JPH036138B2 - - Google Patents
Info
- Publication number
- JPH036138B2 JPH036138B2 JP16882181A JP16882181A JPH036138B2 JP H036138 B2 JPH036138 B2 JP H036138B2 JP 16882181 A JP16882181 A JP 16882181A JP 16882181 A JP16882181 A JP 16882181A JP H036138 B2 JPH036138 B2 JP H036138B2
- Authority
- JP
- Japan
- Prior art keywords
- insulin
- ascochlorin
- mmol
- diabetes
- ethanol
- 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
- SETVRSKZJJWOPA-FLDGXQSCSA-N ascochlorin Chemical class C[C@@H]1CCC(=O)[C@H](C)[C@@]1(C)\C=C\C(\C)=C\CC1=C(O)C(Cl)=C(C)C(C=O)=C1O SETVRSKZJJWOPA-FLDGXQSCSA-N 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000005359 phenoxyalkyl group Chemical group 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- SHZXWVNJUPKTJN-UHFFFAOYSA-N Ascochlorin Natural products CC1CCC(=O)C(C)C1C=CC(C)=CCC1=C(O)C(Cl)=C(C)C(C=O)=C1O SHZXWVNJUPKTJN-UHFFFAOYSA-N 0.000 description 24
- 102000004877 Insulin Human genes 0.000 description 24
- 108090001061 Insulin Proteins 0.000 description 24
- 206010012601 diabetes mellitus Diseases 0.000 description 24
- 229940125396 insulin Drugs 0.000 description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 15
- 239000013078 crystal Substances 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- 238000000921 elemental analysis Methods 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000029142 excretion Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 230000002485 urinary effect Effects 0.000 description 5
- 241000725101 Clea Species 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 208000004880 Polyuria Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 210000000577 adipose tissue Anatomy 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 3
- 201000008980 hyperinsulinism Diseases 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 230000003914 insulin secretion Effects 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 208000031225 myocardial ischemia Diseases 0.000 description 3
- 206010036067 polydipsia Diseases 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 3
- 229960001052 streptozocin Drugs 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- -1 33 parts Substances 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 206010022489 Insulin Resistance Diseases 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
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- HIMXGTXNXJYFGB-UHFFFAOYSA-N alloxan Chemical compound O=C1NC(=O)C(=O)C(=O)N1 HIMXGTXNXJYFGB-UHFFFAOYSA-N 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 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
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 201000010063 epididymitis Diseases 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 235000012631 food intake Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000013632 homeostatic process Effects 0.000 description 2
- VIPHVHVAGBKHGR-UHFFFAOYSA-N hydron;pyridine-2-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CC=N1 VIPHVHVAGBKHGR-UHFFFAOYSA-N 0.000 description 2
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 2
- BNTRVUUJBGBGLZ-UHFFFAOYSA-N hydron;pyridine-4-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=NC=C1 BNTRVUUJBGBGLZ-UHFFFAOYSA-N 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 235000019626 lipase activity Nutrition 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
- OFCCYDUUBNUJIB-UHFFFAOYSA-N n,n-diethylcarbamoyl chloride Chemical compound CCN(CC)C(Cl)=O OFCCYDUUBNUJIB-UHFFFAOYSA-N 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- AWFYPPSBLUWMFQ-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=C2 AWFYPPSBLUWMFQ-UHFFFAOYSA-N 0.000 description 1
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 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
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- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
- 241000222195 Ascochyta Species 0.000 description 1
- VGYPZLGWVQQOST-UHFFFAOYSA-N Ascofuranone Natural products OC=1C(Cl)=C(C)C(C=O)=C(O)C=1CC=C(C)CCC=C(C)C1CC(=O)C(C)(C)O1 VGYPZLGWVQQOST-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 241000830358 Calonectria lauri Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
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- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 1
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- 241001149959 Fusarium sp. Species 0.000 description 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
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- 229920003115 HPC-SL Polymers 0.000 description 1
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- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
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- 241000124008 Mammalia Species 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- NEAPKZHDYMQZCB-UHFFFAOYSA-N N-[2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]ethyl]-2-oxo-3H-1,3-benzoxazole-6-carboxamide Chemical compound C1CN(CCN1CCNC(=O)C2=CC3=C(C=C2)NC(=O)O3)C4=CN=C(N=C4)NC5CC6=CC=CC=C6C5 NEAPKZHDYMQZCB-UHFFFAOYSA-N 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
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- 208000005374 Poisoning Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 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
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- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- VGYPZLGWVQQOST-JUERRSSISA-N ascofuranone Chemical compound OC=1C(Cl)=C(C)C(C=O)=C(O)C=1C\C=C(/C)CC\C=C(/C)[C@@H]1CC(=O)C(C)(C)O1 VGYPZLGWVQQOST-JUERRSSISA-N 0.000 description 1
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- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
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- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
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- 238000006297 dehydration reaction Methods 0.000 description 1
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- 208000016097 disease of metabolism Diseases 0.000 description 1
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- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000225 effect on diabetes Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
- 230000004136 fatty acid synthesis Effects 0.000 description 1
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- 239000003862 glucocorticoid Substances 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
糖尿病は遺伝的素因を背景とし、複雑な環境因
子が関与して発症する典型的な代謝病である。多
種多様な因子の関与によつて発症の直接的な引金
が引かれるところから、糖尿病なる名称は一つの
症候群をあらわすだけであるとする考え方があ
る。しかし一般的には、主として若年層に発症
し、外因性のインスリンを補給しなければ重篤な
障害に陥いる若年型糖尿病と、成人に発症しイン
スリンの補給をほとんど必要としない成人型糖尿
病とに分類されている。後者は発症にさいし肥満
と密接な関係にあることが知られている。このよ
うに治療にさいしてのインスリン注射の要、不要
の差異が見られるにもかかわらず、いづれの型の
糖尿病にも共通していることは、生体内における
インスリン作用の不足が根本的な原因をなしてい
ることである。
インスリンは脊椎動物に不可欠なペプチドホル
モンでグリコーゲン,蛋白質及び脂肪の合成を促
進し、肝臓における糖新生の抑制、脂肪組織にお
ける脂肪分解の抑制、細胞培養における増殖の促
進など多彩な生理作用を示すことが知られてい
る。しかしその最も本質的な作用は動物が摂取し
た食物のエネルギーを食間期ないし絶食期に備え
て体内に貯蔵させる方向に作用する唯一のホルモ
ンである点にある。この点で他のホルモン、例え
ばカテコールアミン類,グルカゴン,ACTH及
び糖コルチコイドなどが生体に貯蔵されたエネル
ギーを放出させる方向に働くのと著しい対照をな
している。
インスリンの作用不足を原因とする糖尿病にた
いしインスリン注射が特効的に作用するのは当然
である。しかしインスリンを過剰に使用すること
は、他のホルモンとのバランスを崩すので好まし
いことではない。したがつて生体内におけるイン
スリン作用を増強できる薬物が存在すれば、イン
スリン非依存性糖尿病に限らずインスリン依存性
糖尿病においてさえも代謝を正常化するうえでも
望ましいことである。
一方糖尿病に限らず耐糖能の低下と高インスリ
ン血症が併存する場合には高率に虚血性心疾患が
発症することが各種疫学的研究から知られてい
る。この場合、耐糖能の悪化はインスリン依存性
組織が、インスリン不感受性に陥つたことが原因
である。したがつて生体は正常なインスリン分泌
量では恒常性を維持できなくなつたため膵臓から
インスリン分泌を増大させその作用不足を補なお
うとする。すなわち一見矛盾した高インスリン血
症と耐糖能の悪化との併存は、インスリン不感受
性に伴う代償性反応である。このような病態にお
いて、組織のインスリン感受性を改善させること
により内因性及び外因性インスリンの作用を増強
する薬物は虚血性心疾患ひいてはその原因をなす
心臓冠状動脈硬化症の予防ならびに治療にきわめ
て有意義と言わなければならない。
本発明者らは多年にわたりインスリン作用を増
強する物質を探索した結果、アスコクロリンの4
−位水酸基をアシル化して得られる新規誘導体に
著明なインスリン作用を増強する性質のあること
を発見し本発明を完成するにいたつた。
アスコクロリンはアスコフラノンをはじめとす
る数種の同族体とともに糸状菌アスコキイタ・ビ
シエ(Ascochyta vicia)によつて産生されるイ
ソブレノイドである(田村ら。J.
Antibiotics.21:539ページ,1968年)。アスコク
ロリンはアスコキイタ・ビシエ以外にも他のいく
つかの糸状菌、例えばフサリウム.sp.
(Fusarium sp.)R.H.Evansら,U.S.patent 3,
546,073,1973年12月8日)。ネクトリア・コク
シネア(Nectria coccinea,D.C.Aldrichら,J.
Chem.Soc.Perkin I,2136ページ,1972年)、シ
リンドロクラデイウムsp.(Cylindrocladium sp.,
加藤ら,J.Antibiotics.24:168ページ,1970年)
及びシリンドロクラデイウム・イリチコラ
(Cylindrocladium ilicicola 湊ら,J.
Antibiotics 25:315ページ,1972年)などの糸
状菌により産生される。アスコクロリンを急速に
生体内に吸収される形態で哺乳動物に投与すると
強い中毒症状を呈し、はなはだしい場合には死亡
する。アスコクロリンの生理作用を損なうことな
しに急性毒性を特異的に弱める手段としては芳香
環4位の水酸基を修飾すればよいことが知られて
いる(細川ら,Agr.Biol.Chem.45:531ページ,
1980年、細川ら,Eur.J.pharmacol.69:429ペー
ジ,1981年)。しかしここで使用された4−0−
メチルアスコクロリンは水溶性に乏しく全身的な
いし経口的に投与したさいの血中濃度が上昇しに
くい欠点があつた。
本発明者らは上記の欠点を改良することを目的
として検討したところ芳香環4位の水酸基をアシ
ル基及びカルバモイル基で修飾した新規誘導体に
優れた作用及び安全性を認め本発明をなすにいた
つた。すなわちアスコクロリンの4−0−アシル
誘導体は、アスコクロリンに酸ハロゲン化物、酸
無水物、場合によつてはシアネート、イソシアネ
ート等の酸の反応性誘導体を縮合剤(ピリジン
類,トリエチルアミンのような3級アミン,ジメ
チルアニリン,アルカリ塩基等)の存在下あるい
は縮合剤を無添加で反応させることによつて製造
される。反応は溶媒なしでも進行するが、収率、
操作性などの観点から通常溶媒中で行なう。溶媒
としは、酸の反応性誘導体との反応が起きないも
のが選ばれる。通常はベンゼン,ジメチルホルム
アミド,エーテル類,クロロホルム,アセトン等
が用いられる。また、縮合剤を溶媒と兼用しても
支障はない。反応の温度範囲は室温から溶媒の沸
点に至るまで巾広くとることができる。しかし大
過剰の酸の反応性誘導体の使用はアスコクロリン
の2,4−ビス−0−アシル誘導体を生成するこ
とがあるので避けるべきである。しかし実施例に
示す反応条件下ではビス体の生成は殆ど抑制され
る。目的生成物の精製は、再結晶、カラムクロマ
トグラフイー、溶媒抽出などの一般的な手段によ
つて行うことができる。
本発明の新規化合物の生理作用を説明するとつ
ぎのとおりである。すなわち健常動物に1週間連
続経口投与すると血糖及び血中脂質が有意に低下
する。この事実は糖尿病及び動脈硬化症に随伴す
る高カロリー血症を改善し、生体に正常な代謝恒
常性を維持させるのに好適である。実際、本発明
の化合物を糖尿病病態モデル動物に経口投与する
と著明な改善作用が認められる。例えば遺伝性肥
満糖尿病マウスC57BL/Ksj(db+/db+)系は高
血糖,高脂血症,肥満,過インスリン血症,イン
スリン抵抗性,多飲多尿,尿糖排泄,血管障害な
ど成人性糖尿病に近似した病態モデルと言われて
いる。この糖尿病マウスに対しては従来の抗糖尿
病薬、たとえばスルホニル尿素系及びビグアナイ
ド系化合物はまつたく効果がない。しかるに本発
明の化合物は摂餌量を減少させることなしに、本
糖尿病に特有の異常を著しく改善した。すなわち
血糖及び尿糖排泄量の低下はもとより、とりわけ
注目に価するのは多飲多尿のような糖尿病固有の
症状が著明に改善されたことである。またアロキ
サン及びストレプトゾトシンによつて誘発された
糖尿病動物に対しても血糖及び血清脂質の低下な
らびに尿糖排泄の減少作用を示した。
本発明の化合物を使用してin ritroにおける作
用機作を検討した実験の結果からこれらの化合物
はインスリンの作用を増強すると同時に部分的に
はインスリンに代替する作用を示すことが明らか
になつた。すなわち本発明の化合物を10-6Mの低
濃度でインスリン存在下に正常ラツト肝臓切片に
作用させると、ぶどう糖の酸化は明らかに促進さ
れた。また糖尿病ラツト肝臓切片にインスリン存
在下で作用させると脂肪酸合成を正常域まで回復
させた。一方インスリン存在下に健常及び糖尿病
動物の副睾丸脂肪組織に作用させるとぶどう糖の
とり込と代謝が亢進した。腎臓の切片に添加した
さいにも同様の反応が認められた。さらに副睾丸
脂肪組織を磨砕して得たミクロソーム画分に本発
明の化合物を作用させると、インスリンを添加し
た場合とまつたく同様にリポ蛋白リパーゼ活性は
亢進し、逆に中性脂肪リパーゼの活性は強く阻害
された。
糖尿病及び健常動物に対する作用ならびにin
vitroにおける実験成績から本発明の化合物が生
体内においてインスリン作用を増強するととも
に、部分的にはその作用を代替していることが推
定される。このような作用はインスリンを除き従
来のいかなる薬物にも見出せないものである。と
りわけ本発明の化合物は経口投与でこのような作
用を示す点で、臨床的な治療面で大きな利点を有
していると言えよう。
本発明の化合物は単独で用いてもよいが通常は
懸濁剤、賦形剤又はその他の補助剤と混合して非
経口投与及び経口投与に適する剤形として製剤化
することが好ましい。好ましい製剤としては、た
とえば注射剤,粒剤,顆粒剤,錠剤,糖依錠,丸
剤,カプセル剤,坐剤などがあげられる。これら
の製剤は常法に従つて、たとえば下記の賦形剤又
は補助剤を用いて製造することができる。
乳糖,蔗糖,種々の澱粉,ぶどう糖,セルロー
ス、メチルセルロース,カルボキシメチルセルロ
ース、ステアリン酸マグネシウム、ラウリル硫酸
塩,タルク,植物油,オクチルデシルトリグリセ
ライド,重炭酸ソーダ,種々のポリソルベート,
ポリエチレングリコール,レシチンならびにこれ
らの2種以上の混合物。
経口投与用製剤は活性成分を10〜55%(重量
比)、注射剤は1〜20%(重量比)の量で含有す
ることが好ましい。
本発明の医薬はヒトならびに動物の糖尿病、動
脈硬化症及び虚血性心疾患の治療と予防に効果的
に使用することができる。本発明の化合物の毒性
はかなり弱く、ラツト及びマウスに対する急性毒
性LD50は経口投与で0.5〜10.0g/Kg以上、腹腔
内投与で150〜500mg/Kgである。
本発明の医薬の用量は病態の種類、症状などに
よつて異なるが例えば注射の場合は成人1人1日
当り5〜1000mg、経口投与の場合には30〜3000
mg、坐薬の場合には5〜1000mgで目的を達するこ
とができる。つぎに製剤例を示す。
4−0−ニコチノイルアスコクロリン100mgを
精製トウモロコシ油20ml、レシチン200mgよりな
る液に溶解し窒素ガスを封入した遮光アンプルに
封入し、常法どおり加圧滅菌する。この液を静脈
点滴用輸液ないしは糖液に懸濁して点滴静注す
る。
経口投与用の錠剤はつぎのように製剤化する。
4−0−ニコチニルアスコクロリンの微粒末(粒
径約2μ)100部に乳糖88部、トウモロコシ澱粉
100部、HPC−SL2部、L−HPC(PO−30)50
部、結晶セルロース33部、ステアリン酸カルシウ
ム5部、タルク10部を加えてよく混合し打錠機を
用いて直径8mm,重量250mgの錠剤に打錠する。
実施例 1
アスコクロリン10g(24.7ミリモル)を乾燥ピ
リジン50mlに溶かす。容器の周囲を氷水にて冷却
し撹拌しつつニコチン酸クロライド塩酸塩6.6g
(37.07ミリモル)を少しづつ加える。加え終つて
から反応容器内の温度を徐々に室温に戻しながら
撹拌を続ける。一昼夜撹拌ののち反応溶液を減圧
濃縮乾固する。残渣をクロロホルム〜水にて分液
抽出し、クロロホルム層をよく水洗したのち無水
硫酸ソーダを加えて脱水乾燥する。脱水後に濾過
して得た液を減圧濃縮し残留する油状物をシリカ
ゲルカラムクロマトグラフイーで分離精製する。
1〜2%メタノールを含むクロロホルムないしは
5%酢酸エチル含有ベンゼンで溶出する目的生成
物の分画を集め減圧濃縮すると粘稠な油状物が得
られる。これをエタノールに溶かして放置すると
目的生成物の結晶が析出する。目的物の結晶9.6
g(76.3%)が得られ、エタノールから再結晶し
た標品は融点159〜160℃である。この物の元素分
析値はC29H32O5ClNとして
理論値:C68.29%,H6.32%,N2.75%
実測値;C68.23%,H6.36%,N2.80%
構造式;
実施例 2
1.0の三角フラスコにアスコクロリン40.5g
(0.1モル)、乾燥ベンゼン50ml、乾燥ピリジン24
ml(0.297モル)を混合し振盪すると均一に溶解
する。この溶液をマグネチツクスタラー上で撹拌
しつつ、ニコチン酸クロライド塩酸塩25.22g
(0.142モル)を加える。室温で3時間撹拌し析出
して懸濁するピリジン塩酸塩を濾過して除去す
る。濾液に水500mlを加えて振盪し水層を除去す
る操作を3回繰り返す。振盪したさい乳濁して分
離が困難の場合には食塩水を加えると良い。ベン
ゼン層を無水硫酸ソーダで乾燥し溶媒を減圧留去
すると粘稠な油状物が得られる。これをエタノー
ル800mlに溶解し放置すると目的物結晶41.0g
(80.4%)が得られた。エタノールから再結晶す
ると融点159〜160℃を示し、元素分析値は
C29H32O5ClNとして
理論値(%);C68.29,H6.32,N2.75
実測値(%);C68.21,H6.32,N2.76
プロトン核磁気共鳴のδ値<100MHz,溶媒
CDCl3,内部標準TMS>0.69(3H,s),0.80
(3H,d),0.82(9H,d),1.70(3H,
s),3.55(2H,d),5.37(1H,d),5.54
(1H,t),5.84(1H,d),7.49(1H,
m),8.55(1H,d),8.96(1H,d),9.42
(1H,s),10.34(1H,s)12.60(1H,
s)
構造式;
実施例 3
アスコクロリン20g(49.4ミリモル)を乾燥し
たピリジン100ml中に溶かしこれにジエチルカル
バモイルクロライド6.9g(49.9ミリモル)を加
えて加熱還流し、約5時間後にジエチルカルバモ
イルクロライド6.9gを加えて更に加熱還流を続
ける。アスコクロリンが反応系から消失したこと
を確認した時点で反応液を減圧濃縮し乾固する。
残渣を水〜ベンゼン系で分液しベンゼン層をよく
水洗したのち、無水硫酸ソーダで乾燥し溶媒を留
去する。残留する油状物をシリカゲルカラムクロ
マトグラフイーで分離精製する。5%酢酸エチル
エステルを含むベンゼンで溶出する目的物の分画
を分取し濃縮乾固すると粘稠な油状物が得られ
る。これをエタノールに溶かし、冷所に放置する
と目的物16g(64%)が結晶として析出した。粗
結晶をエタノールから再結晶すると融点125〜127
℃を示し、元素分析値はC28H38O5ClNとして
理論値(%);C66.72,H7.60,N2.78
実測値(%);C66.85,H7.67,N2.80
プロトン核磁気共鳴<100MHz,CDCl3,内部
標準TMS>のδ値:0.67(3H,s)0.79(3H,
d),0.82(3H,d),1.12〜1.36(6H,
m),1.86(3H,s),2.20〜2.50(3H,
m),2.63(3H,s)、3.30〜3.60(6H,
m),5.35(1H,d),5.42(1H,t),5.89
(1H,d),10.28(1H,s),12.53(1H,
s)
目的物の構造式;
実施例 4
アスコクロリン10g(24.7ミリモル)を乾燥し
たピリジン100mlに溶かし、パラクロロフエノキ
シアセチルクロライド8.0g(39.0ミリモル)を
加えて60〜70℃で5時間加熱撹拌する。つぎに更
にパラクロロフエノキシアセチルクロライド1.0
g(4.9ミリモル)を加えて5時間60〜70℃で加
熱撹拌する。つぎに反応液を減圧濃縮乾固し実施
例3と同様に処理する。シリカゲルカラムクロマ
トグラフイーにて分離精製した油状の目的物をエ
タノールに溶かし、室温に放置すると目的物の結
晶4.7g(33.2%)が析出した。メタノールから
再結晶した標品は融点122〜124℃を示し、元素分
析値はC31H34O6Cl2として
理論値(%);C64.92,H5.98
実測値(%);C64.86,H5.95
プロトン核磁気共鳴<100MHz,CDCl3,内部
標準TMS>のδ値: 0.70(3H,s),0.80(3H,
d),0.83(3H,d),1.87(3H,s)2.66
(3H,s),3.40(2H,d),4.93(2H,
s),5.20(1H,t),5.38(1H,d),5.84
(1H,d),6.92(2H,d),7.30(2H,
d),10.30(1H,s),12.56(1H,s)
目的物の構造式:
実施例 5
アスコクロリン7g(17.3ミリモル)を乾燥し
たピリジン70mlに溶かし、これにパラメトキシベ
ンゾイルクロライド8.0g(46.9ミリモル)を加
えて5時間加熱還流する。その後実施例3と同様
に処理して得られる目的生成物をエタノールに溶
かし、室温に放置すると3.8g(40.8%)の目的
生成物の結晶が析出した。この粗結晶をエタノー
ルで再結晶すると、融点155〜156℃を示し、元素
分析値はC31H35O6Clとして
理論値(%);C69.07,H6.54
実測値(%);C68.82,H6.56
プロトン核磁気共鳴<100MHz,CDCl3,内部
標準TMS>のδ値:0.68(3H,s),0.79(3H,
d),0.82(3H,d),1.70(3H,s),2.67
(3H,s),3.55(2H,d),3.91(3H,
s),5.35(1H,d),5.50(1H,t),5.86
(1H,d),7.01(2H,d),8.16(2H,
d),10.32(1H,s),12.57(1H,s)
目的物の構造式:
実施例 6
アスコクロリン10g(24.7ミリモル)を乾燥ピ
リジン100mlに溶かし、これにパラメトキシカル
ボニルベンゾイルクロライド5.9g(29.6ミリモ
ル)を加えて、60〜70℃で7時間加熱撹拌し、さ
らにパラメトキシカルボニルベンゾイルクロライ
ド5.9g(29.6ミリモル)を追加し、7時間60〜
70℃で加熱撹拌する。その後実施例3と同様に処
理して得られた油状の目的物をエタノールに溶か
して、室温に放置する。目的物結晶3.3g(23.6
%)が析出する。粗結晶をエタノールから再結晶
すると融点147〜148℃を示し、元素分析値は
C32H35O7Clとして
理論値(%);C67.78,H6.22
実測値(%);C67.78,H6.30
プロトン核磁気共鳴<100MHz,CDCl3,内部
標準TMS>のδ値:0.68(3H,s),0.78(3H,
d),0.81(3H,d),1.59(3H,s),2.69
(3H,s),3.55(2H,d),3.99(3H,s)
5.35(1H,d),5.53(1H,t),5.84(1H,
d),10.34(1H,s),12.60(1H,s)
8.14(4H,m)
目的物の構造式:
実施例 7
アスコクロリン20g(49.4ミリモル)を乾燥ピ
リジン100mlに溶かし、これにイソニコチン酸ク
ロライド塩酸塩13.2g(73.7ミリモル)を加え70
℃にて4時間加熱撹拌したのちさらにイソニコチ
ン酸クロライド塩酸塩5g(28.1ミリモル)を追
加して7時間加熱撹拌を続ける。その後実施例3
と同様に処理して得られる目的物油状残渣をエタ
ノールに溶かし、冷所に放置すると、目的物の結
晶7.2g(28.6%)を収得する。粗結晶をエタノ
ールから再結晶すると融点111〜113℃を示し、元
素分析値はC29H32O5ClNとして
理論値(%);C68.30,H6.28
実測値(%);C68.27,H6.31
プロトン核磁気共鳴<100MHz,CDCl3,内部
標準TMS>のδ値:0.68(1H,s)0.78(3H,
d),0.81(3H,d),1.67(3H,s),2.69
(3H,s),3.45(2H,d),5.28(1H,d)
5.35(1H,t),5.83(1H,d),800(2H,
d),8.80(2H,d),10.34(1H,s)
12.61(1H,s)
目的物の構造式:
実施例 8
アスコクロリン5g(12.35ミリモル)を乾燥
ピリジン50mlに溶かし、これにピコリン酸クロラ
イド塩酸塩4.4g(24.7ミリモル)を加え、60℃
にて3時間加熱撹拌したのち、さらにピコリン酸
クロライド塩酸塩1.5g(8.43ミリモル)を追加
し60℃にて7時間加熱撹拌する。その後実施例3
と同様に処理して得られる油状の目的物をエタノ
ールに溶かし、室温に放置すると目的物の結晶
2.0g(32%)を取得する。この粗結晶をエタノ
ールから再結晶すると、融点150〜152℃を示し、
元素分析値はC29H32O5ClNとして
理論値(%);C68.30,H6.28
実測値(%);C68.30,H6.25
プロトン核磁気共鳴<100MHz,CDCl3,内部
標準TMS>のδ値:0.66(3H,s),0.77(3H,
d),0.79(3H,d),1.76(3H,s),2.68
(3H,s),3.55(2H,d),5.26(1H,
d),5.41(1H,t),5.83(1H,d),7.62
(1H,m),7.96(1H,m),8.26(1H,
d),8.87(1H,d),10.33(1H,s),
12.59(1H,s)
目的物の構造式:
実施例 9
遺伝性肥満糖尿病マウスC57BL/Ksj(db+/
db+)に4−0−ニコチノイルアスコクロリン
0.05%を含む飼料(日本クレア,CE−2)を1
週間与えた。薬物を与える直前の1週間と薬物投
与の1週間について摂餌量,飲水量,尿量及び尿
糖排泄量を毎日測定し薬物の影響を検討した。
Diabetes is a typical metabolic disease that develops due to genetic predisposition and the involvement of complex environmental factors. Since the onset of diabetes is directly triggered by the involvement of a wide variety of factors, there is a view that the name diabetes only represents one syndrome. However, in general, there are two types of diabetes: juvenile diabetes, which mainly develops in young people and can lead to serious disorders if exogenous insulin is not supplemented, and adult-type diabetes, which develops in adults and requires little insulin supplementation. It is classified as The latter is known to be closely related to obesity in its onset. Although there are differences in whether insulin injections are necessary or unnecessary for treatment, what all types of diabetes have in common is that the fundamental cause is insufficient insulin action in the body. This is what we do. Insulin is an essential peptide hormone in vertebrates that promotes the synthesis of glycogen, protein, and fat, and exhibits a variety of physiological effects such as suppressing gluconeogenesis in the liver, suppressing lipolysis in adipose tissue, and promoting proliferation in cell culture. It has been known. However, its most essential function is that it is the only hormone that acts to store energy from the food an animal ingests in the body in preparation for the intermeal or fasting period. This is in sharp contrast to other hormones, such as catecholamines, glucagon, ACTH, and glucocorticoids, which act to release energy stored in the body. It is natural that insulin injections have a specific effect on diabetes caused by insufficient insulin action. However, using too much insulin is not a good thing because it disrupts the balance with other hormones. Therefore, the existence of a drug that can enhance insulin action in vivo would be desirable for normalizing metabolism not only in non-insulin-dependent diabetes but even in insulin-dependent diabetes. On the other hand, it is known from various epidemiological studies that ischemic heart disease occurs at a high rate not only in diabetes but also in cases where decreased glucose tolerance and hyperinsulinemia coexist. In this case, deterioration of glucose tolerance is caused by insulin-dependent tissues becoming insulin insensitive. Therefore, the living body is no longer able to maintain homeostasis with the normal amount of insulin secretion, so it tries to compensate for the lack of insulin secretion by increasing insulin secretion from the pancreas. In other words, the seemingly contradictory coexistence of hyperinsulinemia and worsening of glucose tolerance is a compensatory reaction associated with insulin insensitivity. In such pathological conditions, drugs that enhance the action of endogenous and exogenous insulin by improving tissue insulin sensitivity are extremely meaningful for the prevention and treatment of ischemic heart disease and the cause of it, coronary artery sclerosis. I have to say it. As a result of many years of searching for substances that enhance insulin action, the present inventors discovered that ascochlorin 4.
The present inventors discovered that a new derivative obtained by acylating the hydroxyl group at the -position has the property of significantly enhancing insulin action, leading to the completion of the present invention. Ascochlorin is an isobrenoid produced by the filamentous fungus Ascochyta vicia together with several congeners including ascofuranone (Tamura et al. J.
Antibiotics.21:539, 1968). Ascochlorin is also found in some other filamentous fungi, such as Fusarium. sp.
(Fusarium sp.) RHEvans et al., US Patent 3,
546, 073, December 8, 1973). Nectria coccinea (DCAldrich et al., J.
Chem.Soc.Perkin I, page 2136, 1972), Cylindrocladium sp.
Kato et al., J. Antibiotics. 24: 168 pages, 1970)
and Cylindrocladium ilicicola Minato et al., J.
Antibiotics 25:315, 1972) and other filamentous fungi. When ascochlorin is administered to mammals in a form that is rapidly absorbed into the body, severe symptoms of poisoning occur, and in severe cases, death occurs. It is known that a means to specifically weaken the acute toxicity of ascochlorin without impairing its physiological effects is to modify the hydroxyl group at the 4-position of the aromatic ring (Hosokawa et al., Agr. Biol. Chem. 45: 531 page,
(1980, Hosokawa et al., Eur.J.pharmacol.69:429, 1981). However, the 4-0- used here
Methylascochlorin has the disadvantage that it has poor water solubility and is difficult to increase blood concentration when administered systemically or orally. The present inventors investigated with the aim of improving the above-mentioned drawbacks, and found that a new derivative in which the hydroxyl group at the 4-position of the aromatic ring was modified with an acyl group and a carbamoyl group was found to be superior in action and safety, and was able to develop the present invention. Ivy. In other words, the 4-0-acyl derivative of ascochlorin is produced by adding a condensing agent (pyridine, triethylamine, etc.) to ascochlorin, an acid halide, an acid anhydride, or in some cases, a reactive derivative of an acid such as cyanate or isocyanate. amine, dimethylaniline, alkali base, etc.) or without the addition of a condensing agent. The reaction proceeds without solvent, but the yield and
It is usually carried out in a solvent from the viewpoint of operability. A solvent is selected that does not react with the reactive derivative of the acid. Benzene, dimethylformamide, ethers, chloroform, acetone, etc. are usually used. Moreover, there is no problem even if the condensing agent is also used as a solvent. The reaction temperature range can be wide from room temperature to the boiling point of the solvent. However, the use of a large excess of the reactive derivative of the acid should be avoided since it may result in the formation of 2,4-bis-0-acyl derivatives of ascochlorin. However, under the reaction conditions shown in the Examples, the production of bis isomers is almost suppressed. Purification of the desired product can be carried out by common means such as recrystallization, column chromatography, and solvent extraction. The physiological action of the novel compound of the present invention is explained as follows. That is, continuous oral administration for one week to healthy animals significantly lowers blood sugar and blood lipids. This fact is suitable for improving hypercaloremia associated with diabetes and arteriosclerosis and for maintaining normal metabolic homeostasis in the body. In fact, when the compound of the present invention is orally administered to diabetic disease model animals, a marked improving effect is observed. For example, the C57BL/Ksj (db + /db + ) strain of genetically obese diabetic mice exhibits hyperglycemia, hyperlipidemia, obesity, hyperinsulinemia, insulin resistance, polydipsia, polyuria, urinary sugar excretion, and vascular disorders in adults. It is said to be a pathological model similar to sexual diabetes. Conventional antidiabetic drugs, such as sulfonylurea and biguanide compounds, are not very effective against these diabetic mice. However, the compound of the present invention significantly improved the abnormalities characteristic of diabetes without reducing food intake. That is, in addition to the reduction in blood sugar and urinary sugar excretion, what is especially noteworthy is that symptoms specific to diabetes such as polydipsia and polyuria were significantly improved. It also showed a reduction in blood sugar and serum lipids and urinary sugar excretion in diabetic animals induced by alloxan and streptozotocin. The results of experiments using the compounds of the present invention to examine their mechanisms of action in vitro have revealed that these compounds enhance the action of insulin and, at the same time, partially act as a substitute for insulin. That is, when the compound of the present invention was applied to normal rat liver sections in the presence of insulin at a low concentration of 10 -6 M, glucose oxidation was clearly promoted. Furthermore, when applied to liver sections of diabetic rats in the presence of insulin, fatty acid synthesis was restored to the normal range. On the other hand, when insulin was applied to the epididymal adipose tissue of healthy and diabetic animals in the presence of insulin, glucose uptake and metabolism were enhanced. A similar reaction was observed when added to kidney sections. Furthermore, when the compound of the present invention is applied to the microsomal fraction obtained by grinding epididymal adipose tissue, lipoprotein lipase activity is increased in the same way as when insulin is added, and conversely, neutral fat lipase activity is increased. Activity was strongly inhibited. Effects on diabetic and healthy animals and in
Based on experimental results in vitro, it is presumed that the compound of the present invention not only enhances the action of insulin in vivo, but also partially replaces its action. Such an action has not been found in any conventional drug except insulin. In particular, the compound of the present invention can be said to have a great advantage in terms of clinical treatment in that it exhibits such effects upon oral administration. Although the compound of the present invention may be used alone, it is usually preferable to mix it with a suspending agent, excipient, or other auxiliary agent to formulate a dosage form suitable for parenteral and oral administration. Preferred formulations include, for example, injections, granules, granules, tablets, sugar tablets, pills, capsules, and suppositories. These preparations can be manufactured according to conventional methods using, for example, the following excipients or auxiliaries. Lactose, sucrose, various starches, glucose, cellulose, methylcellulose, carboxymethylcellulose, magnesium stearate, lauryl sulfate, talc, vegetable oil, octyldecyl triglyceride, bicarbonate of soda, various polysorbates,
Polyethylene glycol, lecithin, and mixtures of two or more of these. Preparations for oral administration preferably contain the active ingredient in an amount of 10 to 55% (by weight), and injections preferably contain 1 to 20% (by weight). The medicament of the present invention can be effectively used for the treatment and prevention of diabetes, arteriosclerosis and ischemic heart disease in humans and animals. The toxicity of the compounds of the present invention is rather low, with an acute toxicity LD 50 for rats and mice of 0.5 to 10.0 g/Kg or more for oral administration and 150 to 500 mg/Kg for intraperitoneal administration. The dosage of the drug of the present invention varies depending on the type of pathology, symptoms, etc., but for example, in the case of injection, it is 5 to 1000 mg per adult per day, and in the case of oral administration, it is 30 to 3000 mg per day.
mg, or in the case of suppositories, 5 to 1000 mg can achieve the purpose. Next, formulation examples are shown. 100 mg of 4-0-nicotinoyl ascochlorin is dissolved in a solution consisting of 20 ml of purified corn oil and 200 mg of lecithin, sealed in a light-shielding ampoule filled with nitrogen gas, and sterilized under pressure in a conventional manner. This solution is suspended in an intravenous infusion solution or a sugar solution and injected intravenously. Tablets for oral administration are formulated as follows.
100 parts of 4-0-nicotinyl ascochlorin fine powder (particle size approximately 2μ), 88 parts of lactose, and corn starch
100 copies, HPC-SL 2 copies, L-HPC (PO-30) 50
1 part, crystalline cellulose, 33 parts, calcium stearate, 5 parts, and talc, 10 parts, were added, mixed well, and compressed into tablets with a diameter of 8 mm and a weight of 250 mg using a tablet machine. Example 1 10 g (24.7 mmol) of ascochlorin are dissolved in 50 ml of dry pyridine. Cool the surroundings of the container with ice water and add 6.6 g of nicotinic acid chloride hydrochloride while stirring.
(37.07 mmol) little by little. After the addition is complete, the temperature inside the reaction vessel is gradually returned to room temperature while stirring is continued. After stirring all day and night, the reaction solution was concentrated to dryness under reduced pressure. The residue is separated and extracted with chloroform and water, and the chloroform layer is thoroughly washed with water and then dehydrated by adding anhydrous sodium sulfate. After dehydration, the resulting filtrate is concentrated under reduced pressure, and the remaining oil is separated and purified using silica gel column chromatography.
Fractions of the desired product eluted with chloroform containing 1 to 2% methanol or benzene containing 5% ethyl acetate are collected and concentrated under reduced pressure to obtain a viscous oil. If this is dissolved in ethanol and left to stand, crystals of the desired product will precipitate. Object crystal 9.6
g (76.3%), and the preparation recrystallized from ethanol has a melting point of 159-160°C. The elemental analysis values for this product are C 29 H 32 O 5 ClN Theoretical values: C68.29%, H6.32%, N2.75% Actual values: C68.23%, H6.36%, N2.80% Structure formula; Example 2 40.5 g of ascochlorin in a 1.0 Erlenmeyer flask
(0.1 mol), dry benzene 50ml, dry pyridine 24
ml (0.297 mol) and shake to dissolve uniformly. While stirring this solution on a magnetic stirrer, 25.22 g of nicotinic acid chloride hydrochloride was added.
(0.142 mol) is added. The mixture was stirred at room temperature for 3 hours, and the precipitated and suspended pyridine hydrochloride was removed by filtration. Add 500 ml of water to the filtrate, shake it, and remove the aqueous layer. Repeat this operation three times. If the mixture becomes turbid during shaking and is difficult to separate, add saline. The benzene layer is dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure to obtain a viscous oil. When this is dissolved in 800ml of ethanol and left to stand, 41.0g of target crystals are produced.
(80.4%) was obtained. When recrystallized from ethanol, it shows a melting point of 159-160℃, and the elemental analysis value is
As C 29 H 32 O 5 ClN Theoretical value (%); C68.29, H6.32, N2.75 Actual value (%); C68.21, H6.32, N2.76 Proton nuclear magnetic resonance δ value < 100MHz, solvent
CDCl 3 , internal standard TMS > 0.69 (3H, s), 0.80
(3H, d), 0.82 (9H, d), 1.70 (3H,
s), 3.55 (2H, d), 5.37 (1H, d), 5.54
(1H, t), 5.84 (1H, d), 7.49 (1H,
m), 8.55 (1H, d), 8.96 (1H, d), 9.42
(1H, s), 10.34 (1H, s) 12.60 (1H,
s) Structural formula; Example 3 20 g (49.4 mmol) of ascochlorin was dissolved in 100 ml of dry pyridine, and 6.9 g (49.9 mmol) of diethylcarbamoyl chloride was added thereto and heated under reflux. After about 5 hours, 6.9 g of diethylcarbamoyl chloride was added and further heated. Continue reflux. When it is confirmed that ascochlorin has disappeared from the reaction system, the reaction solution is concentrated under reduced pressure to dryness.
The residue is separated between water and benzene, and the benzene layer is thoroughly washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off. The remaining oil is separated and purified by silica gel column chromatography. A viscous oil is obtained by collecting a fraction of the target product eluted with benzene containing 5% acetic acid ethyl ester and concentrating to dryness. When this was dissolved in ethanol and left in a cold place, 16 g (64%) of the target product precipitated as crystals. When the crude crystals are recrystallized from ethanol, the melting point is 125-127.
℃, elemental analysis values are as C 28 H 38 O 5 ClN Theoretical value (%); C66.72, H7.60, N2.78 Actual value (%); C66.85, H7.67, N2.80 δ value of proton nuclear magnetic resonance <100MHz, CDCl 3 , internal standard TMS>: 0.67 (3H, s) 0.79 (3H,
d), 0.82 (3H, d), 1.12~1.36 (6H,
m), 1.86 (3H, s), 2.20~2.50 (3H,
m), 2.63 (3H, s), 3.30~3.60 (6H,
m), 5.35 (1H, d), 5.42 (1H, t), 5.89
(1H, d), 10.28 (1H, s), 12.53 (1H,
s) Structural formula of the target object; Example 4 10 g (24.7 mmol) of ascochlorin is dissolved in 100 ml of dry pyridine, 8.0 g (39.0 mmol) of parachlorophenoxyacetyl chloride is added, and the mixture is heated and stirred at 60-70°C for 5 hours. Next, parachlorophenoxyacetyl chloride 1.0
g (4.9 mmol) and stirred while heating at 60-70°C for 5 hours. Next, the reaction solution was concentrated to dryness under reduced pressure and treated in the same manner as in Example 3. The oily target product separated and purified by silica gel column chromatography was dissolved in ethanol and left at room temperature to precipitate 4.7 g (33.2%) of the target product as crystals. The sample recrystallized from methanol has a melting point of 122-124°C, and the elemental analysis value is C 31 H 34 O 6 Cl 2 Theoretical value (%): C64.92, H5.98 Actual value (%): C64. 86, H5.95 δ value of proton nuclear magnetic resonance <100MHz, CDCl 3 , internal standard TMS>: 0.70 (3H, s), 0.80 (3H,
d), 0.83 (3H, d), 1.87 (3H, s) 2.66
(3H, s), 3.40 (2H, d), 4.93 (2H,
s), 5.20 (1H, t), 5.38 (1H, d), 5.84
(1H, d), 6.92 (2H, d), 7.30 (2H,
d), 10.30 (1H, s), 12.56 (1H, s) Structural formula of target object: Example 5 7 g (17.3 mmol) of ascochlorin is dissolved in 70 ml of dry pyridine, 8.0 g (46.9 mmol) of para-methoxybenzoyl chloride is added thereto, and the mixture is heated under reflux for 5 hours. Thereafter, the desired product obtained by treatment in the same manner as in Example 3 was dissolved in ethanol and allowed to stand at room temperature to precipitate 3.8 g (40.8%) of crystals of the desired product. When this crude crystal is recrystallized with ethanol, it shows a melting point of 155-156℃, and the elemental analysis value is C 31 H 35 O 6 Cl. Theoretical value (%): C69.07, H6.54 Actual value (%): C68 .82, H6.56 δ value of proton nuclear magnetic resonance <100MHz, CDCl 3 , internal standard TMS>: 0.68 (3H, s), 0.79 (3H,
d), 0.82 (3H, d), 1.70 (3H, s), 2.67
(3H, s), 3.55 (2H, d), 3.91 (3H,
s), 5.35 (1H, d), 5.50 (1H, t), 5.86
(1H, d), 7.01 (2H, d), 8.16 (2H,
d), 10.32 (1H, s), 12.57 (1H, s) Structural formula of target object: Example 6 10 g (24.7 mmol) of ascochlorin was dissolved in 100 ml of dry pyridine, 5.9 g (29.6 mmol) of para-methoxycarbonylbenzoyl chloride was added thereto, and the mixture was heated and stirred at 60 to 70°C for 7 hours, and further diluted with para-methoxycarbonylbenzoyl chloride. Added 5.9 g (29.6 mmol) of chloride and heated for 7 hours at 60~
Heat and stir at 70℃. Thereafter, the oily target product obtained by the same treatment as in Example 3 was dissolved in ethanol and left at room temperature. Target crystal 3.3g (23.6
%) is precipitated. When the crude crystals are recrystallized from ethanol, they show a melting point of 147-148℃, and the elemental analysis values are
As C 32 H 35 O 7 Cl Theoretical value (%); C67.78, H6.22 Actual value (%); C67.78, H6.30 δ of proton nuclear magnetic resonance <100MHz, CDCl 3 , internal standard TMS> Value: 0.68 (3H, s), 0.78 (3H,
d), 0.81 (3H, d), 1.59 (3H, s), 2.69
(3H, s), 3.55 (2H, d), 3.99 (3H, s)
5.35 (1H, d), 5.53 (1H, t), 5.84 (1H,
d), 10.34 (1H, s), 12.60 (1H, s)
8.14 (4H, m) Structural formula of target object: Example 7 20 g (49.4 mmol) of ascochlorin was dissolved in 100 ml of dry pyridine, and 13.2 g (73.7 mmol) of isonicotinic acid chloride hydrochloride was added thereto.
After heating and stirring at ℃ for 4 hours, 5 g (28.1 mmol) of isonicotinic acid chloride hydrochloride was further added and heating and stirring was continued for 7 hours. Then Example 3
The target product oily residue obtained by the same treatment as above is dissolved in ethanol and left in a cold place to obtain 7.2 g (28.6%) of the target product crystals. When the crude crystals are recrystallized from ethanol, they show a melting point of 111-113°C, and the elemental analysis values are as C 29 H 32 O 5 ClN Theoretical value (%): C68.30, H6.28 Actual value (%): C68.27 , H6.31 Proton nuclear magnetic resonance <100MHz, CDCl 3 , internal standard TMS> δ value: 0.68 (1H, s) 0.78 (3H,
d), 0.81 (3H, d), 1.67 (3H, s), 2.69
(3H, s), 3.45 (2H, d), 5.28 (1H, d)
5.35 (1H, t), 5.83 (1H, d), 800 (2H,
d), 8.80 (2H, d), 10.34 (1H, s)
12.61 (1H, s) Structural formula of target object: Example 8 5 g (12.35 mmol) of ascochlorin was dissolved in 50 ml of dry pyridine, 4.4 g (24.7 mmol) of picolinic acid chloride hydrochloride was added thereto, and the mixture was heated at 60°C.
After heating and stirring for 3 hours at 60° C., 1.5 g (8.43 mmol) of picolinic acid chloride hydrochloride was added and stirring at 60° C. for 7 hours. Then Example 3
Dissolve the target product in oil form in ethanol and leave it at room temperature to form crystals of the target product.
Obtain 2.0g (32%). When this crude crystal is recrystallized from ethanol, it shows a melting point of 150-152℃,
Elemental analysis values are as C 29 H 32 O 5 ClN Theoretical value (%); C68.30, H6.28 Actual value (%); C68.30, H6.25 Proton nuclear magnetic resonance <100MHz, CDCl 3 , internal standard δ value of TMS>: 0.66 (3H, s), 0.77 (3H,
d), 0.79 (3H, d), 1.76 (3H, s), 2.68
(3H, s), 3.55 (2H, d), 5.26 (1H,
d), 5.41 (1H, t), 5.83 (1H, d), 7.62
(1H, m), 7.96 (1H, m), 8.26 (1H,
d), 8.87 (1H, d), 10.33 (1H, s),
12.59 (1H, s) Structural formula of target object: Example 9 Genetic obese diabetic mouse C57BL/Ksj (db + /
db + ) to 4-0-nicotinoyl ascochlorin
1 feed containing 0.05% (Japan Clea, CE-2)
I gave it a week. Food intake, water consumption, urine volume, and urinary sugar excretion were measured daily for one week immediately before drug administration and one week after drug administration to examine the effects of the drug.
【表】
表から明らかなように4−0−ニコチノイルア
スコクロリンは遺伝性肥満糖尿病マウスの多飲多
尿、尿糖排泄を有意に抑制した。
実施例 10
5週令のddY系雄性マウスに本発明の新規化合
物0.05%を含む飼料(日本クレア,CE−2)を
1週間与え、7日目に屠殺して血中脂質ならびに
血糖を測定した。結果は表2のとおりである。[Table] As is clear from the table, 4-0-nicotinoyl ascochlorine significantly inhibited polydipsia and polyuria and urinary sugar excretion in genetically obese diabetic mice. Example 10 Five-week-old ddY male mice were fed a diet containing 0.05% of the novel compound of the present invention (Clea Japan, CE-2) for one week, sacrificed on the seventh day, and blood lipids and blood sugar were measured. . The results are shown in Table 2.
【表】
上表に示すようにすべての化合物が血糖降下作
用を有する。また4−0−ニコチノイルアスコク
ロリン,4−0−(P−クロロフエノキシ)アセ
チルアスコクロリン及び4−0−イソニコチノイ
ルアスコクロリンは血清脂質低下作用を示した。
実施例 11
5週令のddY系雄性マウス(n=7)の腹腔内
にストレプトゾトシン150mg/Kgを投与し24時間
後から4−0−ニコチノイルアスコクロリン0.05
%を含む飼料で1週間飼育した。対照群には薬物
を含まない同一飼料(日本クレア,CE−2)を
与えた。7日目に屠殺して、血糖ならびに血漿脂
質を測定した。結果は表3のとおりである。[Table] As shown in the table above, all compounds have hypoglycemic effects. Furthermore, 4-0-nicotinoyl ascochlorin, 4-0-(P-chlorophenoxy)acetylar ascochlorin, and 4-0-isonicotinoyl ascochlorin exhibited a serum lipid-lowering effect. Example 11 Streptozotocin 150 mg/Kg was intraperitoneally administered to 5-week-old ddY male mice (n = 7), and 24 hours later, 4-0-nicotinoyl ascochlorine 0.05 was administered intraperitoneally.
% was fed for one week. The control group was given the same drug-free diet (Clea Japan, CE-2). Animals were sacrificed on day 7 and blood glucose and plasma lipids were measured. The results are shown in Table 3.
【表】
表に示すように4−0−ニコチノイルアスコク
ロリンはストレプトゾトシン糖尿病モデルにおい
て、血糖及び血漿中性脂肪の上昇を著明に抑制し
た。
実施例 12
遺伝性肥満糖尿病マウスC57BL/Ksj(db+/
db+)に4−0−ニコチノイルアスコクロリン
0.05%を含む飼料を1週間与えた。同令の対照群
マウスには薬物不含の同一飼料(日本クレア,
CE−2)を与えた。1週間後に屠殺して血糖及
び血中脂質を測定した結果は下記の表に示すとお
りである。[Table] As shown in the table, 4-0-nicotinoyl ascochlorine significantly suppressed increases in blood sugar and plasma triglycerides in the streptozotocin diabetic model. Example 12 Genetic obese diabetic mouse C57BL/Ksj (db + /
db + ) to 4-0-nicotinoyl ascochlorin
Feed containing 0.05% was given for one week. Control group mice of the same age were given the same drug-free diet (Clea Japan,
CE-2) was given. The animals were sacrificed one week later and blood sugar and blood lipids were measured, and the results are shown in the table below.
【表】【table】
【表】
表に示すように4−0−ニコチノイルアスコク
ロリンはこの肥満糖尿病マウスの高脂血症及び高
血糖を顕著に改善した。[Table] As shown in the table, 4-0-nicotinoyl ascochlorine significantly improved hyperlipidemia and hyperglycemia in these obese diabetic mice.
Claims (1)
換されたアミノ基、核にハロゲン原子を有するフ
エノキシアルキル基又は、核に低級アルコキシ基
あるいは低級アルコキシカルボニル基を有するフ
エニル基を意味する。)で表されるアスコクロリ
ン誘導体。[Claims] 1. General formula (In the formula, R means a pyridyl group, an amino group substituted with a lower alkyl group, a phenoxyalkyl group having a halogen atom in the nucleus, or a phenyl group having a lower alkoxy group or a lower alkoxycarbonyl group in the nucleus. ) ascochlorin derivatives.
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP16882181A JPS5869860A (en) | 1981-10-23 | 1981-10-23 | Ascochlorin derivative |
US06/412,075 US4500544A (en) | 1981-09-10 | 1982-08-27 | Ascochlorin derivatives, and pharmaceutical composition containing the same |
CA000410511A CA1192557A (en) | 1981-09-10 | 1982-08-31 | Ascochlorin derivatives, process for preparing the same and pharmaceutical composition containing the same |
MX194321A MX157777A (en) | 1981-09-10 | 1982-09-08 | PROCEDURE FOR THE PREPARATION OF ASCOCHLORINE DERIVATIVES |
DE8282108325T DE3271383D1 (en) | 1981-09-10 | 1982-09-09 | Ascochlorin derivatives; process for preparing the same and pharmaceutical composition containing the same |
EP82108325A EP0074628B1 (en) | 1981-09-10 | 1982-09-09 | Ascochlorin derivatives; process for preparing the same and pharmaceutical composition containing the same |
CS843644A CS245791B2 (en) | 1981-09-10 | 1982-09-09 | Production method of askochlorine derivatives |
AT82108325T ATE20052T1 (en) | 1981-09-10 | 1982-09-09 | ASCOCHLORINE DERIVATIVES, PROCESSES FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
CS826526A CS244911B2 (en) | 1981-09-10 | 1982-09-09 | Production method of askochlorine derivatives |
ES515648A ES8400382A1 (en) | 1981-09-10 | 1982-09-10 | process for preparing the same and pharmaceutical composition containing the same. |
KR8204108A KR880002433B1 (en) | 1981-09-10 | 1982-09-10 | Process for the preparation of ascocloline derivation |
ES522459A ES522459A0 (en) | 1981-09-10 | 1983-05-16 | A PROCEDURE FOR THE PREPARATION OF AN ASCOCHLORINE DERIVATIVE. |
AR84295905A AR242373A1 (en) | 1981-09-10 | 1984-03-02 | A procedure for preparing an ascochlorine derivative. |
US06/607,400 US4542143A (en) | 1981-09-10 | 1984-05-03 | Pyridyl carbonyl ascochlorin derivatives and pharmaceutical compositions containing the same |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP16882181A JPS5869860A (en) | 1981-10-23 | 1981-10-23 | Ascochlorin derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5869860A JPS5869860A (en) | 1983-04-26 |
JPH036138B2 true JPH036138B2 (en) | 1991-01-29 |
Family
ID=15875127
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP16882181A Granted JPS5869860A (en) | 1981-09-10 | 1981-10-23 | Ascochlorin derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5869860A (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0816057B2 (en) * | 1992-09-10 | 1996-02-21 | 田村 學造 | Glycation inhibitors |
JP4553569B2 (en) * | 2003-10-06 | 2010-09-29 | アリジェン製薬株式会社 | Prophylactic / therapeutic agent for cryptosporidiosis containing phenolic derivatives as active ingredients |
-
1981
- 1981-10-23 JP JP16882181A patent/JPS5869860A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS5869860A (en) | 1983-04-26 |
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