methyl 1-[3-(dimethylamino)propyl]indole-3-carboxylate Chemical compound C1=CC=C2C(C(=O)OC)=CN(CCCN(C)C)C2=C1 CUTKAOYBTIKPLC-UHFFFAOYSA-N 0.000 description 1
- UHAAFJWANJYDIS-UHFFFAOYSA-N n,n'-diethylmethanediimine Chemical compound CCN=C=NCC UHAAFJWANJYDIS-UHFFFAOYSA-N 0.000 description 1
- VMESOKCXSYNAKD-UHFFFAOYSA-N n,n-dimethylhydroxylamine Chemical compound CN(C)O VMESOKCXSYNAKD-UHFFFAOYSA-N 0.000 description 1
- JVHPKYBRJQNPAT-UHFFFAOYSA-N n-cyclohexyl-2,2-diphenylethenimine Chemical compound C1CCCCC1N=C=C(C=1C=CC=CC=1)C1=CC=CC=C1 JVHPKYBRJQNPAT-UHFFFAOYSA-N 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 239000002746 neurokinin 2 receptor antagonist Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229940100684 pentylamine Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- ZPLUZNXSYCCJOE-UHFFFAOYSA-N phosphoric acid;propan-2-one Chemical compound CC(C)=O.OP(O)(O)=O ZPLUZNXSYCCJOE-UHFFFAOYSA-N 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003890 substance P antagonist Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 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
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 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
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 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 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 201000005539 vernal conjunctivitis Diseases 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to new peptide compound and a pharmaceutically acceptable salt thereof.
- new peptide compound and a pharmaceutically acceptable salt thereof which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A
- antagonism to a process for preparation thereof, to a pharmaceutical composition comprising the same, and to a use of the same as a medicament.
- one object of the present invention is to provide new and useful peptide compound and a
- Neurokinin B antagonism Neurokinin B antagonism, and the like.
- Another object of the present invention is to provide a process for the preparation of said peptide compound and a salt thereof.
- a further object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising, as an active ingredient, said peptide compound and a
- Still further object of the present invention is to provide a use of said peptide compound or a
- Tachykinin antagonist especially Substance P antagonist, Neurokinin A antagonist or Neurokinin B antagonist, useful for treating or preventing Tachykinin-mediated diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration, and the like; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact
- dermatitis atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like
- inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like
- pains or aches e.g., migraine, headache, toothache, cancerous pain, back pain, etc.
- the like in human being or animals e.g., migraine, headache, toothache, cancerous pain, back pain, etc.
- the object compound of the present invention can be represented by the following general formula (I).
- R 1 is aryl, pyridyl, pyrrolyl, or
- X is CH or N
- Z is -O-, -S- or -NH-
- R 2 is ar(lower)alkyl which may have suitable substituent(s);
- R 3 is lower alkyl which may have suitable substituent(s);
- R 4 is ar(lower)alkyl which may have suitable substituent(s);
- R 6 is hydrogen or lower alkyl
- A is bond, lower alkylene or lower alkenylene; is 0 or N-R 7 in which R 7 is hydrogen or lower alkyl;
- n is an integer of 0 to 2.
- Preferred configuration of the compound (I) can be represented by the following- formula.
- the new peptide compound (I) can be prepared by processes which are illustrated in the following schemes.
- R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , A, X, Y, m and n are each as defined above,
- R a is amidino or (lower alkylthio)(cyanoimino)- methyl
- L is a leaving group
- amino acid, peptides, protective groups, condensing agents, etc. are expressed by the abbreviations according to the IUPAC-IUB (Commission on Biological Nomenclature) which are in common use in the field of this art.
- amino acids and their residues when shown by such abbreviations are meant to be L-configured compounds and residues.
- Suitable pharmaceutically acceptable salts of the starting and object compounds are conventional non-toxic salt and include an acid addition salt such as an organic acid salt (e.g. acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g.
- an organic acid salt e.g. acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.
- an inorganic acid salt e.g.
- nitrate, phosphate, etc. or a salt which an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), or a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt,
- an amino acid e.g. arginine, aspartic acid, glutamic acid, etc.
- a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt,
- dicyclohexylamine salt N,N'-dibenzylethylenediamine salt, etc.), or the like.
- Suitable "aryl” may include phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl, and the like, in which the preferred one is C 6 -C 10 aryl and the most preferred one is phenyl.
- indolyl e.g. indol-1-yl, indol-2-yl,
- benzofuryl e.g. benzofuran-2-yl, benzofuran-3-yl, etc.
- benzothienyl e.g.
- benzothien-2-yl, benzothien-3-yl, etc. indazolyl (e.g. 1H-indazol-1-yl, 1H-indazol-3-yl, etc.), indolinyl (e.g. indolin-2-yl, indolin-3-yl, etc.), and the like, in which the preferred one is indolyl.
- the aryl group and the group represented by the above formula may have one or more, preferably one to three suitable substituents such as lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc.); amino(lower) alkyl (e.g.
- cyano(lower)alkyl e.g. cyanomethyl, cyanoethyl
- amidino(lower)alkyl e.g. amidinomethyl, amidinoethyl, amidinopropyl, amidinobutyl, amidinopentyl, amidinohexyl, etc.
- guanidino(lower)alkyl e.g. guanidinomethyl, guanidinoethyl, guanidinopropyl, guanidinobutyl
- Suitable "lower alkylene” is one having 1 to 6 carbon atom(s) and may include methylene, ethylene, trimethylene, propylene, tetramethylene, methyltrimethylene,
- hexamethylene and the like, in which the preferred one is methylene, ethylene or trimethylene.
- Suitable "lower alkenylene” is one having 2 to 6 carbon atom(s) and may include vinylene, propenylene, and the like, in which the preferred one is vinylene.
- substituent(s) may include a conventional group, which is used in the field of this art such as lower alkyl as exemplified above, carboxy(lower) alkyl (e.g. carboxymethyl, etc.), protected carboxy(lower)alkyl such as esterified carboxy(lower)alkyl, for example, lower alkoxycarbonyl(lower)alkyl (e.g. methoxycarbonylmethyl, etc.), carbamoyl(lower)alkyl (e.g. carbamoylmethyl, carbamoylethyl, etc.), lower alkylamino(lower)alkyl (e.g. dimethylaminomethyl, dimethylaminoethyl, etc.),
- hydroxy(lower)alkyl e.g., hydroxymethyl, hydroxyethyl, etc.
- protected hydroxy(lower)alkyl such as
- acyloxy(lower)alkyl e.g. acetyloxyethyl, etc.
- halo(lower)alkyl e.g. trifluoromethyl, etc.
- Suitable "ar(lower)alkyl which may have suitable substituent (s)” may include a conventional group, which is used in the field of amino acid and peptide chemistry, such as ar (lower)alkyl (e.g. trityl, benzhydryl, benzyl, phenethyl, naphthylmethyl, tolylmethyl, xylylmethyl, mesitylmethyl, etc.), substituted ar(lower)alkyl (e.g., o-fluorobenzyl, m-fluorobenzyl, o-trifluoromethylbenzyl, etc.), and the like.
- ar (lower)alkyl e.g. trityl, benzhydryl, benzyl, phenethyl, naphthylmethyl, tolylmethyl, xylylmethyl, mesitylmethyl, etc.
- ar(lower)alkyl e.g. trityl,
- alkyl-3-cyanoisothioureido](lower)alkyl "[2-lower alkyl-3-cyanoisothioureido](lower)alkyl” and [3-lower alkyl-2-cyanoguanidino](lower)alkyl may be the same as those given in the above.
- Suitable "(lower alkylthio) (cyanoimino)methyl” may include (methylthio)(cyanoimino)methyl,
- Suitable “leaving group” may include lower alkylthio (e.g. methylthio, ethylthio, etc.), substituted or
- pyrrol-1-yl e.g. pyrrol-1-yl
- R 1 , R 2 , R 3 , R 4 , R 6 , A, Y, m and n are as follows.
- R 1 is aryl, preferably C 6 -C 10 aryl (e.g. phenyl, etc.),
- R 5 is hydrogen
- lower alkyl e.g. methyl, etc.
- amino(lower)alkyl e.g. 2-aminoethyl, etc.
- protected amino(lower)alkyl preferably acylamino(lower)alkyl such as lower
- alkoxycarbonylamino(lower)alkyl e.g.
- guanidino(lower)alkyl e.g. 2-guanidinoethyl, etc.
- R 2 is ar(lower)alkyl, preferably C 6 -C 10 ar(lower)alkyl such as phenyl(lower)alkyl (e.g. benzyl, etc.), mono or di(lower)alkylphenyl(lower)alkyl (e.g. 3-tolylmethyl, 3,4-xylylmethyl, etc.), naphthyl(lower)alkyl (e.g.
- R 3 is lower alkyl (e.g. methyl, etc.);
- R 4 is ar(lower)alkyl such as phenyl(lower)alkyl (e.g.
- R 6 is hydrogen or lower alkyl (e.g. methyl, etc.);
- A is bond or lower alkenylene (e.g. vinylene, etc.);
- Y is O or N-R 7 in which R 7 is hydrogen or lower alkyl (e.g.
- n 0 or 1
- n is an integer of 1.
- the compound (I-a) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound
- Suitable reactive derivative at the amino group of the compound (II) may include a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis(trimethylsilyl)acetamide,
- Suitable salts of the compound (II) and its reactive derivative can be referred to the ones as exemplified for the compound (I).
- Suitable reactive derivative at the carboxy group of the compound (III) may include conventional one which is used in the peptide chemistry such as an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. Suitable examples of the reactive
- derivatives may be an acid chloride; an acid azide;
- a mixed acid anhydride within acid such as substituted phosphoric acid [e.g. dialkylphosphoric acid,
- dibenzylphosphoric acid dibenzylphosphoric acid, halogenated phosphoric acid, etc.] dialkylphosphorous acid, sulfurous acid,
- aliphatic carboxylie acid e.g. acetic acid, propionic acid, butyric acid,
- dimethylpyrazole, triazole or tetrazole or an activated ester
- N-hydroxy compound e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
- N-hydroxyphthalimide 1-hydroxy-1H-benzotriazole, etc.]
- These reactive derivatives can optionally be selected from them according to the kind of the
- Suitable salts of the compound (III) and its reactive derivative may be a base salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.], an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e.g.
- trimethylamine salt triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt,
- the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, dichloromethane, ethylene chloride,
- solvents may also be used in a mixture with water.
- a conventional condensing agent such as carbodiimide compound (e.g.
- N-cyclohexyl-N'-(4-dimethylaminocyclohexyl)carbodiimide N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc.
- triphenylphosphine 2-ethyl-7-hydroxybenzisoxazolium salt
- the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine (e.g. triethylamine, etc.), pyridine, N,N-di(lower)alkyl-1,3-propanediamine (e.g. N,N-dimethyl-1,3-propanediamine, etc.),
- an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine (e.g. triethylamine, etc.), pyridine, N,N-di(lower)alkyl-1,3-propanediamine (e.g. N,N-dimethyl-1,3-propanediamine, etc.),
- N-(lower)alkylmorpholine e.g. N-methylmorpholine, etc.
- N,N-di(lower)alkylbenzylamine and the like.
- the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
- the compound (I-c) or a salt thereof can be prepared by subjecting the compound (I-b) or a salt thereof to addition reaction of cyano(lower) alkene.
- Suitable “cyano(lower)alkene” may be acrylonitrile, and the like.
- the present reaction is usually carried out in the presence of a base which is capable of leaving proton from the first position of an indole ring such as Triton B, and the like.
- the present reaction is usually carried out in a solvent such as dioxane, dimethyl sulfoxide,
- reaction temperature is not critical and the reaction is usually carried out under cooling, at ambient temperature or under warming.
- the compound (I-d) or a salt thereof can be prepared by reacting the compound (I-c) or a salt thereof with ammonia or a salt thereof.
- Suitable salt of ammonia may be an acid addition salt as exemplified for the compound (I).
- This reaction can be carried out by a conventional method which is capable of converting a cyano group to an amidino group.
- the compound (I-c) is preferably converted to its imido ether compound as the first step by alcohol (e.g. methanol, ethanol, etc.) in the presence of an acid (e.g. hydrogen chloride, etc.), and then the intermediary imido ether compound are transformed into the object compound (I-d).
- alcohol e.g. methanol, ethanol, etc.
- acid e.g. hydrogen chloride, etc.
- This reaction is usually carried out in the presence of a conventional solvent such as methanol, ethanol or any other solvent which does not adversely affect the
- the reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature or under warming.
- the compound (I-f) or a salt thereof can be prepared by subjecting the compound (I-e) or a salt thereof to removal reaction of the amino-protective group.
- Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium
- alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium hydroxide, etc.
- alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
- alkaline earth metal carbonate e.g. magnesium carbonate, calcium
- alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
- alkali metal acetate e.g. sodium acetate, potassium acetate, etc.
- alkaline earth metal phosphate e.g. magnesium phosphate, calcium phosphate, etc.
- alkali metal hydrogen phosphate e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
- an organic base such as trialkylamine (e.g. trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine,
- Suitable acid may include an organic acid (e.g.
- formic acid acetic acid, propionic acid, etc.
- an inorganic acid e.g. hydrogen chloride, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
- the present hydrolysis is usually carried out in an organic solvent (e.g. ethyl acetate, etc.), water, or a mixed solvent thereof.
- an organic solvent e.g. ethyl acetate, etc.
- the reaction temperature is not critical, and it may suitably be selected in accordance with the kind of the amino-protective group and the removal method.
- the reduction elimination can be applied preferably for elimination of the protective group such as
- the reduction method applicable for the removal reacting may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chromium compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or an inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, etc.); and conventional catalytic reduction in the
- the compound (I-g) or a salt thereof can be prepared by reacting the compound (I-f) or a salt thereof with the compound (IV).
- the reaction can be carried out in the presence of a base as exemplified in Process 1.
- This reaction is usually carried out in a
- the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
- the compound (I-i) or a salt thereof can be prepared by reacting the compound (I-h) or a salt thereof with lower alkylamine.
- Suitable "lower alkylamine” used in this reaction may be C 1 -C 6 alkylamine such as methylamine, ethylamine, propylamine, isopropylamine, butylamine, pentylamine, hexylamine, and the like.
- This reaction is usually carried out in a
- reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
- the compound (I-j) or a salt thereof can be prepared by reacting the compound (I-a) or a salt thereof with the compound (V) or a salt thereof.
- the reaction can be carried out in the presence of a phosphorus compound (e.g. phosphorus pentachloride, etc.) and N,N-dimethylaniline.
- a phosphorus compound e.g. phosphorus pentachloride, etc.
- N,N-dimethylaniline e.g. N,N-dimethylaniline.
- This reaction is usually carried out in a
- the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
- the compound (I-k) or a salt thereof can be prepared by subjecting the compound (II) or its reactive derivative at the amino group or a salt thereof to Mannich reaction.
- the reaction can be carried out in a conventional manner, that is, by the reaction of the compound (II) or its reactive derivative at the amino group or a salt thereof with formalin and a compound of the formula :
- R 1 -H (preferably, indole), in which R 1 is as defined above, or a salt thereof in the presence of acid or base.
- the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like, and in case the object compound can be isolated in a free form, it can be
- the compound (I) and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention.
- the object compound (I) and a pharmaceutically acceptable salt thereof have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism or Neurokinin B antagonism, and therefore are useful for treating or preventing tachykinin-mediated diseases, particularly Substance P-mediated diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration, and the like;
- opthalmic diseases such as conjunctivitis, vernal
- cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like; inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like;
- pains or aches e.g. migraine, headache, toothache, cancerous pain, back pain, etc.; and the like.
- the object compound (I) of the present invention are useful for treating or preventing ophthalmic diseases such as glaucoma, uveitis, and the like; gastrointestinal diseases such as ulcer, ulcerative colitis, irritable bowel syndrome, food allergy, and the like; inflammatory diseases such as nephritis, and the like; circulatory diseases such as hypertension, angina pectoris, cardiac failure,
- thrombosis and the like; epilepsy; spartic paralysis; pollakiuria; dementia; Alzheimer's diseases;
- the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compound, as an active ingredient, in admixture with a pharmaceutically
- compositions such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, topical or external administration.
- pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, topical or external administration.
- preparations may be solid, semi-solid or solutions such as capsules, tablets, dragees, powders, granules,
- suppositories ointments, creams, lotions, inhalants, eye drops, solution, syrups, suspension, emulsion, or the like. If desired, there may be included in these
- the dosage of the compound (I) will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating tachykinin-mediated diseases such as asthma and the like. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
- pellets were resuspended in buffer (5 mM Tris-HCl pH 7.5), homogenized with a teflon homogenizer and centrifuged (14000 xg, 20 min) to yield pellets which were referred to as crude membrane fractions.
- the obtained pallets were stored at -70°C until use.
- Test compound (10 mg/kg) dissolved in dimethyl sulfoxide was orally given 30 minutes before this
- Methyl 1-[3-(N,N-dimethylamino)propyl]indole-3- carboxylate was prepared by reacting methyl
- Benzyl 1-[2-(tert-butoxycarbonylamino)ethyl]indole-3- carboxylate was prepared by reacting benzyl indole-3- carboxylate with 2-(tert-butoxycarbonylamino) ethyl
- 1-methylindole-3-carboxylic acid (190 mg), the product prepared in Preparation 7 (470 mg) and HOBT (150 mg) in dichloromethane (10 ml) was added WSCD (0.20 ml). The mixture was stirred at the same temperature for 35 minutes and at room temperature for 17 hours, during which period triethylamine in two portions (0.04 ml and 0.03 ml) were added to the mixture. To the solution was added
- Example 2-(3) To an ice-cooled solution of the product obtained in Example 2-(3) (0.32 g) in ethyl acetate (10 ml) was added 4N-hydrogen chloride in ethyl acetate (0.19 ml). The reaction mixture was stirred for 5 minutes. After
- Example 7 To an ice-cooled solution of saturated hydrogen chloride in ethanol (25 ml) was added the product obtained in Example 7 (0.45 g). The solution was stirred at the same temperature for 1.5 hours. After concentration, the residue was dissolved in anhydrous ethanol (10 ml). To the solution was added a solution of 4N ammonia in ethanol (47 ml) under ice-cooling. The mixture was stirred at room temperature for 2.5 hours. After concentration, ether was added to the residue, and the resulting
- Example 2-(4) To an ice-cooled solution of the product obtained in Example 2-(4) (3.96 g) in ethyl acetate (40 ml) were added successively anisole (4.0 ml) and 4N hydrogen chloride in ethyl acetate (40 ml). The solution was stirred at the same temperature for 15 minutes and at the room
- Example 11 To a solution of the product obtained in Example 11 (0.55 g) in methanol (5 ml) was added a solution of 40% methylamine in methanol (10 ml) at room temperature. The solution was stirred for 21 hours at the same temperature. After concentration, the residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and
- Example 2 To the product prepared in Example 1 in methylene chloride (40 ml) was added a solution of N,N-dimethyl- aniline (242 mg) dissolved in methylene chloride (10 ml) at -30°C under nitrogen atmosphere and the solution was stirred at the same temperature for fifteen minutes. Then phosphorus pentachloride (416 mg) was added to the
- IR (CHCl 3 ) 3370, 3060, 3020, 2940, 1640, 1600,
- the product prepared in Preparation 7 was distributed between chloroform and aqueous sodium hydrogen carbonate solution and the organic layer was separated and was dried over magnesium sulfate and concentrated in vacuo.
- the residue was dissolved in a mixed solvent of 1,4-dioxane (2 ml) and ethyl acetate (2 ml).
- formalin solution 37%) (0.09 ml) under ice-cooling, and the solution was stirred for one and half hours at this temperature.
- 1-methylindole 150 mg
- 1,4-dioxane (2 ml) was added into the mixture at this temperature.
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Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP93900452A EP0620824A1 (en) | 1992-01-10 | 1993-01-04 | Peptides with tachykinin antagonist activity |
JP5512326A JPH07503711A (en) | 1992-01-10 | 1993-01-04 | Peptides with tachykinin antagonistic activity |
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GB929200535A GB9200535D0 (en) | 1992-01-10 | 1992-01-10 | New compound |
GB9200535.4 | 1992-01-10 |
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WO1993014113A1 true WO1993014113A1 (en) | 1993-07-22 |
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EP (1) | EP0620824A1 (en) |
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GB0326407D0 (en) * | 2003-11-12 | 2003-12-17 | Glaxo Group Ltd | Chemical compounds |
JP2010229034A (en) * | 2007-07-26 | 2010-10-14 | Dainippon Sumitomo Pharma Co Ltd | Bicyclic pyrrole derivative |
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Also Published As
Publication number | Publication date |
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EP0620824A1 (en) | 1994-10-26 |
JPH07503711A (en) | 1995-04-20 |
GB9200535D0 (en) | 1992-02-26 |
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