JPH0473425B2 - - Google Patents
Info
- Publication number
- JPH0473425B2 JPH0473425B2 JP60140103A JP14010385A JPH0473425B2 JP H0473425 B2 JPH0473425 B2 JP H0473425B2 JP 60140103 A JP60140103 A JP 60140103A JP 14010385 A JP14010385 A JP 14010385A JP H0473425 B2 JPH0473425 B2 JP H0473425B2
- Authority
- JP
- Japan
- Prior art keywords
- substituted
- formula
- alkyl group
- different
- mono
- 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 - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims description 81
- -1 tri-substituted phenyl Chemical group 0.000 claims description 35
- 238000011282 treatment Methods 0.000 claims description 34
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 claims description 26
- 230000000202 analgesic effect Effects 0.000 claims description 19
- 101800001982 Cholecystokinin Proteins 0.000 claims description 16
- 102100025841 Cholecystokinin Human genes 0.000 claims description 16
- 229940107137 cholecystokinin Drugs 0.000 claims description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 10
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 8
- 208000002193 Pain Diseases 0.000 claims description 6
- 150000008064 anhydrides Chemical class 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- WHUUTDBJXJRKMK-UHFFFAOYSA-N glutamic acid Chemical class OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 6
- 230000036407 pain Effects 0.000 claims description 6
- 229920001184 polypeptide Polymers 0.000 claims description 6
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical class OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 5
- 208000022531 anorexia Diseases 0.000 claims description 5
- 230000001773 anti-convulsant effect Effects 0.000 claims description 5
- 239000001961 anticonvulsive agent Substances 0.000 claims description 5
- 229960003965 antiepileptics Drugs 0.000 claims description 5
- 206010061428 decreased appetite Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 229960002989 glutamic acid Drugs 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 230000004584 weight gain Effects 0.000 claims description 4
- 235000019786 weight gain Nutrition 0.000 claims description 4
- 235000013922 glutamic acid Nutrition 0.000 claims description 3
- 239000004220 glutamic acid Substances 0.000 claims description 3
- 150000002306 glutamic acid derivatives Chemical class 0.000 claims description 3
- 210000002569 neuron Anatomy 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 239000002948 appetite stimulant Substances 0.000 claims description 2
- 229960005261 aspartic acid Drugs 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 9
- 239000008194 pharmaceutical composition Substances 0.000 claims 6
- 125000000217 alkyl group Chemical group 0.000 claims 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 3
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims 2
- 229940024606 amino acid Drugs 0.000 claims 2
- 235000001014 amino acid Nutrition 0.000 claims 2
- 150000001413 amino acids Chemical class 0.000 claims 2
- 150000001263 acyl chlorides Chemical class 0.000 claims 1
- 238000003975 animal breeding Methods 0.000 claims 1
- 239000000731 choleretic agent Substances 0.000 claims 1
- 230000010534 mechanism of action Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 description 36
- 241000700159 Rattus Species 0.000 description 27
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 24
- 238000012360 testing method Methods 0.000 description 19
- 229940079593 drug Drugs 0.000 description 13
- 239000003814 drug Substances 0.000 description 13
- 229960005181 morphine Drugs 0.000 description 12
- 239000003193 general anesthetic agent Substances 0.000 description 11
- 108010087230 Sincalide Proteins 0.000 description 10
- 238000010609 cell counting kit-8 assay Methods 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 229940035674 anesthetics Drugs 0.000 description 9
- 230000008602 contraction Effects 0.000 description 7
- 210000000232 gallbladder Anatomy 0.000 description 7
- 230000003389 potentiating effect Effects 0.000 description 7
- 108010092674 Enkephalins Proteins 0.000 description 6
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical class C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 230000003042 antagnostic effect Effects 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 241000700199 Cavia porcellus Species 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000000730 antalgic agent Substances 0.000 description 4
- 210000000941 bile Anatomy 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 230000001595 contractor effect Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 3
- 241000699800 Cricetinae Species 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
- 210000002249 digestive system Anatomy 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000003533 narcotic effect Effects 0.000 description 3
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- UCFHLGYZODDCIJ-HACHORDNSA-N (2r)-2-benzamido-3,4-dichloropentanedioic acid Chemical compound OC(=O)C(Cl)C(Cl)[C@@H](C(O)=O)NC(=O)C1=CC=CC=C1 UCFHLGYZODDCIJ-HACHORDNSA-N 0.000 description 2
- LHUMPWOBZPBWRA-VIFPVBQESA-N 3,4-dichloro-n-[(3s)-2,6-dioxooxan-3-yl]benzamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(=O)N[C@@H]1C(=O)OC(=O)CC1 LHUMPWOBZPBWRA-VIFPVBQESA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 150000001509 aspartic acid derivatives Chemical class 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003754 cholecystokinin receptor blocking agent Substances 0.000 description 2
- 230000001989 choleretic effect Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 231100000673 doseâresponse relationship Toxicity 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001228 trophic effect Effects 0.000 description 2
- RJEUERNNQHNSKG-CCKFTAQKSA-N (2s)-2-amino-n-[(2r)-1-[[2-[[(2s)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]amino]-1-oxopropan-2-yl]-3-(4-hydroxyphenyl)propanamide Chemical compound C([C@H](N)C(=O)N[C@H](C)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)C1=CC=C(O)C=C1 RJEUERNNQHNSKG-CCKFTAQKSA-N 0.000 description 1
- RZMLEWIGPJPYLQ-CISYKLKFSA-N (3s)-3-[[(2s)-2-[[(2s)-2-[[2-[[(2s)-2-amino-4-methylsulfanylbutanoyl]amino]acetyl]amino]-3-(1h-indol-3-yl)propanoyl]amino]-4-methylsulfanylbutanoyl]amino]-4-[[(2s)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-4-oxobutanoic acid Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)[C@@H](N)CCSC)C(N)=O)C1=CC=CC=C1 RZMLEWIGPJPYLQ-CISYKLKFSA-N 0.000 description 1
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 1
- BYBJDDZACMHGTC-UHFFFAOYSA-N 5-(dibutylamino)-4-[(3,4-dichlorobenzoyl)amino]-5-oxopentanoic acid Chemical compound CCCCN(CCCC)C(=O)C(CCC(O)=O)NC(=O)C1=CC=C(Cl)C(Cl)=C1 BYBJDDZACMHGTC-UHFFFAOYSA-N 0.000 description 1
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 1
- 241000238876 Acari Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000000114 Pain Threshold Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 108010073383 cholecystokinin hexapeptide Proteins 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- IQFVPQOLBLOTPF-HKXUKFGYSA-L congo red Chemical compound [Na+].[Na+].C1=CC=CC2=C(N)C(/N=N/C3=CC=C(C=C3)C3=CC=C(C=C3)/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)N)=CC(S([O-])(=O)=O)=C21 IQFVPQOLBLOTPF-HKXUKFGYSA-L 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000000185 intracerebroventricular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 230000008558 metabolic pathway by substance Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 229960005195 morphine hydrochloride Drugs 0.000 description 1
- XELXKCKNPPSFNN-BJWPBXOKSA-N morphine hydrochloride trihydrate Chemical compound O.O.O.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XELXKCKNPPSFNN-BJWPBXOKSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 230000037040 pain threshold Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 210000003384 transverse colon Anatomy 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 235000012712 vegetable carbon Nutrition 0.000 description 1
- 239000004108 vegetable carbon Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Description
ç£æ¥äžã®å©çšåé
æ¬çºæã¯çç©åŠç掻æ§ããªããããé¡ã«å¯Ÿãæ®
æ掻æ§ãæããã°ã«ã¿ãã³é
žèªå°äœããã³ã¢ã¹ã
ã©ã®ã³é
žèªå°äœããã³ãã®è£œé æ³ã«é¢ããããã
ãã®èªå°äœã¯ç¹ã«ãæ¶åç³»ãäžæ¢ç¥çµç³»ã®çŸç
ã®
æ²»çã«èŠçæå¶å€ïŒpain killerïŒãšããŠããã
ã³é£æ¬²äžæ¯ãå€å ãŸãã¯å
å æ§ã®çç©åŠç掻æ§ã
ãªããããé¡ãé¢äžããå
šãŠã®çŸæ£ïŒäŸãã°è
«
çïŒã®æ²»çã«æçšã§ããã
çºæã®æ§æãšå¹æ
æ¬çºæã«ä¿ãæ°èŠãªïŒ€ïŒïŒ¬âã°ã«ã¿ãã³é
žèªå°
äœããã³ïŒ€ïŒïŒ¬âã¢ã¹ãã©ã®ã³é
žèªå°äœã¯ãäžèš
äžè¬åŒïŒ»ïŒœã§ç€ºããããŸããã®å»è¬çã«èš±å®¹ã
ããå¡©ããå
å«ããã
åŒäžããšRâ²ã¯äºãã«ç°ãªãOHãŸãã¯R2ã
ïœãR1ããã³R2ã¯åŸèšãšåæ矩ã§ãã
ããªãã¡ãäžèšåŒïŒ»ïŒœã®ååç©ã¯å
·äœçã«ã¯
äžèšåŒïŒ»ïŒ¡ïŒœããã³ïŒ»ïŒ¢ïŒœã®ååç©ã«åé¡ã
ããã
ãåŒäžãïœã¯ïŒãŸãã¯ïŒãR1ã¯ã¢ãããžããã
ã¯ããªçœ®æããšãã«ïŒåäžãããã¯ç°ãªãçŽéã
ããã¯åæç¶C1ãC4ã®ã¢ã«ãã«åºã§çœ®æããã
ã²ã³ã§çœ®æããŸãã¯ã·ã¢ãåºãããã¯ããªãã«ãª
ãã¡ãã«åºã§çœ®æïŒãããã³R2ã¯ã¢ã«ããªããã
ããªãžããŸãã¯ã¢ããããã¯ãžçœ®æã¢ããïŒåäž
ãããã¯ç°ãªãççŽ æ°ïŒãïŒã®çŽéãåæç¶ãã
ãã¯ç°åŒã¢ã«ãã«åºã§çœ®æïŒã§ããã
æ¬çºæã®ä¿è·å¯Ÿè±¡ãšããååç©ã¯ãåºä¹³åç©ã«
é¢ãèå³ããè¬çåŠçæ§è³ªãæããããšãèªãã
ããããããã®æ§è³ªã®ïŒã€ã¯ã¢ã«ãããä»ã®é®ç
å€ã®é®ç掻æ§ãå¢åŒ·ãããããšã§ããã
ãããã®æ§è³ªã¯ãå°ãªããšãäžéšã«ãããŠã³ã¬
ã·ã¹ãããã³ïŒcholecystokininïŒïŒCCKïŒãŸãã¯
ä»ã®çç©åŠç調æŽããããé¡ã«å¯Ÿãã匷åãªæ®æ
掻æ§ïŒããã¯åœè©²ååç©ã®å€ãã«ãã€ãŠç€ºãã
ãïŒã«åºã¥ããã®ãšããŠç解ãããã
åŸã€ãŠãæ¬çºæã«ä¿ãååç©ã¯ãæ¶åç³»ã®çŸç
ãªã©ãçš®ã
ã®äººéã®çŸç
ã®æ²»çãäŸãã°å€§è
žçã
è管æ©èœå€±èª¿ïŒbiliary diskinesiaïŒã®æ²»çã«æ
å©ã«äœ¿çšããããšãã§ãããããã¯ç
å ããã³åŒ·
床ã®çã¿ã®æ²»çã«äœ¿çšããããšãã§ããã
ãŸãæ¬çºæååç©ã¯ãè¬çåŠçç¹æ§ã«åºã¥ãã
CCKãŸãã¯ä»ã®çç©åŠçããªããããé¡ã®çç
åŠçãã€ãã³ïŒç¥çµåäœïŒã¬ãã«ã®å¹³è¡¡å€±èª¿ã«ã
ã粟ç¥çé害ã®æ²»çãžã®äœ¿çšãäºæ³ããããšãã§
ãããŸãé£æ¬²äžæ¯ã®æ²»çã蟲æ¥çšåç©ã®äœéå¢å
ã®ä¿é²ãããã¯çç©åŠç掻æ§ããããé¡ã«ãã€ãŠ
ç
ç现èçºè²ãèµ·ããçŸæ£ïŒäŸãšããŠå€åãè
«
çïŒã®æ²»çãžã®äœ¿çšãäºæ³ãããã
æ¬çºæååç©ã¯åè¿°ã®åŠããåçš®ã®å®éšã¢ãã«
ã«ãããŠãçäœå€ããã³çäœå
ã®äž¡æ¹ã§åŒ·åãªæ
CCK掻æ§ãæãããåŸã€ãŠãæ¬çºæååç©ã¯ã¢
ã«ã¢ããã®èã®ãã®CCKã«ãã€ãŠèªçºãããå
çž®ãçäœå€ããã³çäœå
ã®äž¡æ¹ã§çž®æžãããŠãµã®
ã®çµè
žã®èªçºåçž®ãæå¶ããããã³ã©ããã®èæ±
åæ³ãå¢å€§ããã
ãŸãæ¬çºæååç©ã®èå³ã®ããç¹ã¯ãé®çæ§éº»
é
è¬ããã³é®çæ§é麻é
è¬ã®é®ç掻æ§ã«å¢åŒ·å¹æ
ãæããããšã§ããã
ãã®å¢åŒ·äœçšã¯äºå®ã第ïŒã®æ®µéã«ãããŠã麻
é
å€ã®è¬éãããªãã«æžããããšãã§ããæ²»çä¿
æ°ãããŸãäœäžãããããšãªããããç¥ãããæ
ãŸãããªãå€æ°ã®å¯äœçšãå¶éããããšãã§ã
ãããŸãæ¬çºæã®ååç©ã¯ã麻é
å€ã«ãããŠãã
ç¥ãããŠããèæ§çŸè±¡ã®ããã«è¬çå¹æãäœäžã
ãå Žåã«ããã®é®ç掻æ§ãå床å®å®åãããã®ã«
䜿çšããããšãã§ãããã®å Žåæ²»ççšéãå¢å€§ã
ãå¿
èŠã¯ãªããåŸã€ãŠããã®ãããªéœåã®ããæ²»
çç¹æ§ã¯éº»é
è¬ã®é·æ䜿çšããäžæ¯ã«ããã€ãæ£
è
ãåŸã
ã«è§£æ¯ãããããã«ã圹ç«ã€ã
é麻é
æ§é®çå€ã®å Žåã«ã¯ãé®ç掻æ§ã®å¢å€§äœ
çšãããããšãªãããäžè¬ã«ãããè¬ç©ã«ãã€ãŠ
害ãããèç²èã®ä¿è·äœçšãæããç¹ã§ããããŠ
æçšã§ããã
ãšããããé®çå€ã®æŽ»æ§å¢åŒ·äœçšã¯ã匷åãªé®
ç掻æ§ãæãããšã³ã±ãã¢ãªã³é¡ïŒenkephalinsïŒ
ïŒå
å ççåŠçããããé¡ïŒã®å æ°Žå解ãããã
ã¯ããæ¬çºæã®ååç©ã®èœåãé¢ä¿ããŠãããã
ãã¯ãšã³ã±ãã¢ãªã³é¡èªäœã«ãã倧ããªåæžæã
ãã³ãã倧ããªæŽ»æ§ãä»äžããã
æ¬çºæååç©ã®å»è¬åœ¢æ
ã¯éåžžã®æ¹æ³ã§èª¿è£œã
ããäŸãã°é å€ãã«ãã»ã«å€ãæžæ¿æ¶²å€ã溶液å€
ããã³åå€ã«è£œå€ããããšãã§ãããŸãçµå£ãé
çµå£ãŸãã¯çŽè
žãä»ããŠæäžããããšãã§ããã
掻æ§æåã¯æ£è
ã«å¯ŸããäŸãã°0.1ã10mgïŒäœé
ïŒKgïŒã®éã§æäžãããã
éçµå£æäžã®å Žåãåœè©²ååç©ã®æ°Žæº¶æ§å¡©ïŒäŸ
ãã°ãããªãŠã å¡©ãŸãã¯ä»ã®éæ¯æ§ã®å»è¬çã«èš±
容ãããå¡©ïŒãçšããã®ã奜ãŸããããŸãäžæŽ»æ§
æåãšããŠãå»è¬çšã«äžè¬ã«äœ¿çšãããŠãã賊圢
å€ãçµåå€ãè³éŠå€ãåæ£å€ãçè²å€ã湿最å€ãª
ã©ã®ç©è³ªãçšããããã
æ¬çºæã®ã°ã«ã¿ãã³é
žèªå°äœããã³ã¢ã¹ãã©ã®
ã³é
žèªå°äœã®è£œé æ³ã¯ã
(a) åŒïŒ
ãåŒäžãïœããã³R1ã¯åèšãšåæ矩ã
ã§ç€ºãããååå
ç¡æ°Žç©ãåŒïŒR2HãåŒäžãR2
ã¯åèšãšåæ矩ãã§ç€ºãããã¢ãã³ãšãïŒãïŒ
ã®ã¢ã«æ¯ããã³â20âã30âã®æž©åºŠã«ãŠåå¿ã
ããåå¿æ¶²ããåèšåŒããããã³ãã
ã®ååç©ãååããããããåé¢ãã
å·¥çšãå
å«ããããšãç¹åŸŽãšããããªããåå¿
枩床ã¯â10âã10âã奜ãŸããã
äžèšåŒããã®ååå
ç¡æ°Žç©ã¯ããããŸã§è£œ
é ãããããšã®ãªãæ°èŠãªååç©ã§ããããã
ãååå
ç¡æ°Žç©ããã¯ã
(b) ã°ã«ã¿ãã³é
žãŸãã¯ã¢ã¹ãã©ã®ã³é
žãã·ãšã
ãã³âããŠãã³ïŒSchottenâBaumanïŒã®æ¡ä»¶
äžãåœã¢ã«éã®åŒïŒR1âCOâClïŒåŒäžãR1ã¯
åèšãšåæ矩ïŒã®å¡©åã¢ã·ã«ãšâ20âã30âã®
枩床ã§åå¿ãããŠãåŒïŒ
ã®ïŒ®âã¢ã·ã«åååç©ãåŸã次ãã§
(c) 該ååç©ããããã®ãŸãŸãããã¯çžæº¶æ§ã®
äžæŽ»æ§æº¶åªäžãã¢ã«æ¯ïŒã10ã®ç¡æ°Žé
¢é
žãšâ10
âãéæµæž©åºŠã«ãŠåå¿ããè±æ°Žãã
å·¥çšã«ãã€ãŠã補é ãããã
æ¬çºæã«ä¿ã補é æ³ã®äžé£ã®å·¥çšã®å
šäœããäž
èšåå¿å·¥çšã«èšèŒããã
äžèšã¢ã·ã«åå·¥çšïœã¯ãïŒã15âã®æž©åºŠãïŒã
24æéã®æ¡ä»¶ã§è¡ãã®ã奜ãŸãããçŽïŒâã®æž©åºŠ
ããã³12æéã®æéãæšå¥šãããã
å·¥çšïœã«ãããŠãåå¿æéã¯äŸãã°çŽ30åã12
æéã§ãã€ãŠãçŽïŒæéã奜ãŸãããç¡æ°Žé
¢é
žã®
éã¯ååç©ããïŒã¢ã«ã«å¯ŸãïŒã¢ã«ã奜ãŸã
ãã
ã¢ããåå·¥çšïœã«ãããŠãåŒïŒR2Hã®ã¢ãã³
ãååå
ç¡æ°Žç©ãããšã®ã¢ã«æ¯2.5ãïŒã§å ã
ãããšã奜ãŸãããåå¿ã¯çŽ30åã12æéã奜ãŸ
ããã¯ïŒæéã§è¡ãã
ååç©ããããã³ããã®çžå¯Ÿå²åã¯ã
䜿çšããR1ããã³R2眮æåºã®çš®é¡ã«ãã€ãŠå€å
ãããç°æ§äœïŒ¡ããã³ïŒ¢ã¯ãåå¥çµæ¶ïŒäžèš
衚ããã³ïŒ€ã«ç€ºã溶å€ã䜿çšïŒãŸãã¯å¡©åºæ§åª
äœã§ã®æœåºã«ãã€ãŠåé¢ããããšãã§ããããå¹³
åããŠå€ãæ¹ã®é
žã¯ååç©ããã§ããã
次ã«å®æœäŸãæããŠãæ¬çºæãããå
·äœçã«èª¬
æããã
å®æœäŸ ïŒ
ïŒïŒïŒâãžã¯ããââãã³ãŸã€ã«ã°ã«ã¿ãã³
é
žïŒååç©ïŒ¡âïŒïŒã®è£œé ïŒâ
200mlã®1Nâçé
žãããªãŠã äžã®14.7ïœïŒ0.1ã¢
ã«ïŒã®ïŒ¬âã°ã«ã¿ãã³é
žã®æº¶æ¶²ãïŒâã«å·åŽãã
ããã«æ¹æããã³å·åŽäžã100mlã®1Nâçé
žãã
ãªãŠã ããã³21ïœïŒ0.1ã¢ã«ïŒã®ïŒïŒïŒâã¯ãã
ãã³ãŸã€ã«ã¯ããªããçŽ30åã«ããã€ãŠåæã«æ·»
å ãããæ··åç©ã12æéæŸçœ®ããŠåå¿ããããã
ããæ¿HClã§ã³ã³ãŽâèµ€è²ïŒCongoredïŒãšãªã
ãŸã§é
žæ§åããçæããæ²æŸ±ç©ãæ¿Ÿå»ãããæ®æž£
ãH2Oããåçµæ¶ãããèç¹141ã145âãTLC
ïŒäžèšè¡šåç
§ïŒãRfïŒ0.46ãåé24.5ïœïŒåç76.4
ïŒ
ïŒã
äžèšãšåæ§ãªæ¹æ³ã§åŒããã®ååç©ïŒå
ã®å
å¿å·¥çšåç
§ïŒã®å
šãŠã補é ãããåŸãããååç©
ãäžèšè¡šïŒ¡ã«ç€ºãïŒãªããããããåå®ããç¹æ§
å€ãåçããã³çµæ¶åã«çšãã溶å€ã䜵èšïŒã
INDUSTRIAL APPLICATION FIELD OF THE INVENTION The present invention relates to glutamic acid and aspartic acid derivatives having antagonistic activity against biologically active polypeptides, and a method for producing the same. These derivatives are particularly useful as pain killers in the treatment of diseases of the digestive system and central nervous system, as well as anorexia and all diseases in which exogenous or endogenous biologically active polypeptides are involved, e.g. Tumors). Structure and Effects of the Invention The novel D,L-glutamic acid derivative and D,L-aspartic acid derivative according to the present invention are represented by the following general formula [], and also include pharmaceutically acceptable salts thereof. [In the formula, R and Râ² are different from each other and are OH or R 2 ,
n, R 1 and R 2 have the same meanings as described below.] That is, the compound of the above formula [] is specifically classified into the compounds of the following formulas [A] and [B]. [In the formula, n is 1 or 2, R 1 is mono-, di- or tri-substituted phenyl (substituted with the same or different linear or branched C 1 -C 4 alkyl group, substituted with halogen, or cyano group or tri-substituted phenyl) (substituted with a fluoromethyl group), and R 2 is morpholino, piperidino or mono- or di-substituted amino (substituted with the same or different straight chain, branched or cyclic alkyl group having 1 to 8 carbon atoms)] of the present invention It is recognized that the compounds to be protected have interesting pharmacological properties with respect to mammals. One of these properties is that it can enhance the analgesic activity of morphine and other analgesics. These properties are understood to be based, at least in part, on strong antagonistic activity toward cholecystokinin (CCK) or other biological regulatory peptides, which is exhibited by many of the compounds in question. be done. The compounds according to the invention can therefore be advantageously used in the treatment of various human diseases, such as diseases of the digestive system, for example in the treatment of colitis or biliary diskinesia, or in the treatment of etiology and severity. It can be used to treat pain. Furthermore, based on the pharmacological properties, the compound of the present invention has
The use of CCK or other biological polypeptides in the treatment of psychological disorders due to imbalances in physiological neuron levels, as well as in the treatment of anorexia, weight gain in agricultural animals, can be envisaged. Use in the treatment of diseases (eg, perhaps tumors) in which pathological cell development occurs through the promotion of or biologically active peptides is also envisaged. As mentioned above, the compound of the present invention has strong anti-inflammatory properties both in vitro and in vivo in various experimental models.
Has CCK activity. Accordingly, the compounds of the invention reduce CCK-induced contractions of the guinea pig gallbladder both in vitro and in vivo, inhibit induced contractions of the rabbit colon, and increase bile secretion in rats. It is also interesting that the compounds of the invention have an enhancing effect on the analgesic activity of analgesic anesthetics and analgesic non-anesthetics. This potentiating effect in fact makes it possible to considerably reduce the dose of anesthetic agent in the first stage, limiting a number of well-known undesirable side effects without significantly reducing the therapeutic index. The compounds of the invention can also be used to re-stabilize their analgesic activity when their pharmacological efficacy has decreased due to the well-known tolerance phenomenon in anesthetics, in which case the therapeutic dose can be increased. do not have to. Such advantageous therapeutic properties therefore also serve to gradually detoxify patients who have become addicted to the long-term use of anesthetics. Non-narcotic analgesics are extremely useful not only in their ability to increase analgesic activity but also in their ability to protect the gastric mucosa, which is generally damaged by such drugs. In particular, the activity-enhancing effect of analgesics is due to enkephalins, which have strong analgesic activity.
The ability of the compounds of the invention to block the hydrolysis of (endogenous physiological peptides) is relevant. This confers a greater half-life and greater activity than the enkephalins themselves. Pharmaceutical forms of the compounds of the invention can be prepared in a conventional manner, for example in tablets, capsules, suspensions, solutions and suppositories, and can be administered orally, parenterally or rectally. can.
The active ingredient is administered to the patient in an amount of, for example, 0.1 to 10 mg/kg body weight. For parenteral administration, it is preferred to use a water-soluble salt of the compound, such as the sodium salt or other non-toxic pharmaceutically acceptable salt. In addition, as inactive ingredients, substances commonly used for pharmaceutical purposes such as excipients, binders, fragrances, dispersants, colorants, and wetting agents are used. The method for producing glutamic acid derivatives and aspartic acid derivatives of the present invention is as follows: (a) Formula: [In the formula, n and R 1 have the same meanings as above] An intramolecular anhydride represented by the formula: R 2 H [In the formula, R 2
has the same meaning as above], and 1 to 5
The above formulas [A] and [B] are obtained from the reaction solution at a molar ratio of -20°C to 30°C.
The method is characterized in that it includes a step of collecting the compounds and separating them. Note that the reaction temperature is preferably -10°C to 10°C. The intramolecular anhydride of the above formula [] is a novel compound that has never been produced before. Such intramolecular anhydride [ ] is obtained by (b) converting glutamic acid or aspartic acid under Schotten-Bauman conditions in an equimolar amount of the formula: R 1 -CO-Cl (wherein R 1 is as defined above). The formula: Then, (c) the compound [ ] is mixed with acetic anhydride in a molar ratio of 1 to 10 in a molar ratio of 1 to 10 in a compatible inert solvent.
It is produced by a process of reaction and dehydration at temperatures ranging from °C to reflux. The entire series of steps of the production method according to the present invention is described in the reaction steps below. The above acylation step b is carried out at a temperature of 0 to 15°C, 1 to
Preferably it is carried out under conditions of 24 hours, with a temperature of about 5° C. and a time of 12 hours recommended. In step c, the reaction time is, for example, about 30 minutes to 12
The time period is preferably about 3 hours, and the amount of acetic anhydride is preferably 3 mol per 1 mol of the compound []. In the amidation step a, the amine of formula: R 2 H is preferably added in a molar ratio of 2.5 to 1 with the intramolecular anhydride [], and the reaction is carried out for about 30 minutes to 12 hours, preferably 3 hours. The relative proportions of compounds [A] and [B] are:
It varies depending on the type of R 1 and R 2 substituents used. Isomers A and B can be separated by fractional crystallization (using the solvents shown in Tables C and D below) or by extraction in basic media, but on average the more acid is compound [B] It is. Next, the present invention will be explained in more detail with reference to Examples. Example 1 Preparation of 3,4-dichloro-N-benzoylglutamic acid (compound A-4): - A solution of 14.7 g (0.1 mol) of L-glutamic acid in 200 ml of 1N sodium carbonate was cooled to 5°C,
To this, with stirring and cooling, 100 ml of 1N sodium carbonate and 21 g (0.1 mol) of 3,4-chlorobenzoyl chloride are added simultaneously over about 30 minutes. The mixture is left to react for 12 hours. This is acidified with concentrated HCl to a Congo red color and the precipitate that forms is filtered off. The residue is recrystallized from H2O . Melting point 141-145â, TLC
(See table below), Rf=0.46. Yield 24.5g (yield 76.4
%). All compounds of formula [] (see previous reaction steps) are prepared in the same manner as above. The resulting compounds are shown in Table A below (characteristic values for identifying them, yields, and solvents used for crystallization are also listed).
ãè¡šããtableã
ãè¡šã
å®æœäŸ ïŒ
ïŒïŒïŒâãžã¯ãããã³ãŸã€ã«ã°ã«ã¿ãã³é
žç¡æ°Ž
ç©ïŒè¡šïŒ¢ã®ååç©ïŒ¢âïŒïŒã®è£œé ïŒâ
30.6ïœïŒ0.3ã¢ã«ïŒã®ç¡æ°Žé
¢é
žããã³60mlã®ã€
ãœãããã«ãšãŒãã«ãã32.0ïœïŒ0.1ã¢ã«ïŒã®ïŒïŒ
ïŒâãžã¯ãããã³ãŸã€ã«ã°ã«ã¿ãã³é
žã«å ããã
ãããåå¿æ¶²ãéæµïŒ73ã77âïŒäžã§ïŒæéå ç±
ããããããå·åŽãããéããå°éã®ãšãŒãã«ã§
æŽã€ãŠæ®çç¡æ°Žé
¢é
žãé€å»ãã也ç¥ããããã®ã
ãã«ããŠ27.0ïœãåŸãïŒåç89.3ïŒ
ïŒãèç¹188ã
190âã
äžèšãšåæ§ãªæ¹æ³ã§åŒããã®ååç©ïŒå
ã®å
å¿å·¥çšåç
§ïŒã®å
šãŠã補é ããããããã®ååç©
ã®å€æ°ã®å
·äœäŸãäžèšè¡šïŒ¢ã«ç€ºãïŒãªããããã
ãåå®ããç¹æ§å€ããã³åçã䜵èšïŒã[Table] Example 2 Preparation of 3,4-dichlorobenzoylglutamic anhydride (compound B-4 in Table B): - 30.6 g (0.3 mol) acetic anhydride and 60 ml isopropyl ether to 32.0 g (0.1 mol) 3,
Add to 4-dichlorobenzoylglutamic acid.
The reaction solution is heated under reflux (73-77°C) for 2 hours. It is cooled, filtered, washed with a little ether to remove residual acetic anhydride, and dried. 27.0 g are thus obtained (yield 89.3%). Melting point 188~
190â. All of the compounds of formula [] (see previous reaction steps) are prepared in the same manner as above. A number of specific examples of these compounds are shown in Table B below (characteristic values and yields for identifying them are also listed).
ãè¡šããtableã
ãè¡šã
å®æœäŸ ïŒ
ïŒïŒ¬âïŒâïŒïŒïŒïŒâãžã¯ãããã³ãŸã€ã«ã¢
ããïŒâïŒâïŒãžâïœâããã«ã¢ããïŒâïŒâãª
ããœãã³ã¿ã³é
žïŒè¡šïŒ£ã®ååç©ïŒ£âïŒïŒã®è£œ
é ïŒâ
30.2ïœïŒ0.1ã¢ã«ïŒã®ïŒïŒïŒâãžã¯ãããã³ãŸ
ã€ã«ã°ã«ã¿ãã³é
žç¡æ°Žç©ãåå¿åšã«å
å¡«ãã100
mlã®æ°Žäžã§æžæ¿ãããåå¿æ¶²ãçŽïŒâã«å·åŽãã
32.2ïœïŒ0.25ã¢ã«ïŒã®ãžâïœâããã«ã¢ããã15
åã«ããã€ãŠæäžããã
ãã®æž©åºŠã§æ··åç©ãæŸçœ®ããŠïŒæéåå¿ããã
æ°·é
¢é
žã§é
žæ§åããããããæ¿Ÿéããæ°Žã§äžæ§ã«
ãªããŸã§æŽãã也ç¥ããããã®ããã«ããŠ16.4ïœ
ãåŸãïŒåç38ïŒ
ïŒãèç¹81ã83âïŒã€ãœããã
ã«ãšãŒãã«ããæ¶åºïŒãTLCãRfïŒ0.92ã
äžèšãšåæ§ãªæ¹æ³ã§åŒããããã³ãã
ã®ååç©ïŒå
ã®åå¿å·¥çšåç
§ïŒã®å
šãŠã補é ã
ãããããã®ååç©ã®å€æ°ã®å
·äœäŸãäžèšè¡šïŒ£ã
ãã³ïŒ€ã«ç€ºãïŒãªããããããåå®ããç¹æ§å€ã
ãã³åçã䜵èšïŒã[Table] Example 3 Preparation of D,L-4-(3,4-dichlorobenzoylamino)-5-(di-n-butylamino)-5-oxopentanoic acid (compound C-6 in Table C): - Charge 30.2 g (0.1 mol) of 3,4-dichlorobenzoylglutamic anhydride to the reactor and
ml of water. The reaction solution was cooled to about 5°C,
32.2 g (0.25 mol) of di-n-butylamino
Remove for several minutes. The mixture was left to react at this temperature for 3 hours,
Acidify with glacial acetic acid. This is filtered, washed with water until neutral, and dried. In this way 16.4g
(yield 38%). Melting point: 81-83°C (crystallized from isopropyl ether). TLC, Rf = 0.92. Expressions [A] and [B] in the same manner as above
(see previous reaction steps). A number of specific examples of these compounds are shown in Tables C and D below (characteristic values and yields identifying them are also listed).
ãè¡šããtableã
ãè¡šããtableã
ãè¡šããtableã
ãè¡šã
æ¬çºæã®ä¿è·å¯Ÿè±¡ã§ããååç©ã«ãã€ãŠç€ºãã
ãé®ç掻æ§ã¯ã麻é
å€ã®é®ç掻æ§ã®å¢åŒ·äœçšãã
ã³è©²å¢åŒ·äœçšãéæããã¡ã«ããºã ã®äž¡æ¹ãå®èšŒ
ããäžé£ã®è¬çè©Šéšã«ãã€ãŠäŸç€ºãããã
å®éšNo.ïŒïŒããŒã«ã»ããªãã¯ã»ãã¹ãïŒTail
Flick TestïŒã«ããã©ããã®é®çæ§éº»é
è¬ã®
ç¡çèŠã®å¢å€§
ãããæ¹æ³ã¯ããªã¹ãJ.Pharmacol.Exp.
Ther.ãïŒ143ã141ã148é ã1964幎ïŒã«èšèŒã®
æ¹æ³ã§ããã
絶é£ããŠããªãäœéçŽ150ã200ïœã®éã®ã©ã
ãã䜿çšãããã·ããã«ïŒã€ã®ãã€ã³ããéž
ã³ãç±æºïŒ75âïŒã§ç
§å°ããã©ãããã·ããã
åãããªãã§ãã€ãšããŠããæéïŒç§åäœïŒã
枬å®ãããç±æºäžã§æ倧æéïŒç§éãéžã³ãã
ã®åŸãããã®å Žåããã©ãããååºããŠçµç¹é
害ãåé¿ããã枬å®ã¯ãè¬å€ã®åŠçã®åïŒå¯Ÿ
ç
§ïŒããã³åŸã«è¡ããæ¬çºæã®è¬å€ïŒ10mgïŒ
KgïŒã®æäžã¯ãã¢ã«ããïŒïŒmgïŒKgïŒã®æäžå
10åããã³çŽåã«è
¹è£å
ã«è¡ããåã
ã®ã©ãã
ã®å€åçã¯ã次åŒã§ç®åºããã
å€åçïŒïŒ
ïŒ
ïŒåŠçåŸã®æéïŒç§ïŒâ管çæéïŒç§ïŒïŒïŒâ管çæ
éïŒç§ïŒÃ100
枬å®ã¯é®çå€ã®åŠçãã10ã20ã30ã45ã60
ããã³90ååŸã«è¡ãã
åŸãããçµæãè¡šïŒã«ç€ºãã該衚ã«è¢«åŠçã°
ã«ãŒãããã³æäžéãçèŠã®æœäŒããå¹³åå€å
çïŒïŒå¹ã®ã°ã«ãŒãã«ã€ããŠèšç®ïŒãïŒã90å
éã«èšç®ããå¹³åå€ïŒÂ±S.E.ïŒããã³ã¢ã«ãã
åç¬ãŸãã¯æ¬çºæååç©ãšäœµçšããŠæäžããæœ
åšèœæ¯ãèšé²ããã
è¡šïŒã®ããŒã¿ãããè©ŠéšçšéïŒ10mgïŒKgi.p.ïŒ
ã«ãããŠãã»ãšãã©ã®æŽ»æ§çæç©ã®å Žåã¢ã«ã
ãã®æŽ»æ§ãå¢åŒ·ãããã®æŽ»æ§ãã¢ã«ããåç¬ã®
çŽïŒåã®æŽ»æ§ãŸã§äžããã®ãèªãããããTable: The analgesic activity exhibited by the compounds protected by the present invention has been exemplified by a series of pharmacological tests demonstrating both the potentiating effect on the analgesic activity of anesthetic agents and the mechanism by which this potentiating effect is achieved. Ru. Experiment No. 1: Tail flick test (Tail
Increased analgesia of analgesic anesthetics in rats by Flick Test. Such a method is described by Harris, J. Pharmacol.
The method described in "Ther." ( 143 , pp. 141-148, 1964). Male rats weighing about 150-200 g without fasting are used. Select one point on the tip, irradiate it with a heat source (75°C), and measure the time (in seconds) that the rat stays still without moving the tip. A maximum time of 8 seconds under the heat source is chosen, after which the rats are removed in each case to avoid tissue damage. Measurements are taken before (control) and after drug treatment. Drug of the present invention (10mg/
Kg) was administered before the administration of morphine (2 mg/Kg).
Do it abdominally and vaginally for 10 minutes and just before. The rate of change for each rat is calculated using the following formula. Rate of change (%) = Time after treatment (seconds) - Administration time (seconds) / 8 - Administration time (seconds) x 100 Measurements were taken at 10, 20, 30, 45, 60 from the analgesic treatment.
and after 90 minutes. The results obtained are shown in Table 1. The table shows the treated group and dose, the mean rate of latent change in pain sensation (calculated for a group of 5 animals), the mean value (±SE) calculated from 1 to 90 minutes, and morphine alone or in combination with the compound of the invention. Record the administered potency ratio. From the data in Table 1, the test dose (10mg/Kgi.p.)
It has been found that most active products potentiate the activity of morphine, increasing its activity to about three times that of morphine alone.
ãè¡šããtableã
ãè¡šããtableã
ãè¡šã
å®éšNo.ïŒïŒãããã»ãã¬ãŒãã»ãã¹ãïŒHotâ
plate testïŒ
ãããæ¹æ³ã¯ããšãã€ãã®ãJ.Pharmac.
Exp.Ther.ãïŒ107ã385é ã1953幎ïŒã«èšèŒã®
æ¹æ³ã§ããã
絶é£ããŠããªãäœéçŽ150ïœã®éã®ã©ããã°
ã«ãŒãïŒïŒå¹ïŒã䜿çšããã
éæãªåæ±å®¹åšã®åºã®éå±ãã¬ãŒããå
±æ²žæ··
åç©ïŒã¢ã»ãã³ïŒã®é
žãšãã«ïŒïŒïŒïŒïŒã§55±
ïŒâã«å ç±ãã®äžã«ã©ãããèŒããã
åå¿æéã¯ãã©ããããããã»ãã¬ãŒãã«çœ®
ãããšãã®æç¹ããã©ããã足ããªããããã
ãã¯å®¹åšããé£ã³åºãããšãããŸã§ã®ééæé
ãšããã管çåå¿æéã¯ãè¬å€æäžã®10åãã
ã³ïŒåå䞊ã³ã«æäžããŠãã10ã20ã30ã45ã
60ããã³90ååŸã«æž¬å®ãããæ倧æé30ç§éã©
ããããã¬ãŒãäžã«æŸçœ®ããã
çæç©ã®æäžã«å¯Ÿããå¿çã¯ãæ£åžžãªåå¿æ
éã®å°ãªããšãïŒåã§ããã°éœæ§ãšã¿ãªããåŸ
ãããçµæãè¡š2aããã³2bã«ç€ºãããããè¡š
ã«ã被åŠçã°ã«ãŒããæäžéããã³ãã¬ãŒãäž
ã®æ»åšæéïŒéœæ§å¿çã®æ°ïŒåŠçåæ°ã§è¡šç€ºïŒ
ãèšé²ããã[Table] Experiment No. 2: Hot plate test (Hot-
plate test) Such a method is described by Edei et al. in J.Pharmac.
Exp. Ther.'' ( 107 , p. 385, 1953). A group of 5 non-fasted male rats weighing approximately 150 g are used. Metal plate at the bottom of a transparent cylindrical container [55± with azeotrope (acetone/ethyl formate = 1:1)
Heat to 1â] and place the rat on top. The reaction time is the time interval from when the rat is placed on the hot plate until the rat licks its paw or attempts to jump out of the container. Control reaction times were 10 and 5 minutes before drug administration and 10, 20, 30, 45,
Measure after 60 and 90 minutes. Leave the rat on the plate for a maximum of 30 seconds. A response to product administration is considered positive if it is at least twice the normal reaction time. The results obtained are shown in Tables 2a and 2b. The table lists the treated group, dose and time spent on the plate (expressed as number of positive responses/number of treatments).
Record.
ãè¡šã
äžèšè¡šã®çµæãããååç©ïŒ£â20ã¯ïŒmgïŒKg
i.p.ã®æäžéã§ããããããã·ããšã³ã®é®ç掻
æ§ã®ïŒåã«åã¶ããšãèªãããããå®éã®æ倧
å¹æã¯10mgïŒKgi.p.ã®æäžéã«ãããŠåŸãããã[Table] From the results in the table above, compound C-20 is 3mg/Kg
Even at ip doses, twice the analgesic activity of propoxyphene is observed. The actual maximum effect is obtained at a dose of 10 mg/Kgi.p.
ãè¡šããtableã
ãè¡šã
è¡š2bã®çµæãããæ¬çºæååç©ã¯æäžéïŒ
mgïŒKgi.p.ã§ããããããã·ããšã³ãã¡ã¿ãã³
ã®é®ç掻æ§ã®å°ãªããšãïŒåã«åã¶ããšãèªã
ãããã
é麻é
è¬ã®é®ç掻æ§ãå¢å€§ããã«ã¯ãæ¬çºæ
è¬å€ã®æäžéãå€ãããå¿
èŠããããäžè¬ã«æ
äžéã倧ããçšèãã掻æ§ã瀺ãã
å®éšNo.ïŒïŒã©ããã®çµç®ããšãã¯ã«ãã€ãŠè§£é€ã
ããå
å 麻é
å€ã®é®ç掻æ§ã«å¯Ÿããæ¬çºæåå
ç©ã®åœ±é¿ïŒããŒã«ã»ããªãã¯ã»ãã¹ãã§æž¬å®ïŒ
ãããæ¹æ³ã¯ãã«ã€ã¹ãã®ããžãšã€ã»ããŠãŒ
ãã¹ã¯ïŒJ.Neurosc.ïŒãïŒïŒã358é ã1961幎ïŒ
ã«èšèŒã®æ¹æ³ã§ããã絶é£ããŠããªãéã®ã©ã
ãïŒäœéçŽ200ïœïŒã䜿çšããã
ã©ããã®å足ã«60Hzâ2.5ïœïŒ¡ã®é»æµãïŒç§
æ¯ã«ïŒç§éã®æç¶ãã«ã¹ã§20åéé©çšããŠãã©
ããã«ã¹ãã¬ã¹ãè² è·ããã
ãã®ã¹ãã¬ã¹èŠå¶ã«ãããå
å 麻é
å€ã®è§£é€
ãèªçºãããé»æ°åºæ¿åŸçŽã¡ã«ãã©ãããè¡šïŒ
ã«ç€ºãæéã§ããŒã«ã»ããªãã¯ã»ãã¹ãã«ä»
ãã
ååç©ã¯é»æ°ã·ãšãã¯ã®çŽåã«i.v.ïŒéèå
ïŒ
æäžããïŒæäžéã¯è¡šïŒã«ç€ºãïŒã[Table] From the results in Table 2b, it can be seen that the compound of the present invention
mg/Kgi.p. is at least twice the analgesic activity of propoxyphen or methadone. In order to increase the analgesic activity of non-narcotic drugs, it is necessary to increase the dose of the drug of the present invention, and generally the larger the dose, the more significant the activity. Experiment No. 3: Effect of the compounds of the present invention on the analgesic activity of endogenous anesthetics released by transdermal ticks in rats (measured by tail flick test). .Neurosc.)â ( 1 , 358 pages, 1961)
This is the method described in . Male rats (weighing about 200 g) that are not fasted are used. Rats are stressed by applying a 60 Hz - 2.5 mA current to their paws with 1 second duration pulses every 5 seconds for 20 minutes. This stress regulation induces release of endogenous anesthetics. Immediately after electrical stimulation, rats were
Subject to tail flick test for the times indicated. The compound is given IV (intravenously) just before the electric shock.
(Dosages are shown in Table 3).
ãè¡šããtableã
ãè¡šããtableã
ãè¡šããtableã
ãè¡šã
è¡šïŒã®ããŒã¿ãããæ¬çºæååç©ã¯ïŒmgïŒKg
ã®æäžéã§ããå
å ãšã³ã±ãã¢ãªã³é¡ã®é®ç掻
æ§ã極ããŠéèŠãªçšåºŠã«å¢å€§ãããããšãèªã
ãããããã®å¢å€§ã¯æäžéã«äŸåãããã®å¢å€§
å¹æã¯å®éäžã匷床ããã³æç¶æ§å
±ã«æäžéã«
äŸåããã
å®éšNo.ïŒïŒæ¬çºæååç©ã«ãã€ãŠèªçºããããšã³
ã±ãã¢ãªã³é¡ã®é®ç掻æ§ã®å¢åŒ·äœçš
æ¬çºæååç©ã®äœçšã¡ã«ããºã ã®ïŒã€ãå³ã¡
å
å ãšã³ã±ã¢ãªã³é¡ã®é
µçŽ å解ã®æå¶äœçšãã
ãšãã¯ããããã以äžã«ç€ºãå®éšãè¡ããããŒ
ãã«ãã®ãã©ã€ãã»ãµã€ãšã³ã¹ïŒLife
ScienceïŒãïŒïŒã281ã191é ã1970幎ïŒã«èšèŒ
ã®æ¹æ³ã«åŸã€ãŠè¬å€ãè³å
宀ïŒi.c.v.ïŒæäžã
å¯èœãªãããããããäœé150ã200ïœã®éã©ã
ãïŒïŒå¹ã°ã«ãŒãã§äœ¿çšïŒã®å³åŽå®€ã«ã«ããŠãŒ
ã¬ãå·®ã蟌ãã
次ãã§ã©ããã«è¡šïŒã«ç€ºãæäžéã®åœè©²åœå
åç©ã泚å°ïŒi.c.v.ïŒããåŸçŽã¡ã«ã3ÎŒïœã®ïŒ€
âã¢ã©âã¡ããªãã³âãšã³ã±ãã¢ãªã³ã¢ãã
ïŒDALAïŒã§åŠçãããåèšããŒã«ã»ããªã
ã¯ã»ãã¹ãã§è¡šïŒã«ç€ºãæéã«ãŠç¡çèŠãè©Šéš
ããã
è¡šïŒã®ããŒã¿ãããè©Šéšæåã®ãšã³ã±ãã¢ãª
ã³ã¢ããïŒDALAïŒã®é®çå¹æã«å¯Ÿããå¢åŒ·
äœçšïŒåŒ·åºŠããã³æç¶æ§ã®äž¡æ¹ã«ãããŠïŒãèª
ããããšãã§ããã
æäžé0.01ÎŒïœïŒKgã«ãããŠã極ããŠéèŠãª
ãã®æŽ»æ§ã¯ããšã³ã±ãã¢ãªã³é¡ã®ç©è³ªä»£è¬ã«å¿
çããé
µçŽ ïŒïŒçš®ãŸãã¯è€æ°çš®ïŒã«å¯Ÿããæå¶
掻æ§ã«é¢ä¿ãããšæãããã[Table] From the data in Table 3, the compound of the present invention is 1 mg/Kg.
It has been observed that even doses of 100% can increase the analgesic activity of endogenous enkephalins to a very important degree. This increase is dose dependent, and the effect of this increase is dose dependent in nature, both in intensity and duration. Experiment No. 4: Enhancement of the analgesic activity of enkephalins induced by the compounds of the present invention In order to check one of the mechanisms of action of the compounds of the present invention, that is, the inhibitory effect on enzymatic degradation of endogenous enkephalins, the following procedure was performed. do an experiment. âLife Sciencesâ by Noble et al.
Male rats (used in groups of 5 rats) weighing 150-200 g were used to enable intracerebroventricular (icv) administration of the drug according to the method described in "Science" ( 6 , pp. 281-191, 1970). Insert the cannula into the right side of the chamber. Rats were then injected (icv) with the relevant compound at the doses shown in Table 4, and immediately after, 3 ÎŒg of D
- Treatment with ara-methionine-enkephalinamide (DALA). Analgesia is tested using the tail flick test at the times shown in Table 4. From the data in Table 4, it can be seen that the test component enkephalinamide (DALA) has an enhancing effect (both in intensity and duration) on the analgesic effect. This activity, which is extremely important even at a dose of 0.01 ÎŒg/Kg, is thought to be related to the inhibitory activity of enkephalins against enzyme(s) that responds to the metabolism of substances.
ãè¡šããtableã
ãè¡šã
å®éšNo.ïŒïŒã©ããã«ã¢ã«ããã»HClãç¹°è¿ãæäž
ããŠèªçºãããèæ§ã®çºçŸã«å¯Ÿããæ¬çºæååŠ
ç©ã®æäœçš
ã¢ã«ããã«ãã€ãŠèªçºãããèæ§ã®çºçŸãå
æãããæ¬çºæååç©ã®èœåã枬å®ããããã
æ¬çºæååç©ã®è©Šéšãè¡ããäœéçŽ200ã250ïœ
ã®éã©ããã°ã«ãŒãïŒïŒå¹ïŒã䜿çšããã
åã©ããïŒçççã«åŠçãã察ç
§ã°ã«ãŒãã
é€ãïŒã«ã¯ã第ïŒåŠçïŒæéïŒïŒãã24æéã®
ééã§ïŒmgïŒKgã®ã¢ã«ããå¡©é
žå¡©i.p.ãšå
±ã«10
mgïŒKgi.p.ã®åœè©²ååç©ïŒã¢ã«ããã®ã¿ã§åŠç
ããã°ã«ãŒãã¯é€ãïŒãäžããã
åŠçãã15ã30ã45ããã³60ååŸã«çèŠåå€
ã®æž¬å®ãããŒã«ã»ããªãã¯ãã¹ãã§è¡ãã
è¡šïŒã«ç€ºãããŒã¿ã¯æž¬å®ïŒåã®å¹³åå€ã§ãã€
ãŠãè¬å€åŠçã®ååŸã®æœäŒæéïŒçã¿çŸåºïŒã®
å€åçã瀺ãã
ãŸãè¡šïŒã«ã¯ãè¬å€åŠçã°ã«ãŒãã察ç
§ã°ã«
ãŒãããã³ã¢ã«ããåŠçã°ã«ãŒããšæ¯èŒããŠå
çš®æéã§æž¬å®ããã¹ããŠãŒãã³ãã®ïœå€ã瀺ã
ããŠããã[Table] Experiment No. 5: Anti-effect of the chemical of the present invention against the development of tolerance induced by repeated administration of morphine/HCl to rats. To measure ability;
The compounds of the present invention are tested. Weight approximately 200-250g
A group of 6 male rats are used. Each rat (excluding the physiologically treated control group) was given 10 doses of morphine hydrochloride ip at 5 mg/Kg at 24 hour intervals from the first treatment (time 0).
mg/Kgi.p. of the compound (except for the group treated with morphine alone). Pain thresholds are measured by tail flick test 15, 30, 45 and 60 minutes after treatment. The data shown in Table 5 is the average value of four measurements and shows the rate of change in latency time (pain appearance) before and after drug treatment. Also shown in Table 5 are Student's t values measured at various times comparing the drug treated group to the control group and the morphine treated group.
ãè¡šããtableã
ãè¡šã
ç®åºååž°çŽç·ïŒ
ã°ã«ãŒãBïŒïŒæŽ»æ§ïŒâ0.327ÃæéïŒ48.41(çžé¢ä¿
æ°ïŒ0.95)
ã°ã«ãŒãCïŒïŒæŽ»æ§ïŒâ0.118ÃæéïŒ45.08(çžé¢ä¿
æ°ïŒ0.76)
ã°ã«ãŒãDïŒïŒæŽ»æ§ïŒâ0.320ÃæéïŒ67.97(çžé¢ä¿
æ°ïŒ0.93)
ã°ã«ãŒãEïŒïŒæŽ»æ§ïŒâ0.251ÃæéïŒ66.47(çžé¢ä¿
æ°ïŒ0.89)
ã°ã«ãŒãFïŒïŒæŽ»æ§ïŒâ0.314ÃæéïŒ70.38(rïŒ0.9
6)
ã°ã«ãŒãGïŒïŒæŽ»æ§ïŒâ0.245ÃæéïŒ66.06(rïŒ0.7
9)
è¡šïŒã®ããŒã¿ããã³ç®åºååž°çŽç·ã«ããã°ã
第ïŒåŠçããå®éšã®æåŸãŸã§ãã°ã«ãŒãã
ã¯ã¢ã«ããã®ã¿ã§åŠçããã°ã«ãŒããã掻æ§
ãææã«å€§ã§ããããšãèªããããã
æŽã«ç¬¬ïŒåŠçåŸãã¢ã«ããã°ã«ãŒãã¯ææã«
察ç
§ã°ã«ãŒããšç°ãªããäžæ¹ã°ã«ãŒããã¯
168æéã®æçµåŠçãŸã§ã察ç
§ãšæ¯èŒããŠåªã
ã掻æ§ãç¶æããŠããããšãèªããããã
ãŸãç®åºååž°çŽç·ãããã¢ã«ããã°ã«ãŒãã®
掻æ§ã¯ïŒæ¥ç®ã®åŠçã§ïŒã«äœäžããã®ã«å¯Ÿãã
ã°ã«ãŒããã¯ïŒæ¥ç®ãš16æ¥ç®ã®éã«äžæŽ»æ§
ã®ã¬ãã«ã«å°éããã®ãèªããããã
次ã«æ¬çºæååç©ã®æCCK掻æ§ãæããã
ã掻æ§ããã³èæ±åæ³ä¿é²æŽ»æ§ãäŸç€ºããã
çäœå€ã«ãããã¢ã«ã¢ããèã®ãã¡æCCK掻
æ§
ã¢ã«ã¢ããèã®ãã®çžŠçãã¯ã¬ãã¹
ïŒKrebsïŒã®ååšäžé
žçŽ ïŒCO2ïŒ95ïŒïŒãïŒ
ïŒæ··åç©ã§çµ¶ããé
žååŠçããªãã枩床32â
ã«ãŠéèçšæµŽã«å
¥ãããç倧åçž®ãåå€æåš
ïŒforce transducerïŒã§æ€åºããèšé²ããã
10ÎŒïœïŒmlæ¿åºŠã®CCKâïŒãçšããŠèã®ãã
åçž®ããã該CCKã®åçž®å¹æã«å¯Ÿããæ¬çºæ
ååç©ã®æ®æ掻æ§ãç°ãªãæ¿åºŠã§æž¬å®ãã
ED50å€ïŒå³ã¡ãCCKã®åçž®å¹æã®50ïŒ
ãæ®æ
ãããååç©æ¿åºŠãÎŒïœïŒmlïŒã枬å®ããã
åŸãããçµæãäžèšè¡šã«èšèŒããã該衚ã«è©Š
éšååç©ããã³EDå€ïŒåååç©ã«ã€ããŠå°ãª
ããšãïŒåã®å®éšãã¹ãããååž°æ³ã§ç®åºïŒã
瀺ãã[Table] Calculated regression line:
Group B: = activity = -0.327 x time + 48.41 (correlation coefficient = 0.95)
Group C: = activity = -0.118 x time + 45.08 (correlation coefficient = 0.76)
Group D: = activity = -0.320 x time + 67.97 (correlation coefficient = 0.93)
Group E: = activity = -0.251 x time + 66.47 (correlation coefficient = 0.89)
Group F: = activity = -0.314 x time + 70.38 (r = 0.9
6)
Group G: = activity = -0.245 x time + 66.06 (r = 0.7
9)
According to the data in Table 5 and the calculated regression line,
From the third treatment to the end of the experiment, groups C to G
It was observed that the activity was significantly greater than that of group B treated with morphine alone. Furthermore, after the fifth treatment, the morphine group differed significantly from the control group, while groups C-G
It is observed that superior activity is maintained compared to the control until the final treatment of 168 hours. Also, from the calculated regression line, the activity of the morphine group decreased to 0 on the 6th day of treatment, whereas
Groups C-G are seen to reach a level of inactivity between days 9 and 16. Next, the anti-CCK activity, anticonvulsant activity and choleretic activity of the compounds of the present invention will be illustrated. Anti-CCK activity in guinea pig gall in vitro Longitudinal sections of guinea pig gallbladder were incubated with oxygen/CO 2 (95:5, V/
V) Temperature 32â while constantly oxidizing the mixture
Place in a diaphragm bath. Isometric contractions are detected and recorded with a force transducer. CCK-8 at a concentration of 10 ÎŒg/ml was used to contract the gallbladder, and the antagonistic activity of the compound of the present invention against the contractile effect of CCK was measured at different concentrations,
The ED50 value (ie, the concentration of compound capable of antagonizing 50% of the contractile effect of CCK, ÎŒg/ml) is determined. The results obtained are listed in the table below. The table shows the test compounds and the ED values (calculated by regression method from at least three experimental tests for each compound).
ãè¡šããtableã
ãè¡šããtableã
ãè¡šã
è¡šïŒã®ããŒã¿ãããæ¬çºæååç©ã¯æŽ»æ§ã®å€§ã
ãååç©ïŒäŸãã°ååç©ïŒ£âïŒïŒã®å Žåãäžå®æ¿
床ã§CCKâïŒã®æŽ»æ§ã50ïŒ
æ®æããããã¯ç¹å®
æ®æå€ã®çŽ10åã«éããéåžžã«ãããã掻æ§ç¹ç°
æ§ã瀺ãã
çäœå€ã®ç 究ã確蚌ãããããçŸå Žã®ã¢ã«ã¢ã
ãã®èã®ãã«å¯Ÿãèå³ã®é«ãååç©ã®å¹Ÿã€ããç
äœå
ã§è©Šéšããã
䜿çšæ¹æ³ã¯ãã«ã³ã°ãã«ã°ïŒLjungbergïŒã®
ãSvensk.Farm.Tidskr.ãïŒ68ã351ã354é ã1964
幎ïŒã«èšèŒãããŠããã
ãŠã¬ã¿ã³ã§éº»é
ããäœéçŽ400ïœã®ã¢ã«ã¢ãã
ã䜿çšãããè©Šéšç©è³ªãé žéèã«æ³šå°ããã
è©Šéšç©è³ªã«å¯Ÿããèã®ãã®å¿çããåå€æåšã§
æ€åºãããã€ã¯ãåéèšïŒmicrodynamometerïŒ
ã§èšé²ãããæé©åçž®çšéã10nïœïŒKgã®CCKâ
ïŒãšããŠéžã¶ãè©Šéšããæ®æååç©ãED50ã®èš
ç®ãã§ããããã«æäžéãå¢å€§ããŠæäžãããã®
éã¯10nïœïŒKgi.v.ã®CCKâïŒã®åçž®å¹æã®50ïŒ
ãæå¶ãããçšéïŒmgïŒKgi.v.åäœïŒã§ããã
åŸãããçµæãè¡šïŒã«ç€ºãã該衚ã«ã䜿çšéã
ãã³å¹æïŒCCKâïŒã®åçž®å¹æã®æå¶çã§è¡šç€ºïŒ
䞊ã³ã«ED50ãèšèŒããã[Table] From the data in Table 6, the compound of the present invention antagonizes CCK-8 activity by 50% at a certain concentration in the case of a highly active compound (for example, compound C-7), which is about 10 times that of a specific antagonist. , and exhibits excellent activity specificity. To corroborate the in vitro studies, some of the compounds of interest will be tested in vivo on guinea pig gallbladders in the field. Instructions for use are from Ljungberg's Svensk.Farm.Tidskr., 68 , pp. 351-354, 1964.
year). Guinea pigs weighing approximately 400 g are used, which are anesthetized with urethane. The test substance is injected into the jugular vein. The response of the gallbladder to the test substance is detected with a force transducer and a microdynamometer.
Record with . Optimal contraction dose of 10ng/Kg CCK-
Select as 8. The antagonist compound to be tested is administered in increasing doses to allow calculation of ED50, which is 50% of the contractile effect of CCK-8 at 10 ng/Kgi.v.
This is the dose (in mg/Kgi.v.) that can suppress the The results obtained are shown in Table 7. The table shows the usage amount and effect (expressed as inhibition rate of contraction effect of CCK-8).
Also state the ED50.
ãè¡šããtableã
ãè¡šã
ãããã®çµæãããå
ã®çäœå€å®éšã§ããã€ã
ããšãå®è³ªçã«ç¢ºèªããããå³ã¡ãæ¬çºæååç©
ã¯æ¥µããŠåŒ·åãªCCKæ®æå€ã§ãããååç©ïŒ£â
ïŒããã³ïŒ£âïŒã®å Žåã®0.1mgïŒKgã®åŠãäœãæ¿
床ã«ãããŠããCCKâïŒã«ãã€ãŠèªçºïŒççåŠ
çæ¿åºŠããæããã«é«ãæ¿åºŠã§ãïŒãããèã®ã
åçž®ããããã¯ããããšãã§ããã
ãŸãæ¬çºæååç©ãå
šæ¶åç³»ã«å¯ŸããŠåãŒãæ
ãããã掻æ§ãé¡èã«èªããããã
ãã®æŽ»æ§ã¯ããŠã¹ã®æ€ç©æ§ççŽ ãã¹ã
ïŒvegetable carbon testïŒïŒèè
žéã®ç§»è¡é床ïŒ
ã§æž¬å®ããçµæã次衚ã«ç€ºãã[Table] These results essentially confirm what was found in the previous in vitro experiments. That is, the compound of the present invention is an extremely strong CCK antagonist, and the compound C-
Concentrations as low as 0.1 mg/Kg in the case of CCK-6 and C-7 can block gallbladder contraction induced by CCK-8 (even at concentrations clearly higher than physiological concentrations). In addition, the anticonvulsant activity exerted by the compounds of the present invention on the entire digestive system is also significantly observed. This activity was measured in a mouse vegetable carbon test (speed of gastrointestinal transit).
The results are shown in the table below.
ãè¡šããtableã
ãè¡šã
ççåŠçç¶æ³ã«ããå¯æ¥ããããç¹ç°çãªæã
ããã掻æ§ãã以äžã®å®éšã§äŸç€ºããã
麻é
ãããŠãµã®ã®è
¹ãåéããŠã暪è¡çµè
žãé¡
瀺ããããåºå®ãããã€ã³ãã«æºæ°Žããå°çãæ¿
å
¥ãããããå§åå€æåšïŒpressure transducerïŒ
ãžãæºæ°Žããããªãšãã¬ã³ã«ããŠãŒã¬ã§æ¥ç¶ã
ãã
ççåŠçæ¡ä»¶ã«é¢ããŠæé©æ床ãåºå®ããçæ
ç©ã倧è
¿éèã«æäžããã100nïœïŒKgã®CCKã®
æäžã§åçž®ãèªçºããã
æ¬çºæååç©ã®æŽ»æ§ãè¡šïŒã«ç€ºããTABLE A more specific anticonvulsant activity more closely related to the physiological situation is illustrated in the following experiments. Make an incision in the abdomen of an anesthetized rabbit to reveal the transverse colon. A small ball filled with water is inserted into a fixed point and used as a pressure transducer.
Connect with a polyethylene cannula filled with water. The optimal sensitivity is fixed with respect to physiological conditions and the product is administered into the femoral vein. Administration of 100 ng/Kg CCK induces contractions. Table 9 shows the activity of the compounds of the present invention.
ãè¡šã
ãããããŒã¿ã«ãããæ¬çºæã®è©Šéšååç©ã¯ã
å
ã«èã®ãã®å Žåã«ç€ºãããšåæ§ã«ãCCKãé«
çšéïŒ100nïœïŒKgïŒã§æäžããŠèªçºãããè
žå
çž®ã«å¯Ÿãæ®æäœçšããæããããšã瀺ãããã
æè¯ã®ååç©ã䜿çšããå Žåãæãããã掻æ§
ã¯ïŒãïŒmgïŒKgã®æ¥µããŠäœçšéã§ç€ºãããã
ãããã®ååç©ã®ä»ã®èå³ããç¹åŸŽã¯ãããã
ãèæ±æµéãããªãã«å¢å€§ããããšã§ããã
以äžã«ç€ºãå®éšãè¡ãããŠã¬ã¿ã³ã§éº»é
ããã©
ããã®è管ã«ã«ããŠãŒã¬ããããªãšãã¬ã³ããŠãŒ
ãã«æ¥ç¶ããå°éãšå
±ã«æ¿å
¥ããèæ±ãæ¡éã
ããæ¡éã¯ãè©Šéšååç©ã®éèå
æäžã®åã«ïŒæ
éãæŽã«æäžåŸã«ïŒæéè¡ããéããè©Šæã®éé
ã30åééã§ã¯ããã
ã©ããã®è±æ°Žãé²æ¢ããããã0.5mlã®çç溶
液ã30åééã§ããŒã¿ã«ïŒml以å
ã«æäžãããæ¬
çºæååç©ã®å¹Ÿã€ãã«ã€ããŠåŸãããçµæã次衚
ã«ç€ºããED50ã§è¡šç€ºããããããã¯å¯Ÿç
§å€ïŒè¬
å€åŠçåã®ïŒæéæ¡éäžã«æž¬å®ããå¹³åå€ïŒã«å¯Ÿ
ããè¬å€åŠçåŸã«èæ±æµéã®50ïŒ
å¢å€§ãèµ·ããã
ãåäœmlïŒKgi.v.ã®ç©è³ªéïŒïŒæéã«ããã€ãŠæž¬
å®ããå¹³åå€ïŒã§ããã
ãããããŒã¿ãããåœè©²ååç©ã¯åŒ·åãªèæ±å
æ³ä¿é²æŽ»æ§ãæããããšãæšå¯ããããè©Šéšåå
ç©ã®å¹³åED50ã¯ïŒã25mgïŒKgã§ãæäžéãšè¬ç
åŠçå¿çãé¡èã«äžèŽããïŒå®éã®çžé¢ä¿æ°ã¯å
š
ãŠã®å Žå0.90ãã倧ã§ããïŒã[Table] According to such data, the test compound of the present invention:
As previously shown in the case of the gallbladder, CCK is also shown to have an antagonistic effect on the intestinal contraction induced by administration at a high dose (100 ng/Kg). When using the best compounds, anticonvulsant activity is shown at very low doses of 1-3 mg/Kg. Another interesting feature of these compounds is that they significantly increase bile flow rate. Perform the experiment shown below. A cannula is inserted into the bile duct of a rat anesthetized with urethane, together with a small needle connected to a polyethylene tube, and bile is collected. Collections are made 1 hour before and 2 hours after intravenous administration of test compound, and collected samples are weighed at 30 minute intervals. To prevent dehydration of the rats, administer 0.5 ml of physiological solution every 30 minutes for a total of no more than 3 ml. The results obtained for some of the compounds of the invention are shown in the following table. It is expressed as ED50, which is the amount of substance in ml/Kgi.v. that can cause a 50% increase in bile circulation after drug treatment compared to the control value (average value measured during one hour of collection before drug treatment). (average value measured over 2 hours). From such data, it is inferred that the compound has a strong choleretic activity. The average ED50 of the test compounds is 5-25 mg/Kg, with remarkable agreement between dose and pharmacological response (actual correlation coefficients are greater than 0.90 in all cases).
ãè¡šããtableã
ãè¡šã
åœè©²ååç©ã®ã»ãšãã©ã«ãã€ãŠç€ºãããæ
CCK掻æ§ãã人ã®é£æ¬²äžæ¯ã®æ²»çã«ãŸãã¯èŸ²æ¥
çšåç©ã®é£æ¬²ä¿é²å€ãšããŠæå©ã«äœ¿çšããããšã
ã仮説ãããšãã¯ããããã以äžã«ç€ºãå®éšãè¡
ãã
10å¹ã®ã°ã«ãŒãã«åããäœéçŽ160ïœã®éã©ã
ãã䜿çšãããåã°ã«ãŒãã«ïŒé±éã«ããã€ãŠã
衚瀺çšéã®è¬å€ãæ¯æ¥äžããã
ãããªãŠã 塩圢ç¶ã®è¬å€ãæ°Žã«æº¶è§£ãã
H2O10mlïŒKgã®å®¹éã§æäžããäžæ¹ã察ç
§ã°ã«
ãŒãã«ã¯å容éã®æ°Žã®ã¿ãäžããã
æ¯é±èšç®ããã飌ææ¶è²»ã®å¹³åå€ããã³åã°ã«
ãŒãã®å¹³åäœéã䞊ã³ã«åçš®ã®åŠçã°ã«ãŒããã
ã³å¯Ÿç
§ã°ã«ãŒãããèšç®ããã¹ããŠãŒãã³ãã®ïœ
å€ã次衚ã«ç€ºãã
è¡š11ããã³12ã®ããŒã¿ãããïŒæ¥çšé0.3mgïŒ
Kgã®ååç©ïŒ£âïŒã¯å¯Ÿç
§ãšæ¯èŒããŠé£Œææ¶è²»ãçŽ
15ïŒ
å¢å€§ãããã®ãèªããããããã®å¢å€§ã¯ä»ã®
çšéè©Šéšã§çŽ30ïŒ
ã§ãããåžžã«æ¥µããŠéèŠã§ã
ãã
åŠçã©ããã®äœéå¢å ã¯ã察ç
§ã©ããã®äœéå¢
å ãšæ¯èŒããŠé¡äŒŒã®çµéããšããåœè©²ç 究æé
äžãâïŒã§åŠçããå
šãŠã®ã°ã«ãŒãã¯å¯Ÿç
§ã©ã
ãããææã«å€§ããªäœéå¢å ãããããã[Table] The anti-inflammatory properties exhibited by most of the compounds
To check the hypothesis that CCK activity could be advantageously used in the treatment of anorexia in humans or as an appetite stimulant in agricultural animals, the following experiments are performed. Male rats weighing approximately 160 g divided into groups of 10 are used. For each group for 3 weeks,
Give the indicated dose of drug daily. The drug in the form of sodium salt is dissolved in water,
A volume of 10 ml/Kg of H 2 O is administered, while the control group receives the same volume of water only. Average feed consumption and average body weight for each group, calculated weekly, and Student's t calculated from various treatment and control groups.
The values are shown in the table below. From the data in Tables 11 and 12, the daily dose of 0.3mg/
Kg of Compound C-7 reduced feed consumption by approximately
A 15% increase is permitted. This increase is approximately 30% in other dose studies and is always extremely significant. The weight gain of treated rats follows a similar course compared to that of control rats. During the study period, all groups treated with C-7 produced significantly greater weight gain than control rats.
ãè¡šããtableã
ãè¡šããtableã
ãè¡šããtableã
ãè¡šããtableã
ãè¡šã
CCKâïŒã«ãã€ãŠèªçºãããèµèã®è
ºçã®å¢æ®
ã®æå¶äœçš
æ£åžžãªèµè现èããã³èµèè
ºçã®CCKã®æ é€
掻æ§ã«å¯Ÿããæã³ã¬ã·ã¹ãããã³å¹æã®æã匷å
ãªæ¬çºæååç©ãå³ã¡ååç©ïŒ£âïŒã«ã€ããŠç 究
ããã
éãã ã¹ã¿ãŒã®é ¬ã®ãã«ãèµèè
ºçã®ïŒÃ105
è
«ç现èã®æžæ¿æ¶²ãæ¥çš®ãããæ¥çš®ããïŒæ¥åŸã«
ãã ã¹ã¿ãŒãã©ã³ãã ã«ïŒã€ã®10å¹ã°ã«ãŒãã«å
ãããå³ã¡ã察ç
§ã°ã«ãŒããïŒæ¥ïŒå10ÎŒïœïŒKg
ã®CCKâïŒã§åŠçããã°ã«ãŒããïŒæ¥ïŒåïŒ
mgïŒKgi.p.ã®ååç©ïŒ£âïŒã§åŠçããã°ã«ãŒãã
ããã³ååç©ïŒ£âïŒãšCCKâïŒã§ããããäžèš
ãšåæ§ã«ããŠåæã«åŠçããã°ã«ãŒãã«åããã
15æ¥éã®åŠçåŸã«ãã ã¹ã¿ãŒã殺ããæ£åžžãªèµ
èããã³é ¬ã®ãã®æ¥çš®ããèµèè
«çãéããéé
ãã¯ãããDNAãæœåºããéåžžã®æ¹æ³ã§æž¬å®ã
ããåŸãããçµæãè¡š13ã«ç€ºããå¹³åå€ïŒÂ±S.
E.ïŒã§è¡šç€ºã[Table] Inhibitory effect on the growth of pancreatic adenocarcinoma induced by CCK-8 The compound of the present invention, which has the most potent anticholecystokinin effect on the trophic activity of CCK in normal pancreatic cells and pancreatic adenocarcinoma, That is, compound C-7 will be studied. 1Ã10 5 pancreatic adenocarcinoma in the cheek sac of a male hamster
Inoculate a suspension of tumor cells. Five days after inoculation, hamsters are randomly divided into four groups of 10. i.e. control group, 10ÎŒg/Kg three times a day
Group treated with CCK-8, 3 times a day 5
a group treated with compound C-7 at mg/Kgi.p.
and compounds C-7 and CCK-8, respectively, in the same manner as above. After 15 days of treatment, the hamsters are sacrificed, the normal pancreas and the inoculated pancreatic tumor in the cheek pouch are collected and weighed. Extract the DNA and measure using standard methods. The results obtained are shown in Table 13. Mean value (±S.
Displayed in E.).
ãè¡šããtableã
ãè¡šã
è¡š13ã®ããŒã¿ã«ããã°ãæ£åžžãªèµè现èã«å¯Ÿã
æ é€æŽ»æ§ãæããã³ã¬ã·ã¹ãããã³ãã«ã¢ã³
ïŒCCKâïŒã®ãã«ã¢ã³ã¯ççåŠç掻æ§æåã§ã
ãïŒã¯ãèµèç·çã®å¢æ®ãåºæ¿ããããšããã
ãã匷åãªç¹æ®CCKæ®æå€ã§ããååç©ïŒ£âïŒ
ã¯ããããã®CCKâïŒã®äœçšã極ããŠææã«æ®
æããã
äžèšã®å®éšããŒã¿ã«ããã°ãæ¬çºæã®ä¿è·å¯Ÿè±¡
ã§ããååç©ïŒ£âïŒãŸãã¯ä»ã®æã³ã¬ã·ã¹ããã
ã³ååç©ã®äœ¿çšããå
å æ§çç©åŠç掻æ§ããªãã
ããé¡ïŒç¹ã«CCKïŒã«ãã€ãŠæç¶ãããè
«çã
äŸãã°èè
žè
«çããã³èµèè
«çã®æ²»çã«ç¹ã«å¥œé©
ãªçµæãããããããšã確信ãããã
ãŸããããå®éšããŒã¿ã«ããã°ãæ¬çºæã®è¬å€
ãã¢ã«ãããããã¯ä»ã®é®çè¬ïŒéº»é
æ§ãããã¯
é麻é
æ§ã®ãããããå«ãïŒãšå
±ã«äœ¿çšããããš
ã«ããæ²»çäžèããå·æ°ããããããç
å ã®èŠç
ã緩解ãããããã«å»è
ãããããŠé«ãé¢å¿ãæ
ã€ãŠããååç©ãæäŸãåŸãããšã瀺ããŠããã
ãã®æ²»çã¯ç¹ã«éº»é
å€ã®é·ææäžã®å Žåã«å¿
èŠãš
ãªããšæããããã®å Žåè¬ãç¿æ
£ãšãªããªããã
ãããã¯å°ãªããšã蚱容ãããéçã®ç¯å²å
ã«ç¶
æããããšã極ããŠå¿
èŠã§ãããæŽã«ã麻é
è¬ã®
é·æ䜿çšã«äŸåããããã«ãªã€ãæ£è
ã®è§£æ¯ã«ã
ãããçšããããšã¯ãå€åã䞊ã¯ãããæ²»ç瀟äŒ
ã®é¢å¿ãåŒã¶ãã®ãšæãããã
ãŸãäžèšå®éšããŒã¿ããããããã®ååç©ãè
è
žç³»ã®åçš®ç
ççç¶ã®æ²»çãäŸãã°äžè¬ã«ããã
ãæ§çå矀ã®æ²»çãçã¿è»œæžããã³ç¹ã«è管æ©èœ
äžå
šãéæãªçµè
žã®æ²»çã«æçšã§ããããšãèªã
ãããã
以äžã®ããšãããæ¬çºæååç©ã«å¯Ÿãããã®å€
æ°ã«ãã€ãŠç€ºããã匷åãªæCCK掻æ§ãé£æ¬²äž
æ¯ã®æ²»çãŸãã¯ççåŠçãã€ãã³ã¬ãã«ã®CCK
ãããã¯ä»ã®çç©åŠç掻æ§ããããé¡ã®å¹³è¡¡å€±èª¿
ã«é¢é£ããSNCã®ç
ççç¶ã®æ²»çã«ããã奜é©
ãªæ²»ççšéã確èªããããšãã§ããã[Table] According to the data in Table 13, cholecystokinin hormone (CCK-8 hormone is a physiologically active component), which has trophic activity on normal pancreatic cells, stimulates the growth of pancreatic cancer. I understand. Compound C-7, a potent specialized CCK antagonist
very significantly antagonizes these effects of CCK-8. According to the above experimental data, the use of compound C-7 or other anti-cholecystokinin compounds protected by the present invention is sustained by endogenous biologically active polypeptides, in particular CCK. tumor,
It is believed that this will lead to particularly favorable results in the treatment of, for example, gastrointestinal and pancreatic tumors. Such experimental data also indicate that the use of the agents of the present invention in conjunction with morphine or other analgesics (both narcotic and non-narcotic) represents a significant therapeutic innovation, relieving the etiological pain. This suggests that we may be able to provide compounds that are of great interest to physicians.
This treatment may be especially necessary in the case of long-term administration of anesthetics, in which case the drug may become habit-forming or
Or at least it is extremely necessary to keep it within acceptable limits. Moreover, their use in the detoxification of patients who have become dependent on long-term use of anesthetics is likely to be of extraordinary therapeutic community interest. The above experimental data also confirm that these compounds are useful in the treatment of various pathological conditions of the gastrointestinal system, such as in the treatment of spasmodic syndromes in general and pain relief and in particular in the treatment of biliary insufficiency and irritable colon. Based on the above, we conclude that the compounds of the present invention exhibit potent anti-CCK activity, which is demonstrated by many of them, in the treatment of anorexia, or in the treatment of CCK at physiological neuron levels.
Alternatively, suitable therapeutic uses of other biologically active peptides in the treatment of pathological symptoms of SNC related to imbalance may be identified.
Claims (1)
ã¯ïŒãŸãã¯ïŒãR1ã¯ã¢ãããžãããã¯ããªçœ®æ
ããšãã«ïŒåäžãããã¯ç°ãªãçŽéãããã¯åæ
ç¶C1ãC4ã®ã¢ã«ãã«åºã§çœ®æãããã²ã³ã§çœ®æã
ãŸãã¯ã·ã¢ãåºãããã¯ããªãã«ãªãã¡ãã«åºã§
眮æïŒãããã³R2ã¯ã¢ã«ããªãããããªãžããŸã
ã¯ã¢ããããã¯çœ®æã¢ããïŒåäžãããã¯ç°ãªã
ççŽ æ°ïŒãïŒã®çŽéãåæç¶ãããã¯ç°åŒã¢ã«ã
ã«åºã§çœ®æïŒã§ãã ã§ç€ºãããå»è¬çã«æŽ»æ§ãªïŒ€ïŒïŒ¬âã°ã«ã¿ãã³é ž
èªå°äœãŸãã¯ïŒ€ïŒïŒ¬âã¢ã¹ãã©ã®ã³é žèªå°äœããŸ
ãã¯ãã®å»è¬çã«èš±å®¹ãããå¡©ã ïŒ ïŒ²ãOHã§Râ²ãR2ãïœãïŒãR1ãïŒïŒïŒâãž
ã¡ãã«ããšãã«ãŸãã¯ïŒïŒïŒâãžã¯ããããšã
ã«ãããã³R2ãC4ãC5ã®çŽéã¢ã«ãã«åºã§ãžçœ®
æãããã¢ããã§ããåèšç¬¬ïŒé èšèŒã®ã°ã«ã¿ã
ã³é žèªå°äœãŸãã¯ãã®å»è¬çã«èš±å®¹ãããå¡©ã ïŒ ïŒ²ãR2ã§Râ²ãOHãïœãïŒãR1ãïŒâã·ã¢ã
ããšãã«ãããã³R2ãC4ãC5ã®çŽéã¢ã«ãã«åº
ã§ãžçœ®æãããã¢ããã§ããåèšç¬¬ïŒé èšèŒã®ã°
ã«ã¿ãã³é žèªå°äœãŸãã¯ãã®å»è¬çã«èš±å®¹ããã
å¡©ã ïŒ æŽ»æ§æåãšããŠåŒã åŒäžããšRâ²ã¯äºãã«ç°ãªãOHãŸãã¯R2ãïœ
ã¯ïŒãŸãã¯ïŒãR1ã¯ã¢ãããžãããã¯ããªçœ®æ
ããšãã«ïŒåäžãããã¯ç°ãªãçŽéãããã¯åæ
ç¶C1ãC4ã®ã¢ã«ãã«åºã§çœ®æãããã²ã³ã§çœ®æã
ãŸãã¯ã·ã¢ãåºãããã¯ããªãã«ãªãã¡ãã«åºã§
眮æïŒãããã³R2ã¯ã¢ã«ããªãããããªãžããŸã
ã¯ã¢ããããã¯ãžçœ®æã¢ããïŒåäžãããã¯ç°ãª
ãççŽ æ°ïŒãïŒã®çŽéãåæç¶ãããã¯ç°åŒã¢ã«
ãã«åºã§çœ®æïŒã§ãã ã§ç€ºãããååç©ãŸãã¯ãã®å»è¬çã«èš±å®¹ããã
å¡©ãå å«ããããšãç¹åŸŽãšããçç©åŠç掻æ§ããª
ããããé¡ãç¹ã«ã³ã¬ã·ã¹ãããã³ã®ççåŠçã
ã€ãã³ã¬ãã«ã§ã®å¹³è¡¡å€±èª¿ã«ä¿ãSNCã®çŸç ã®
æ²»ççšå»è¬çµæç©ã ïŒ æŽ»æ§æåãšããŠåŒã åŒäžããšRâ²ã¯äºãã«ç°ãªãOHãŸãã¯R2ãïœ
ã¯ïŒãŸãã¯ïŒãR1ã¯ã¢ãããžãããã¯ããªçœ®æ
ããšãã«ïŒåäžãããã¯ç°ãªãçŽéãããã¯åæ
ç¶C1ãC4ã®ã¢ã«ãã«åºã§çœ®æãããã²ã³ã§çœ®æã
ãŸãã¯ã·ã¢ãåºãããã¯ããªãã«ãªãã¡ãã«åºã§
眮æïŒãããã³R2ã¯ã¢ã«ããªãããããªãžããŸã
ã¯ã¢ããããã¯ãžçœ®æã¢ããïŒåäžãããã¯ç°ãª
ãççŽ æ°ïŒãïŒã®çŽéãåæç¶ãããã¯ç°åŒã¢ã«
ãã«åºã§çœ®æïŒã§ãã ã§ç€ºãããååç©ãŸãã¯ãã®å»è¬çã«èš±å®¹ããã
å¡©ãå å«ããããšãç¹åŸŽãšããæããããè¬ãšã
ãŠçšããå»è¬çµæç©ã ïŒ æŽ»æ§æåãšããŠåŒã åŒäžããšRâ²ã¯äºãã«ç°ãªãOHãŸãã¯R2ãïœ
ã¯ïŒãŸãã¯ïŒãR1ã¯ã¢ãããžãããã¯ããªçœ®æ
ããšãã«ïŒåäžãããã¯ç°ãªãçŽéãããã¯åæ
ç¶C1ãC4ã®ã¢ã«ãã«åºã§çœ®æãããã²ã³ã§çœ®æã
ãŸãã¯ã·ã¢ãåºãããã¯ããªãã«ãªãã¡ãã«åºã§
眮æïŒãããã³R2ã¯ã¢ã«ããªãããããªãžããŸã
ã¯ã¢ããããã¯ãžçœ®æã¢ããïŒåäžãããã¯ç°ãª
ãççŽ æ°ïŒãïŒã®çŽéãåæç¶ãããã¯ç°åŒã¢ã«
ãã«åºã§çœ®æïŒã§ãã ã§ç€ºãããååç©ãŸãã¯ãã®å»è¬çã«èš±å®¹ããã
å¡©ãå å«ããããšãç¹åŸŽãšããèæ±åæ³ä¿é²è¬ãš
ããŠçšããå»è¬çµæç©ã ïŒ æŽ»æ§æåãšããŠåŒã åŒäžããšRâ²ã¯äºãã«ç°ãªãOHãŸãã¯R2ãïœ
ã¯ïŒãŸãã¯ïŒãR1ã¯ã¢ãããžãããã¯ããªçœ®æ
ããšãã«ïŒåäžãããã¯ç°ãªãçŽéãããã¯åæ
ç¶C1ãC4ã®ã¢ã«ãã«åºã§çœ®æãããã²ã³ã§çœ®æã
ãŸãã¯ã·ã¢ãåºãããã¯ããªãã«ãªãã¡ãã«åºã§
眮æïŒãããã³R2ã¯ã¢ã«ããªãããããªãžããŸã
ã¯ã¢ããããã¯ãžçœ®æã¢ããïŒåäžãããã¯ç°ãª
ãççŽ æ°ïŒãïŒã®çŽéãåæç¶ãããã¯ç°åŒã¢ã«
ãã«åºã§çœ®æïŒã§ãã ã§ç€ºãããååç©ãŸãã¯ãã®å»è¬çã«èš±å®¹ããã
å¡©ãå å«ããããšãç¹åŸŽãšããé£æ¬²äžæ¯ã®æ²»ççš
å»è¬çµæç©ã ïŒ æŽ»æ§æåãšããŠåŒã åŒäžããšRâ²ã¯äºãã«ç°ãªãOHãŸãã¯R2ãïœ
ã¯ïŒãŸãã¯ïŒãR1ã¯ã¢ãããžãããã¯ããªçœ®æ
ããšãã«ïŒåäžãããã¯ç°ãªãçŽéãããã¯åæ
ç¶C1ãC4ã®ã¢ã«ãã«åºã§çœ®æãããã²ã³ã§çœ®æã
ãŸãã¯ã·ã¢ãåºãããã¯ããªãã«ãªãã¡ãã«åºã§
眮æïŒãããã³R2ã¯ã¢ã«ããªãããããªãžããŸã
ã¯ã¢ããããã¯ãžçœ®æã¢ããïŒåäžãããã¯ç°ãª
ãççŽ æ°ïŒãïŒã®çŽéãåæç¶ãããã¯ç°åŒã¢ã«
ãã«åºã§çœ®æïŒã§ãã ã§ç€ºãããååç©ãŸãã¯ãã®å»è¬çã«èš±å®¹ããã
å¡©ãå å«ããããšãç¹åŸŽãšããã³ã¬ã·ã¹ãããã³
ãåæ§ã®äœçšæ©åºãæããçç©åŠç掻æ§ããªãã
ããé¡ãé¢äžããè «çã®æ²»ççšå»è¬çµæç©ã ïŒ æŽ»æ§æåãšããŠåŒã åŒäžããšRâ²ã¯äºãã«ç°ãªãOHãŸãã¯R2ãïœ
ã¯ïŒãŸãã¯ïŒãR1ã¯ã¢ãããžãããã¯ããªçœ®æ
ããšãã«ïŒåäžãããã¯ç°ãªãçŽéãããã¯åæ
ç¶C1ãC4ã®ã¢ã«ãã«åºã§çœ®æãããã²ã³ã§çœ®æã
ãŸãã¯ã·ã¢ãåºãããã¯ããªãã«ãªãã¡ãã«åºã§
眮æïŒãããã³R2ã¯ã¢ã«ããªãããããªãžããŸã
ã¯ã¢ããããã¯ãžçœ®æã¢ããïŒåäžãããã¯ç°ãª
ãççŽ æ°ïŒãïŒã®çŽéãåæç¶ãããã¯ç°åŒã¢ã«
ãã«åºã§çœ®æïŒã§ãã ã§ç€ºãããååç©ãŸãã¯ãã®å»è¬çã«èš±å®¹ããã
å¡©ãå å«ãããã€é®çè¬ã䜵çšããããšãç¹åŸŽãš
ãã人ã®çã¿æå¶å€ãšããŠçšããå»è¬çµæç©ã ïŒïŒ 蟲æ¥çšåç©ã®äœéå¢å é床ãé«ããããã
該åç©ã®é£æ¬²ä¿é²å€ãšããŠäœ¿çšããã掻æ§æåãš
ããŠåŒã åŒäžããšRâ²ã¯äºãã«ç°ãªãOHãŸãã¯R2ãïœ
ã¯ïŒãŸãã¯ïŒãR1ã¯ã¢ãããžãããã¯ããªçœ®æ
ããšãã«ïŒåäžãããã¯ç°ãªãçŽéãããã¯åæ
ç¶C1ãC4ã®ã¢ã«ãã«åºã§çœ®æãããã²ã³ã§çœ®æã
ãŸãã¯ã·ã¢ãåºãããã¯ããªãã«ãªãã¡ãã«åºã§
眮æïŒãããã³R2ã¯ã¢ã«ããªãããããªãžããŸã
ã¯ã¢ããããã¯ãžçœ®æã¢ããïŒåäžãããã¯ç°ãª
ãççŽ æ°ïŒãïŒã®çŽéãåæç¶ãããã¯ç°åŒã¢ã«
ãã«åºã§çœ®æïŒã§ãã ã§ç€ºãããååç©ã®å°ãªããšãïŒçš®ãå«æããå
ç©é£Œè²çšè£œå€ã ïŒïŒ åŒã åŒäžããšRâ²ã¯äºãã«ç°ãªãOHãŸãã¯R2ãïœ
ã¯ïŒãŸãã¯ïŒãR1ã¯ã¢ãããžãããã¯ããªçœ®æ
ããšãã«ïŒåäžãããã¯ç°ãªãçŽéãããã¯åæ
ç¶C1ãC4ã®ã¢ã«ãã«åºã§çœ®æãããã²ã³ã§çœ®æã
ãŸãã¯ã·ã¢ãåºãããã¯ããªãã«ãªãã¡ãã«åºã§
眮æïŒãããã³R2ã¯ã¢ã«ããªãããããªãžããŸã
ã¯ã¢ããããã¯ãžçœ®æã¢ããïŒççŽ æ°ïŒãïŒã®çŽ
éãåæç¶ãããã¯ç°åŒã¢ã«ãã«åºã§çœ®æïŒã§ã
ã ã§ç€ºãããïŒïŒ¬âã°ã«ã¿ãã³é žèªå°äœãŸãã¯
ïŒïŒ¬âã¢ã¹ãã©ã®ã³é žèªå°äœããŸãã¯ãã®å»è¬
çã«èš±å®¹ãããå¡©ã®è£œé æ³ã§ãã€ãŠã (a) åŒã åŒäžãïœããã³R1ã¯åèšãšåæ矩 ã§ç€ºãããååå ç¡æ°Žç©ãåŒïŒR2HåŒäžãR2
ã¯åèšãšåæ矩ã§ç€ºãããã¢ãã³ãšãïŒãïŒ
ã®ã¢ã«æ¯ããã³â20âã30âã®æž©åºŠã«ãŠåå¿ã
ããåå¿æ¶²ããåèšåŒïŒ»ïŒœã«ãããŠïŒ²ãOH
ã§Râ²ãR2ãããã³ïŒ²ãR2ã§Râ²ãOHã§ããåå
ç©ãååããããããåé¢ããå·¥çšãå å«ãã
補é æ³ã ïŒïŒ åèšç¬¬ïŒïŒé ã®(a)å·¥çšã§çšããåŒïŒ»ïŒœã®
ååå ç¡æ°Žç©ãã (b) ã°ã«ã¿ãã³é žãŸãã¯ã¢ã¹ãã©ã®ã³é žãã·ãšã
ãã³âããŠãã³ã®æ¡ä»¶äžãåœã¢ã«éã®åŒïŒR1
âCOâClã®å¡©åã¢ã·ã«ãšâ20âã30âã®æž©åºŠ
ã§åå¿ãããŠãåŒïŒ ã®ïŒ®âã¢ã·ã«åååç©ãåŸã次ã㧠(c) 該ååç©ïŒ»ïŒœããã®ãŸãŸãããã¯çžæº¶æ§ã®
äžæŽ»æ§æº¶åªäžãã¢ã«æ¯ïŒã10ã®ç¡æ°Žé ¢é žãšâ10
âãéæµæž©åºŠã«ãŠåå¿ããè±æ°Žãã å·¥çšã«ãã€ãŠåŸãåèšç¬¬ïŒïŒé èšèŒã®æ¹æ³ã ïŒïŒ ïœãïŒãR1ãïŒïŒïŒâãžã¡ãã«ããšãã«
ãŸãã¯ïŒïŒïŒâãžã¯ããããšãã«ãããã³R2ã
C4ãC5ã®çŽéã¢ã«ãã«åºã§ãžçœ®æãããã¢ãã
ã§ããåèšç¬¬ïŒïŒé ãŸãã¯ç¬¬ïŒïŒé èšèŒã®æ¹æ³ã ïŒïŒ ïœãïŒãR1ãïŒâã·ã¢ãããšãã«ããã
ã³R2ãC4ãC5ã®çŽéã¢ã«ãã«åºã§ãžçœ®æããã
ã¢ããã§ããåèšç¬¬ïŒïŒé ãŸãã¯ç¬¬ïŒïŒé èšèŒã®
æ¹æ³ã[Claims] 1 formula, [In the formula, R and Râ² are different from each other and are OH or R 2 , n
is 1 or 2, R 1 is mono-, di- or tri-substituted phenyl (substituted with the same or different linear or branched C 1 -C 4 alkyl group, substituted with halogen,
or substituted with a cyano group or a trifluoromethyl group), and R 2 is morpholino, piperidino or mono- or substituted amino (substituted with the same or different straight chain, branched or cyclic alkyl group having 1 to 8 carbon atoms) ] A pharmaceutically active D,L-glutamic acid derivative or a D,L-aspartic acid derivative, or a pharmaceutically acceptable salt thereof. 2 R is OH, R' is R 2 , n is 2, R 1 is 3,4-dimethylphenyl or 3,4-dichlorophenyl, and R 2 is a C 4 to C 5 linear alkyl group The glutamic acid derivative according to item 1 above, which is a substituted amino acid or a pharmaceutically acceptable salt thereof. 3. The compound according to item 1 above, wherein R is R 2 , R' is OH, n is 2, R 1 is 4-cyanophenyl, and R 2 is amino di-substituted with a C 4 to C 5 linear alkyl group. A glutamic acid derivative or a pharmaceutically acceptable salt thereof. 4 Formula as active ingredient, [In the formula, R and Râ² are different from each other and are OH or R 2 , n
is 1 or 2, R 1 is mono-, di- or tri-substituted phenyl (substituted with the same or different linear or branched C 1 -C 4 alkyl group, substituted with halogen,
or substituted with a cyano group or a trifluoromethyl group), and R 2 is morpholino, piperidino or mono- or di-substituted amino (substituted with the same or different straight-chain, branched or cyclic alkyl group having 1 to 8 carbon atoms); Biologically active polypeptides characterized by comprising a compound represented by [1] or a pharmaceutically acceptable salt thereof, particularly for the treatment of SNC diseases related to imbalance at the physiological neuron level of cholecystokinin. Therapeutic pharmaceutical composition. 5 Formula as active ingredient, [In the formula, R and Râ² are different from each other and are OH or R 2 , n
is 1 or 2, R 1 is mono-, di- or tri-substituted phenyl (substituted with the same or different linear or branched C 1 -C 4 alkyl group, substituted with halogen,
or substituted with a cyano group or a trifluoromethyl group), and R 2 is morpholino, piperidino or mono- or di-substituted amino (substituted with the same or different straight-chain, branched or cyclic alkyl group having 1 to 8 carbon atoms); A pharmaceutical composition for use as an anticonvulsant, characterized by comprising a compound represented by the following formula or a pharmaceutically acceptable salt thereof. 6 Formula as active ingredient, [In the formula, R and Râ² are different from each other and are OH or R 2 , n
is 1 or 2, R 1 is mono-, di- or tri-substituted phenyl (substituted with the same or different linear or branched C 1 -C 4 alkyl group, substituted with halogen,
or substituted with a cyano group or a trifluoromethyl group), and R 2 is morpholino, piperidino or mono- or di-substituted amino (substituted with the same or different straight-chain, branched or cyclic alkyl group having 1 to 8 carbon atoms); A pharmaceutical composition for use as a choleretic agent, characterized by comprising a compound represented by the following or a pharmaceutically acceptable salt thereof. 7 Formula as active ingredient, [In the formula, R and Râ² are different from each other and are OH or R 2 , n
is 1 or 2, R 1 is mono-, di- or tri-substituted phenyl (substituted with the same or different linear or branched C 1 -C 4 alkyl group, substituted with halogen,
or substituted with a cyano group or a trifluoromethyl group), and R 2 is morpholino, piperidino or mono- or di-substituted amino (substituted with the same or different straight-chain, branched or cyclic alkyl group having 1 to 8 carbon atoms); A pharmaceutical composition for treating anorexia, comprising a compound represented by the following or a pharmaceutically acceptable salt thereof. 8 Formula as active ingredient, [In the formula, R and Râ² are different from each other and are OH or R 2 , n
is 1 or 2, R 1 is mono-, di- or tri-substituted phenyl (substituted with the same or different linear or branched C 1 -C 4 alkyl group, substituted with halogen,
or substituted with a cyano group or a trifluoromethyl group), and R 2 is morpholino, piperidino or mono- or di-substituted amino (substituted with the same or different straight-chain, branched or cyclic alkyl group having 1 to 8 carbon atoms); A pharmaceutical composition for the treatment of tumors involving cholecystokinin or biologically active polypeptides having a similar mechanism of action, characterized by comprising a compound represented by the following formula or a pharmaceutically acceptable salt thereof: thing. 9 Formula as active ingredient, [In the formula, R and Râ² are different from each other and are OH or R 2 , n
is 1 or 2, R 1 is mono-, di- or tri-substituted phenyl (substituted with the same or different linear or branched C 1 -C 4 alkyl group, substituted with halogen,
or substituted with a cyano group or a trifluoromethyl group), and R 2 is morpholino, piperidino or mono- or di-substituted amino (substituted with the same or different straight-chain, branched or cyclic alkyl group having 1 to 8 carbon atoms); A pharmaceutical composition for use as a pain suppressant for humans, which comprises a compound represented by the following formula or a pharmaceutically acceptable salt thereof, and is used in combination with an analgesic. 10 To increase the rate of weight gain of agricultural animals,
It is used as an appetite stimulant in animals, and as an active ingredient it contains the formula, [In the formula, R and Râ² are different from each other and are OH or R 2 , n
is 1 or 2, R 1 is mono-, di- or tri-substituted phenyl (substituted with the same or different linear or branched C 1 -C 4 alkyl group, substituted with halogen,
or substituted with a cyano group or a trifluoromethyl group), and R 2 is morpholino, piperidino or mono- or di-substituted amino (substituted with the same or different straight-chain, branched or cyclic alkyl group having 1 to 8 carbon atoms); A preparation for animal breeding containing at least one compound represented by: 11 formula, [In the formula, R and Râ² are different from each other and are OH or R 2 , n
is 1 or 2, R 1 is mono-, di- or tri-substituted phenyl (substituted with the same or different linear or branched C 1 -C 4 alkyl group, substituted with halogen,
or substituted with a cyano group or a trifluoromethyl group), and R 2 is morpholino, piperidino or mono- or di-substituted amino (substituted with a straight-chain, branched or cyclic alkyl group having 1 to 8 carbon atoms). A method for producing a D,L-glutamic acid derivative or a D,L-aspartic acid derivative shown, or a pharmaceutically acceptable salt thereof, comprising (a) the formula: [In the formula, n and R 1 have the same meanings as above] An intramolecular anhydride represented by the formula: R 2 H [In the formula, R 2
is the same meaning as above] and 1 to 5
The reaction was carried out at a molar ratio of
A manufacturing method comprising the steps of recovering and separating a compound in which R' is R 2 and R is R 2 and R' is OH. 12 The intramolecular anhydride of the formula [ ] used in step (a) of Section 11 above, (b) glutamic acid or aspartic acid under Schotten-Bauman conditions in an equimolar amount of the formula: R 1
-CO-Cl is reacted with acyl chloride at a temperature of -20°C to 30°C, formula: (c) The compound [] is treated as such or with acetic anhydride in a molar ratio of 1 to 10 in a compatible inert solvent.
12. The method according to the above item 11, which is obtained by a step of reacting and dehydrating at a temperature of .degree. C. to reflux. 13 n is 2, R 1 is 3,4-dimethylphenyl or 3,4-dichlorophenyl, and R 2 is
13. The method according to the above item 11 or 12, wherein the amino acid is di-substituted with a C4 to C5 straight chain alkyl group. 14. The method according to item 11 or 12, wherein 14n is 2, R1 is 4-cyanophenyl, and R2 is amino di-substituted with a C4 - C5 linear alkyl group.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT67644A/84 | 1984-06-25 | ||
IT67644/84A IT1178982B (en) | 1984-06-25 | 1984-06-25 | GLUDAMIC ACID DERIVATIVES HAVING ANTAGONIST ACTIVITIES ON BIOACTIVE POLIPEP TIDES AND PROCEDURE FOR THEIR PREPARATION |
IT68070A/84 | 1984-10-26 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS6144855A JPS6144855A (en) | 1986-03-04 |
JPH0473425B2 true JPH0473425B2 (en) | 1992-11-20 |
Family
ID=11304166
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP60140103A Granted JPS6144855A (en) | 1984-06-25 | 1985-06-25 | Glutamic acid derivatives and aspartic acid derivatives antagonistic against biologically active polypeptides and manufacture |
Country Status (3)
Country | Link |
---|---|
JP (1) | JPS6144855A (en) |
IT (1) | IT1178982B (en) |
ZA (1) | ZA854660B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1217123B (en) * | 1987-02-05 | 1990-03-14 | Rotta Research Lab | OPTICALLY ACTIVE DERIVATIVES OF ACID 5 PENTILAMINE 5 OXO PENTANOIC R WITH ANTAGONIST ACTIVITY OF THE CHOLECISTOKININ AND PROCEDURE FOR THEIR PREPARATION |
-
1984
- 1984-06-25 IT IT67644/84A patent/IT1178982B/en active
-
1985
- 1985-06-20 ZA ZA854660A patent/ZA854660B/en unknown
- 1985-06-25 JP JP60140103A patent/JPS6144855A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS6144855A (en) | 1986-03-04 |
ZA854660B (en) | 1986-02-26 |
IT8467644A1 (en) | 1985-12-25 |
IT1178982B (en) | 1987-09-16 |
IT8467644A0 (en) | 1984-06-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5602179A (en) | Optically-active derivatives of (R) 5-pentylamino-5-oxopentanoic acid with antagonistic activity towards cholecystokinin and a method for their preparation | |
DE3522506C2 (en) | ||
EP0237522B1 (en) | Pharmaceutically active derivatives of tryptophan and pharmaceutical compositions containing them | |
US5977161A (en) | Kappa-opiate agonists effective in the treatment of postoperative ileus | |
US4218474A (en) | Derivatives of L- and DL-4-hydroxyphenylglycine | |
US4038416A (en) | Pharmaceutical composition and method of the use thereof | |
LT3918B (en) | 2,4- and 2,5- substituted pyridin-n-oxides, methods for the production thereof, pharmaceutical compositions and preparation the same | |
EP0286643B1 (en) | Pharmaceutically active derivatives of glutamic and aspartic acids | |
WO1996031470A1 (en) | Novel heterocyclic compounds | |
DE69816520T2 (en) | Treatment of infections caused by unicellular organisms | |
JPH0473425B2 (en) | ||
FI73207B (en) | PROFESSIONAL FRAMSTAELLNING AV EN NY N- (1-ALLYL-2-PYRROLIDINYLMETHYL-2-METHOXY-4-AMINO-5-METHYL SULFAMOYL BENZENIDE. | |
EP0498830B1 (en) | Glutamic and aspartic acid derivatives with antigastrin activity and a method for their preparation | |
KR100258336B1 (en) | New analgesic and nootropic drugs | |
WO1996031500A1 (en) | Novel heterocyclic compounds | |
US4596826A (en) | Carboxylic acid amide compounds and their derivatives | |
DE3211501A1 (en) | 1 (2H) -ISOCHINOLONES AND THEIR SALTS WITH ACIDS AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS | |
US4156009A (en) | Diazepine derivatives | |
US4289770A (en) | 2-Benzoyl-4-nitroanilides and their use as medicaments | |
US4939129A (en) | Uses of 4-(3-phosphono-2-propenyl)-2-pierazinecarboxylic acid | |
NZ199008A (en) | 2,3,3a,4,5,6-hexahydro-ih-indolo(3,2,1-de)(1,5)-naphthyridines | |
JP3713271B6 (en) | Use of 3,5-diamino-6- (2,3-dichlorophenyl) -1,2,4-triazine for the treatment of edema and pain | |
KR820001303B1 (en) | Process for the preparation if phenethanol amines | |
KR820001020B1 (en) | Methods of preparing new derivatives of 4-amino 5-alkyl sulphonyl ortho - anisamides | |
Powell et al. | The pharmacological action of chelerythrine |