JPH045269A - Cyclohexane carbohydroxamic acid derivative, enzyme inhibitor and anti-ulcer agent - Google Patents
Cyclohexane carbohydroxamic acid derivative, enzyme inhibitor and anti-ulcer agentInfo
- Publication number
- JPH045269A JPH045269A JP2106517A JP10651790A JPH045269A JP H045269 A JPH045269 A JP H045269A JP 2106517 A JP2106517 A JP 2106517A JP 10651790 A JP10651790 A JP 10651790A JP H045269 A JPH045269 A JP H045269A
- Authority
- JP
- Japan
- Prior art keywords
- group
- acid
- formula
- aralkyl
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003699 antiulcer agent Substances 0.000 title claims abstract description 13
- 239000002532 enzyme inhibitor Substances 0.000 title claims description 8
- 229940125532 enzyme inhibitor Drugs 0.000 title claims description 6
- RFWDAWXPYZTVSN-UHFFFAOYSA-N n-hydroxycyclohexanecarboxamide Chemical class ONC(=O)C1CCCCC1 RFWDAWXPYZTVSN-UHFFFAOYSA-N 0.000 title 1
- 239000002253 acid Substances 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 13
- 125000003118 aryl group Chemical group 0.000 claims abstract description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 abstract description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 15
- 238000006243 chemical reaction Methods 0.000 abstract description 15
- 230000002401 inhibitory effect Effects 0.000 abstract description 15
- 108010046334 Urease Proteins 0.000 abstract description 14
- 108091005804 Peptidases Proteins 0.000 abstract description 10
- 239000004365 Protease Substances 0.000 abstract description 6
- UAFHRUBCOQPFFM-UHFFFAOYSA-N 1-(aminomethyl)cyclohexane-1-carboxylic acid Chemical compound NCC1(C(O)=O)CCCCC1 UAFHRUBCOQPFFM-UHFFFAOYSA-N 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 abstract description 3
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 230000000694 effects Effects 0.000 description 18
- 239000000243 solution Substances 0.000 description 14
- 208000025865 Ulcer Diseases 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- 231100000397 ulcer Toxicity 0.000 description 10
- 102000035195 Peptidases Human genes 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- -1 inorganic acid salts Chemical class 0.000 description 8
- 229940012957 plasmin Drugs 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 108010088842 Fibrinolysin Proteins 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 5
- 238000005520 cutting process Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- FHRSHSOEWXUORL-HDJSIYSDSA-N cetraxate Chemical compound C1C[C@@H](C[NH3+])CC[C@@H]1C(=O)OC1=CC=C(CCC([O-])=O)C=C1 FHRSHSOEWXUORL-HDJSIYSDSA-N 0.000 description 4
- 229950009533 cetraxate Drugs 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229960001380 cimetidine Drugs 0.000 description 3
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000027119 gastric acid secretion Effects 0.000 description 3
- 210000001156 gastric mucosa Anatomy 0.000 description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000003944 tolyl group Chemical group 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 2
- 206010007027 Calculus urinary Diseases 0.000 description 2
- 241000589876 Campylobacter Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 108060005987 Kallikrein Proteins 0.000 description 2
- 102000001399 Kallikrein Human genes 0.000 description 2
- 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 2
- 241001465754 Metazoa Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 230000000288 anti-kallikrein effect Effects 0.000 description 2
- 230000000767 anti-ulcer Effects 0.000 description 2
- 229940030225 antihemorrhagics Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000004202 carbamide Substances 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
- 231100000749 chronicity Toxicity 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000002874 hemostatic agent Substances 0.000 description 2
- GGQOPZKTDHXXON-UHFFFAOYSA-N hexane;methanol Chemical compound OC.CCCCCC GGQOPZKTDHXXON-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 2
- 229960000401 tranexamic acid Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- 101710081722 Antitrypsin Proteins 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- BYMMIQCVDHHYGG-UHFFFAOYSA-N Cl.OP(O)(O)=O Chemical compound Cl.OP(O)(O)=O BYMMIQCVDHHYGG-UHFFFAOYSA-N 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010060891 General symptom Diseases 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
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000219470 Mirabilis Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910017912 NH2OH Inorganic materials 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 101000605527 Rattus norvegicus Kallikrein-1 Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 102000057032 Tissue Kallikreins Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 208000009911 Urinary Calculi Diseases 0.000 description 1
- RRUDCFGSUDOHDG-UHFFFAOYSA-N acetohydroxamic acid Chemical compound CC(O)=NO RRUDCFGSUDOHDG-UHFFFAOYSA-N 0.000 description 1
- 229960001171 acetohydroxamic acid Drugs 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000001475 anti-trypsic effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 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
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide 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
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 239000000460 chlorine Chemical group 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000023652 chronic gastritis Diseases 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- RSAZYXZUJROYKR-UHFFFAOYSA-N indophenol Chemical compound C1=CC(O)=CC=C1N=C1C=CC(=O)C=C1 RSAZYXZUJROYKR-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- 235000019698 starch Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 239000002601 urease inhibitor Substances 0.000 description 1
- 208000008281 urolithiasis Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、新規なシクロヘキサンカルボンヒドロキサム
酸誘導体に関し、さらに詳しくは、蛋白分解酵素阻害活
性とウレアーゼ阻害活性を併せ持つシクロヘキサンカル
ボンヒドロキサム酸誘導体またはその薬学的に許容し得
る塩、およびそれを有効成分とする抗潰瘍剤などとして
有用な酵素阻害剤に関する。Detailed Description of the Invention (Industrial Field of Application) The present invention relates to a novel cyclohexanecarbonhydroxamic acid derivative, and more particularly, to a cyclohexanecarbonhydroxamic acid derivative having both protease inhibitory activity and urease inhibitory activity, or its pharmaceutical composition. The present invention relates to an enzyme inhibitor useful as an anti-ulcer agent, etc., containing the same as an active ingredient.
（従来の技術）
生体内には数多くの種類の酵素が存在しており、様々な
疾患との関連が知られている。例えば、プラスミン、ト
リプシン、カリクレイン等の蛋白分解酵素も例外ではな
く、何らかの理由によって異常に活性化されると、種々
の疾患を誘発することが知られている。例えば、血液中
にプラスミンが多量に存在すると出血性疾患を生ずる。(Prior Art) Many types of enzymes exist in living bodies and are known to be associated with various diseases. For example, proteolytic enzymes such as plasmin, trypsin, and kallikrein are no exception, and are known to induce various diseases if they are abnormally activated for some reason. For example, the presence of large amounts of plasmin in the blood causes bleeding disorders.
また、プラスミンは胃潰瘍の発生あるいは進行に関与す
ることが知られている〔日本消化器病学会大会講演要旨
集 １９８８． Ｐ２Ｏ９４，Ｊａｐａｎ、 Ｊ、 Ｐ
ｈａｒｍａｃｏｌ、 ５０゜７２ （１９８９） ）。Additionally, plasmin is known to be involved in the development or progression of gastric ulcers [Collection of abstracts from the Japanese Society of Gastroenterology Conference 1988. P2O94, Japan, J, P
harmacol, 50°72 (1989)).
したがって、これらの蛋白分解酵素を阻害する活性を有
する物質は、様々の疾患の治療薬として有用であり、従
来よりその開発が検討されてきた。例えば、抗プラスミ
ン剤は止血剤、抗潰瘍剤、抗炎症剤として有用であり、
抗トリプシン剤はスイ炎治療剤として、抗カリクレイン
剤は抗潰瘍剤などとして有用である。Therefore, substances having the activity of inhibiting these proteolytic enzymes are useful as therapeutic agents for various diseases, and their development has been studied for some time. For example, antiplasmin agents are useful as hemostatic agents, anti-ulcer agents, and anti-inflammatory agents;
Anti-trypsin agents are useful as agents for treating rhinitis, and anti-kallikrein agents are useful as anti-ulcer agents.
一方、蛋白分解酵素と共に疾患との関連が知られている
酵素にウレアーゼがある。ウレアーゼは尿素をアンモニ
アと二酸化炭素に分解する酵素であるが、哺乳動物にお
いて検出されるウレアーゼ活性は、共生あるいは感染し
た微生物由来であることが知られている。さらに、ウレ
アーゼと疾患の関連については、例えば、プロテウス
ミラビリス感染による尿路結石症があり、また近年、慢
性胃炎、胃潰瘍の発症や進行に強力なウレアーゼ活性を
有するカンピロバクタ−ピロリが関与していることが示
唆されている。〔例えば、Ｊ、 ｏｆＣｌｉｎｉｃａｌ
Ｍｉｃｒｏｂｉｏｌｏｇｙ ２６．５ Ｐ８３１ （
１９８８） 、治療 ７１巻 １０号 Ｐ２Ｏ９３（１
９８９））しかし、ウレアーゼ阻害剤の医薬品への応用
については、アセトヒドロキサム酸を尿路結石症治療剤
として使用する試みがなされているにすぎない。本発明
に比較的構造の近い物質としてセトラキサートやトラネ
キサム酸などが知られているが、これらの物質は、抗プ
ラスミン活性などの蛋白分解酵素阻害活性を有している
もので、抗ウレアーゼ活性を併せ持つ物質は知られてい
ない。On the other hand, along with proteolytic enzymes, urease is an enzyme known to be associated with diseases. Urease is an enzyme that decomposes urea into ammonia and carbon dioxide, and it is known that the urease activity detected in mammals is derived from commensal or infected microorganisms. Furthermore, regarding the relationship between urease and disease, see e.g.
Urinary tract stone disease is caused by Iris mirabilis infection, and in recent years, it has been suggested that Campylobacter pylori, which has strong urease activity, is involved in the onset and progression of chronic gastritis and gastric ulcer. [For example, J, of Clinical
Microbiology 26.5 P831 (
1988), Treatment Vol. 71 No. 10 P2O93 (1
(989)) However, regarding the pharmaceutical application of urease inhibitors, only attempts have been made to use acetohydroxamic acid as a therapeutic agent for urolithiasis. Cetraxate and tranexamic acid are known as substances with a structure relatively similar to the present invention, but these substances have protease inhibitory activities such as anti-plasmin activity, and also have anti-urease activity. substance is unknown.
また、抗潰瘍剤として数多くの薬剤が知られ、かつ販売
されている。例えば、防御型抗潰瘍剤の塩酸セトラキサ
ートや強力な胃酸分泌抑制作用を持つヒスタミンＨ２受
容体拮抗薬であるシメチジンが代表例として挙げられる
。In addition, many drugs are known and sold as anti-ulcer agents. For example, representative examples include cetraxate hydrochloride, a protective anti-ulcer agent, and cimetidine, a histamine H2 receptor antagonist that has a strong gastric acid secretion suppressing effect.
塩酸セトラキサートの抗潰瘍活性は、特に慢性潰瘍に対
して必ずしも満足するものでないため、主にシメチジン
などの胃酸分泌抑制剤との併用療法が必要となる。また
、シメチジンは強力な胃酸分泌抑制作用を有しており、
潰瘍の治癒率も上昇したが、抗男性ホルモン作用、無顆
粒球症等の副作用が知られ、さらに、潰瘍の再発、慢性
化、抵抗性潰瘍の発生といった問題がある。Since the anti-ulcer activity of cetraxate hydrochloride is not necessarily satisfactory, especially for chronic ulcers, combination therapy with a gastric acid secretion suppressant such as cimetidine is required. In addition, cimetidine has a strong inhibitory effect on gastric acid secretion.
Although the ulcer healing rate has increased, side effects such as anti-androgen effects and agranulocytosis are known, and there are further problems such as ulcer recurrence, chronicity, and development of resistant ulcers.
（発明が解決しようとする課題）
本発明は、かかる従来技術の問題点を解決して、蛋白分
解酵素阻害活性とウレアーゼ阻害活性を併せ持つ物質、
およびそれを有効成分とする抗潰瘍剤などの医薬品とし
て有用な酵素阻害剤の開発を目的とする。(Problems to be Solved by the Invention) The present invention solves the problems of the prior art and provides a substance that has both protease inhibitory activity and urease inhibitory activity.
The aim is to develop enzyme inhibitors containing this enzyme as an active ingredient that are useful as anti-ulcer agents and other pharmaceuticals.
（課題を解決するための手段）
本発明者らは、前記の課題を解決するため鋭意研究を重
ねた結果、新規のシクロヘキサンカルボンヒドロキサム
酸誘導体が優れた蛋白分解酵素阻害活性とウレアーゼ阻
害活性を有し、さらに、強力な抗潰瘍活性を有すること
を見出し、本発明を完成するに至った。(Means for Solving the Problems) As a result of intensive research to solve the above problems, the present inventors discovered that a new cyclohexanecarbonhydroxamic acid derivative has excellent protease inhibitory activity and urease inhibitory activity. Furthermore, they discovered that it has strong anti-ulcer activity, leading to the completion of the present invention.
すなわち、本発明は、一般式（Ｎ
（式中、Ｒ１はＨ１炭素数１〜５のアルキル、アリール
あるいはアラルキルを表し、Ｒ２，Ｒ３は同一または異
なってＨ１炭素数１から５のアルキル基、グアニル基、
あるいは置換基を有してもよいアリール基またはアラル
キル基を表す。ただし、Ｒ２およびＲ３が同時にＨには
ならない。）で示されるシクロヘキサンカルボンヒドロ
キサム酸誘導体またはその薬学的に許容し得る塩を有効
成分とする抗潰瘍剤などとして有効な酵素阻害剤を提供
せんとするものである。That is, the present invention relates to the general formula (N (wherein R1 represents an alkyl, aryl, or aralkyl group having 1 to 5 carbon atoms in H1, and R2 and R3 are the same or different and represent an alkyl group in H1 having 1 to 5 carbon atoms, guanyl). basis,
Alternatively, it represents an aryl group or an aralkyl group that may have a substituent. However, R2 and R3 do not become H at the same time. It is an object of the present invention to provide an enzyme inhibitor which is effective as an anti-ulcer agent and contains a cyclohexanecarbonhydroxamic acid derivative represented by () or a pharmaceutically acceptable salt thereof as an active ingredient.
上記薬学的に許容し得る塩としては、アミノ基部分の塩
として、例えば、塩酸塩、臭化水素塩、硫酸塩などの無
機酸塩、コハク酸塩、クエン酸塩、トルエンスルホン酸
塩等の有機酸塩を挙げることができ、また、ヒドロキサ
ム酸の塩としては、例えば、ナトリウム、カリウム等の
無機金属塩や、トリエチルアミン、ピリジン等の有機塩
を挙げることができる。Examples of the above pharmaceutically acceptable salts include salts of the amino group, such as inorganic acid salts such as hydrochloride, hydrobromide, and sulfate, succinate, citrate, and toluenesulfonate. Examples of hydroxamic acid salts include inorganic metal salts such as sodium and potassium salts, and organic salts such as triethylamine and pyridine.
一般式（１）で示される新規ヒドロキサム酸誘導体には
、シス−トランス異性体が含まれるが、トランス体が特
に好ましい。一般式（Ｉ）におけるＲ’ としては、水
素原子の他に、例えばメチル基、エチル基、イソプロピ
ル基、ｔ−ブチル基などのような炭素数１から５までの
アルキル基、例えばフェニル基、ナフチル基、トルイル
基などのようなアリール基、例えばベンジル基、フェニ
ルエチル基、ｐ−メチルベンジル基などのようなアルキ
ル部分の炭素数が１から５までのアラルキル基などが挙
げられる。また、Ｒ２およびＲ３としては、水素原子、
グアニル基の他に、例えばメチル基、エチル基、イソプ
ロピル基、ｔ −ブチル基などのような炭素数１から５
までのアルキル基、例えばフェニル基、ナフチル基、ト
ルイル基などのようなアリール基、例えばベンジル基、
フェニルエチル基、Ｐ−メチルベンジル基などのような
アルキル部分の炭素数が１から５までのアラルキル基な
どが挙げられる。この場合、アリール基およびアラルキ
ル基は官能基を有してもよく、官能基としては、−置換
から三置換までの、例えば、フッ素基、塩素基、臭素基
などのようなノ１０ゲン基、例えばメトキシ基、エトキ
シ基、イソプロポキシ基などのような炭素数１から５ま
でのアルコキシ基、カルボキシル基、アミノ基、ニトロ
基、アミノカルボニル基などが挙げられる。The novel hydroxamic acid derivative represented by the general formula (1) includes cis-trans isomers, but the trans isomer is particularly preferred. R' in general formula (I) includes, in addition to a hydrogen atom, an alkyl group having 1 to 5 carbon atoms such as a methyl group, an ethyl group, an isopropyl group, a t-butyl group, an example is a phenyl group, a naphthyl group, etc. Examples include aryl groups such as a tolyl group, a tolyl group, and an aralkyl group in which the alkyl moiety has 1 to 5 carbon atoms, such as a benzyl group, a phenylethyl group, a p-methylbenzyl group, and the like. Moreover, as R2 and R3, a hydrogen atom,
In addition to the guanyl group, there are 1 to 5 carbon atoms, such as methyl, ethyl, isopropyl, t-butyl, etc.
Alkyl groups such as phenyl, naphthyl, tolyl, etc., aryl groups such as benzyl,
Examples include aralkyl groups in which the alkyl moiety has 1 to 5 carbon atoms, such as phenylethyl group and P-methylbenzyl group. In this case, the aryl group and the aralkyl group may have a functional group, and examples of the functional group include -substituted to trisubstituted groups such as fluorine, chlorine, bromine, etc. Examples include alkoxy groups having 1 to 5 carbon atoms such as methoxy, ethoxy, and isopropoxy groups, carboxyl groups, amino groups, nitro groups, and aminocarbonyl groups.
一般式（１）の本発明化合物は、次式（ＩＩ）（式中、
ＲＺ、Ｒ３は前述と同意味を表す。）で示されるアミノ
メチルシクロヘキサンカルボン酸またはその反応性誘導
体に、次式（Ｉ［［）％式％（）
（式中、Ｒ１は前述と同意味を表す。）で示される化合
物と反応させるか、あるいはＮＨ２ＯＨで示されるヒド
ロキシルアミンと反応させた後、さらに次式（ＩＶ）
Ｒ’−Ｈａ ｌ （ＩＶ）
（式中、Ｒ１は前述と同意味を表し、Ｈａｌはハロゲン
原子を表す。）
で示される化合物を反応させることによって製造される
。The compound of the present invention of general formula (1) has the following formula (II) (wherein,
RZ and R3 represent the same meanings as above. ), or a reactive derivative thereof, is reacted with a compound represented by the following formula (I[[)% formula%() (wherein R1 represents the same meaning as above). , or after reacting with hydroxylamine represented by NH2OH, the following formula (IV) R'-Hal (IV) (wherein, R1 represents the same meaning as above, and Hal represents a halogen atom) Produced by reacting the indicated compounds.
削代（ｎ）のアミノメチルシクロヘキサンカルボン酸の
反応性誘導体としては、酸クロリド、酸プロミドなどの
酸ハライド、混合酸無水物、メチル、エチル、フェニル
、ｐ−ニトロフェニルエステル、２，４−ジニトロフェ
ニルエステルなどのエステル誘導体が挙げられるが、操
作の簡便さ、反応選択性および収率の向上のために、メ
チル、エチルなどのような低級アルキルエステル誘導体
が望ましい。Reactive derivatives of aminomethylcyclohexanecarboxylic acid for cutting allowance (n) include acid halides such as acid chloride and acid bromide, mixed acid anhydrides, methyl, ethyl, phenyl, p-nitrophenyl ester, 2,4-dinitro Examples include ester derivatives such as phenyl ester, but lower alkyl ester derivatives such as methyl, ethyl, etc. are preferred for ease of operation, improvement in reaction selectivity, and yield.
削代（ＩＩ）のアミノメチルシクロヘキサンカルボン酸
の反応性誘導体と削代（ＩＩ［）の化合物との反応は、
反応に不活性な溶媒の存在下に実施されるが、溶媒とし
ては、メタノール、エタノール、ＴＨＦ、１，４−ジオ
キサンが好ましい。この場合、前代（ＩＩ［）の化合物
の使用量は、アミノメチルシクロヘキサンカルボン酸誘
導体に対して１〜１０当量、特に好ましくは１〜３当量
である。反応温度は、例えば−５０°Ｃ−１５０°Ｃ１
好ましくは副反応を抑制するため、−１０″Ｃ〜４０°
Ｃで行われる。The reaction between the reactive derivative of aminomethylcyclohexanecarboxylic acid in the cutting allowance (II) and the compound in the cutting allowance (II[) is as follows:
The reaction is carried out in the presence of a solvent inert to the reaction, and methanol, ethanol, THF, and 1,4-dioxane are preferred as the solvent. In this case, the amount of the compound (II[) used is 1 to 10 equivalents, particularly preferably 1 to 3 equivalents, relative to the aminomethylcyclohexanecarboxylic acid derivative. The reaction temperature is, for example, -50°C-150°C1
Preferably -10"C to 40° to suppress side reactions.
It is done in C.
削代（ＩＶ）の化合物によるアルキル化反応は、反応に
不活性な溶媒の存在下に実施されるが、溶媒としては、
ＴＨＦ、１．４−ジオキサンが好ましい。この場合、削
代（ＩＶ）の化合物の使用量は、アミノメチルシクロヘ
キサンカルボンヒドロキサム酸誘導体に対して１〜１０
当量、特に好ましくは１〜３当量である。反応温度は、
例えば−５０°Ｃ〜１５０℃、好ましくは副反応を抑制
するため、−１０”Ｃ〜４０°Ｃで行われる。この場合
、反応の選択性、収率の向上のために、求核性のない２
級あるいは３級塩基、例えば、トリエチルアミン、ジイ
ソプロピルアミン、ピリジンなどの有機塩基の存在下行
うのが望ましく、この場合、有機塩基の使用量は、アミ
ノメチルシクロヘキサンカルボンヒドロキサム酸誘導体
に対して１〜１０当量、特に好ましく１〜３当量である
。The alkylation reaction using the compound of cutting allowance (IV) is carried out in the presence of a solvent inert to the reaction, but as a solvent,
THF and 1,4-dioxane are preferred. In this case, the amount of the compound used as the cutting allowance (IV) is 1 to 10% relative to the aminomethylcyclohexanecarbonhydroxamic acid derivative.
equivalents, particularly preferably 1 to 3 equivalents. The reaction temperature is
For example, the temperature is -50°C to 150°C, preferably -10"C to 40°C to suppress side reactions. In this case, in order to improve reaction selectivity and yield, nucleophilic No 2
It is preferable to carry out the reaction in the presence of an organic base such as a grade or tertiary base such as triethylamine, diisopropylamine, or pyridine. , particularly preferably 1 to 3 equivalents.
次に、酵素阻害活性測定法を説明する。Next, a method for measuring enzyme inhibitory activity will be explained.
１）抗プラスミン活性の測定
阻害剤を０．０５Ｍトリス塩酸緩衝液（ｐ Ｈ７゜５）
に溶解して全体を０．４ｄとし、ここへ基質である１、
１５ｍＭのＳ−２２５１溶液を０． １−加え、３７°
Ｃの恒温槽中で５分間インキュベーションし、ヒトプラ
スミン溶液０．１ｍｌを添加し、３７°Ｃで１０分間反
応させる。２％クエン酸溶液２ＩＩｄｌを加えて反応を
停止した後、生成したバラニトロアニリンの吸光度を４
０５ ｎｍで測定し、阻害剤無しの時の５０％の吸光度
を示す阻害剤の濃度をＩＣ３゜として求めた。1) Measurement of anti-plasmin activity The inhibitor was added to 0.05M Tris-HCl buffer (pH 7°5).
The substrate 1,
15mM S-2251 solution was added to 0. 1-Add, 37°
Incubate for 5 minutes in a constant temperature bath at 37°C, add 0.1 ml of human plasmin solution, and react at 37°C for 10 minutes. After stopping the reaction by adding 2 dl of 2% citric acid solution, the absorbance of the produced varanitroaniline was reduced to 4
The concentration of the inhibitor was measured at 0.05 nm, and the concentration of the inhibitor at which the absorbance was 50% of that in the absence of the inhibitor was determined as IC3°.
２） 抗カリクレイン活性の測定
阻害剤を０．０５Ｍ１−リス塩酸緩衝液（ｐＨ７゜５）
に溶解して全体を０．４ｄとし、ここへ８２３０２の１
．１５ｍＭ溶液０．１１ｄを加え、３７℃の恒温槽中で
５分間インキュベーションし、ブタの膵臓カリクレイン
０．１ユニット／ＮＩＲＫＯ０１−を添加し、３７°Ｃ
で１０分間インキュベーションした後、２％クエン酸溶
液を加え反応を停止する。生成したバラニトロアニリン
の吸光度を４０５ｎｍで測定し、阻害剤無しの時の５０
％の吸光度を示す阻害剤の濃度をＩＣ，、として求めた
。2) Measurement of anti-kallikrein activity The inhibitor was added to 0.05M 1-Lis-HCl buffer (pH 7.5).
Melt it to make the whole 0.4d, and add 1 of 82302 here.
．． Add 0.11 d of 15mM solution, incubate for 5 minutes in a constant temperature bath at 37°C, add 0.1 units of porcine pancreatic kallikrein/NIRKO01-, and incubate at 37°C.
After incubation for 10 minutes, 2% citric acid solution is added to stop the reaction. The absorbance of the produced varanitroaniline was measured at 405 nm, and the absorbance of 50 nm without inhibitor was measured.
The concentration of the inhibitor exhibiting % absorbance was determined as IC, .
３）抗ウレアーゼ活性の測定
阻害剤を０．０５Ｍリン塩酸緩衝液（ｐＨ７゜０）に溶
解して全体を０．５ｄとし、尿素の５０ｍＭ水溶液０．
１ｄを加え、３７°Ｃの恒温槽中で５分間インキュベー
ションし、５３μｇ／ｌＲ１１のウレアーゼ溶液（バチ
ルス属細菌由来）を加え、３７°Ｃで１０分間反応させ
る。９０°Ｃで５分間熱処理した後、インドフェノール
法によって生成したアンモニアを定量する。阻害剤無し
の時の５０％のアンモニア生成を示すときの阻害剤濃度
をＩＣ３゜とじて求めた。3) Measurement of anti-urease activity The inhibitor was dissolved in 0.05M phosphate-hydrochloric acid buffer (pH 7.0) to make a total of 0.5d, and a 50mM aqueous solution of urea was added to 0.5d.
1d and incubate for 5 minutes in a constant temperature bath at 37°C, add 53 μg/l R11 urease solution (derived from Bacillus bacteria), and react at 37°C for 10 minutes. After heat treatment at 90°C for 5 minutes, the ammonia produced is determined by the indophenol method. The inhibitor concentration at which ammonia production was 50% of that in the absence of the inhibitor was determined by dividing the IC3°.
表１に本発明の化合物（実施例１〜３に記載の化合物１
〜３）および対照物質の酵素阻害活性を示す。（ＩＣ，
。： ｍＭ）
表１に示すように、本発明の化合物は、強力な蛋白分解
酵素阻害活性を有するだけでなく、きわめて強力な抗ウ
レアーゼ活性を有していることがわかる。Table 1 shows the compounds of the present invention (compound 1 described in Examples 1 to 3).
~3) and the enzyme inhibitory activity of control substances. (IC,
. :mM) As shown in Table 1, it can be seen that the compounds of the present invention not only have strong protease inhibitory activity, but also extremely strong anti-urease activity.
表１
ぞれの損傷を実体顕微鏡（１０倍率）で観察し、その長
さの総和（ｍｍ）を以て潰瘍係数とし、下記の式により
抑制率を算出する。なお、被験薬剤は塩酸エタノール投
与３０分前に経口投与する。Table 1 Each lesion was observed with a stereomicroscope (10x magnification), the sum of the lengths (mm) was used as the ulcer coefficient, and the inhibition rate was calculated using the following formula. The test drug is orally administered 30 minutes before the administration of hydrochloric acid and ethanol.
抑制率（χ）＝
次に、本発明の化合物が消化性潰瘍の治療に有効である
ことを示すために、実験潰瘍である塩酸エタノール潰瘍
に対する効果を検討した。以下に実験方法と結果（表２
）を示す。Inhibition rate (χ) = Next, in order to demonstrate that the compounds of the present invention are effective in treating peptic ulcers, the effects on hydrochloric acid ethanol ulcers, which are experimental ulcers, were investigated. Below are the experimental methods and results (Table 2
) is shown.
体重１８０ｇ前後のＳＤ系雄性う・ントを１群８匹とし
、２４４時間絶した後、１５０ｍＭ・６０％エタノール
ｌｄ／匹を経口投与する。塩酸エタノール投与１時間後
に、脱血致死させて胃を摘出し、２％ホルマリン液１０
１１１！を胃内に注入後、さらに固液に１０分間浸し、
軽度に固定する。胃を天竜に沿って切開し、腺胃部に発
生しているそれ表２
塩酸エタノール潰瘍モデルに対して、本発明の前記一般
式（Ｉ）で示される化合物から選ばれた化合物が強力な
防御因子増強作用により潰瘍生成を抑制していることは
、表２の結果より明らかに示されている。A group of 8 male SD animals weighing around 180 g were starved for 244 hours, and then 150 mM 60% ethanol was orally administered per animal. One hour after administration of hydrochloric acid and ethanol, the patient was sacrificed by exsanguination, the stomach was removed, and 10% of 2% formalin solution was added.
111! After injecting into the stomach, immerse it in a solid liquid for 10 minutes,
Fix lightly. The stomach was incised along the tenryu, and a compound selected from the compounds represented by the general formula (I) of the present invention showed strong protection against the hydrochloric acid ethanol ulcer model. The results in Table 2 clearly show that ulcer formation is suppressed by the factor-enhancing effect.
次に、急性毒性試験について述べる。Next, we will discuss the acute toxicity test.
体重２５ｇ前後のｄｄＹ系雄性マウスを１群５匹とし、
６時間絶食後使用した。被験薬物は水溶液または０．５
％に懸濁させ、０．２１Ｒ１／Ｌｏｇの容量で経口投与
した。投与後の一般症状および死亡発現の有無を７日間
観察した。表３に結果を示すが、本発明の一般式（１）
で示される化合物から選ばれた化合物は、２０００■／
ｋｇの投与により、いずれも死亡例がなく、中毒症状も
認められないことから、ＬＤ、。値は２０００■／ｋｇ
以上と極めて安全性の高い薬物であると推定された。A group of 5 male ddY mice weighing around 25 g,
It was used after fasting for 6 hours. The test drug is an aqueous solution or 0.5
% and administered orally at a volume of 0.21 R1/Log. After administration, general symptoms and the presence or absence of death were observed for 7 days. The results are shown in Table 3, and the general formula (1) of the present invention
The compound selected from the compounds shown is 2000■/
LD, because there were no deaths and no symptoms of toxicity were observed after administration of 1.5 kg. The value is 2000■/kg
Based on the above, it was estimated that the drug was extremely safe.
表３
以上の結果より、本発明の化合物は、酵素阻害剤特に抗
潰瘍剤として有用である。さらに、抗ウレアーゼ活性を
有することから、胃粘膜においてカンピロバクタ−由来
のウレアーゼを阻害し、胃粘膜を防御し、潰瘍の再発や
慢性化の抑制効果も期待できる。Table 3 From the above results, the compounds of the present invention are useful as enzyme inhibitors, particularly as antiulcer agents. Furthermore, since it has anti-urease activity, it can be expected to inhibit Campylobacter-derived urease in the gastric mucosa, protect the gastric mucosa, and suppress ulcer recurrence and chronicity.
一般式（Ｉ）の化合物またはその塩を抗潰瘍剤として用
いる場合、投与形態としては、経口投与あるいは非経口
投与のいずれでもよい。投与量は投与方法、症状、年令
などにより異なるが、一般式（Ｉ）の化合物として、１
同量約０．１〜３０■／ｋｇ体重程度、１日１〜３回程
度投与するのが望ましい。一般式（１）の化合物または
その塩は、通常、製剤用担体として調製した製剤の形で
投与される。When the compound of general formula (I) or a salt thereof is used as an antiulcer agent, the administration mode may be either oral or parenteral administration. The dosage varies depending on the administration method, symptoms, age, etc., but as a compound of general formula (I), 1
It is desirable to administer the same amount of about 0.1 to 30 cm/kg body weight, about 1 to 3 times a day. The compound of general formula (1) or a salt thereof is usually administered in the form of a preparation prepared as a pharmaceutical carrier.
製剤用担体としては、製剤分野において常用され、かつ
、一般式（１）の化合物またはその塩と反応しない物質
、例えば、ゼラチン、乳糖、デンプン、結晶セルロース
、カルボキシメチルセルロース、植物油、軽質無水ケイ
酸、プロピレングリコールなどがあげられる。Pharmaceutical carriers include substances that are commonly used in the pharmaceutical field and do not react with the compound of general formula (1) or its salts, such as gelatin, lactose, starch, crystalline cellulose, carboxymethyl cellulose, vegetable oil, light silicic anhydride, Examples include propylene glycol.
剤型としては、錠剤、カプセル剤、顆粒剤、散在などの
固体製剤、またはシロップ、エリキシル剤、注射剤など
の液体製剤などが挙げられる。これらの製剤は、常法に
したがって調製される。また、錠剤は周知の方法でコー
ティングしてもよい。Dosage forms include solid preparations such as tablets, capsules, granules, and scatterings, and liquid preparations such as syrups, elixirs, and injections. These formulations are prepared according to conventional methods. Tablets may also be coated using known methods.
注射剤の場合には、一般式（Ｉ）の化合物またはその塩
を水に溶解させて調製するが、必要に応じて生理食塩水
あるいはブドウ糖溶液に溶解させてもよい。In the case of an injection, the compound of general formula (I) or a salt thereof is prepared by dissolving it in water, but if necessary, it may be dissolved in physiological saline or glucose solution.
（実施例）
実施例１
ｔ−４−グアニルメチルシクロヘキサンカルボンヒドロ
キサム酸・塩酸塩（化合物１）の合成ヒドロキシアミン
塩酸塩１．７５ｇ （２４，４ｍｍｏｌ）をメタノール
１５１Ｅｉ！に溶解し、これに水酸化カリウム２．６５
ｇ （４０，３ｍｍｏｌ）のメタノール溶液１０１ｄを
加えた。析出した結晶を濾過し、その濾液にエチル−ｔ
−４−グアニルメチルシクロヘキサンカルボン酸エステ
ル３．０ｇ （１２゜２ｍｍｏｌ）のメタノール１５ｄ
溶液を滴下した。２時間室温で攪拌後、析出した結晶を
濾集し、エタノールに溶解し、濃塩酸を加えた後に濃縮
した。(Example) Example 1 Synthesis of t-4-guanylmethylcyclohexanecarbonhydroxamic acid hydrochloride (Compound 1) 1.75 g (24.4 mmol) of hydroxyamine hydrochloride was mixed with 151 Ei of methanol! 2.65% of potassium hydroxide is dissolved in this.
A methanol solution 101d of g (40.3 mmol) was added. The precipitated crystals were filtered, and the filtrate was added with ethyl-t.
-4-guanylmethylcyclohexanecarboxylic acid ester 3.0g (12゜2mmol) methanol 15d
The solution was added dropwise. After stirring at room temperature for 2 hours, the precipitated crystals were collected by filtration, dissolved in ethanol, and concentrated after addition of concentrated hydrochloric acid.
これを熱水から再結し、結晶を真空乾燥して、ｔ−４−
グアニルメチルシクロヘキサンカルボンヒドロキサム酸
・塩酸塩２． ６９ｇ （１０，８＋＊ｍ。This is re-crystallized from hot water, the crystals are vacuum dried, and t-4-
Guanylmethylcyclohexanecarbonhydroxamic acid hydrochloride 2. 69g (10,8+*m.
ｌ）を収率８８．１％で得た。1) was obtained in a yield of 88.1%.
Ｉ Ｒ（ＫＢ ｒ ） ： ３３５０．３２００．２
９３０．１６６５゜１６５０ １４８０ｃｍ−’
ＮＭＲ（ＤＭＳＯｄｈ）：０．５−２．５（ｍ、ｌ０Ｈ
）＋ ３゜００（ｍ、２Ｈ）、 ７．２２（ｓ、５
Ｈ）、 ７．８８（ｂ、ＬＨ）、 １０．４０（ｓ
、ＬＨ）
塩化第二鉄呈色反応：陽性
実施例２
ｔ−４−ベンジルアミノメチルシクロヘキサンカルボン
ヒドロキサム酸（化合物２）の合成ヒドロキシアミン塩
酸塩１．７５ｇ （２４，４ｍｍｏ ｌ ）をメタノー
ル１５ｄに溶解し、これに水酸化カリウム２． ６５
ｇ （４０，３ｍｍｏｌ）のメタノール溶液１０ａ２を
加えた。析出した結晶を濾過し、その濾液にエチル−ｔ
−４−ベンジルアミノメチルシクロヘキサンカルポン酸
エステル３．３６ｇ（１２，２ｎ＋ｍｏｌ）のメタノー
ル１５ｄ溶液を滴下した。２時間室温で攪拌後、析出し
た結晶を濾集し、エタノールに溶解し、濃塩酸を加え、
ｐＨ２にした後に濃縮した。これをメタノール−ヘキサ
ンから再結し、結晶を真空乾燥して、ｔ−４−ベンジル
アミノメチルシクロヘキサンカルボンヒドロキサム酸２
． ９５ ｇ （１１，２６ｔｍｏｌ）を収率９２．３
％で得た。IR(KBr): 3350.3200.2
930.1665°1650 1480cm-' NMR (DMSOdh): 0.5-2.5 (m, 10H
) + 3゜00 (m, 2H), 7.22 (s, 5
H), 7.88 (b, LH), 10.40 (s
, LH) Ferric chloride color reaction: Positive example 2 Synthesis of t-4-benzylaminomethylcyclohexanecarbonhydroxamic acid (compound 2) 1.75 g (24.4 mmol) of hydroxyamine hydrochloride was dissolved in 15 d of methanol. Add potassium hydroxide to this 2. 65
A methanol solution 10a2 of g (40.3 mmol) was added. The precipitated crystals were filtered, and the filtrate was added with ethyl-t.
A methanol 15d solution of 3.36 g (12.2 n+mol) of -4-benzylaminomethylcyclohexanecarboxylic acid ester was added dropwise. After stirring at room temperature for 2 hours, the precipitated crystals were collected by filtration, dissolved in ethanol, and concentrated hydrochloric acid was added.
After adjusting the pH to 2, it was concentrated. This was recrystallized from methanol-hexane, the crystals were dried under vacuum, and t-4-benzylaminomethylcyclohexanecarbonhydroxamic acid 2
．． 95 g (11,26 tmol) with a yield of 92.3
Obtained in %.
Ｉ Ｒ（Ｋ Ｂ ｒ ） ： ３３５０．３１８０．
２９３０．１６６５゜１６２０、１５００．１４５０．
１４３０ｃｍ−’ＮＭＲ（ＤＭＳＯ−ｄｈ）：０．５−
２．３軸、ＩＩＨ）、 ２゜８０（ｄ、２Ｈ）、 ３．
７３（ｓ、２Ｈ）、 ７．２２（ｓ、５Ｈ）、 ８．０
０（ｂ、１１（）。I R (K B r ): 3350.3180.
2930.1665°1620, 1500.1450.
1430cm-'NMR (DMSO-dh): 0.5-
2.3 axis, IIH), 2°80 (d, 2H), 3.
73 (s, 2H), 7.22 (s, 5H), 8.0
0(b, 11().
１０．３５（ｓ、１Ｂ）
塩化第二鉄呈色反応：陽性
実施例３
ｔ−４−ジベンジルアミノメチルシクロヘキサンカルボ
ンヒドロキサム酸（化合物３）の合成ヒドロキシアミン
塩酸塩１．７５ｇ （２４，４ｍｍｏｌ）をメタノール
１５ＩＲ１に溶解し、これに水酸化カリウム２． ６５
ｇ （４０，３ｍｍｏｌ）のメタノール溶液１０１ｄ
を加えた。析出した結晶を濾過し、その濾液にエチル−
ｔ−４−ジベンジルアミノメチルシクロヘキサンカルポ
ン酸エステル３．４６ｇ （１２，２＋ｎｍｏｌ）のメ
タノール１５Ｎ１溶液を滴下した。２時間室温で攪拌後
、析出した結晶を濾集し、エタノールに溶解し、濃塩酸
を加え、ｐＨ２にした後に濃縮した。これをメタノール
−ヘキサンから再結し、結晶を真空乾燥して、ｔ−４−
ジベンジルアミノメチルシクロヘキサンカルボンヒドロ
キサム酸４． ０９ｇ （１１，５９ａ＋ｍｏｌ）を収
率９５．０％で得た。10.35 (s, 1B) Ferric chloride color reaction: Positive Example 3 Synthesis of t-4-dibenzylaminomethylcyclohexanecarbonhydroxamic acid (Compound 3) Hydroxyamine hydrochloride 1.75 g (24.4 mmol) was dissolved in methanol 15IR1, and potassium hydroxide 2. 65
methanol solution 101d of g (40.3 mmol)
added. The precipitated crystals were filtered, and the filtrate was added with ethyl
A solution of 3.46 g (12,2+nmol) of t-4-dibenzylaminomethylcyclohexanecarboxylic acid ester in 15N1 methanol was added dropwise. After stirring at room temperature for 2 hours, the precipitated crystals were collected by filtration, dissolved in ethanol, concentrated hydrochloric acid was added, the pH was adjusted to 2, and the mixture was concentrated. This was re-crystallized from methanol-hexane, the crystals were dried in vacuo, and t-4-
Dibenzylaminomethylcyclohexanecarbonhydroxamic acid4. 09g (11,59a+mol) was obtained in a yield of 95.0%.
Ｉ Ｒ（ＫＢ ｒ ） ： ３３４０．３１８５．２
９３０．１６６５゜１６２０、 １６００． １５００
． １４５０． １４３０ｃｍ−’ＮＭ Ｒ（Ｄ Ｍ
Ｓ Ｏｄ ６） ： ０．５−２．３（ｍ、］、ＯＨ）
、２゜８３（ｄ、２Ｈ）、３．７８（ｓ、４Ｈ）、７．
２２（ｓ、ｌ０Ｈ）、８．１０（ｂ、ＩＨ）、 １０
．４０（ｓ、ＩＨ）
塩化第二鉄呈色反応：陽性
実施例４（錠剤の製剤例）
ｔ−４−グアニルメチルシクロヘキサンカルボンヒドロ
キサム酸・塩酸塩 ・・・・・１００■軽質無水ケイ
酸 ・・・・・１００■結晶セルロース
・・・・・ ５０■カルボキシメチルセルロ
ースカルシウム・・・・ ２５■
タルク ４■乳糖
・・・・・６９■
ステアリン酸マグネシウム ・・・・・ ２■常法に
したがって、上記各成分を混和して顆粒状とし、圧縮成
型して１錠３５０■の錠剤を製造した。IR(KBr): 3340.3185.2
930.1665°1620, 1600. 1500
．． 1450. 1430cm-'NM R(DM
S Od 6): 0.5-2.3 (m, ], OH)
, 2°83 (d, 2H), 3.78 (s, 4H), 7.
22 (s, 10H), 8.10 (b, IH), 10
．． 40 (s, IH) Ferric chloride color reaction: Positive Example 4 (Tablet formulation example) t-4-guanylmethylcyclohexanecarbonhydroxamic acid hydrochloride...100 ■Light silicic anhydride... ...100■Crystalline cellulose
... 50 ■ Carboxymethyl cellulose calcium ... 25 ■ Talc 4 ■ Lactose
...69 ■ Magnesium stearate ... 2 ■ According to a conventional method, the above ingredients were mixed into granules, and the mixture was compression molded to produce tablets of 350 cm each.
（発明の効果）
本発明で得られる酵素阻害剤の有効成分である前記一般
式（Ｉ）のシクロヘキサンカルボンヒドロキサム酸誘導
体は、前記の実験結果から明らかなとおり、プラスミン
、カリクレインおよびウレアーゼに対し非常に強力な阻
害活性を有する。本発明の化合物は、従来公知の薬剤、
例えば、セトラキサートやトラネキサム酸と異なり、蛋
白分解酵素だけでなくウレアーゼも強力に阻害する。し
たがって、本発明で得られる酵素阻害剤は、止血剤、抗
炎症剤としてだけでなく新しい機能、すなわち、胃粘膜
におけるカンピロバクタ−由来のウレアーゼを阻害し、
防御する機能をもった抗潰瘍剤としても極めて有用であ
る。(Effects of the Invention) As is clear from the above experimental results, the cyclohexanecarbonhydroxamic acid derivative of the general formula (I), which is the active ingredient of the enzyme inhibitor obtained in the present invention, is highly effective against plasmin, kallikrein, and urease. Has strong inhibitory activity. The compound of the present invention is a conventionally known drug,
For example, unlike cetraxate and tranexamic acid, it strongly inhibits not only proteolytic enzymes but also urease. Therefore, the enzyme inhibitor obtained in the present invention not only acts as a hemostatic agent and an anti-inflammatory agent, but also has new functions, namely, inhibits Campylobacter-derived urease in the gastric mucosa,
It is also extremely useful as an anti-ulcer agent with a protective function.
本発明は、詳細に、かつ、特にその具体化においては実
施例をもって述べてきたが、本発明の精神と範囲から外
れることがないならば、本発明のなかで各種の変化や変
更ができることは、この技術分野の者には明らかであろ
う。Although the present invention has been described in detail and particularly with reference to embodiments thereof, various changes and modifications may be made thereto without departing from the spirit and scope of the invention. , should be obvious to those skilled in this technical field.
手続補正書 平成３年 ７月１８日Procedural amendment July 18, 1991
Claims (3)
ルあるいはアラルキルを表し、Ｒ＾２、Ｒ＾３は同一ま
たは異なってＨ、炭素数１から５のアルキル基、グアニ
ル基、あるいは置換基を有してもよいアリール基または
アラルキル基を表す。ただし、Ｒ＾２およびＲ＾３が同
時にＨにはならない。）で示されるシクロヘキサンカル
ボンヒドロキサム酸誘導体または薬学的に許容し得る塩
。(1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 represents H, alkyl, aryl, or aralkyl having 1 to 5 carbon atoms, R^2, R ^3 are the same or different and represent H, an alkyl group having 1 to 5 carbon atoms, a guanyl group, or an aryl group or aralkyl group which may have a substituent.However, R^2 and R^3 are simultaneously H ) or a pharmaceutically acceptable salt thereof.
ルあるいはアラルキルを表し、Ｒ＾２、Ｒ＾３は同一ま
たは異なってＨ、炭素数１から５のアルキル基、グアニ
ル基、あるいは置換基を有してもよいアリール基または
アラルキル基を表す。ただし、Ｒ＾２およびＲ＾３が同
時にＨにはならない。）で示されるシクロヘキサンカル
ボンヒドロキサム酸誘導体または薬学的に許容し得る塩
を有効成分として含有する酵素阻害剤。(2) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 represents H, alkyl, aryl, or aralkyl having 1 to 5 carbon atoms, R^2, R ^3 are the same or different and represent H, an alkyl group having 1 to 5 carbon atoms, a guanyl group, or an aryl group or aralkyl group which may have a substituent.However, R^2 and R^3 are simultaneously H An enzyme inhibitor containing a cyclohexanecarbonhydroxamic acid derivative or a pharmaceutically acceptable salt as an active ingredient.
ルあるいはアラルキルを表し、Ｒ＾２、Ｒ＾３は同一ま
たは異なってＨ、炭素数１から５のアルキル基、グアニ
ル基、あるいは置換基を有してもよいアリール基または
アラルキル基を表す。ただし、Ｒ＾２およびＲ＾３が同
時にＨにはならない。）で示されるシクロヘキサンカル
ボンヒドロキサム酸誘導体または薬学的に許容し得る塩
を有効成分として含有する抗潰瘍剤。(3) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 represents H, alkyl, aryl, or aralkyl having 1 to 5 carbon atoms, R^2, R ^3 are the same or different and represent H, an alkyl group having 1 to 5 carbon atoms, a guanyl group, or an aryl group or aralkyl group which may have a substituent.However, R^2 and R^3 are simultaneously H An anti-ulcer agent containing a cyclohexanecarbonhydroxamic acid derivative or a pharmaceutically acceptable salt as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2106517A JPH045269A (en) | 1990-04-24 | 1990-04-24 | Cyclohexane carbohydroxamic acid derivative, enzyme inhibitor and anti-ulcer agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2106517A JPH045269A (en) | 1990-04-24 | 1990-04-24 | Cyclohexane carbohydroxamic acid derivative, enzyme inhibitor and anti-ulcer agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH045269A true JPH045269A (en) | 1992-01-09 |
Family
ID=14435603
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2106517A Pending JPH045269A (en) | 1990-04-24 | 1990-04-24 | Cyclohexane carbohydroxamic acid derivative, enzyme inhibitor and anti-ulcer agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH045269A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102056403A (en) * | 2009-10-26 | 2011-05-11 | 株式会社电装 | Printed wiring board |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6197064U (en) * | 1980-04-05 | 1986-06-21 |
-
1990
- 1990-04-24 JP JP2106517A patent/JPH045269A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6197064U (en) * | 1980-04-05 | 1986-06-21 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102056403A (en) * | 2009-10-26 | 2011-05-11 | 株式会社电装 | Printed wiring board |
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