JPH0374644B2 - - Google Patents
Info
- Publication number
- JPH0374644B2 JPH0374644B2 JP62074211A JP7421187A JPH0374644B2 JP H0374644 B2 JPH0374644 B2 JP H0374644B2 JP 62074211 A JP62074211 A JP 62074211A JP 7421187 A JP7421187 A JP 7421187A JP H0374644 B2 JPH0374644 B2 JP H0374644B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- pyrido
- compounds
- group
- active ingredient
- 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
- -1 1H-tetrazol-5-yl group Chemical group 0.000 claims description 14
- 239000004480 active ingredient Substances 0.000 claims description 7
- 208000019423 liver disease Diseases 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 17
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 206010067125 Liver injury Diseases 0.000 description 4
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- 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 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 231100000234 hepatic damage Toxicity 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000008818 liver damage Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- VFMCUTPRJLZEEW-UHFFFAOYSA-N 4h-pyrido[1,2-a]pyrimidine Chemical group C1=CC=CN2CC=CN=C21 VFMCUTPRJLZEEW-UHFFFAOYSA-N 0.000 description 2
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 230000003908 liver function Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 150000008518 pyridopyrimidines Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000012453 sprague-dawley rat model Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 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
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- AHEKJZJJBQLTDU-UHFFFAOYSA-N 2-[9-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-4-oxopyrido[1,2-a]pyrimidin-3-yl]acetic acid Chemical compound C1=CC(C(C)=O)=C(O)C(CCC)=C1OCC1=CC=CN2C(=O)C(CC(O)=O)=CN=C12 AHEKJZJJBQLTDU-UHFFFAOYSA-N 0.000 description 1
- ZHUGMHHNJBXFEP-UHFFFAOYSA-N 4-oxopyrido[1,2-a]pyrimidine-3-carbonitrile Chemical compound C1=CC=CN2C(=O)C(C#N)=CN=C21 ZHUGMHHNJBXFEP-UHFFFAOYSA-N 0.000 description 1
- FPXDWQCNXFONMN-UHFFFAOYSA-N 4h-pyrido[1,2-a]pyrimidine-3-carboxylic acid Chemical compound C1=CC=CN2CC(C(=O)O)=CN=C21 FPXDWQCNXFONMN-UHFFFAOYSA-N 0.000 description 1
- MEHVNFLSXDINEV-UHFFFAOYSA-N 9-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-3-(2h-tetrazol-5-yl)pyrido[1,2-a]pyrimidin-4-one;potassium Chemical group [K].C1=CC(C(C)=O)=C(O)C(CCC)=C1OCC1=CC=CN2C(=O)C(C=3NN=NN=3)=CN=C12 MEHVNFLSXDINEV-UHFFFAOYSA-N 0.000 description 1
- WXWWEFZPRLRGFL-UHFFFAOYSA-N 9-methyl-3-(2h-tetrazol-5-yl)pyrido[1,2-a]pyrimidin-4-one;potassium Chemical compound [K].CC1=CC=CN(C2=O)C1=NC=C2C1=NN=NN1 WXWWEFZPRLRGFL-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 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 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 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 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- WMFYOYKPJLRMJI-UHFFFAOYSA-N Lercanidipine hydrochloride Chemical compound Cl.COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)CN(C)CCC(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 WMFYOYKPJLRMJI-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 101710098398 Probable alanine aminotransferase, mitochondrial Proteins 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- YDPLDMLRERBXAV-UHFFFAOYSA-N aluminum;triazide Chemical compound [Al+3].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] YDPLDMLRERBXAV-UHFFFAOYSA-N 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 239000003874 central nervous system depressant Substances 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 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
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003536 tetrazoles Chemical group 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
産業上の利用分野
本発明はピリド[1,2−a]ピリミジン化合
物又はその塩を有効成分とする肝疾患治療剤に関
する。
従来の技術
従来のピリドピリミジン系化合物において、
1H−テトラゾール−5−イル基を含有するもの
としては、特開昭54−36294号公報に抗アレルギ
ー作用を示す9−メチル−3−(1H−テトラゾー
ル−5−イル)−4H−ピリド[1,2−a]ピリ
ミジン−4−オンカリウム塩(以下「化合物α」
と略す)が、また、カルボキシ基を含有するもの
としては、特開昭49−14495号公報に中枢神経抑
制作用を示す9−ベンジルオキシ−4−オキソ−
ピリド[1,2−a]ピリミジン−3−カルボン
酸(以下「化合物β」と略す)が夫々報告されて
いる。
発明が解決しようとする問題点
しかしながら、これらの公報には、化合物α又
はβが肝機能を有意に改善する旨の示唆は全くな
く、本発明者らの実験によつても、良好な肝保護
効果を確認するまでには至らなかつた。そこで、
本発明者らは、化合物α及びβの周辺化合物を探
索した結果、ピリド[1,2−a]ピリミジン環
の9位が4−アセチル−3−ヒドロキシ−2−n
−プロピルフエノキシメチル基で置換された化合
物が、顕著な肝障害改善作用を具備することを知
り、本発明に到達した。
問題点を解決するための手段
本発明によれば、下記一般式[]:
(式中、Aは1H−テトラゾール−5−イル基
又はカルボキシメチル基を表わす。)
で示されるピリド[1,2−a]ピリミジン化合
物又はそれの生理学的に許容される塩を有効成分
とする肝疾患治療剤が提供される。
本発明の有効成分である前記一般式[]のピ
リド[1,2−a]ピリミジン化合物及びそれの
生理学的に許容される塩(以下これらを単に「ピ
リドピリミジン化合物[]」と略す)の代表例
としては、9−[(4−アセチル−3−ヒドロキシ
−2−n−プロピルフエノキシ)メチル]−3−
(1H−テトラゾール−5−イル)−4H−ピリド
[1,2−a]ピリミジン−4−オンカリウム塩
(以下「化合物1」と仮称する)及び[9−(4−
アセチル−3−ヒドロキシ−2−n−プロピルフ
エノキシメチル)−4−オキソ−ピリド[1,2
−a]ピリミジン−3−イル]酢酸(以下「化合
物2」と仮称する)が挙げられる。
化合物1は、9−[(4−アセチル−3−ヒドロ
キシ−2−n−プロピルフエノキシ)メチル]−
3−シアノ−4H−ピリド[1,2−a]ピリミ
ジン−4−オンを、例えばアジ化アルミニウムを
用いてテトラゾール環形成し、ついで水酸化カリ
ウムエタノール溶液でもつてカリウム塩とするこ
とにより製造することができる(特願昭61−
205188号実施例1及び12参照)。また、化合物2
は、[9−(4−アセチル−3−ヒドロキシ−2−
n−プロピルフエノキシメチル)−4−オキソ−
ピリド[1,2−a]ピリミジン−3−イル]酢
酸エチルエステルを、例えば水酸化ナトリウムを
用いて加水分解することにより製造することがで
きる(特願昭61−86034号実施例2参照)。
本発明の肝疾患治療剤は、経口又は非経口で投
与され、その用量は患者の年令、症状、体重又は
性別等により決定される。一般的には、有効成分
であるピリドピリミジン化合物[]の一日用量
は、経口で1mg〜20g、好ましくは5mg〜4g
が、非経口で0.1mg〜3.5g、好ましくは1mg〜1
gが夫々適当である。用法としては、かかる用量
の範囲内で一日あたり1〜8回、好ましくは1〜
4回に分けて使用するのが適当である。
また、本発明の肝疾患治療剤には、上述の一日
用量が保持できる範囲内において、有効成分のピ
リドピリミジン化合物[]に生理的に無害な固
体又は液体の製剤担体を配合した種々の薬剤組成
物も包含する。この薬剤組成物は、錠剤、丸剤、
カプセル剤、散剤、細粒剤、顆粒剤、水剤、シロ
ツプ剤、懸濁剤、乳剤又は注射剤の形態を採るこ
とができる。製剤担体としては、かかる形態に通
常用いられるものであればよく、これには、例え
ば、トウモロコシ澱粉、デキストリン、α,βも
しくはγ−シクロデキストリン、ブドウ糖、乳
糖、シヨ糖、メチルセルロース、カルボキシメチ
ルセルロースカルシウム、結晶セルロース、ステ
アリン酸マグネシウム、アルギン酸ナトリウム、
ウイテプソールW35、ウイテプソールE85、ポリ
ビニルアルコールもしくは軽質無水ケイ酸などの
賦形剤、結合剤もしくは崩壊剤;タルク、ステア
リン酸、ワツクス類、ヒドロキシプロピルセルロ
ースもしくは硼酸などの滑沢剤;セラツク、酢酸
フタル酸セルロースもしくはポリビニルアセタル
ジエチルアミノアセテートなどの被覆剤;グリセ
リン、プロピレングリコールもしくはマンニトー
ルなどの溶解補助剤;ポリオキシエチレンステア
レート、ポリオキシエチレンセチルアルコールエ
テル、アラビアゴムもしくはポリビニルピロリド
ンなどの乳化剤もしくは懸濁化剤;ソルビトー
ル、ツイーン80、スパン60もしくは油脂類等の安
定化剤;各種の溶剤;又は適当な香料もしくはシ
ロツプが挙げられる。
本発明を実施例及び製剤例をもつて更に説明す
る。
実施例 1
(肝障害改善試験)
7週齢のスプラーグ・ドーリー(Sprague−
Dawley)系雄性ラツトを1群5匹として用い、
四塩化炭素又はD−ガラクトサミンによつて誘発
される肝障害に対するピリドピリミジン化合物
[]の改善作用を経口及び腹腔内の二種類の投
与形態で試験した。被験化合物としては、化合物
1、化合物2、化合物α及び化合物βを用いた。
試験は、各ラツトに予め被験化合物を投与し、つ
いで四塩化炭素0.5ml/Kg又はD−ガラクトサミ
ン700mg/Kgを腹腔内投与し、24時間絶食後にお
ける血清中のグルタミン酸−オキザ口酢酸トラン
スアミナーゼ(以下GOTと略す)、グルタミン酸
−ピルビン酸トランスアミナーゼ(以下GPTと
略す)、アルカリホスフアターゼ(以下ALPと略
す)及びビリルビン(以下TBILと略す)の各濃
度を測定することにより行つた。四塩化炭素の投
与は、被験化合物を1日1回の割合で4日間連続
投与し、その最終投与の30分後に、また、D−ガ
ラクトサミンの投与は、被験化合物を1回投与
し、その3時間後に夫々実施した。被験化合物の
1回投与量は、経口では100及び250mg/Kgに、腹
腔内では10及び25mg/Kgに設定した。血清は、各
ラツトの全血をエーテル麻酔下で心臓より採取
し、これを3000r.p.m.で10分間遠心分離すること
により調製した。GOT、GPT、ALP及びTBIL
の各濃度は、セントリフイケム(CentrifiChem)
試薬(ベーカー社製)及びセントリフイケムシス
テム600自動分析装置(ベーカー社製)を用い、
カルメン改良法、ロブレスキー・アンド・ラデユ
ー(Wroblewski and Ladue)改良法、ベセセ
ブ・ローリー・ブロツク(Besesev Lowry
Brock)改良法及びジアゾ法[クリニカル・ケミ
ストリー(Clinical Chemistry)24巻58頁1978
年、同23巻、887頁1977年、同29巻751頁1983年及
び同19巻1366頁1973年]に準じて夫々測定した。
結果を第1表に示す。なお、同表中のコントロー
ル群とは四塩化炭素又はD−ガラクトサミンのみ
を投与し、被験化合物は投与しなかつた群を意味
する。
INDUSTRIAL APPLICATION FIELD The present invention relates to a liver disease therapeutic agent containing a pyrido[1,2-a]pyrimidine compound or a salt thereof as an active ingredient. Conventional technology In conventional pyridopyrimidine compounds,
Among those containing 1H-tetrazol-5-yl group, 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido [1 , 2-a] pyrimidin-4-one potassium salt (hereinafter "compound α")
9-benzyloxy-4-oxo-, which exhibits a central nervous system depressant effect, is described in Japanese Patent Application Laid-open No. 14495/1983 as a carboxy group-containing compound.
Pyrido[1,2-a]pyrimidine-3-carboxylic acid (hereinafter abbreviated as "compound β") has been reported. Problems to be Solved by the Invention However, there is no suggestion in these publications that compounds α or β significantly improve liver function, and experiments by the present inventors have shown that compounds α or β significantly improve liver function. I haven't been able to confirm the effect. Therefore,
As a result of searching for compounds surrounding compounds α and β, the present inventors found that the 9-position of the pyrido[1,2-a]pyrimidine ring is 4-acetyl-3-hydroxy-2-n
The present invention was achieved based on the finding that a compound substituted with a -propylphenoxymethyl group has a remarkable effect of improving liver damage. Means for Solving the Problems According to the present invention, the following general formula []: (In the formula, A represents a 1H-tetrazol-5-yl group or a carboxymethyl group.) The active ingredient is a pyrido[1,2-a]pyrimidine compound or a physiologically acceptable salt thereof. A therapeutic agent for liver disease is provided. Pyrido[1,2-a]pyrimidine compounds of the general formula [ ] and physiologically acceptable salts thereof (hereinafter simply referred to as "pyridopyrimidine compounds []"), which are the active ingredients of the present invention. A typical example is 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-
(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (hereinafter tentatively named "Compound 1") and [9-(4-
Acetyl-3-hydroxy-2-n-propylphenoxymethyl)-4-oxo-pyrido [1,2
-a]pyrimidin-3-yl]acetic acid (hereinafter tentatively named "Compound 2"). Compound 1 is 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-
Producing 3-cyano-4H-pyrido[1,2-a]pyrimidin-4-one by forming a tetrazole ring using, for example, aluminum azide, and then converting it into a potassium salt with an ethanolic potassium hydroxide solution. (Special application 1986-
205188, Examples 1 and 12). Also, compound 2
is [9-(4-acetyl-3-hydroxy-2-
n-propylphenoxymethyl)-4-oxo-
It can be produced by hydrolyzing pyrido[1,2-a]pyrimidin-3-yl]acetic acid ethyl ester using, for example, sodium hydroxide (see Example 2 of Japanese Patent Application No. 1986-86034). The liver disease therapeutic agent of the present invention is administered orally or parenterally, and the dose is determined depending on the patient's age, symptoms, body weight, sex, etc. Generally, the daily dose of the active ingredient pyridopyrimidine compound [ ] is 1 mg to 20 g orally, preferably 5 mg to 4 g.
but parenterally 0.1 mg to 3.5 g, preferably 1 mg to 1
g is appropriate. The dosage range is 1 to 8 times per day, preferably 1 to 8 times per day.
It is appropriate to use it in four parts. In addition, the liver disease therapeutic agent of the present invention includes various formulations in which the active ingredient pyridopyrimidine compound [ ] is blended with a physiologically harmless solid or liquid pharmaceutical carrier within the range that can maintain the above-mentioned daily dose. Also included are pharmaceutical compositions. This pharmaceutical composition may include tablets, pills,
It can take the form of capsules, powders, fine granules, granules, solutions, syrups, suspensions, emulsions or injections. Pharmaceutical carriers may be those commonly used in such forms, such as corn starch, dextrin, α, β or γ-cyclodextrin, glucose, lactose, sucrose, methylcellulose, calcium carboxymethylcellulose, Crystalline cellulose, magnesium stearate, sodium alginate,
Uitepsol W35, Uitepsol E85, excipients, binders or disintegrants such as polyvinyl alcohol or light silicic anhydride; lubricants such as talc, stearic acid, waxes, hydroxypropylcellulose or boric acid; shellac, cellulose acetate phthalate or coating agents such as polyvinyl acetal diethylamino acetate; solubilizing agents such as glycerin, propylene glycol or mannitol; emulsifying or suspending agents such as polyoxyethylene stearate, polyoxyethylene cetyl alcohol ether, gum arabic or polyvinylpyrrolidone; Stabilizers such as sorbitol, Tween 80, Span 60 or fats and oils; various solvents; or suitable flavorings or syrups may be included. The present invention will be further explained with examples and formulation examples. Example 1 (Liver damage improvement test) 7-week-old Sprague-Dawley (Sprague-Dawley)
Dawley strain male rats were used (5 rats per group).
The ameliorating effect of a pyridopyrimidine compound [ ] on liver damage induced by carbon tetrachloride or D-galactosamine was tested in two administration forms: oral and intraperitoneal. Compound 1, Compound 2, Compound α, and Compound β were used as test compounds.
In the test, the test compound was administered to each rat in advance, and then 0.5 ml/Kg of carbon tetrachloride or 700 mg/Kg of D-galactosamine was administered intraperitoneally to each rat. This was done by measuring the concentrations of GOT), glutamate-pyruvate transaminase (hereinafter referred to as GPT), alkaline phosphatase (hereinafter referred to as ALP), and bilirubin (hereinafter referred to as TBIL). Carbon tetrachloride was administered once a day for 4 consecutive days, 30 minutes after the last dose, and D-galactosamine was administered once a day, 30 minutes after the final dose. They were carried out after hours. The single dose of the test compound was set at 100 and 250 mg/Kg orally and 10 and 25 mg/Kg intraperitoneally. Serum was prepared by collecting whole blood from the heart of each rat under ether anesthesia and centrifuging it at 3000 rpm for 10 minutes. GOT, GPT, ALP and TBIL
Each concentration of CentrifiChem
Using reagents (manufactured by Baker) and Centrifuichem System 600 automatic analyzer (manufactured by Baker),
Carmen improved method, Wroblewski and Ladue improved method, Besesev Lowry
Brock) improved method and diazo method [Clinical Chemistry, Vol. 24, p. 58, 1978
Vol. 23, p. 887, 1977, Vol. 29, p. 751, 1983, and Vol. 19, p. 1366, 1973].
The results are shown in Table 1. The control group in the same table means a group to which only carbon tetrachloride or D-galactosamine was administered, but no test compound was administered.
【表】
実施例 2
(急性毒性試験)
5週齢のddY系雄性マウス及びスプラーグ・ド
ーリー系雄性ラツトを用い、ピリドリミジン化合
物[]の急性毒性(LD50)を試験した。化合
物1及び化合物2ともに、LD50値は、マウスで
は経口で4.0g/Kg以上、静脈内で100mg/Kg以上
であつた。同じく、ラツトでは経口で、4.0g/
Kg以上、静脈内で200mg/Kg以上であつた。
製剤例 1
(錠剤)
重量(%)
(1) 化合物1 10.0
(2) 乳 糖 56.0
(3) トウモロコシ澱粉 15.0
(4) 結晶セルロース 15.0
(5) ヒドロキシプロピルセルロース 3.0(6) ステアリン酸マグネシウム 1.0
100.0
上述の(1)〜(5)を混合し、水を添加して造粒し、
ついで乾燥した。得られた顆粒を整粒したのち、
(6)を加えて混合し、これを圧縮成形して1錠100
mgの錠剤を調製した。
製剤例 2
(カプセル剤)
重量(%)
(1) 化合物2 10.0
(2) 乳 糖 65.5
(3) トウモロコシ澱粉 20.0
(4) ヒドロキシプロピルセルロース 3.0
(5) 軽質無水ケイ酸 0.5(6) ステアリン酸マグネシウム 1.0
100.0
常法に従つて、上述の成分を混和して顆粒とし
た。これをカプセルに充填し、1個100mgのカプ
セル剤を調製した。
発明の効果
第1表から明らかなように、化合物1及び2
は、化合物α及びβに比べ、極めて良好な肝障害
改善作用を示すことが認められる。従つて、ピリ
ドピリミジン化合物[]を有効成分として含有
する薬剤は、肝疾患治療剤として利用することが
できる。[Table] Example 2 (Acute toxicity test) The acute toxicity (LD 50 ) of the pyridrimidine compound [] was tested using 5-week-old male ddY mice and male Sprague-Dawley rats. The LD 50 values of both Compound 1 and Compound 2 were 4.0 g/Kg or more for oral administration and 100 mg/Kg or more for intravenous administration in mice. Similarly, in rats, 4.0g/orally
200 mg/Kg or more intravenously. Formulation example 1 (tablet) Weight (%) (1) Compound 1 10.0 (2) Lactose 56.0 (3) Corn starch 15.0 (4) Crystalline cellulose 15.0 (5) Hydroxypropyl cellulose 3.0 (6) Magnesium stearate 1.0 100.0 Above (1) to (5) are mixed, water is added and granulated,
Then it was dried. After sizing the obtained granules,
Add (6) and mix, compression mold this and make 1 tablet 100.
mg tablets were prepared. Formulation example 2 (capsule) Weight (%) (1) Compound 2 10.0 (2) Lactose 65.5 (3) Corn starch 20.0 (4) Hydroxypropyl cellulose 3.0 (5) Light silicic anhydride 0.5 (6) Magnesium stearate 1.0 100.0 The above ingredients were mixed to form granules according to a conventional method. This was filled into capsules to prepare capsules each weighing 100 mg. Effect of the invention As is clear from Table 1, compounds 1 and 2
was found to exhibit extremely good liver damage-improving effects compared to compounds α and β. Therefore, a drug containing a pyridopyrimidine compound [ ] as an active ingredient can be used as a therapeutic agent for liver diseases.
Claims (1)
又はカルボキシメチル基を表わす。) で示されるピリド[1,2−a]ピリミジン化合
物又はそれの生理学的に許容される塩を有効成分
とする肝疾患治療剤。[Claims] 1. General formula (In the formula, A represents a 1H-tetrazol-5-yl group or a carboxymethyl group.) The active ingredient is a pyrido[1,2-a]pyrimidine compound or a physiologically acceptable salt thereof. Liver disease treatment agent.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62074211A JPS63243082A (en) | 1987-03-30 | 1987-03-30 | Remedy for liver disease |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62074211A JPS63243082A (en) | 1987-03-30 | 1987-03-30 | Remedy for liver disease |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS63243082A JPS63243082A (en) | 1988-10-07 |
JPH0374644B2 true JPH0374644B2 (en) | 1991-11-27 |
Family
ID=13540629
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP62074211A Granted JPS63243082A (en) | 1987-03-30 | 1987-03-30 | Remedy for liver disease |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS63243082A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0653209A4 (en) * | 1992-07-30 | 1997-03-19 | Tokyo Tanabe Co | Remedy for inflammatory intestinal diseases. |
-
1987
- 1987-03-30 JP JP62074211A patent/JPS63243082A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS63243082A (en) | 1988-10-07 |
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