DE3816360A1 - (-)-Menthyl 2-amino-1,4-dihydropyridinedicarboxylates - Google Patents
(-)-Menthyl 2-amino-1,4-dihydropyridinedicarboxylatesInfo
- Publication number
- DE3816360A1 DE3816360A1 DE19883816360 DE3816360A DE3816360A1 DE 3816360 A1 DE3816360 A1 DE 3816360A1 DE 19883816360 DE19883816360 DE 19883816360 DE 3816360 A DE3816360 A DE 3816360A DE 3816360 A1 DE3816360 A1 DE 3816360A1
- Authority
- DE
- Germany
- Prior art keywords
- formula
- salts
- compounds
- amino
- menthyl
- 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.)
- Withdrawn
Links
- NWOLKEISJGOMED-UHFFFAOYSA-N 2-amino-2-(5-methyl-2-propan-2-ylcyclohexyl)oxycarbonyl-3,4-dihydro-1H-pyridine-3-carboxylic acid Chemical class CC1CCC(C(C1)OC(=O)C2(C(CC=CN2)C(=O)O)N)C(C)C NWOLKEISJGOMED-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 230000000144 pharmacologic effect Effects 0.000 claims abstract description 8
- -1 2-nitrophenyl Chemical group 0.000 claims description 52
- 150000003839 salts Chemical class 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- 150000001409 amidines Chemical class 0.000 claims description 5
- 230000002490 cerebral effect Effects 0.000 claims description 5
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 4
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 230000002093 peripheral effect Effects 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- 206010041277 Sodium retention Diseases 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 150000001851 cinnamic acid derivatives Chemical class 0.000 claims description 3
- 208000029078 coronary artery disease Diseases 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000000468 ketone group Chemical group 0.000 claims description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 230000004087 circulation Effects 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 238000011321 prophylaxis Methods 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000002253 acid Substances 0.000 description 9
- 230000036772 blood pressure Effects 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- IWYCSEDITBFDOT-UHFFFAOYSA-N (5-methyl-2-propan-2-ylcyclohexyl) 2-[(3-nitrophenyl)methylidene]-3-oxobutanoate Chemical compound C1(CC(C(CC1)C(C)C)OC(C(=CC1=CC(=CC=C1)[N+](=O)[O-])C(C)=O)=O)C IWYCSEDITBFDOT-UHFFFAOYSA-N 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical group C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 2
- DWBVURAGFFCDHB-UHFFFAOYSA-N 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=C(N)NC(C)=C(C(O)=O)C1C1=CC=CC([N+]([O-])=O)=C1 DWBVURAGFFCDHB-UHFFFAOYSA-N 0.000 description 2
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- BVDUEIBLBPCQCW-UHFFFAOYSA-N NC=1NC(=C(C(C1C(=O)O)C1=C(C=CC=C1)Cl)C(=O)O)C Chemical compound NC=1NC(=C(C(C1C(=O)O)C1=C(C=CC=C1)Cl)C(=O)O)C BVDUEIBLBPCQCW-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 238000009530 blood pressure measurement Methods 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000009460 calcium influx Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229960003883 furosemide Drugs 0.000 description 2
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 230000035488 systolic blood pressure Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229940124549 vasodilator Drugs 0.000 description 2
- 239000003071 vasodilator agent Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- QSVQIPXQOCAWHP-UHFFFAOYSA-N (5-methyl-2-propan-2-ylcyclohexyl) 3-oxobutanoate Chemical compound CC(C)C1CCC(C)CC1OC(=O)CC(C)=O QSVQIPXQOCAWHP-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SZLZWPPUNLXJEA-UHFFFAOYSA-N 11,17-dimethoxy-18-[3-(3,4,5-trimethoxy-phenyl)-acryloyloxy]-yohimbane-16-carboxylic acid methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(OC)C1OC(=O)C=CC1=CC(OC)=C(OC)C(OC)=C1 SZLZWPPUNLXJEA-UHFFFAOYSA-N 0.000 description 1
- PKHPZNKXOBWFCX-UHFFFAOYSA-N 2-(4-hydroxy-3-phenylbenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C(C=2C=CC=CC=2)=C1 PKHPZNKXOBWFCX-UHFFFAOYSA-N 0.000 description 1
- YGTUPRIZNBMOFV-UHFFFAOYSA-N 2-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C=C1 YGTUPRIZNBMOFV-UHFFFAOYSA-N 0.000 description 1
- GCIIKUMFZZHXBE-UHFFFAOYSA-N 2-amino-4-(2,1,3-benzoxadiazol-4-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound CC1=C(C(C(=C(N1)N)C(=O)O)C2=CC=CC3=NON=C32)C(=O)O GCIIKUMFZZHXBE-UHFFFAOYSA-N 0.000 description 1
- TYJXWNHTXWZHHR-UHFFFAOYSA-N 2-amino-4-(2,3-dichlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=C(N)NC(C)=C(C(O)=O)C1C1=CC=CC(Cl)=C1Cl TYJXWNHTXWZHHR-UHFFFAOYSA-N 0.000 description 1
- JZIXRORMBMZVRR-UHFFFAOYSA-N 2-amino-6-methyl-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=C(N)NC(C)=C(C(O)=O)C1C1=CC=CC=C1C(F)(F)F JZIXRORMBMZVRR-UHFFFAOYSA-N 0.000 description 1
- JIVPVXMEBJLZRO-CQSZACIVSA-N 2-chloro-5-[(1r)-1-hydroxy-3-oxo-2h-isoindol-1-yl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC([C@@]2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-CQSZACIVSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 description 1
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 1
- VCPBYLUDWGYFIQ-UHFFFAOYSA-N 4-benzyl-3-(butylamino)-5-sulfamoylbenzoic acid Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1CC1=CC=CC=C1 VCPBYLUDWGYFIQ-UHFFFAOYSA-N 0.000 description 1
- UJRFKPXGAPWRBG-UHFFFAOYSA-N 4-chloro-2-sulfamoylbenzoic acid Chemical compound NS(=O)(=O)C1=CC(Cl)=CC=C1C(O)=O UJRFKPXGAPWRBG-UHFFFAOYSA-N 0.000 description 1
- LBXHRAWDUMTPSE-AOOOYVTPSA-N 4-chloro-N-[(2S,6R)-2,6-dimethyl-1-piperidinyl]-3-sulfamoylbenzamide Chemical compound C[C@H]1CCC[C@@H](C)N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 LBXHRAWDUMTPSE-AOOOYVTPSA-N 0.000 description 1
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
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- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- RTAPDZBZLSXHQQ-UHFFFAOYSA-N 8-methyl-3,7-dihydropurine-2,6-dione Chemical class N1C(=O)NC(=O)C2=C1N=C(C)N2 RTAPDZBZLSXHQQ-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
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- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- KGPOKFKSZVKXIP-UHFFFAOYSA-N CC1=C(C(C(=C(N1)N)C(=O)O)C2=CC=CC=C2OC(F)F)C(=O)O Chemical compound CC1=C(C(C(=C(N1)N)C(=O)O)C2=CC=CC=C2OC(F)F)C(=O)O KGPOKFKSZVKXIP-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 206010052895 Coronary artery insufficiency Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
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- 238000001226 reprecipitation Methods 0.000 description 1
- SMSAPZICLFYVJS-QEGASFHISA-N rescinnamine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)\C=C\C1=CC(OC)=C(OC)C(OC)=C1 SMSAPZICLFYVJS-QEGASFHISA-N 0.000 description 1
- 229960001965 rescinnamine Drugs 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 1
- 230000000054 salidiuretic effect Effects 0.000 description 1
- 230000000894 saliuretic effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000004873 systolic arterial blood pressure Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- AGHANLSBXUWXTB-UHFFFAOYSA-N tienilic acid Chemical compound ClC1=C(Cl)C(OCC(=O)O)=CC=C1C(=O)C1=CC=CS1 AGHANLSBXUWXTB-UHFFFAOYSA-N 0.000 description 1
- 229960000356 tienilic acid Drugs 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Description
Die Erfindung betrifft neue Amine, Verfahren zu ihrer Herstellung, ihre Verwendung und sie enthaltende Arzneimittel. Die erfindungsgemäßen Verbindungen werden in der pharmazeutischen Industrie zur Herstellung von Arzneimitteln eingesetzt.The invention relates to new amines, processes for their preparation, their use and medicines containing them. The compounds of the invention are used in the pharmaceutical industry for the manufacture of pharmaceuticals.
Es ist bekannt, daß bestimmte, auf verschiedene Weise substituierte 1,4-Dihydropyridinderivate pharmakologisch nützliche Eigenschaften aufweisen. Überraschenderweise wurde nun gefunden, daß die unten näher beschriebenen neuen Verbindungen besonders interessante pharmakologische Eigenschaften aufweisen, durch die sie sich von den Verbindungen des Standes der Technik in vorteilhafter Weise unterscheiden.It is known that certain 1,4-dihydropyridine derivatives substituted in various ways have pharmacologically useful properties. Surprisingly it has now been found that the new compounds described in more detail below have particularly interesting pharmacological properties, by which they differ from the compounds of the prior art in an advantageous manner Differentiate way.
Gegenstand der Erfindung sind neue Amine der Formel IThe invention relates to new amines of the formula I.
worin Cy einen Cyclus der Formelwherein Cy is a cycle of the formula
darstellt, in dem Y Sauerstoff (O), Schwefel (S), Vinylen (-CH=CH-), Azomethin (-CH=N-) oder eine Gruppe der Formelrepresents in which Y represents oxygen (O), sulfur (S), vinylene (-CH = CH-), azomethine (-CH = N-) or a group of the formula
bedeutet,means
R1Amino (NH₂) bedeutet, R2Wasserstoff, 1-6C-Alkyl oder 3-7C-Alkoxyalkyl bedeutet, R3einen (-)-Menthylrest darstellt, R4 und R5gleich oder verschieden sind und Wasserstoff, Hydroxy, Halogen, Nitro, Cyano, Trifluormethyl, 1-4C-Alkyl, 1-4C-Alkoxy, ganz oder teilweise durch Fluor substituiertes 1-4C-Alkoxy, 1-4C-Alkoxycarbonyl, 2-5C-Acyl, Amino oder Mono- oder Di-1-4C-alkylamino bedeuten und R61-6C-Alkyl oder 3-7C-Alkoxyalkyl bedeutet,R1 means amino (NH₂), R2 is hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl, R3 represents a (-) menthyl radical, R4 and R5 are the same or different and are hydrogen, hydroxy, halogen, Nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, in whole or in part 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 2-5C-acyl substituted by fluorine, Amino or mono- or di-1-4C-alkylamino mean and R61-6C-alkyl or 3-7C-alkoxyalkyl means
und die Salze dieser Verbindungen.and the salts of these compounds.
1-6C-Alkyl ist geradkettig oder verzweigt und bedeutet beispielsweise einen Hexyl-, Neopentyl-, Isopentyl-, Butyl-, i-Butyl-, sec.-Butyl-, t-Butyl-, Propyl-, Isopropyl- oder insbesondere Ethyl- oder Methylrest.1-6C-alkyl is straight-chain or branched and means, for example, one Hexyl, neopentyl, isopentyl, butyl, i-butyl, sec.-butyl, t-butyl, propyl, Isopropyl or especially ethyl or methyl radical.
3-7C-Alkoxyalkyl steht beispielsweise für einen Ethoxyethyl-, Propoxyethyl-, Isopropoxyethyl-, Butoxyethyl-, Methoxypropyl-, 2-Methoxy-1-methylethyl-, 2- Ethoxy-1-methylethyl- oder insbesondere Methoxyethylrest.3-7C-Alkoxyalkyl stands for example for an ethoxyethyl, propoxyethyl, Isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl, 2- Ethoxy-1-methylethyl or in particular methoxyethyl radical.
Der (-)-Menthylrest ist der Rest, der sich vom (1R : 3R : 4S)-p-Menthanol-(3) herleitet.The (-) - menthyl residue is the residue derived from (1R: 3R: 4S) -p-menthanol- (3).
Halogen im Sinne der Erfindung bedeutet Brom, Fluor und insbesondere Chlor. Halogen in the sense of the invention means bromine, fluorine and especially chlorine.
1-4C-Alkyl ist geradkettig oder verzweigt und bedeutet beispielsweise einen Butyl-, i-Butyl-, sec.-Butyl-, t-Butyl-, Propyl-, Isopropyl-, Ethyl- oder insbesondere Methylrest.1-4C-alkyl is straight-chain or branched and means, for example, a butyl, i-butyl, sec.-butyl, t-butyl, propyl, isopropyl, ethyl or in particular Methyl residue.
1-4C-Alkoxy enthält neben dem Sauerstoffatom einen der vorstehend genannten 1-4C-Alkylreste. Bevorzugt sind der Methoxy- und der Ethoxyrest.1-4C-alkoxy contains one of the above in addition to the oxygen atom 1-4C alkyl groups. The methoxy and ethoxy radicals are preferred.
Ganz oder teilweise durch Fluor substituiertes 1-4C-Alkoxy ist beispielsweise 1,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy oder insbesondere Difluormethoxy.All or part of fluorine-substituted 1-4C-alkoxy is, for example 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or in particular Difluoromethoxy.
1-4C-Alkoxycarbonyl enthält neben der Carbonylgruppe einen der vorstehend genannten 1-4C-Alkoxyreste. Bevorzugt sind der Methoxycarbonyl- und der Ethoxycarbonylrest.1-4C-Alkoxycarbonyl contains one of the above in addition to the carbonyl group 1-4C alkoxy groups. The methoxycarbonyl and the ethoxycarbonyl radical are preferred.
2-5C-Acyl enthält neben der Carbonylgruppe einen der vorstehend genannten 1-4C-Alkylreste. Bevorzugt ist der Acetylrest.2-5C-acyl contains one of the above in addition to the carbonyl group 1-4C alkyl groups. The acetyl radical is preferred.
Mono- oder Di-1-4C-alkylamino enthält neben dem Stickstoffatom einen oder zwei der vorstehend genannten 1-4C-Alkylreste. Bevorzugt ist Di-1-4C-alkylamino, und hier insbesondere Dimethyl-, Diethyl- oder Diisopropylamino.Mono- or di-1-4C-alkylamino contains one or two in addition to the nitrogen atom the aforementioned 1-4C-alkyl radicals. Di-1-4C-alkylamino is preferred, and here in particular dimethyl-, diethyl- or diisopropylamino.
Als Salze kommen alle Salze mit Säuren in Betracht. Besonders erwähnt seien die pharmakologisch verträglichen Salze der in der pharmazeutischen Industrie üblicherweise verwendeten anorganischen und organischen Säuren. Pharmakologisch unverträgliche Salze, die beispielsweise bei der Herstellung der erfindungsgemäßen Verbindungen im industriellen Maßstab als Verfahrensprodukte zunächst anfallen können, werden durch dem Fachmann bekannte Verfahren in pharmakologisch verträgliche Salze übergeführt. Als solche eignen sich beispielsweise wasserlösliche und wasserunlösliche Säureadditionssalze, wie das Hydrochlorid, Hydrobromid, Hydroiodid, Phosphat, Nitrat, Sulfat, Acetat, Citrat, Gluconat, Benzoat, Hibenzat, Fendizoat, Butyrat, Sulfosalicylat, Maleat, Laurat, Malat, Fumarat, Succinat, Oxalat, Tartrat, Amsonat, Metembonat, Stearat, Tosilat, 2-Hydroxy-3-naphthoat, 3-Hydroxy-2-naphthoat oder Mesilat, aber auch Salze mit Bumetanid, Furosemid, Azosemid, Galosemid, Besunid, Piretanid, Etacrynsäure, Tienilinsäure oder 4-Chlor-sulfamoyl-benzoesäure. All salts with acids can be considered as salts. They are particularly worth mentioning pharmacologically acceptable salts commonly used in the pharmaceutical industry used inorganic and organic acids. Pharmacological incompatible salts, for example in the manufacture of the invention Industrial-scale compounds initially arise as process products can, by methods known to those skilled in pharmacological tolerated salts transferred. Water-soluble, for example, are suitable as such and water-insoluble acid addition salts such as the hydrochloride, hydrobromide, Hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, Hibenzate, fendizoate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, Succinate, oxalate, tartrate, amsonate, metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate, but also salts with bumetanide, Furosemide, azosemide, galosemide, besunid, piretanide, etacrynic acid, tienilic acid or 4-chloro-sulfamoyl-benzoic acid.
Hervorzuhebende erfindungsgemäße Verbindungen sind solche der Formel I, worinCompounds according to the invention which are to be emphasized are those of the formula I in which
CyPhenyl, 2-Nitrophenyl, 3-Nitrophenyl, 2-Cyanophenyl, 3-Cyanophenyl, 2- (1,1,2,2-Tetrafluorethoxy)-phenyl, 3-(1,1,2,2-Tetrafluorethoxy)-phenyl, 2-Difluormethoxyphenyl, 3-Difluormethoxyphenyl, 2-Chlorphenyl, 3-Chlorphenyl, 2,3-Dichlorphenyl, 2-Fluorphenyl, 3-Fluorphenyl, 2-Trifluormethylphenyl, 3-Trifluormethylphenyl, 2-Pyridyl, 3-Pyridyl oder Benzoxdiazolyl bedeutet, R1Amino (NH₂) bedeutet, R2Methyl oder Ethyl bedeutet, R3einen (-)-Menthylrest darstellt und R6Methyl, Ethyl oder Isopropyl bedeutet,CyPhenyl, 2-nitrophenyl, 3-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 2- (1,1,2,2-tetrafluoroethoxy) phenyl, 3- (1,1,2,2-tetrafluoroethoxy) phenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-pyridyl, 3-pyridyl or benzoxdiazolyl, R1 means amino (NH₂), R2 means methyl or ethyl, R3 represents a (-) menthyl residue and R6 denotes methyl, ethyl or isopropyl,
und ihre Salze.and their salts.
Bevorzugte erfindungsgemäße Verbindungen sind solche der Formel I, worinPreferred compounds according to the invention are those of the formula I in which
Cy3-Nitrophenyl, 2-Chlorphenyl, 2,3-Dichlorphenyl oder 2-Trifluormethylphenyl bedeutet, R1Amino (NH₂) bedeutet, R2Methyl bedeutet, R3einen (-)-Menthylrest darstellt und R6Methyl oder Ethyl bedeutet,Cy3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl or 2-trifluoromethylphenyl means R1 means amino (NH₂), R2Methyl means R3 represents a (-) menthyl residue and R6 denotes methyl or ethyl,
und ihre Salze.and their salts.
Als erfindungsgemäße Verbindungen seien beispielsweise genannt:
2-Amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbons-äure-3-
ethyl-5-(-)-menthylester,
2-Amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbons-äure-5-(-)-
menthyl-3-methylester,
2-Amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbons-äure-5-(-)-
Menthyl-3-(propyl-2)-ester,
2-Amino-1,4-dihydro-6-methyl-4-(2-trifluormethylphenyl)-pyridin-3,5--dicarbon
säure-3-ethyl-5-(-)-menthylester,
2-Amino-1,4-dihydro-6-methyl-4-(2-difluormethoxyphenyl)-pyridin-3,5--dicarbon
säure-3-ethyl-5-(-)-menthylester,
2-Amino-1,4-dihydro-6-methyl-4-(2-difluormethoxyphenyl)-pyridin-3,5--dicarbon
säure-5-(-)-menthyl-3-methylester,
2-Amino-4-(2,3-dichlorphenyl)-1,4-dihydro-6-methylpyridin-3,5-dicarb-on
säure-5-ethyl-3-(-)-menthylester,
2-Amino-4-(2,1,3-benzoxdiazol-4-yl)-1,4-dihydro-6-methylpyridin-3,5--dicarbon
säure-3-ethyl-5-(-)-menthylester,
2-Amino-1,4-dihydro-6-methyl-4-(2-pyridyl)-pyridin-3,5-dicarbonsäure--5-(-)-men
thyl-3-methylester,
2-Amino-1,4-dihydro-6-methyl-4-(2-trifluormethylphenyl)-pyridin-3,5--dicarbon
säure-5-(-)-menthyl-3-methylester,
2-Amino-4-(2,3-dichlorphenyl)-1,4-dihydro-6-methylpyridin-3,5-dicarb-onsäure-5-
(-)-menthyl-3-methylester,
2-Amino-4-(2,1,3-benzoxdiazol-4-yl)-1,4-dihydro-6-methylpyridin-3,5--dicarbon
säure-5-(-)-menthyl-3-methylester,
2-Amino-1,4-dihydro-6-methyl-4-(2-pyridyl)-pyridin-3,5-dicarbonsäure--3-ethyl-
5-(-)-menthylester,
2-Amino-4-(2-chlorphenyl)-1,4-dihydro-6-methylpyridin-3,5-dicarbonsä-ure-3-
ethyl-5-(-)-menthylester,
2-Amino-4-(2-chlorphenyl)-1,4-dihydro-6-methylpyridin-3,5-dicarbonsä-ure-5-(-)-
menthyl-3-methylester,
und ihre Salze.The following compounds may be mentioned as examples:
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid 3-ethyl-5 - (-) - menthyl ester,
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid 5 - (-) - menthyl-3-methyl ester,
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid 5 - (-) - menthyl-3- (propyl-2) ester,
2-amino-1,4-dihydro-6-methyl-4- (2-trifluoromethylphenyl) pyridine-3,5-dicarboxylic acid 3-ethyl-5 - (-) - menthyl ester,
2-amino-1,4-dihydro-6-methyl-4- (2-difluoromethoxyphenyl) pyridine-3,5-dicarboxylic acid 3-ethyl-5 - (-) - menthyl ester,
2-amino-1,4-dihydro-6-methyl-4- (2-difluoromethoxyphenyl) pyridine-3,5-dicarboxylic acid 5 - (-) - menthyl-3-methyl ester,
2-amino-4- (2,3-dichlorophenyl) -1,4-dihydro-6-methylpyridin-3,5-dicarb-one acid 5-ethyl-3 - (-) - menthyl ester,
2-amino-4- (2,1,3-benzoxdiazol-4-yl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylic acid 3-ethyl-5 - (-) - menthyl ester,
2-amino-1,4-dihydro-6-methyl-4- (2-pyridyl) pyridine-3,5-dicarboxylic acid - 5 - (-) - methyl 3-methyl ester,
2-amino-1,4-dihydro-6-methyl-4- (2-trifluoromethylphenyl) pyridine-3,5-dicarboxylic acid 5 - (-) - menthyl-3-methyl ester,
2-amino-4- (2,3-dichlorophenyl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylic acid 5-(-) - menthyl-3-methyl ester,
2-amino-4- (2,1,3-benzoxdiazol-4-yl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylic acid 5-(-) - menthyl-3-methyl ester,
2-amino-1,4-dihydro-6-methyl-4- (2-pyridyl) pyridine-3,5-dicarboxylic acid - 3-ethyl-5 - (-) - menthyl ester,
2-amino-4- (2-chlorophenyl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylic acid, 3-ethyl-5 - (-) - menthyl ester,
2-amino-4- (2-chlorophenyl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylic acid 5 - (-) - menthyl-3-methyl ester,
and their salts.
Die Verbindungen der Formel I besitzen mindestens vier Chiralitätszentren, und zwar drei im (-)-Menthylrest und eins in der 4-Position des 1,4-Dihydropyridinringes. Die Erfindung umfaßt sowohl alle Enantiomeren als auch alle Diastereomeren sowie Racemate und Gemische von Verbindungen der Formel I. Die Verbindungen der Formel I mit unterschiedlicher Konfiguration in der 4-Position des Dihydropyridinenringes und im restlichen Molekül übereinstimmender Konfiguration sind zueinander diastereomer.The compounds of formula I have at least four centers of chirality, and three in the (-) - menthyl radical and one in the 4-position of the 1,4-dihydropyridine ring. The invention encompasses both all enantiomers and all diastereomers as well as racemates and mixtures of compounds of formula I. The compounds of formula I with different configuration in the 4-position of the dihydropyridine ring and in the rest of the molecule of the same configuration are diastereomeric to each other.
Ein weiterer Gegenstand der Erfindung ist ein Verfahren zur Herstellung der erfindungsgemäßen Verbindungen und ihrer Salze. Das Verfahren ist dadurch gekennzeichnet, daß man Another object of the invention is a method for producing the invention Compounds and their salts. The process is characterized by that he
- a) Zimtsäurederivate der Formel II mit Amidinen der Formel III odera) cinnamic acid derivatives of the formula II with amidines of the formula III or
- b) Ketoverbindungen der Formel IV mit Amidinen der Formel III und Aldehyden der Formel V umsetzt und gewünschtenfalls anschließend erhaltene Salze in die freien Basen oder erhaltene Basen in die Salze überführt, wobei Cy, R1, R2, R3, R4, R5 und R6 die oben angegebenen Bedeutungen haben und wobei die Ausgangsverbindungen als solche oder in Form ihrer Salze eingesetzt werden.b) keto compounds of the formula IV with amidines of the formula III and aldehydes of the formula V implemented and, if desired, subsequently obtained salts converted into the free bases or bases obtained into the salts, where Cy, R1, R2, R3, R4, R5 and R6 have the meanings given above and where the starting compounds are used as such or in the form of their salts .
Ausgestaltungen des Verfahrens sind solche, bei denen in den Formeln II bis V die Substituenten bzw. Symbole Cy, R1, R2, R3, R4, R5 und R6 die in den Unter- und Nebenansprüchen angegebenen Bedeutungen haben.Refinements of the method are those in which in the formulas II to V the substituents or symbols Cy, R1, R2, R3, R4, R5 and R6 which in the sub- and secondary claims have the meanings given.
Das Verfahren gemäß Variante a und b wird in geeigneten, vorzugsweise inerten organischen Lösungsmitteln durchgeführt. Beispielsweise seien genannt Alkohole, wie t-Butanol, Methanol, Isopropanol oder insbesondere Ethanol, Kohlenwasserstoffe, wie Toluol oder Xylol, Ether, wie Dioxan, Diethylether, Tetrahydrofuran, Glykolmonoethylether, Glykoldimethylether oder sonstige, beispielsweise polare Lösungsmittel wie Dimethylformamid, Dimethylsulfoxid, Acetonitril oder Hexamethylphosphorsäuretriamid, oder chlorierte Kohlenwasserstoffe wie Methylenchlorid, Chloroform oder Tetrachlorethylen.The process according to variants a and b is carried out in suitable, preferably inert organic solvents. Examples include alcohols, such as t-butanol, methanol, isopropanol or in particular ethanol, hydrocarbons, such as toluene or xylene, ethers such as dioxane, diethyl ether, tetrahydrofuran, Glycol monoethyl ether, glycol dimethyl ether or other, for example polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile or Hexamethylphosphoric triamide, or chlorinated hydrocarbons such as methylene chloride, Chloroform or tetrachlorethylene.
Die Reaktionstemperaturen können - je nach Reaktivität der Edukte - in einem weiten Bereich variieren. Im allgemeinen wird die Umsetzung bei Temperaturen zwischen 20°C und 150°C, vorzugsweise zwischen 20°C und 100°C, insbesondere bei der Siedetemperatur des verwendeten Lösungsmittels durchgeführt.The reaction temperatures - depending on the reactivity of the starting materials - in one vary wide range. In general, the reaction at temperatures between 20 ° C and 150 ° C, preferably between 20 ° C and 100 ° C, especially at the boiling point of the solvent used.
Die Durchführung des erfindungsgemäßen Verfahrens gemäß Variante a erfolgt in Gegenwart einer Base, beispielsweise in Gegenwart eines Alkalialkoholates, wie Natriummethylat oder Natriumethylat.The method according to the invention according to variant a is carried out in Presence of a base, for example in the presence of an alkali alcoholate, such as Sodium methylate or sodium ethylate.
Die Isolierung und Reinigung der erfindungsgemäßen Substanzen erfolgt in an sich bekannter Weise z. B. derart, daß man das Lösungsmittel im Vakuum abdestilliert und den erhaltenen Rückstand aus einem geeigneten Lösungsmittel umkristallisiert oder einer der üblichen Reinigungsmethoden, wie beispielsweise der Säulenchromatographie an geeignetem Trägermaterial, unterwirft. Die Trennung von Diasteromeren erfolgt in für den Fachmann bekannter Weise, beispielsweise durch Umkristallisation oder durch Chromatografie.The substances according to the invention are isolated and purified in known way z. B. such that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or one of the usual cleaning methods, such as column chromatography on a suitable support. The separation of diasteromers is carried out in a manner known to those skilled in the art, for example by recrystallization or by chromatography.
Säureadditionssalze erhält man durch Auflösen der freien Base in einem geeigneten Lösungsmittel, z. B. in einem chlorierten Kohlenwasserstoff, wie Methylenchlorid oder Chloroform, oder einem niedermolekularen aliphatischen Alkohol (Ethanol, Isopropanol), das die gewünschte Säure enthält oder dem die gewünschte Säure anschließend zugegeben wird. Acid addition salts are obtained by dissolving the free base in a suitable one Solvents, e.g. B. in a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (Ethanol, isopropanol), which contains the desired acid or which the desired Acid is then added.
Die Salze werden durch Filtrieren, Umfällen, Ausfällen mit einem Nichtlösungsmittel für das Anlagerungssalz oder durch Verdampfen des Lösungsmittels gewonnen.The salts are obtained by filtration, reprecipitation, precipitation with a non-solvent obtained for the addition salt or by evaporating the solvent.
Erhaltene Salze können durch Alkalisierung, z. B. mit wäßriger Ammoniaklösung, in die freien Basen umgewandelt werden, welche wiederum in Säureadditionssalze übergeführt werden können. Auf diese Weise lassen sich pharmakologisch nicht verträgliche Säureadditionssalze in pharmakologisch verträgliche Säureadditionssalze umwandeln.Salts obtained can by alkalization, e.g. B. with aqueous ammonia solution, be converted into the free bases, which in turn into acid addition salts can be transferred. In this way, pharmacologically tolerated acid addition salts in pharmacologically tolerated acid addition salts convert.
Die Ausgangsverbindungen sind literaturbekannt oder können in Analogie zu literaturbekannten Methoden hergestellt werden. Die Zimtsäurederivate II können beispielsweise in Analogie zu G. Jones ["The Knoevenagel Condensation" in Org. Reactions, Vol. XV, 204f (1967)] hergestellt werden. Die Amidine III können nach H. Yamanaka et al., Heterocycles 1976, 1854 hergestellt werden. Die Ketoverbindungen IV können gemäß D. Borrmann ["Umsetzung von Diketen mit Alkoholen, Phenolen und Mercaptanen" in Houben-Weyl, Methoden der Organischen Chemie, Vol. VII/4, 230ff (1968)] oder Y. Oikawa et al [J. Org. Chem. 43, 2087 (1978)] hergestellt werden.The starting compounds are known from the literature or can be obtained in analogy to those known from the literature Methods are made. The cinnamic acid derivatives II can for example in analogy to G. Jones ["The Knoevenagel Condensation" in Org. Reactions, Vol. XV, 204f (1967)]. The amidines III can according to H. Yamanaka et al., Heterocycles 1976, 1854. The keto compounds IV can according to D. Borrmann ["implementation of diketene with alcohols, Phenols and Mercaptans "in Houben-Weyl, Methods of Organic Chemistry, Vol. VII / 4, 230ff (1968)] or Y. Oikawa et al [J. Org. Chem. 43, 2087 (1978)] will.
Die vorstehenden Herstellungsverfahren sind lediglich zur Verdeutlichung angegeben, und die Herstellung der erfindungsgemäßen Verbindungen der Formel I ist nicht auf diese Verfahren beschränkt. Vielmehr ist auch jede Modifikation dieser Verfahren in gleicher Weise für die Herstellung der erfindungsgemäßen Verbindungen anwendbar.The above manufacturing processes are given for illustration only, and the preparation of the compounds of formula I according to the invention not limited to these procedures. Rather, every modification is this Process in the same way for the preparation of the compounds according to the invention applicable.
Die folgenden Herstellungsbeispiele sollen die Erfindung näher erläutern, ohne sie einzuschränken. Schmp. bedeutet Schmelzpunkt, h steht für Stunden, min für Minuten, Kp. steht für Siedepunkt, Zers. bedeutet Zersetzung.The following production examples are intended to explain the invention in more detail without restrict them. Mp. Means melting point, h stands for hours, min for Minutes, Kp. Stands for boiling point, dec. means decomposition.
Zu 18,67 g Amidinoessigsäureethylester und 8,33 g 2-Acetyl-3-(3-nitrophenyl)- acrylsäure-(-)-menthylester in 80 ml Ethanol tropft man in der Siedehitze eine aus 1,15 g Natrium und 50 ml Ethanol bereitete Natriumethylatlösung innerhalb von 60 min zu und kocht die Reaktionsmischung anschließend noch 2 h unter Rückfluß. Nach dem Einengen des Reaktionsansatzes wird der erhaltene Rückstand zwischen Essigsäureethylester, Natriumhydrogencarbonatlösung und anschließend Wasser verteilt. Die organische Phase engt man nach dem Trocknen über Natriumsulfat ein und chromatographiert den erhaltenen Rückstand über eine Kieselgelsäule mit Dichlormethan-Ethanol (99+1) als Eluens. Die eingeengte Produktfraktion ergibt 19 g eines fest aufgeschäumten Rückstandes, der in Diethylether/Petrolether umkristallisiert wird. Man erhält die Titelverbindung als feine farblose Nadeln vom Schmp. 154-55°C. Ausbeute: 17,1 g. To 18.67 g of ethyl amidinoacetate and 8.33 g of 2-acetyl-3- (3-nitrophenyl) - acrylic acid - (-) - menthyl ester in 80 ml of ethanol is added dropwise at the boiling point sodium ethylate solution prepared from 1.15 g sodium and 50 ml ethanol within of 60 min and the reaction mixture is then refluxed for a further 2 h. After concentrating the reaction mixture, the residue obtained is between Ethyl acetate, sodium hydrogen carbonate solution and then water distributed. The organic phase is concentrated after drying over sodium sulfate and chromatograph the residue obtained on a silica gel column with dichloromethane-ethanol (99 + 1) as the eluent. The restricted product fraction gives 19 g of a solidly foamed residue, in diethyl ether / petroleum ether is recrystallized. The title compound is obtained as a fine colorless Needles with a melting point of 154-55 ° C. Yield: 17.1 g.
15,6 g Acetessigsäure-(-)-menthylester und 9,8 g 3-Nitrobenzaldehyd werden in 160 ml Benzol mit 8 ml Eisessig und 0,7 ml Piperidin versetzt und dann das Gemisch am Wasserabscheider unter Rückfluß solange zum Sieden erhitzt, bis sich ca. 1,2 ml Wasser abgeschieden haben. Nach Abkühlen wird die Lösung mit Wasser und verdünnter Natriumhydrogencarbonat-Lösung gewaschen, über Natriumsulfat getrocknet und im Vakuum zur Trockene eingeengt. Das zurückbleibende zähe, gelborange Öl wird ohne weitere Reinigung weiter umgesetzt. 15.6 g of acetoacetic acid - (-) - menthyl ester and 9.8 g of 3-nitrobenzaldehyde are in 160 ml of benzene are mixed with 8 ml of glacial acetic acid and 0.7 ml of piperidine and then the mixture heated to boiling on the water separator under reflux until about 1.2 ml of water. After cooling the solution with water and dilute sodium hydrogen carbonate solution, over sodium sulfate dried and concentrated to dryness in vacuo. The remaining tough, yellow-orange oil is reacted further without further purification.
Die erfindungsgemäßen Verbindungen der Formel I und ihre Salze besitzen wertvolle Eigenschaften, die sie gewerblich verwertbar machen. Sie stellen insbesondere wirksame Vasodilatoren mit coronartherapeutischen Eigenschaften dar. Die pharmakologische Wirksamkeit der erfindungsgemäßen Verbindungen, die gepaart ist mit einer geringen Toxizität, zeigt sich insbesondere in einer langsam eintretenden, starken und langanhaltenden Blutdrucksenkung. Darüber hinaus besitzen die erfindungsgemäßen Verbindungen hemmende Wirkung auf den Calciumeinstrom sowie fördernde Wirkung auf den Kaliumausstrom von Zellen, glattmuskulär relaxierende und peripher, coronar, cerebral und renal gefäßerweiternde sowie salidiuretische, antithrombotische, antiarteriosklerotische und günstige hämorheologische Eigenschaften.The compounds of the formula I according to the invention and their salts have valuable ones Properties that make them commercially usable. You pose in particular effective vasodilators with coronary therapeutic properties. The pharmacological activity of the compounds of the invention, the paired is with a low toxicity, is particularly evident in a slow entering, strong and long-lasting lowering of blood pressure. Furthermore the compounds according to the invention have an inhibitory effect on calcium influx as well as a promoting effect on the potassium outflow of cells, smooth muscle relaxing and peripheral, coronary, cerebral and renal vasodilator as well salidiuretic, antithrombotic, antiarteriosclerotic and inexpensive hemorheological properties.
In ihrer ausgezeichneten Wirksamkeit, die gepaart ist mit einer geringen Toxizität und dem Fehlen wesentlicher Nebenwirkungen, unterscheiden sich die erfindungsgemäßen Verbindungen in überraschender und vorteilhafter Weise von den Verbindungen des Standes der Technik.In its excellent effectiveness, which is paired with a low toxicity and the absence of significant side effects, the invention differs Connections in a surprising and advantageous manner from the Prior art compounds.
Als besonders überraschend ist die Tatsache zu werten, daß die erfindungsgemäßen (-)-Menthylester eine wesentlich stärkere und insbesondere länger anhaltende Wirkung als die bekannten Methyl- oder Ethylester, aber auch als die enantiomeren (+)-Menthylester zeigen. Vor allem letztere Tatsache war für den Fachmann nicht vorhersehbar, da aufgrund der in der Europäischen Patentanmeldung 26 317 offenbarten Befunde zu erwarten gewesen wäre, daß die pharmakologische Wirkung nicht durch die unterschiedliche Konfiguration im chiralen Esterrest, sondern einzig durch die Konfiguration des Kohlenstoffs in 4-Position des Dihydropyridinringes beeinflußt wird.The fact that the inventive (-) - menthyl ester a much stronger and especially longer lasting Effect as the known methyl or ethyl esters, but also as the enantiomers (+) - Show menthyl ester. The latter fact in particular was for the Specialist not predictable because of the in the European patent application 26 317 results were to be expected that the pharmacological Not effective due to the different configuration in the chiral Ester residue, but only by the configuration of the carbon in the 4-position of the dihydropyridine ring is affected.
Als vorteilhafte Eigenschaften der Verbindungen I sind beispielsweise zu nennen: das Ausmaß der Blutdrucksenkung, das lange Anhalten der Blutdrucksenkung, die gute Steuerbarkeit der Blutdrucksenkung, die überraschend geringe und bei wiederholter Gabe verschwindende Herzfrequenzsteigerung, die ausgezeichnete Bioverfügbarkeit, die große therapeutische Breite, das Fehlen zentraler Nebenwirkungen, das Fehlen kinetischer Interaktionen mit anderen Substanzen, das Ausbleiben einer Toleranzentwicklung, die ausgewogenen physikalischen Eigenschaften und die große Stabilität. Examples of advantageous properties of the compounds I are: the extent of the drop in blood pressure, the prolonged persistence of the drop in blood pressure, the good controllability of lowering blood pressure, the surprisingly low and at repeated dosing heart rate increase, the excellent Bioavailability, the wide therapeutic range, the lack of central side effects, the lack of kinetic interactions with other substances, the absence a development of tolerance, the balanced physical properties and the great stability.
Die ausgezeichnete Wirksamkeit der erfindungsgemäßen Verbindungen der Formel I und ihrer Salze gestattet ihren Einsatz in der Humanmedizin, wobei als Indikation insbesondere primäre (essentielle) und sekundäre, arterielle und pulmonale Hypertonien aller Schweregrade, koronare Herzkrankheiten (Koronarinsuffizienz, Angina pectoris, Myocardinfarkt etc.), periphere und cerebrale Zirkulationsstörungen (Gehirnschlag, temporäre cerebrale Durchblutungsstörungen, Migräne, Schwindel, renale Arterienverengung etc.), hypertrophe Kardiomyopathie, Herzinsuffizienz, Krankheiten, die auf einer erhöhten Wasser- und Natriumretention beruhen und Krankheiten, die auf einem erhöhten Calciumeinstrom beruhen, wie z. B. Spasmen glattmuskulärer Organe (Atemwege, Gastrointestinaltrakt, Urogenitaltrakt etc.) sowie Arrhythmie, Arteriosklerose und Zellschädigungen verschiedener Genese (z. B. Hypoxie) in Betracht kommen.The excellent activity of the compounds of the formula I according to the invention and their salts allow their use in human medicine, being used as an indication especially primary (essential) and secondary, arterial and pulmonary Hypertensions of all degrees of severity, coronary heart diseases (coronary insufficiency, Angina pectoris, myocardial infarction, etc.), peripheral and cerebral circulation disorders (Stroke, temporary cerebral circulatory disorders, migraines, Dizziness, renal artery narrowing etc.), hypertrophic cardiomyopathy, heart failure, Diseases based on increased water and sodium retention and diseases that are based on an increased calcium influx, such as e.g. B. Spasms of smooth muscle organs (respiratory tract, gastrointestinal tract, urogenital tract etc.) as well as arrhythmia, arteriosclerosis and cell damage of various Genesis (e.g. hypoxia) can be considered.
Ein weiterer Gegenstand der Erfindung ist daher ein Verfahren zur Behandlung von Säugetieren, insbesondere Menschen, die an einer der obengenannten Krankheiten erkrankt sind. Das Verfahren ist dadurch gekennzeichnet, daß man dem erkrankten Individuum eine therapeutisch wirksame und pharmakologisch verträgliche Menge einer oder mehrerer Verbindungen der Formel I verabreicht.Another object of the invention is therefore a method for treatment of mammals, especially humans suffering from any of the above diseases are ill. The method is characterized in that the sick Individual a therapeutically effective and pharmacologically acceptable Amount of one or more compounds of formula I administered.
Gegenstand der Erfindung sind außerdem die Verbindungen der Formel I zur Anwendung bei der Behandlung der genannten Krankheiten.The invention also relates to the compounds of the formula I for use in the treatment of the diseases mentioned.
Ebenso umfaßt die Erfindung die Verwendung von Verbindungen der Formel I bei der Herstellung von Arzneimitteln, die zur Bekämpfung der genannten Krankheiten eingesetzt werden.The invention also encompasses the use of compounds of the formula I in the manufacture of medicines to combat the diseases mentioned be used.
Ein weiterer Gegenstand der Erfindung sind Arzneimittel, die eine oder mehrere Verbindungen der allgemeinen Formel I enthalten.Another object of the invention are pharmaceuticals, the one or more Contain compounds of general formula I.
Die Arzneimittel werden nach an sich bekannten, dem Fachmann geläufigen Verfahren hergestellt. Als Arzneimittel werden die erfindungsgemäßen pharmakologisch wirksamen Verbindungen (=Wirkstoffe) entweder als solche oder vorzugsweise in Kombination mit geeigneten pharmazeutischen Hilfsstoffen in Form von Tabletten, Dragees, Kapseln, Suppositorien, Pflastern (z. B. als TTS), Emulsionen, Suspensionen, Aerosolen, Sprays, Salben, Cremes, Gelen oder Lösungen eingesetzt, wobei der Wirkstoffgehalt vorteilhafterweise zwischen 0,1 und 95% beträgt.The pharmaceuticals are manufactured according to methods known per se and familiar to the person skilled in the art produced. The medicinal products according to the invention are pharmacological active compounds (= active ingredients) either as such or preferably in Combination with suitable pharmaceutical excipients in the form of tablets, Coated tablets, capsules, suppositories, plasters (e.g. as TTS), emulsions, suspensions, Aerosols, sprays, ointments, creams, gels or solutions are used, wherein the active ingredient content is advantageously between 0.1 and 95%.
Welche Hilfsstoffe für die gewünschten Arzneimittelformulierungen geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. Neben Lösemitteln, Gelbildnern, Suppositoriengrundlagen, Tablettenhilfsstoffen und anderen Wirkstoffträgern können beispielsweise Antioxidantien, Dispergiermittel, Emulgatoren, Entschäumer, Geschmackskorrigentien, Konservierungsmittel, Lösungsvermittler, Farbstoffe oder insbesondere Permeationspromotoren und Komplexbildner (z. B. Cyclodextrine) verwendet werden.Which excipients are suitable for the desired pharmaceutical formulations are familiar to a person skilled in the art on the basis of his specialist knowledge. In addition to solvents, Gel formers, suppository bases, tablet excipients and other active substances For example, antioxidants, dispersants, emulsifiers, Defoamers, flavoring agents, preservatives, solubilizers, Dyes or in particular permeation promoters and complexing agents (e.g. cyclodextrins) can be used.
Die Wirkstoffe können oral, rektal, per inhalationem oder parenteral (insbesondere perlingual, intravenös oder percutan) appliziert werden.The active substances can be administered orally, rectally, by inhalation or parenterally (in particular perlingually, intravenously or percutaneously).
Im allgemeinen hat es sich in der Humanmedizin als vorteilhaft erwiesen, den oder die Wirkstoffe bei oraler Gabe in einer Tagesdosis von etwa 0,01 bis etwa 10, vorzugsweise 0,05 bis 5 mg/kg Körpergewicht, gewünschtenfalls in Form mehrerer, vorzugsweise 1 bis 4 Einzelgaben zur Erzielung des gewünschten Ergebnisses zu verabreichen. Bei einer parenteralen Behandlung können ähnliche bzw. (insbesondere bei der intravenösen Verabreichung der Wirkstoffe) in der Regel niedrigere Dosierungen zur Anwendung kommen. Bei einschleichender Dosierung wird zu Beginn der Behandlung eine geringere Dosis verabreicht, dann langsam auf eine höhere Dosis übergegangen. Nach Erreichen des gewünschten Therapieerfolges wird wieder auf eine niedrigere Dosis zurückgegangen.In general, it has proven advantageous in human medicine that or the active ingredients when administered orally in a daily dose of about 0.01 to about 10, preferably 0.05 to 5 mg / kg body weight, if desired in the form of several, preferably 1 to 4 single doses to achieve the desired result to administer. With parenteral treatment, similar or (especially when the active ingredients are administered intravenously) lower doses are used. With creeping dosage if a lower dose is given at the start of treatment, then slowly switched to a higher dose. After reaching the desired therapeutic success will go back to a lower dose.
Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applikationsart der Wirkstoffe kann durch jeden Fachmann aufgrund seines Fachwissens leicht erfolgen.The determination of the optimal dosage and type of application required The active ingredients can easily be used by any specialist on the basis of their specialist knowledge respectively.
Sollen die erfindungsgemäßen Verbindungen und/oder ihre Salze zur Behandlung der genannten Krankheiten eingesetzt werden, so können die pharmazeutischen Zubereitungen auch einen oder mehrere andere pharmakologisch aktive Bestandteile anderer Arzneimittelgruppen, wie andere Vasodilatoren, Antihypertensiva, alpha-1-Rezeptorenblocker, alpha-2-Rezeptorstimulatoren, beta-1-Rezeptorenblocker, beta-2-Rezeptorstimulatoren, ACE-Hemmstoffe, Nitroverbindungen, Cardiotonika, Diuretika, Saluretika, Alkaloide, Analgetika, Lipidsenker, Antikoagulantien, Anticholinergika, Methylxanthine, Antiarrhythmika, Antihistaminika, Dipaminstimulatoren, Serotonin-Rezeptorenblocker etc., wie Nifedipin, Dihydralazin, Prazosin, Clonidin, Atenolol, Labetalol, Fenoterol, Captopril, Isosorbiddinitrat, Digoxin, Milrinon, Mefrusid, Clopamid, Spironolacton, Chlorthalidon, Furosemid, Polythiazid, Hydrochlorothiazid, Reserpin, Dihydroergocristin, Rescinnamin, Rauwolfia-Gesamtalkaloide, Acetylsalicylsäure, Bezafibrat, Warfarin, Atropin, Theophyllin, Lidocain, Astemizol, Bromocryptin, Ketanserin etc. enthalten. Should the compounds of the invention and / or their salts for treatment of the diseases mentioned, the pharmaceutical preparations also one or more other pharmacologically active ingredients other groups of drugs, such as other vasodilators, antihypertensives, alpha-1 receptor blockers, alpha-2 receptor stimulators, beta-1 receptor blockers, beta-2 receptor stimulators, ACE inhibitors, nitro compounds, cardiotonics, Diuretics, saluretics, alkaloids, analgesics, lipid-lowering agents, anticoagulants, Anticholinergics, methylxanthines, antiarrhythmics, antihistamines, dipamine stimulators, Serotonin receptor blockers etc., such as nifedipine, dihydralazine, Prazosin, clonidine, atenolol, labetalol, fenoterol, captopril, isosorbide dinitrate, Digoxin, milrinone, mefruside, clopamide, spironolactone, chlorthalidone, furosemide, Polythiazide, hydrochlorothiazide, reserpine, dihydroergocristine, rescinnamine, Total rauwolfia alkaloids, acetylsalicylic acid, bezafibrate, warfarin, Atropine, theophylline, lidocaine, astemizole, bromocryptine, ketanserin etc. included.
Die antihypertensive Wirksamkeit der erfindungsgemäßen Verbindungen kann am Modell der spontan hypertonen Ratte nachgewiesen werden.The antihypertensive activity of the compounds according to the invention can be modeled the spontaneously hypertensive rat can be detected.
Zur Bestimmung der antihypertensiven Wirkung werden die unten aufgeführten Verbindungen in den angegebenen Dosen an vier aufeinanderfolgenden Tagen an je 6 männlichen Ratten (Stamm SHR/N/Ibm/Bm, 250-350 g) mit genetisch bedingtem Hochdruck (systolischer Blutdruck<180 mm Hg) täglich einmal mittels Schlundsonde verabfolgt. Die Messung des Blutdrucks erfolgt jeweils 6 und gegebenenfalls 2 oder 24 Stunden nach Substanzgabe.The compounds listed below are used to determine the antihypertensive effect in the indicated doses on four consecutive days on 6 each male rats (strain SHR / N / Ibm / Bm, 250-350 g) with genetically determined high pressure (systolic blood pressure <180 mm Hg) once a day by gavage administered. The blood pressure is measured 6 and possibly 2 or 24 hours after substance administration.
Die Blutdruckmessung wird in einer Wärmekammer bei 36°C vorgenommen, um eine bessere Durchblutung der Schwanzarterie zu erreichen. Hierzu werden die Tiere in perforierte Lochblechkäfige verbracht und 20-40 Min. nach Beginn der Aufwärmung gemessen. Zur Messung des systolischen arteriellen Drucks wird eine ringförmige Manschette mit aufblasbarer Gummimembran zur Unterbindung der Durchblutung und ein ringförmiger Piezokristallaufnehmer zur Erfassung der Pulswellen auf den Schwanz aufgeschoben. Nach erfolgter Unterbindung des Blutstroms in der Schwanzarterie wird der Manschettendruck kontinuierlich reduziert. Die Wiederkehr der Pulswellen bei Druckablassen wird automatisch als systolischer Blutdruck erkannt und ausgedruckt (Bühler, R. et al.: Microprocessor-based automation of blood pressure measurement in the conscious rat. Proceedings of the 4th international symposium on rats with spontaneous hypertension and related studies, Rascher, R. et al. [Eds.], Schattauer Verlag, Stuttgart, New York, 1982, S. 410-413). Pulssignale und Druckverlauf werden zur Auswertung graphisch aufgezeichnet.The blood pressure measurement is carried out in a warming chamber at 36 ° C to achieve better blood flow to the tail artery. For this, the animals placed in perforated sheet metal cages and 20-40 minutes after warming up measured. To measure the systolic arterial pressure, a ring-shaped cuff with inflatable rubber membrane to prevent the Blood circulation and a ring-shaped piezocrystal transducer to record the Pulse waves pushed onto the tail. After the blood flow has been stopped in the tail artery the cuff pressure is continuously reduced. The return of the pulse waves at pressure relief is automatically as systolic blood pressure recognized and printed out (Bühler, R. et al .: Microprocessor-based automation of blood pressure measurement in the conscious rat. Proceedings of the 4th international symposium on rats with spontaneous hypertension and related studies, Rascher, R. et al. [Eds.], Schattauer Verlag, Stuttgart, New York, 1982, pp. 410-413). Pulse signals and pressure curve are used for evaluation recorded graphically.
Zur Gewöhnung an den Meßvorgang werden die Tiere vor Substanzprüfung 14 Tage trainiert. In der zweiten Trainingswoche werden Blutdruck-Vorwerte erhoben. Tiergruppen, die Substanz erhalten, werden gegen eine Kontrollgruppe geprüft. In der anschließenden Tabelle werden die untersuchten Verbindungen durch laufende Nummern gekennzeichnet, die mit den jeweiligen Beispielnummern übereinstimmen. To get used to the measuring process, the animals are given 14 days before the substance test trained. In the second week of training, blood pressure pre-values are collected. Animal groups that received substance are tested against a control group. In the table below, the examined connections are shown by running Numbers marked that match the respective sample numbers.
Tabelle I gibt für die Vertreter der erfindungsgemäßen Verbindungen die prozentuale Senkung des Blutdrucks (BP) nach oraler Verabreichung bei der Ratte wieder.Table I gives the percentages for the representatives of the compounds according to the invention Lowering blood pressure (BP) after oral administration in the rat again.
Claims (7)
- a) Zimtsäurederivate der Formel II mit Amidinen der Formel III oder
- b) Ketoverbindungen der Formel IV mit Amidinen der Formel III und Aldehyden der Formel V umsetzt und gewünschtenfalls anschließend erhaltene Salze in die freien Basen oder erhaltene Basen in die Salze überführt, wobei Cy, R1, R2, R3, R4, R5 und R6 die in Anspruch 1 angegebenen Bedeutungen haben und wobei die Ausgangsverbindungen als solche oder in Form ihrer Salze eingesetzt werden.
- a) cinnamic acid derivatives of the formula II with amidines of the formula III or
- b) keto compounds of the formula IV with amidines of the formula III and aldehydes of the formula V implemented and, if desired, subsequently obtained salts converted into the free bases or bases obtained into the salts, where Cy, R1, R2, R3, R4, R5 and R6 have the meanings given in claim 1 and wherein the starting compounds as such or in the form of their salts be used.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH189787 | 1987-05-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE3816360A1 true DE3816360A1 (en) | 1988-12-08 |
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ID=4221146
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19883816360 Withdrawn DE3816360A1 (en) | 1987-05-18 | 1988-05-13 | (-)-Menthyl 2-amino-1,4-dihydropyridinedicarboxylates |
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| Country | Link |
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| DE (1) | DE3816360A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1958627A2 (en) | 2007-01-04 | 2008-08-20 | Symrise GmbH & Co. KG | Use of certain menthyl-3-oxocarbonic acid esters as physiological cooling agents |
-
1988
- 1988-05-13 DE DE19883816360 patent/DE3816360A1/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1958627A2 (en) | 2007-01-04 | 2008-08-20 | Symrise GmbH & Co. KG | Use of certain menthyl-3-oxocarbonic acid esters as physiological cooling agents |
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