JPS623812B2 - - Google Patents
Info
- Publication number
- JPS623812B2 JPS623812B2 JP55039221A JP3922180A JPS623812B2 JP S623812 B2 JPS623812 B2 JP S623812B2 JP 55039221 A JP55039221 A JP 55039221A JP 3922180 A JP3922180 A JP 3922180A JP S623812 B2 JPS623812 B2 JP S623812B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- group
- hydroxy
- general formula
- propoxy
- 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.)
- Expired
Links
- 239000000739 antihistaminic agent Substances 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000005359 phenoxyalkyl group Chemical group 0.000 claims description 5
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical group C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 49
- -1 2-methyl-2-phenylpropyl Chemical group 0.000 description 39
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 14
- 230000001387 anti-histamine Effects 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 239000003826 tablet Substances 0.000 description 11
- 229960001340 histamine Drugs 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 8
- 229920002472 Starch Polymers 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- 239000008107 starch Substances 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 235000001727 glucose Nutrition 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- ZUGRYLJRHKHZLR-UHFFFAOYSA-N 1h-quinolin-2-one;hydrochloride Chemical compound Cl.C1=CC=C2NC(=O)C=CC2=C1 ZUGRYLJRHKHZLR-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229940125715 antihistaminic agent Drugs 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 230000008602 contraction Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 208000003251 Pruritus Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 235000012211 aluminium silicate Nutrition 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 125000005606 carbostyryl group Chemical group 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 2
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 206010012442 Dermatitis contact Diseases 0.000 description 2
- 102000000543 Histamine Receptors Human genes 0.000 description 2
- 108010002059 Histamine Receptors Proteins 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001466453 Laminaria Species 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N beta-monoglyceryl stearate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000007803 itching Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- 239000003112 inhibitor Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
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- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 208000010753 nasal discharge Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- 235000019198 oils Nutrition 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
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- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Landscapes
- Quinoline Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は抗ヒスタミン剤に関する。更に詳しく
は本発明は一般式
〔式中R1は水素原子、低級アルキル基又はフエニ
ルアルキル基を示す。R2はフエニル基、フエニ
ルアルキル基、ヒドロキシアルキル基、低級アル
ケニル基、シクロアルキル基又はフエノキシアル
キル基を示す。R3は水素原子、低級アルキル
基、低級アルケニル基、シクロアルキル基、フエ
ニル基又はフエニルアルキル基を示す。またこの
R2及びR3は結合する窒素原子と共に他の窒素原
子もしくは酸素原子を介し又は介することなく五
員又は六員の飽和ヘテロ環を形成してもよい。カ
ルボスチリル骨格の３位及び４位の炭素間結合は
一重結合又は二重結合を示す。〕
で表わされるカルボスチリル誘導体又はその酸付
加塩を有効成分として含有することを特徴とする
抗ヒスタミン剤に係るものである。
上記一般式〔１〕で表わされる化合物は公知の
化合物もしくは新規化合物である。而して一般式
〔１〕で表わされる化合物のうち公知の化合物に
ついては、β−アドレナリン作働神経遮断作用を
有し不整脈及び狭心症の治療薬として有用である
ことが知られている。
本発明者らは、上記一般式〔１〕で表わされる
化合物につき鋭意研究を重ねた結果、之等化合物
が上記β−アドレナリン作働神経遮断作用からは
全く予測できない抗ヒスタミン作用を有し、それ
故抗ヒスタミン剤として有用であることを見い出
した。本発明はこの新しい知見に基づいて完成さ
れたものである。
抗ヒスタミン剤は、グツドマン・ギルマン 薬
理書〔上〕 薬物治療の基礎と臨床、第781〜835
頁、廣川書店発行（1974年）、新応用薬理学 羽
野壽著、第307〜319頁、氷井書店（1970）、新薬
と臨床、第20巻、第11号、第129〜133頁（1971）
及び基礎と臨床、第10巻、第10号、第17〜27頁
（1976）にも記載されている通り、アレルギーの
抗原抗体反応による結合型ヒスタミンの遊離を抑
制するのではなく、遊離した活性型ヒスタミンと
ヒスタミン受容体との結合を阻止（競合的拮抗）
して抗ヒスタミン作用を発現する。それ故本発明
の抗ヒスタミン剤はヒスタミンとヒスタミン受容
体との結合に起因する種々の疾病、例えばくしや
み、鼻汁、目と鼻と喉のかゆみなどの呼吸気道の
アレルギー症状、枯草熱、花粉症、急性ジンマシ
ン（かゆみ、浮腫、発赤等）、血管浮腫、痒
症、アトピー性皮膚炎、昆虫の刺傷、ウルシかぶ
れなどの接触性皮膚炎、血清病の際のジンマシン
や浮腫性障害、アレルギー性鼻炎、アレルギー性
結膜炎や角膜炎等のアレルギー性疾患の治療薬ま
たは了防薬として有効である。また本発明の抗ヒ
スタミン剤はヒスタミン以外のオータコイド類が
重要な役割を果たしていると思われる全身アナフ
イラキシーを治療する際に補助薬として用いられ
る。さらに本発明の抗ヒスタミン剤は胃の酸分泌
能を測定するための診断薬としても使用される。
上記一般式〔１〕に於てR1、R2及びR3で示さ
れる各基はより具体的には次の通りである。
低級アルキル基………炭素数１〜４の直鎖もしく
は分枝状アルキル基、例：メチル、エチル、プ
ロピル、イソプロピル、ブチル、tert−ブチル
基等。
フエニルアルキル基………フエニル基を置換基と
して有する炭素数１〜４の直鎖もしくは分枝状
アルキル基、例：ベンジル、２−フエニルエチ
ル、１−フエニルエチル、２−メチル−２−フ
エニルプロピル、４−フエニルブチル、１・１
−ジメチル−２−フエニルエチル、２−メチル
−３−フエニルプロピル基等。
ヒドロキシアルキル基………ヒドロキシ基を置換
基として有する炭素数１〜４の直鎖もしくは分
枝状アルキル基、例：ヒドロキシメチル、２−
ヒドロキシエチル、３−ヒドロキシプロピル、
４−ヒドロキシブチル、１−ヒドロキシエチ
ル、１・１−ジメチル−２−ヒドロキシエチル
基等。
低級アルケニル基………炭素数２〜４の直鎖もし
くは分枝状アルケニル基、例：アリル、２−ブ
テニル、１−メチルアリル、２−メチルアリル
基等。
シクロアルキル基………炭素数３〜７のシクロア
ルキル基、例：シクロプロピル、シクロブチ
ル、シクロペンチル、シクロヘキシル、シクロ
ヘプチル基等。
フエノキシアルキル基………フエノキシ基を置換
基として有する炭素数１〜４の直鎖もしくは分
枝状アルキル基、例：フエノキシメチル、２−
フエノキシエチル、１−フエノキシエチル、２
−メチル−２−フエノキシプロピル、４−フエ
ノキシブチル、１・１−ジメチル−２−フエノ
キシエチル、２−メチル−３−フエノキシプロ
ピル基等。
R2及びR3が結合する窒素原子と共に他の窒素原
子もしくは酸素原子を介し又は介することなく形
成し得る五員又は六員の飽和ヘテロ環の残基……
…例：１−ピペラジニル、ピペリジノ、ピロリジ
ノ、モルホリノ基等。
上記フエニルアルキル基及びフエノキシアルキ
ル基を構成するフエニル基並びにR2及びR3で示
されるフエニル基としては、そのフエニル環上に
１〜３個の置換基を有していてもよい。斯かる置
換基としては例えばメトキシ、エトキシ、プロポ
キシ、イソプロポキシ、ブトキシ、tert−ブトキ
シ等のアルコキシ基、カルバモイル基、メチレン
ジオキシ基、エチレンジオキシ基等を挙げること
ができる。而して斯かる置換基を有するフエニル
基としては例えば４−メトキシフエニル、３・４
−ジメトキシフエニル、３・４−メチレンジオキ
シフエニル、３・４・５−トリメトキシフエニル
等を挙げることができる。
フエニルアルキル基：２−（３・４−ジメトキシ
フエニル）エチル、２−（３・４−メチレンジ
オキシフエニル）エチル、２−（４−カルバモ
イルフエニル）エチル基等。
フエノキシアルキル基：２−（３・４−ジメトキ
シフエノキシ）エチル、２−（３・５−ジメト
キシフエノキシ）エチル、２−（３・４−エチ
レンジオキシフエノキシ）エチル、２−（４−
カルバモイルフエノキシ）エチル等。
上記ヘテロ環の残基は前述の低級アルキル基を
置換基として有していてもよい。斯かるヘテロ環
の残基としては例えば４−メチル−１−ピペラジ
ニル、４−エチル−１−ピペラジニル、３−メチ
ル−１−ピペラジニル、２−メチルピペリジノ、
４−エチルピペリジノ等を挙げることができる。
本発明の抗ヒスタミン剤の有効成分である一般
式〔１〕の化合物又はその酸付加塩のうち代表的
なものを以下に挙げる。
Γ５−（２−ヒドロキシ−３−ベンジルアミノプ
ロポキシ）−３・４−ジヒドロカルボスチリル
塩酸塩（化合物１）
Γ５−（２−ヒドロキシ−３−ピペリジノプロポ
キシ）−３・４−ジヒドロカルボスチリル塩酸
塩（化合物２）
Γ５−（２−ヒドロキシ−３−モルホリノプロポ
キシ）−３・４−ジヒドロカルボスチリル塩酸
塩（化合物３）
Γ１−ベンジル−５−〔２−ヒドロキシ−３−（４
−メチル−１−ピペラジニル）プロポキシ〕−
３・４−ジヒドロカルボスチリル塩酸塩（化合
物４）
Γ５−〔２−ヒドロキシ−３−（Ｎ−メチル−Ｎ−
ベンジルアミノ）プロポキシ〕−３・４−ジヒ
ドロカルボスチリルフマル酸塩（化合物５）
Γ１−メチル−５−〔２−ヒドロキシ−３−（β−
３・４−ジメトキシフエネチルアミノ）プロポ
キシ〕−３・４−ジヒドロカルボスチリル塩酸
塩（化合物６）
Γ１−ベンジル−５−〔２−ヒドロキシ−３−（β
−３・４−ジメトキシフエネチルアミノ）プロ
ポキシ〕−３・４−ジヒドロカルボスチリル塩
酸塩（化合物７）
Γ５−〔２−ヒドロキシ−３−（１・１−ジメチル
−２−フエニルエチルアミノ）プロポキシ〕−
３・４−ジヒドロカルボスチリル塩酸塩（化合
物８）
Γ１−ベンジル−５−〔２−ヒドロキシ−３−（１
−メチル−２−フエノキシエチルアミノ）プロ
ポキシ〕−３・４−ジヒドロカルボスチリル塩
酸塩（化合物９）
Γ５−〔２−ヒドロキシ−３−（２−フエノキシエ
チルアミノ）プロポキシ〕−３・４−ジヒドロ
カルボスチリル塩酸塩（化合物10）
Γ５｛２−ヒドロキシ−３−〔２−（４−メトキシ
フエノキシ）エチルアミノ〕プロポキシ｝−
３・４−ジヒドロカルボスチリル塩酸塩（化合
物11）
Γ５−｛２−ヒドロキシ−３−〔２−（３・５−ジ
メトキシフエノキシ）エチルアミノ〕プロポキ
シ｝−３・４−ジヒドロカルボスチリル塩酸塩
（化合物12）
Γ１−メチル−３−｛２−ヒドロキシ−３−〔２−
（４−メトキシフエノキシ）エチルアミノ〕プ
ロポキシ｝−３・４−ジヒドロカルボスチリル
塩酸塩（化合物13）
Γ５−｛２−ヒドロキシ−３−〔２−（４−カルバ
モイルフエノキシ）エチルアミノ〕プロポキ
シ｝−３・４−ジヒドロカルボスチリル塩酸塩
（化合物14）
Γ５−〔２−ヒドロキシ−３−（Ｎ−シクロヘキシ
ル−β−フエネチルアミノ）プロポキシ〕−
３・４−ジヒドロカルボスチリル塩酸塩（化合
物15）
Γ５−〔２−ヒドロキシ−３−（Ｎ−メチル−β−
３・４−ジメトキシフエネチルアミノ）プロポ
キシ〕−３・４−ジヒドロカルボスチリル塩酸
塩（化合物16）
Γ５−〔２−ヒドロキシ−３−（α−フエネチルア
ミノ）プロポキシ〕−３・４−ジヒドロカルボ
スチリル塩酸塩（化合物17）
Γ５−（２−ヒドロキシ−３−（β−フエネチルア
ミノ）プロポキシ〕−３・４−ジヒドロカルボ
スチリル塩酸塩（化合物18）
Γ５−〔２−ヒドロキシ−３−（Ｎ・Ｎ−ジフエニ
ルアミノ）プロポキシ〕−３・４−ジヒドロカ
ルボスチリル塩酸塩（化合物19）
Γ５−〔２−ヒドロキシ−３−（Ｎ−メチル−β−
フエネチルアミノ）プロポキシ〕−３・４−ジ
ヒドロカルボスチリル塩酸塩（化合物20）
Γ５−〔２−ヒドロキシ−３−（Ｎ−シクロヘキシ
ル−ベンジルアミノ〕プロポキシ〕−３・４−
ジヒドロカルボスチリル塩酸塩（化合物21）
Γ５−〔２−ヒドロキシ−３−（Ｎ・Ｎ−ジベンジ
ルアミノ）プロポキシ〕−３・４−ジヒドロカ
ルボスチリル塩酸塩（化合物22）
Γ７−〔２−ヒドロキシ−３−（Ｎ−メチル−ベン
ジルアミノ）プロポキシ〕−３・４−ジヒドロ
カルボスチリル塩酸塩（化合物23）
Γ８−〔２−ヒドロキシ−３−（Ｎ−メチル−ベン
ジルアミノ）プロポキシ〕−３・４−ジヒドロ
カルボスチリル塩酸塩（化合物24）
Γ１−メチル−５−〔２−ヒドロキシ−３−（Ｎ−
メチル−ベンジルアミノ）プロポキシ〕−３・
４−ジヒドロカルボスチリル塩酸塩（化合物
25）
Γ５−〔２−ヒドロキシ−３−（Ｎ・Ｎ−ジベンジ
ルアミノ）プロポキシ〕カルボスチリル塩酸塩
（化合物26）
Γ５−〔２−ヒドロキシ−３−〔Ｎ−メチル−（２
−ヒドロキシエチル）アミノ〕プロポキシ｝−
３・４−ジヒドロシユウ酸塩（化合物27）
Γ５−〔２−ヒドロキシ−３−（２−ヒドロキシエ
チルアミノ）プロポキシ〕−３・４−ジヒドロ
カルボスチリルシユウ酸塩（化合物28）
Γ１−メチル−５−｛２−ヒドロキシ−３−〔２−
（３・５−ジメトキシフエノキシ）エチルアミ
ノ〕プロポキシ｝−３・４−ジヒドロカルボス
チリル塩酸塩（化合物29）
Γ５−（２−ヒドロキシ−３−アリルアミノプロ
ポキシ）−３・４−ジヒドロカルボスチリル塩
酸塩（化合物30）
Γ５−（２−ヒドロキシ−３−アニリノプロポキ
シ）−３・４−ジヒドロカルボスチリル塩酸塩
（化合物31）
Γ５−〔２−ヒドロキシ−３−（Ｎ−メチル−シク
ロヘキシルアミノ）プロポキシ〕−３・４−ジ
ヒドロカルボスチリル塩酸塩（化合物32）
Γ５−〔２−ヒドロキシ−３−（Ｎ−メチル−アニ
リノ）プロポキシ〕−３・４−ジヒドロカルボ
スチリル塩酸塩（化合物33）
Γ５−〔２−ヒドロキシ−３−（Ｎ・Ｎ−ジアリル
アミノ）プロポキシ〕−３・４−ジヒドロカル
ボスチリル塩酸塩（化合物34）
Γ６−〔２−ヒドロキシ−３−（Ｎ−メチル−ベン
ジルアミノ）プロポキシ〕−３・４−ジヒドロ
カルボスチリル塩酸塩（化合物35）
Γ５−〔２−ヒドロキシ−３−（Ｎ−メチル−ベン
ジルアミノ）プロポキシ〕カルボスチリル塩酸
塩（化合物36）
Γ１−ベンジル−５−〔２−ヒドロキシ−３−（１
−メチル−２−フエノキシエチルアミノ）プロ
ポキシ〕カルボスチリル塩酸塩（化合物37）
Γ５−〔２−ヒドロキシ−３−（α−フエネチルア
ミノ）プロポキシ〕カルボスチリル塩酸塩（化
合物38）
Γ５−〔２−ヒドロキシ−３−（Ｎ・Ｎ−ジフエニ
ル）プロポキシ〕カルボスチリル塩酸塩（化合
物39）
Γ５−〔２−ヒドロキシ−３−（Ｎ−メチル−β−
フエネチルアミノ）プロポキシ〕カルボスチリ
ル塩酸塩（化合物40）
上記一般式〔１〕で表わされるカルボスチリル
誘導体は例えば下記反応行程式−１に示す如く一
般式〔２〕で表わされる３−ハロゲノプロポキシ
カルボスチリル誘導体に一般式〔３〕で表わされ
るアミンを反応させることにより容易に製造され
る。また一般式〔１〕で表わされるカルボスチリ
ル誘導体は下記反応行程式−２に示す如く一般式
〔４〕で表わされる２・３−エポキシプロポキシ
カルボスチリル誘導体に一般式〔３〕で表わされ
るアミンを反応させることによつても製造され
る。
〔式中Ｘはハロゲン原子を示す。R1、R2及びR3は
前記に同じ。〕
一般式〔２〕の化合物、一般式〔３〕の化合物
及び一般式〔４〕の化合物はいずれも公知化合物
である。
一般式〔２〕の化合物と一般式〔３〕の化合物
との反応は脱ハロゲン化水素剤の存在下もしくは
不存在下適当な溶媒中にて行なわれる。脱ハロゲ
ン化水素剤としては例えば水酸化ナトリウム、水
酸化カリウム、炭酸ナトリウム、炭酸カリウム等
を挙げることができる。本発明では一般式〔３〕
の化合物自身、脱ハロゲン化水素剤として使用し
得る。溶媒としてはメタノール、エタノール、イ
ソプロパノール等の低級アルコール類、ジオキサ
ン、テトラヒドロフラン等のエーテル類等を例示
できる。一般式〔２〕の化合物と一般式〔３〕の
化合物との使用割合としては、脱ハロゲン化水素
剤の存在下に反応を行なう場合には通常前者に対
して後者を等モル〜過剰量、好ましくは等モル〜
３倍モル量とするのがよく、また脱ハロゲン化水
素剤の不存在下に反応を行なう場合には通常前者
に対して後者を大過剰量、好ましくは３〜８倍モ
ル量とするのがよい。上記脱ハロゲン化水素剤の
使用量としては一般式〔２〕の化合物に対して通
常等モル〜過剰量、好ましくは等モル〜３倍モル
量とするのがよい。該反応は通常０〜100℃、好
ましくは室温〜80℃にて行なわれ、一般に１〜10
時間程度で反応は終了する。
一般式〔４〕の化合物と一般式〔３〕の化合物
との反応は適当な溶媒にて行なわれる。溶媒とし
ては上記一般式〔２〕の化合物と一般式〔３〕の
化合物との反応に於て用いられる溶媒を広く使用
できる。一般式〔４〕の化合物と一般式〔３〕の
化合物との使用割合としては通常前者に対して後
者を等モル〜過剰量、好ましくは等モル〜３倍モ
ル量とするのがよい。該反応は通常０〜100℃、
好ましくは室温〜80℃にて行なわれ、一般に１〜
10時間程度で反応は終了する。
斯くして得られる一般式〔１〕のカルボスチリ
ル誘導体は通常の分離手段により容易に単離精製
できる。斯かる分離手段としては溶媒抽出法、溶
媒稀釈法、蒸留法、再結晶性、液体クロマトグラ
フイー等を例示できる。
本発明の抗ヒスタミン剤は上記一般式〔１〕で
表わされる化合物又はその酸付加塩を有効成分と
して含有する。上記酸付加塩を形成し得る酸は医
薬的に許容される通常の酸でよく、これには例え
ば塩化水素、臭化水素等のハロゲン化水素、硫
酸、リン酸、酢酸、シユウ酸、コハク酸、酒石
酸、マロン酸、フマル酸、メタンスルホン酸等が
包含される。また上記本発明の抗ヒスタミン剤の
有効成分とする一般式〔１〕で表わされる化合物
又はその酸付加塩は之等の光学異性体の形態で利
用することもできる。
一般式〔１〕の化合物及びその酸付加塩は、之
を抗ヒスタミン剤として用いるに当り、通常製剤
的担体と共に製剤組成物の形態とされる。担体と
しては使用形態に応じた薬剤を調製するのに通常
使用される充填剤、増量剤、結合剤、付湿剤、崩
壊剤、表面活性剤、滑沢剤等の稀釈剤あるいは賦
形剤を例示できる。
抗ヒスタミン剤の投与単位形態としては各種の
形態を治療目的に応じて選択でき、その代表的な
ものとして錠剤、丸剤、散剤、液剤、懸濁剤、乳
剤、顆粒剤、カプセル剤、坐剤、注射剤（液剤、
懸濁剤等）、軟膏剤等を例示できる。錠剤の形態
に成形するに際しては、担体としてこの分野で従
来公知のものを広く使用でき、例えば乳糖、白
糖、塩化ナトリウム、ブドウ糖液、尿素、デンプ
ン、炭酸カルシウム、カオリン、結晶セルロー
ス、ケイ酸等の賦形剤、水、エタノール、プロパ
ノール、単シロツプ、ブドウ糖、デンプン液、ゼ
ラチン溶液、カルボキシメチルセルロース、セラ
ツク、メチルセルロース、リン酸カリウム、ポリ
ビニルピロリドン等の結合剤、乾燥デンプン、ア
ルギン酸ナトリウム、カンテン末、ラミナリア
末、炭酸水素ナトリウム、炭酸カルシウム、ツウ
イン、ラウリル硫酸ナトリウム、ステアリン酸モ
ノグリセリド、デンプン、乳糖等の崩壊剤、白
糖、ステアリン、カカオバター、水素添加油等の
崩壊抑制剤、第四級アンモニウム塩基、ラウリル
硫酸ナトリウム等の吸収促進剤、グリセリン、デ
ンプン等の保湿剤、デンプン、乳糖、カオリン、
ベントナイト、コロイド状ケイ酸等の吸着剤、精
製タルク、ステアリン酸塩、ホウ酸末、マクロゴ
ール、固体ポリエチレングリコール等の滑沢剤等
を例示できる。丸剤の形態に成形するに際して
は、担体としてこの分野で従来公知のものを広く
使用でき、例えばブドウ糖、乳糖、デンプン、カ
カオ脂、硬化植物油、カオリン、タルク等の賦形
剤、アラビアゴム末、トウガント末、ゼラチン、
エタノール等の結合剤、ラミナリア、カンテン等
の崩壊剤等を例示できる。更に錠剤は必要に応じ
通常の剤皮を施した錠剤例えば糖衣錠、ゼラチン
被包錠、腸溶被錠、フイルムコーテイング錠ある
いは二重錠、多層錠とすることができる。坐剤の
形態に成形するに際しては、担体として従来公知
のものを広く使用でき、例えばポリエチレングリ
コール、カカオ脂、高級アルコール、高級アルコ
ールのエステル類、ゼラチン、半合成グリセライ
ド等を挙げることができる。注射剤として調製さ
れる場合には液剤及び懸濁剤は殺菌され且つ血液
と等張であるのが好ましく、これら液剤、乳剤及
び懸濁剤の形態に成形するのに際しては、稀釈剤
としてこの分野に於いて慣用されているものをす
べて使用でき、例えば水、エチルアルコール、プ
ロピレングリコール、エトキシ化イソステアリル
アルコール、ポリオキシ化イソステアリルアルコ
ール、ポリオキシエチレンソルビツト、ソルビタ
ンエステル等を挙げることができる。なおこの場
合等張性の溶液を調製するに充分な量の食塩、ブ
ドウ糖あるいはグリセリンを治療剤中に含有せし
めてもよく、また通常の溶解補助剤、緩衝剤、無
痛化剤、保存剤等を更に必要に応じて着色剤、保
存剤、香料、風味剤、甘味剤等や他の医薬品を該
治療剤中に含有せしめてもよい。ペースト、クリ
ーム及びゲルの形態に成形するに際しては、稀釈
剤としてこの分野で従来公知のものを広く使用で
き、例えば白色ワセリン、パラフイン、グリセリ
ン、セルロース誘導体、ポリエチレングリコー
ル、シリコン、ベントナイト等を例示できる。
抗ヒスタミン剤中に含有させるべき一般式
〔１〕の化合物又はその酸付加塩の量は特に限定
されず広範囲に適宜選択されるが、通常全組成物
中１〜70重量％とするのがよい。
また上記抗ヒスタミン剤は、その使用に際し特
に制限はなく各種形態に応じた方法で投与され
る。例えば錠剤、丸剤、液剤、懸濁剤、乳剤、顆
粒剤及びカプセル剤の場合には経口投与され、注
射剤の場合には単独であるいはブドウ糖、アミノ
酸等の通常の補液と混合して静脈内投与され、さ
らに必要に応じて単独で筋肉内、皮内、皮下若し
くは腹腔内投与され、坐剤の場合には直腸内投与
され、また軟膏剤の場合には塗布される。
本発明の抗ヒスタミン剤としての投与量は使用
目的、症状等により適宜選択され、通常一般式
〔１〕の化合物又はその酸付加塩を１日当り40μ
ｇ〜２mg／Kg・day程度含有する製剤組成物を３
〜４回に分けて投与すればよい。
薬理試験
試験管内に於て抗ヒスタミン作用を測定する代
表的な方法としてモルモツトの摘出回腸を用いる
方法（以下「方法Ａ」という）が一般に認められ
ているところであり、本発明に於ても方法Ａに従
つて試験管内に於ける抗ヒスタミン作用を測定し
た。
方法Ａによる抗ヒスタミン作用試験
体重300〜500ｇの雄性モルモツトを放血して殺
し、回盲部より口側15cmの回腸を摘出しタイロー
ド液（NaCl8.0ｇ、KCl0.2ｇ、CaCl20.2ｇ、グル
コース1.0ｇ、NaHCO31.0ｇ、NaH2PO4・
2H2O0.065ｇ及びMgCl2・6H2O0.2135ｇに水を加
え全量を1000mlとしたもの）に入れた。次に組織
を2.5〜3.0cmに切りタイロード液30mlを満たした
浴に懸垂した。その浴を36℃に保ち、CO25％及
びO295％の混合ガスを通じた。10分後ヒスタミ
ン10-6Mを投与して組織の感受性を調べたのちに
ヒスタミンによる用量−反応曲線（コントロー
ル）を得た。コントロールの用量−反応が一定し
た後に供試化合物10-6ｇ／mlを投与し、５分後に
ヒスタミンを投与して用量−反応曲線を得た。収
縮は等張性トランスジユーサー〔日本光電TD−
112S〕を介してペンレコーダーに記録した。コ
ントロールのヒスタミンの最大収縮を100％と
し、ヴアン−ロツサムの方法〔J.M.Van
Rossam、Arch.Int.Pharmacodyn.、143、299
（1963）参照〕に従い、下記式を用いてPA2を
算出した。
PA2＝PAx＋log（ｘ−１） ………
〔式中、PAx＝供試化合物濃度（ｇ／ml）の負の
対数、ｘ＝ＡB／Ａpを示し、ＡBは供試化合物存
在下において50％収縮に必要なヒスタミンの用量
（ｇ／ml）、Ａpは供試化合物非存在下において50
％収縮に必要なヒスタミンの用量（ｇ／ml）を示
す。〕
本試験においては、供試化合物の濃度は10-6
ｇ／mlであるから、PAx＝log10-6＝６となる。
また式より、供試化合物の抗ヒスタミン作用が
強い程ｘ即ちＡB／Ａpが大きくなり、PA2値が大
となることが判る。得られた結果を下記第１表に
示す。
The present invention relates to antihistamines. More specifically, the present invention relates to the general formula [In the formula, R 1 represents a hydrogen atom, a lower alkyl group, or a phenyl alkyl group. R 2 represents a phenyl group, a phenylalkyl group, a hydroxyalkyl group, a lower alkenyl group, a cycloalkyl group, or a phenoxyalkyl group. R 3 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a phenyl group, or a phenyl alkyl group. Also this
Together with the nitrogen atom to which they are bonded, R 2 and R 3 may form a five- or six-membered saturated heterocycle with or without another nitrogen atom or oxygen atom. The carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond. ] The present invention relates to an antihistamine agent characterized by containing a carbostyril derivative represented by the following or an acid addition salt thereof as an active ingredient. The compound represented by the above general formula [1] is a known compound or a new compound. Among the compounds represented by the general formula [1], known compounds are known to have a β-adrenergic nerve blocking action and are useful as therapeutic agents for arrhythmia and angina pectoris. As a result of extensive research into the compound represented by the above general formula [1], the present inventors found that such compounds have an antihistamine effect that could not be predicted from the above β-adrenergic nerve blocking effect. It has been found that it is useful as an antihistamine. The present invention was completed based on this new knowledge. Antihistamines are described in Gutsman Gilman's Book of Pharmacology [Part 1] Fundamentals and Clinical Practice of Drug Treatment, Nos. 781-835.
Page, Hirokawa Shoten Publishing (1974), New Applied Pharmacology by Hisashi Hano, pp. 307-319, Hii Shoten (1970), New Drugs and Clinical Practice, Vol. 20, No. 11, No. 129-133 (1971) )
As also described in Basic and Clinical Studies, Vol. 10, No. 10, pp. 17-27 (1976), rather than suppressing the release of bound histamine due to allergic antigen-antibody reactions, the release activity Blocks the binding of type histamine to histamine receptors (competitive antagonism)
and exerts antihistamine action. Therefore, the antihistamine of the present invention can be used to treat various diseases caused by the binding of histamine to histamine receptors, such as allergic symptoms of the respiratory tract such as combing, nasal discharge, itching of the eyes, nose, and throat, hay fever, hay fever, and acute Ging machine (itching, edema, redness, etc.), angioedema, pruritus, atopic dermatitis, contact dermatitis such as insect stings, sumac rash, gin machine and edema disorders during serum sickness, allergic rhinitis, allergies It is effective as a therapeutic or preventive drug for allergic diseases such as sexual conjunctivitis and keratitis. Furthermore, the antihistamine of the present invention can be used as an adjunct in treating systemic anaphylaxis in which autacoids other than histamine are thought to play an important role. Furthermore, the antihistamine of the present invention can also be used as a diagnostic agent for measuring the acid secretion ability of the stomach. More specifically, each group represented by R 1 , R 2 and R 3 in the above general formula [1] is as follows. Lower alkyl group: a linear or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl group, etc. Phenyl alkyl group: a straight chain or branched alkyl group having 1 to 4 carbon atoms having a phenyl group as a substituent, e.g. benzyl, 2-phenylethyl, 1-phenylethyl, 2-methyl-2-phenylpropyl , 4-phenylbutyl, 1.1
-dimethyl-2-phenylethyl, 2-methyl-3-phenylpropyl groups, etc. Hydroxyalkyl group: a straight chain or branched alkyl group having 1 to 4 carbon atoms having a hydroxy group as a substituent, e.g. hydroxymethyl, 2-
hydroxyethyl, 3-hydroxypropyl,
4-hydroxybutyl, 1-hydroxyethyl, 1,1-dimethyl-2-hydroxyethyl group, etc. Lower alkenyl group: a linear or branched alkenyl group having 2 to 4 carbon atoms, such as allyl, 2-butenyl, 1-methylallyl, 2-methylallyl, etc. Cycloalkyl group: cycloalkyl group having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl group, etc. Phenoxyalkyl group: a straight-chain or branched alkyl group having 1 to 4 carbon atoms having a phenoxy group as a substituent, e.g. phenoxymethyl, 2-
Phenoxyethyl, 1-phenoxyethyl, 2
-Methyl-2-phenoxypropyl, 4-phenoxybutyl, 1,1-dimethyl-2-phenoxyethyl, 2-methyl-3-phenoxypropyl groups, etc. A residue of a five- or six-membered saturated heterocycle that can be formed with the nitrogen atom to which R 2 and R 3 are bonded, with or without intervening another nitrogen or oxygen atom...
...Example: 1-piperazinyl, piperidino, pyrrolidino, morpholino group, etc. The phenyl group constituting the above phenylalkyl group and phenoxyalkyl group and the phenyl group represented by R 2 and R 3 may have 1 to 3 substituents on the phenyl ring. Examples of such substituents include alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy, carbamoyl groups, methylenedioxy groups, and ethylenedioxy groups. Examples of the phenyl group having such a substituent include 4-methoxyphenyl, 3.4
-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4,5-trimethoxyphenyl, and the like. Phenylalkyl group: 2-(3,4-dimethoxyphenyl)ethyl, 2-(3,4-methylenedioxyphenyl)ethyl, 2-(4-carbamoylphenyl)ethyl group, etc. Phenoxyalkyl group: 2-(3,4-dimethoxyphenoxy)ethyl, 2-(3,5-dimethoxyphenoxy)ethyl, 2-(3,4-ethylenedioxyphenoxy)ethyl, 2-(4-
carbamoylphenoxy)ethyl, etc. The above-mentioned heterocyclic residue may have the above-mentioned lower alkyl group as a substituent. Examples of such heterocyclic residues include 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 3-methyl-1-piperazinyl, 2-methylpiperidino,
Examples include 4-ethylpiperidino. Representative compounds of the general formula [1] or acid addition salts thereof, which are the active ingredients of the antihistamine agent of the present invention, are listed below. Γ5-(2-hydroxy-3-benzylaminopropoxy)-3,4-dihydrocarbostyryl hydrochloride (Compound 1) Γ5-(2-hydroxy-3-piperidinopropoxy)-3,4-dihydrocarbostyryl hydrochloride Salt (Compound 2) Γ5-(2-hydroxy-3-morpholinopropoxy)-3,4-dihydrocarbostyryl hydrochloride (Compound 3) Γ1-Benzyl-5-[2-hydroxy-3-(4
-Methyl-1-piperazinyl)propoxy]-
3,4-dihydrocarbostyryl hydrochloride (compound 4) Γ5-[2-hydroxy-3-(N-methyl-N-
benzylamino)propoxy]-3,4-dihydrocarbostyryl fumarate (compound 5) Γ1-methyl-5-[2-hydroxy-3-(β-
3,4-dimethoxyphenethylamino)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 6) Γ1-benzyl-5-[2-hydroxy-3-(β
-3,4-dimethoxyphenethylamino)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 7) Γ5-[2-hydroxy-3-(1,1-dimethyl-2-phenylethylamino) Propoxy]-
3,4-dihydrocarbostyril hydrochloride (compound 8) Γ1-benzyl-5-[2-hydroxy-3-(1
-Methyl-2-phenoxyethylamino)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 9) Γ5-[2-hydroxy-3-(2-phenoxyethylamino)propoxy]-3. 4-dihydrocarbostyryl hydrochloride (compound 10) Γ5{2-hydroxy-3-[2-(4-methoxyphenoxy)ethylamino]propoxy}-
3,4-dihydrocarbostyril hydrochloride (compound 11) Γ5-{2-hydroxy-3-[2-(3,5-dimethoxyphenoxy)ethylamino]propoxy}-3,4-dihydrocarbostyril hydrochloride (Compound 12) Γ1-methyl-3-{2-hydroxy-3-[2-
(4-methoxyphenoxy)ethylamino]propoxy}-3,4-dihydrocarbostyryl hydrochloride (compound 13) Γ5-{2-hydroxy-3-[2-(4-carbamoylphenoxy)ethylamino] propoxy}-3,4-dihydrocarbostyryl hydrochloride (compound 14) Γ5-[2-hydroxy-3-(N-cyclohexyl-β-phenethylamino)propoxy]-
3,4-dihydrocarbostyril hydrochloride (compound 15) Γ5-[2-hydroxy-3-(N-methyl-β-
3,4-dimethoxyphenethylamino)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 16) Γ5-[2-hydroxy-3-(α-phenethylamino)propoxy]-3,4-dihydrocarbostyryl Hydrochloride (Compound 17) Γ5-(2-hydroxy-3-(β-phenethylamino)propoxy]-3,4-dihydrocarbostyryl hydrochloride (Compound 18) Γ5-[2-hydroxy-3-(N・N- Diphenylamino)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 19) Γ5-[2-hydroxy-3-(N-methyl-β-
phenethylamino)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 20) Γ5-[2-hydroxy-3-(N-cyclohexyl-benzylamino]propoxy]-3,4-
Dihydrocarbostyril hydrochloride (Compound 21) Γ5-[2-hydroxy-3-(N·N-dibenzylamino)propoxy]-3,4-dihydrocarbostyryl hydrochloride (Compound 22) Γ7-[2-Hydroxy- 3-(N-methyl-benzylamino)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 23) Γ8-[2-hydroxy-3-(N-methyl-benzylamino)propoxy]-3,4- Dihydrocarbostyril hydrochloride (compound 24) Γ1-methyl-5-[2-hydroxy-3-(N-
Methyl-benzylamino)propoxy]-3.
4-dihydrocarbostyril hydrochloride (compound
25) Γ5-[2-hydroxy-3-(N・N-dibenzylamino)propoxy]carbostyril hydrochloride (compound 26) Γ5-[2-hydroxy-3-[N-methyl-(2
-Hydroxyethyl)amino]propoxy}-
3,4-dihydroxalate (compound 27) Γ5-[2-hydroxy-3-(2-hydroxyethylamino)propoxy]-3,4-dihydrocarbostyryl oxalate (compound 28) Γ1-methyl-5 -{2-hydroxy-3-[2-
(3,5-dimethoxyphenoxy)ethylamino]propoxy}-3,4-dihydrocarbostyryl hydrochloride (compound 29) Γ5-(2-hydroxy-3-allylaminopropoxy)-3,4-dihydrocarbostyryl Hydrochloride (Compound 30) Γ5-(2-hydroxy-3-anilinopropoxy)-3,4-dihydrocarbostyryl hydrochloride (Compound 31) Γ5-[2-Hydroxy-3-(N-methyl-cyclohexylamino) propoxy]-3,4-dihydrocarbostyril hydrochloride (compound 32) Γ5-[2-hydroxy-3-(N-methyl-anilino)propoxy]-3,4-dihydrocarbostyril hydrochloride (compound 33) Γ5- [2-hydroxy-3-(N・N-diallylamino)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 34) Γ6-[2-hydroxy-3-(N-methyl-benzylamino)propoxy] -3,4-dihydrocarbostyril hydrochloride (compound 35) Γ5-[2-hydroxy-3-(N-methyl-benzylamino)propoxy]carbostyril hydrochloride (compound 36) Γ1-benzyl-5-[2- Hydroxy-3-(1
-Methyl-2-phenoxyethylamino)propoxy]carbostyril hydrochloride (compound 37) Γ5-[2-hydroxy-3-(α-phenethylamino)propoxy]carbostyril hydrochloride (compound 38) Γ5-[2- Hydroxy-3-(N・N-diphenyl)propoxy]carbostyril hydrochloride (compound 39) Γ5-[2-hydroxy-3-(N-methyl-β-
Phenethyl amino) propoxy] carbostyryl hydrochloride (compound 40) The carbostyryl derivative represented by the above general formula [1] is, for example, a 3-halogenopropoxy carbostyryl derivative represented by the general formula [2] as shown in the following reaction scheme-1. It is easily produced by reacting the amine represented by the general formula [3]. Further, the carbostyril derivative represented by the general formula [1] is obtained by adding an amine represented by the general formula [3] to the 2,3-epoxypropoxy carbostyril derivative represented by the general formula [4] as shown in the following reaction scheme-2. It can also be produced by reaction. [In the formula, X represents a halogen atom. R 1 , R 2 and R 3 are the same as above. ] The compound of general formula [2], the compound of general formula [3], and the compound of general formula [4] are all known compounds. The reaction between the compound of general formula [2] and the compound of general formula [3] is carried out in a suitable solvent in the presence or absence of a dehydrohalogenating agent. Examples of the dehydrohalogenation agent include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and the like. In the present invention, general formula [3]
The compounds themselves can be used as dehydrohalogenating agents. Examples of the solvent include lower alcohols such as methanol, ethanol, and isopropanol, and ethers such as dioxane and tetrahydrofuran. When the reaction is carried out in the presence of a dehydrohalogenating agent, the ratio of the compound of general formula [2] and the compound of general formula [3] is usually an equimolar to excess amount of the latter to the former; Preferably equimolar ~
It is preferable to use 3 times the molar amount, and when the reaction is carried out in the absence of a dehydrohalogenating agent, the latter is usually in large excess of the former, preferably 3 to 8 times the molar amount. good. The amount of the above-mentioned dehydrohalogenating agent to be used is usually an equimolar to an excess amount, preferably an equimolar to 3 times the molar amount of the compound of general formula [2]. The reaction is usually carried out at a temperature of 0 to 100°C, preferably room temperature to 80°C, and is generally carried out at a temperature of 1 to 10°C.
The reaction completes in about an hour. The reaction between the compound of general formula [4] and the compound of general formula [3] is carried out in a suitable solvent. As the solvent, a wide variety of solvents can be used which are used in the reaction between the compound of the above general formula [2] and the compound of the general formula [3]. The ratio of the compound of general formula [4] and the compound of general formula [3] to be used is usually an equimolar to excess amount, preferably an equimolar to three times the molar amount of the latter relative to the former. The reaction is usually carried out at 0 to 100°C,
It is preferably carried out at room temperature to 80°C, and generally 1 to 80°C.
The reaction completes in about 10 hours. The carbostyryl derivative of general formula [1] thus obtained can be easily isolated and purified by conventional separation means. Examples of such separation means include solvent extraction, solvent dilution, distillation, recrystallization, and liquid chromatography. The antihistamine agent of the present invention contains a compound represented by the above general formula [1] or an acid addition salt thereof as an active ingredient. The acids capable of forming the above acid addition salts may be conventional pharmaceutically acceptable acids, such as hydrogen halides such as hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, oxalic acid, succinic acid, etc. , tartaric acid, malonic acid, fumaric acid, methanesulfonic acid, and the like. Further, the compound represented by the general formula [1] or its acid addition salt, which is used as an active ingredient in the antihistamine agent of the present invention, can also be used in the form of optical isomers thereof. When using the compound of general formula [1] and its acid addition salt as an antihistamine, it is usually put into the form of a pharmaceutical composition together with a pharmaceutical carrier. As carriers, diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, etc., which are commonly used to prepare drugs according to the usage form, can be used. I can give an example. Various dosage unit forms of antihistamines can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections. agent (liquid agent,
suspensions, etc.), ointments, etc. When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaria powder Disintegrants such as sodium bicarbonate, calcium carbonate, Twin, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, quaternary ammonium base, lauryl sulfate Absorption enhancers such as sodium, humectants such as glycerin and starch, starch, lactose, kaolin,
Examples include adsorbents such as bentonite and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, macrogol, and solid polyethylene glycol. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, Tugant powder, gelatin,
Examples include binders such as ethanol, and disintegrants such as laminaria and agar. Furthermore, the tablets can be made into conventionally coated tablets, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets, if necessary. When forming into a suppository, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood, and when formed into the form of solutions, emulsions and suspensions, they are used as diluents in the art. All those commonly used in the art can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, and the like. In this case, the therapeutic agent may contain a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution, and may also contain conventional solubilizing agents, buffers, soothing agents, preservatives, etc. Furthermore, coloring agents, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals may be included in the therapeutic agent, if necessary. When forming into a paste, cream or gel form, a wide range of diluents conventionally known in this field can be used, such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like. The amount of the compound of the general formula [1] or its acid addition salt to be contained in the antihistamine is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 70% by weight based on the total composition. Furthermore, there are no particular restrictions on the use of the above-mentioned antihistamines, and they can be administered in a manner appropriate for various forms. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules, and capsules, it is administered orally, and in the case of injections, it is administered intravenously alone or mixed with normal replenishing fluids such as glucose and amino acids. If necessary, it can be administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally; in the case of a suppository, it can be administered rectally; and in the case of an ointment, it can be applied. The dosage of the antihistamine of the present invention is appropriately selected depending on the purpose of use, symptoms, etc., and usually the compound of general formula [1] or its acid addition salt is administered at a dose of 40 μl per day.
3 to 2 mg/Kg/day
It may be administered in ~4 doses. Pharmacological Test A method using isolated guinea pig ileum (hereinafter referred to as "method A") is generally accepted as a typical method for measuring antihistamine action in vitro, and method A is also used in the present invention. The antihistamine effect was measured in vitro according to the following. Antihistamine effect test according to method A Male guinea pigs weighing 300 to 500 g were killed by exsanguination, the ileum 15 cm proximal to the ileocecal region was removed, and Tyrode's solution (NaCl 8.0 g, KCl 0.2 g, CaCl 2 0.2 g, glucose 1.0g, NaHCO 3 1.0g, NaH 2 PO 4・
Water was added to 0.065 g of 2H 2 O and 0.2135 g of MgCl 2 .6H 2 O to make a total volume of 1000 ml). The tissue was then cut into 2.5-3.0 cm pieces and suspended in a bath filled with 30 ml of Tyrode's solution. The bath was kept at 36° C. and passed through a gas mixture of 5% CO 2 and 95% O 2 . After 10 minutes, 10 -6 M of histamine was administered to examine tissue sensitivity, and a dose-response curve (control) with histamine was obtained. After the control dose-response had stabilized, 10 -6 g/ml of the test compound was administered, and 5 minutes later histamine was administered to obtain a dose-response curve. Contraction is performed using an isotonic transducer [Nihon Kohden TD-
112S] and recorded on a pen recorder. The maximum contraction of control histamine was taken as 100%, and the Van-Rotsam method [JMVan
Rossam, Arch.Int.Pharmacodyn., 143 , 299
(1963)], PA 2 was calculated using the following formula. PA 2 = PAx + log (x-1) ...... [In the formula, PAx = negative logarithm of the test compound concentration (g/ml), x = A B /A p , where A B is the concentration of the test compound in the presence of the test compound. The dose of histamine (g/ml) required for 50% contraction, A p is 50% in the absence of the test compound.
The dose of histamine (g/ml) required for % contraction is shown. ] In this test, the concentration of the test compound was 10 -6
g/ml, so PAx=log10 -6 =6.
Furthermore, from the formula, it can be seen that the stronger the antihistamine effect of the test compound, the larger x, that is, A B /A p , and the larger the PA 2 value. The results obtained are shown in Table 1 below.
【表】【table】
【表】
上記第１表から明らかな通り一般式〔１〕で表
わされる化合物は優れた抗ヒスタミン作用を発揮
する。
急性毒性試験
化合物２及び化合物３のLD50値をラツト
（雄）に静脈内投与して求めたところ下記の通り
であつた。
供試化合物 静脈内投与（mg／Kg）
化合物２ 48.7
化合物３ 50.7
化合物１、化合物４〜40についても同様に
LD50値を求めたところ、いずれの化合物も40
mg／Kg以上と低毒性であつた。
以下に、一般式〔１〕の化合物の製造例を参考
例として掲げ、さらに製剤例を掲げる。
参考例 １
５−（３−クロル−２−ヒドロキシプロポキ
シ）−３・４−ジヒドロカルボスチリル4.8ｇ及び
アリルアミン2.7ｇをメタノール50mlに混和し、
撹拌下50〜60℃で５時間反応させる。反応液を減
圧下に濃縮乾固し、残渣をクロロホルム80mlに溶
解したのちクロロホルム層を５％炭酸水素ナトリ
ウム水溶液で３回、次いで水で３回洗浄する。無
水硫酸ナトリウムで乾燥後溶媒を留去し、得られ
る残渣をベンゼンから再結晶して無色針状晶の５
−（２−ヒドロキシ−３−アリルアミノプロポキ
シ）−３・４−ジヒドロカルボスチリル1.5ｇを得
る。
融点124〜126℃
得られる化合物に飽和HCl／メタノール10mlを
加え減圧下溶媒を留去後メタノールから再結晶し
て無色不定形晶の５−（２−ヒドロキシ−３−ア
リルアミノプロポキシ）−３・４−ジヒドロカル
ボスチリル塩酸塩を得る。
融点196〜198℃
参考例 ２
５−（２・３−エポキシプロポキシ）−３・４−
ジヒドロカルボスチリル2.0ｇ及びアニリン1.1ｇ
をメタノール60mlに分散し、50〜60℃で３時間反
応させた後減圧濃縮する。残留物に濃塩酸５ml及
びエタノール30mlを加え均一に溶解したのちアセ
トン200mlを加えると結晶が析出する。析出結晶
を取、乾燥しメタノール−エーテルから再結晶
して無色不定形晶の５−（２−ヒドロキシ−３−
アニリノプロポキシ）−３・４−ジヒドロカルボ
スチリル塩酸塩1.8ｇを得る。
融点236〜237℃（分解）
上記参考例と同様にして下記参考例３〜６の化
合物を得た。[Table] As is clear from Table 1 above, the compound represented by the general formula [1] exhibits excellent antihistamine action. Acute toxicity test The LD 50 values of Compound 2 and Compound 3 were determined by intravenous administration to rats (male) and were as follows. Test compound Intravenous administration (mg/Kg) Compound 2 48.7 Compound 3 50.7 Similarly for Compound 1 and Compounds 4 to 40
When the LD 50 value was determined, all compounds were 40
The toxicity was low, exceeding mg/Kg. Below, production examples of the compound of general formula [1] are listed as reference examples, and further formulation examples are listed. Reference Example 1 4.8 g of 5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyryl and 2.7 g of allylamine were mixed in 50 ml of methanol,
The reaction is allowed to proceed for 5 hours at 50-60°C with stirring. The reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in 80 ml of chloroform, and the chloroform layer was washed three times with a 5% aqueous sodium bicarbonate solution and then three times with water. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was recrystallized from benzene to give colorless needle-like crystals.
1.5 g of -(2-hydroxy-3-allylaminopropoxy)-3,4-dihydrocarbostyryl is obtained. Melting point: 124-126℃ Add 10 ml of saturated HCl/methanol to the obtained compound, distill off the solvent under reduced pressure, and recrystallize from methanol to obtain colorless amorphous crystals of 5-(2-hydroxy-3-allylaminopropoxy)-3. 4-dihydrocarbostyril hydrochloride is obtained. Melting point 196-198℃ Reference example 2 5-(2,3-epoxypropoxy)-3,4-
Dihydrocarbostyril 2.0g and aniline 1.1g
Disperse in 60 ml of methanol, react at 50-60°C for 3 hours, and then concentrate under reduced pressure. Add 5 ml of concentrated hydrochloric acid and 30 ml of ethanol to the residue to dissolve it uniformly, and then add 200 ml of acetone to precipitate crystals. The precipitated crystals were collected, dried, and recrystallized from methanol-ether to give colorless amorphous crystals of 5-(2-hydroxy-3-
1.8 g of (anilinopropoxy)-3,4-dihydrocarbostyryl hydrochloride are obtained. Melting point: 236 to 237°C (decomposition) Compounds of Reference Examples 3 to 6 below were obtained in the same manner as in the above Reference Examples.
【表】【table】
【表】
製剤例 １
通常の方法で１錠中下記組成物の錠剤を製造し
た。
化合物５ ５mg
コーンスターチ 132mg
マグネシウムステアレート 18mgラクトース 45mg
計 200mg
製剤例 ２
通常の方法で１錠中下記組成物の錠剤を製造し
た。
化合物９ 10mg
コーンスターチ 130mg
マグネシウムステアレート 18mgラクトース 42mg
計 200mg[Table] Formulation Example 1 Tablets containing the following composition were manufactured in a conventional manner. Compound 5 5 mg Corn starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Formulation Example 2 Tablets having the following composition in one tablet were manufactured in a conventional manner. Compound 9 10mg Corn starch 130mg Magnesium stearate 18mg Lactose 42mg Total 200mg
Claims (1)
ルアルキル基を示す。R2はフエニル基、フエニ
ルアルキル基、ヒドロキシアルキル基、低級アル
ケニル基、シクロアルキル基又はフエノキシアル
キル基を示す。R3は水素原子、低級アルキル
基、低級アルケニル基、シクロアルキル基、フエ
ニル基又はフエニルアルキル基を示す。またこの
R2及びR3は結合する窒素原子と共に他の窒素原
子もしくは酸素原子を介し又は介することなく五
員又は六員の飽和ヘテロ環を形成してもよい。カ
ルボスチリル骨格の３位及び４位の炭素間結合は
一重結合又は二重結合を示す。〕 で表わされるカルボスチリル誘導体又はその酸付
加塩を有効成分として含有することを特徴とする
抗ヒスタミン剤。[Claims] 1. General formula [In the formula, R 1 represents a hydrogen atom, a lower alkyl group, or a phenyl alkyl group. R 2 represents a phenyl group, a phenylalkyl group, a hydroxyalkyl group, a lower alkenyl group, a cycloalkyl group, or a phenoxyalkyl group. R 3 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a phenyl group, or a phenyl alkyl group. Also this
Together with the nitrogen atom to which they are bonded, R 2 and R 3 may form a five- or six-membered saturated heterocycle with or without another nitrogen atom or oxygen atom. The carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond. ] An antihistamine agent characterized by containing a carbostyril derivative represented by the following or its acid addition salt as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3922180A JPS568319A (en) | 1980-03-26 | 1980-03-26 | Antihistamine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3922180A JPS568319A (en) | 1980-03-26 | 1980-03-26 | Antihistamine |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP53161558 Division |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS568319A JPS568319A (en) | 1981-01-28 |
| JPS623812B2 true JPS623812B2 (en) | 1987-01-27 |
Family
ID=12547076
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3922180A Granted JPS568319A (en) | 1980-03-26 | 1980-03-26 | Antihistamine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS568319A (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5889890U (en) * | 1981-12-11 | 1983-06-17 | 三菱重工業株式会社 | Structure to prevent incorrect loading of core components in fast breeder reactors |
| JPH07285940A (en) * | 1988-08-10 | 1995-10-31 | Otsuka Pharmaceut Co Ltd | Carbostyril derivative |
| JP2711437B2 (en) * | 1988-08-10 | 1998-02-10 | 大塚製薬 株式会社 | Carbostyril derivative |
| US5198448A (en) * | 1988-08-10 | 1993-03-30 | Otsuka Pharmaceutical Company, Limited | Cardiotonics |
| DK391189A (en) * | 1988-08-10 | 1990-02-11 | Otsuka Pharma Co Ltd | carbostyril derivatives |
| TW201305B (en) * | 1991-04-03 | 1993-03-01 | Otsuka Pharma Co Ltd | |
| JP2719740B2 (en) * | 1992-01-23 | 1998-02-25 | 大塚製薬 株式会社 | Cardiotonic |
| DE69316018T2 (en) * | 1992-09-18 | 1998-04-16 | Otsuka Pharma Co Ltd | CARBOSTYRILE DERIVATIVES AS AN ANTIARRHYTMICS |
| JPH06183976A (en) * | 1992-09-18 | 1994-07-05 | Otsuka Pharmaceut Co Ltd | Antiarrhythmic agent |
| IL126458A (en) | 1996-04-09 | 2004-06-20 | Nps Pharma Inc | Calcium receptor inhibiting calcilytic compounds |
| US6818660B2 (en) | 1996-04-09 | 2004-11-16 | Nps Pharmaceuticals, Inc. | Calcilytic compounds |
| US7202261B2 (en) | 1996-12-03 | 2007-04-10 | Nps Pharmaceuticals, Inc. | Calcilytic compounds |
| TW483881B (en) | 1996-12-03 | 2002-04-21 | Nps Pharma Inc | Calcilytic compounds |
-
1980
- 1980-03-26 JP JP3922180A patent/JPS568319A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS568319A (en) | 1981-01-28 |
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