MXPA98008644A - Amques of substitute isoquinolin-3-carboxylic acid, its preparation and its employment as a medicine - Google Patents
Amques of substitute isoquinolin-3-carboxylic acid, its preparation and its employment as a medicineInfo
- Publication number
- MXPA98008644A MXPA98008644A MXPA/A/1998/008644A MX9808644A MXPA98008644A MX PA98008644 A MXPA98008644 A MX PA98008644A MX 9808644 A MX9808644 A MX 9808644A MX PA98008644 A MXPA98008644 A MX PA98008644A
- Authority
- MX
- Mexico
- Prior art keywords
- hydrogen
- formula
- chloro
- alkoxy
- compounds
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 16
- 239000003814 drug Substances 0.000 title claims description 14
- KVMMIDQDXZOPAB-UHFFFAOYSA-N isoquinoline-3-carboxylic acid Chemical compound C1=CC=C2C=NC(C(=O)O)=CC2=C1 KVMMIDQDXZOPAB-UHFFFAOYSA-N 0.000 title 1
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 98
- 239000001257 hydrogen Substances 0.000 claims abstract description 98
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 49
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 44
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 44
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 31
- 239000000460 chlorine Substances 0.000 claims abstract description 30
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 30
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 30
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 30
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims abstract description 22
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 20
- 239000011780 sodium chloride Substances 0.000 claims abstract description 19
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 11
- 239000011737 fluorine Substances 0.000 claims abstract description 11
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 11
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims abstract description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000005159 cyanoalkoxy group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 104
- -1 hydroxy, benzyloxy Chemical group 0.000 claims description 79
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 65
- 239000004471 Glycine Substances 0.000 claims description 35
- 210000004185 Liver Anatomy 0.000 claims description 30
- 102000004079 Prolyl Hydroxylases Human genes 0.000 claims description 29
- 108010043005 Prolyl Hydroxylases Proteins 0.000 claims description 29
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 22
- 150000002148 esters Chemical class 0.000 claims description 18
- 230000036570 collagen biosynthesis Effects 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 9
- 230000003176 fibrotic Effects 0.000 claims description 9
- HZAXFHJVJLSVMW-UHFFFAOYSA-N ethanolamine Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- PBYMYAJONQZORL-UHFFFAOYSA-N 1-methylisoquinoline Chemical compound C1=CC=C2C(C)=NC=CC2=C1 PBYMYAJONQZORL-UHFFFAOYSA-N 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 210000004072 Lung Anatomy 0.000 claims description 3
- 210000003491 Skin Anatomy 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 3
- 210000003734 Kidney Anatomy 0.000 claims description 2
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-JMRXTUGHSA-N ditritium Chemical group [3H][3H] UFHFLCQGNIYNRP-JMRXTUGHSA-N 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 15
- 231100000240 steatosis hepatitis Toxicity 0.000 abstract description 5
- KKSZSACCVDIWIE-UHFFFAOYSA-N isoquinoline-3-carboxamide Chemical class C1=CC=C2C=NC(C(=O)N)=CC2=C1 KKSZSACCVDIWIE-UHFFFAOYSA-N 0.000 abstract description 3
- 125000005415 substituted alkoxy group Chemical group 0.000 abstract 2
- 230000003389 potentiating Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 229960002449 Glycine Drugs 0.000 description 33
- 239000000243 solution Substances 0.000 description 23
- 239000000047 product Substances 0.000 description 22
- 239000000126 substance Substances 0.000 description 19
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 18
- 229920001436 collagen Polymers 0.000 description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 108010035532 Collagen Proteins 0.000 description 14
- 102000008186 Collagen Human genes 0.000 description 14
- 229960005188 collagen Drugs 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 241000700159 Rattus Species 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 229940002612 prodrugs Drugs 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- 210000000056 organs Anatomy 0.000 description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 229950005499 carbon tetrachloride Drugs 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229960002591 Hydroxyproline Drugs 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 230000000875 corresponding Effects 0.000 description 5
- 238000005755 formation reaction Methods 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- PMMYEEVYMWASQN-DMTCNVIQSA-N trans-L-hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 5
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 210000004027 cells Anatomy 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XTPRSWPAZJPVMR-UHFFFAOYSA-N 2-hydroxyethylazanide Chemical class [NH-]CCO XTPRSWPAZJPVMR-UHFFFAOYSA-N 0.000 description 3
- AJCWNHFAYQKMGS-UHFFFAOYSA-N 7-butoxy-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid Chemical compound OC1=C(C(O)=O)N=C(Cl)C2=CC(OCCCC)=CC=C21 AJCWNHFAYQKMGS-UHFFFAOYSA-N 0.000 description 3
- 229940088598 Enzyme Drugs 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 3
- VIAFLMPQBHAMLI-UHFFFAOYSA-N PyBOP Chemical compound F[P-](F)(F)(F)(F)F.C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=CC=CC=C2N=N1 VIAFLMPQBHAMLI-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000004761 fibrosis Effects 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 238000005805 hydroxylation reaction Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000007127 saponification reaction Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- DMQVYDQPAAUUPJ-UHFFFAOYSA-N 1-chloro-4-hydroxy-6-phenylmethoxyisoquinoline-3-carboxylic acid Chemical compound C=1C2=C(O)C(C(=O)O)=NC(Cl)=C2C=CC=1OCC1=CC=CC=C1 DMQVYDQPAAUUPJ-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- SJZRECIVHVDYJC-UHFFFAOYSA-M 4-hydroxybutyrate Chemical group OCCCC([O-])=O SJZRECIVHVDYJC-UHFFFAOYSA-M 0.000 description 2
- UCYDSZOMEGWSBR-UHFFFAOYSA-N 6-butoxy-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid Chemical compound ClC1=NC(C(O)=O)=C(O)C2=CC(OCCCC)=CC=C21 UCYDSZOMEGWSBR-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 102000004266 Collagen Type IV Human genes 0.000 description 2
- 108010042086 Collagen Type IV Proteins 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 210000003743 Erythrocytes Anatomy 0.000 description 2
- 206010019668 Hepatic fibrosis Diseases 0.000 description 2
- 210000003494 Hepatocytes Anatomy 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical class ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N Pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 229960001412 Pentobarbital Drugs 0.000 description 2
- 210000002966 Serum Anatomy 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical class ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- DNSWCJFEFMKKCA-UHFFFAOYSA-N [NH-]CC(O)=O Chemical compound [NH-]CC(O)=O DNSWCJFEFMKKCA-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000003510 anti-fibrotic Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 150000007942 carboxylates Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000037319 collagen production Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002440 hepatic Effects 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000000640 hydroxylating Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000001681 protective Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 230000017105 transposition Effects 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical compound C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QKJMMOXAZPSGCV-UHFFFAOYSA-N 1,6,7-trichloro-4-hydroxyisoquinoline-3-carboxylic acid Chemical compound C1=C(Cl)C(Cl)=CC2=C(O)C(C(=O)O)=NC(Cl)=C21 QKJMMOXAZPSGCV-UHFFFAOYSA-N 0.000 description 1
- POWGLHFKMJBSGU-UHFFFAOYSA-N 1-chloro-4-hydroxy-7-phenylmethoxyisoquinoline-3-carboxylic acid Chemical compound C1=CC2=C(O)C(C(=O)O)=NC(Cl)=C2C=C1OCC1=CC=CC=C1 POWGLHFKMJBSGU-UHFFFAOYSA-N 0.000 description 1
- SSYBEOBLHWJCQS-UHFFFAOYSA-N 1-chloro-4-hydroxy-N-(2-hydroxyethyl)-6-methoxyisoquinoline-3-carboxamide Chemical compound ClC1=NC(C(=O)NCCO)=C(O)C2=CC(OC)=CC=C21 SSYBEOBLHWJCQS-UHFFFAOYSA-N 0.000 description 1
- QFNFXYPFSYJCDF-UHFFFAOYSA-N 1-hydroxy-2H-isoquinolin-3-one Chemical class C1=CC=CC2=C(O)NC(=O)C=C21 QFNFXYPFSYJCDF-UHFFFAOYSA-N 0.000 description 1
- KYWCUACNBIYDNL-UHFFFAOYSA-N 1-oxo-2H-isoquinoline-3-carboxylic acid Chemical compound C1=CC=C2C(=O)NC(C(=O)O)=CC2=C1 KYWCUACNBIYDNL-UHFFFAOYSA-N 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N 2,2'-bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical class CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- FGLBSLMDCBOPQK-UHFFFAOYSA-N 2-Nitropropane Chemical compound CC(C)[N+]([O-])=O FGLBSLMDCBOPQK-UHFFFAOYSA-N 0.000 description 1
- 102000008490 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Human genes 0.000 description 1
- 108010020504 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Proteins 0.000 description 1
- CFCNTIFLYGKEIO-UHFFFAOYSA-N 2-isocyanoacetic acid Chemical compound OC(=O)C[N+]#[C-] CFCNTIFLYGKEIO-UHFFFAOYSA-N 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- BRARRAHGNDUELT-UHFFFAOYSA-N 3-Hydroxypicolinic acid Chemical compound OC(=O)C1=NC=CC=C1O BRARRAHGNDUELT-UHFFFAOYSA-N 0.000 description 1
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N 3-aminopropanol Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 1
- SOYBEXQHNURCGE-UHFFFAOYSA-N 3-ethoxypropan-1-amine Chemical compound CCOCCCN SOYBEXQHNURCGE-UHFFFAOYSA-N 0.000 description 1
- NJRZBEQOJNIDPD-UHFFFAOYSA-N 3-sulfanylpyridine-2-carboxamide Chemical class NC(=O)C1=NC=CC=C1S NJRZBEQOJNIDPD-UHFFFAOYSA-N 0.000 description 1
- LUJFMSVALOJFLS-UHFFFAOYSA-N 4-butoxyphthalic acid Chemical compound CCCCOC1=CC=C(C(O)=O)C(C(O)=O)=C1 LUJFMSVALOJFLS-UHFFFAOYSA-N 0.000 description 1
- RJHQPXBACQKFGY-UHFFFAOYSA-N 4-hydroxy-1-oxo-6-phenylmethoxy-2H-isoquinoline-3-carboxylic acid Chemical compound C1=C2C(O)=C(C(=O)O)NC(=O)C2=CC=C1OCC1=CC=CC=C1 RJHQPXBACQKFGY-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to: new isoquinoline-3-carboxylic acid amides of the formula I, in which R 1 signifies hydrogen or chlorine, R 2 signifies hydrogen, alkyl, alkoxy, chloro, trofluoromethyl, hydroxy or benzyloxy, which is optionally substituted, or fluoroalkoxy of the formula -O- (CH2) x-CfH (2f + 1-g) Fg, with X = 0 and 1, f = 1-5 and g = 1 a (2f + 1), R3 means hydrogen, alkyl, alkoxy , fluorine, chlorine, cyano, trifluoromethyl, hydroxy or benzyloxy, which is optionally substituted, or fluoroalkoxy of the above formula, R4 and R5 are hydrogen, alkyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, alkoxy or fluoroalkoxy of the above formula, including physiologically effective salts, are potent propyl-4-hydroxylase inhibitors that do not cause steatosis
Description
Substituted isoquinoline-3-carboxylic acid amides, their preparation and their use as medicaments
The invention relates to substituted isoquinoline-3-carboxylic acid amides, their preparation and their use as inhibitors of prolyl-4-hydroxylase, and their use as medicaments for the treatment of fibrotic diseases. Compounds that inhibit prolyl hydroxylase enzymes determine a very selective inhibition of collagen biosynthesis by influencing specific hydroxylation reactions of collagen. In its course, proline or lysine bound to proteins is hydroxylated by the enzymes prolylhydroxylase or lysylhydroxylase. If this reaction is suppressed by inhibitors, then a non-functional and subhydroxylated collagen molecule results that can be delivered by the cells only in a small amount to the extracellular space. Subhydroxylated collagen can not be incorporated into the collagen matrix and degraded by proteolysis very easily. As a consequence of these effects, the amount of collagen extracellularly deposited is reduced overall. Therefore, prolyl hydroxylase inhibitors are suitable substances in the therapy of diseases in which the deposition of collagens cooperates decisively in the pathological condition. They include, among others, fibrosis of the lungs, liver and skin (scleroderma and scars after burns, injuries and surgical interventions), as well as atherosclerosis. It is known that the enzyme prolylhydroxylase is effectively inhibited by pyridine-2,4- and -2,5-di-carboxylic acid (K. ajamaa et al., Eur. J. Biochem. 138 (1984) 239- 245). However, these compounds are active in cell culture as inhibitory substances only in very high concentrations (Tschan, G. et al., Biochem.
238 (1987) 625 to 633). Prodrugs of pyridine-2, 4 (5) -dicarboxylates are also known. These are described in EP-A-0 590 520 and EP-A-0 562 512. N-oxalylglycines, as inhibitors of pro-lyl-4-hydroxylase, are known from J. Med. Chem. 1992, 35, 2652 to 2658 (Cun? Iffe et al.) And EP-A-0 457 163 (Baader et al.). N- (carboxymethyl) amide of 3-hydroxypyridine-2-carboxylic acid is known from G. Yolles et al. in: Bull. Soc. Chim. Fr. 1965, 8, 2252 to 2259. N- ((4-hydroxyisoquinslin-3-yl) carbonyl) glycine and N - ((7-bromo-4-hydroxyisoquinolin-3-yl) carbonyl) glycine are known from of Biochem. Soc. Trans. 1991, 19, 812 to 815 (Franklin et al.), Wherein in the case of N- ((4-hydroxyiso-quinolin-3-yl) carbonyl) glycine the activity in vivo on collagen biosynthesis is weak. Hydroxyquinolinecarboxylic acid glycylamides are also mentioned herein. In T.J. Franklin in "Therapeutic Approaches to Organ Fibrosis", Int. J. Biochem. Cell. Biol., 1997, vol. 29, n ° 1, 79-89 is reported, in the case of N- ((7-bromo-4-hydroxyisoquinolin-3-yl) carbonyl) glycine, together with the in vivo inhibition of collagen biosynthesis, a toxic effect on the liver (steatosis) in rats. EP-A-0 661 269 describes substituted heterocyclic carboxylic acid amides and their use as prolyl-4-hydroxylase inhibitors and as inhibitors of collagen biosynthesis. The mission was to search for more strongly inhibitors of prolyl hydroxylase. In addition, there was a mission to search for effective inhibitors of prolyl hydroxylase that do not determine steatosis. It was then found that new iso-quinoline-3-carboxylic acid amides are surprisingly strong prolyl-4-hydroxylase inhibitors that do not determine steatosis.
The compounds according to the invention correspond to the general formula I
wherein R 1 signifies hydrogen or chlorine, R 2 signifies hydrogen, alkyl (C 1 C, alkoxy (C 1 -C 8), chloro, trifluoromethyl, hydroxy or benzyloxy, which is optionally substituted by substituents of the C 1 Cs), alkoxy (Ci-Cs), or fluoroalkoxy series of the formula -O- [CH 2] x-CfH (2f + 1-g) Fg, with x = 0 and 1, f = 1-5 and g = 1 a (2f + 1), R 3 is hydrogen, alkyl, fluorine, chlorine, cyano, trifluoromethyl, hydroxy or benzyloxy, which is optionally substituted with substituents of the alkyl, alkoxy CL- series. CC,), or fluoroalkoxy of the formula -0- [CH2] x-CfH (2f + 1-g) Fg, wherein x, f and g are defined as above, R4 and R5 mean hydrogen, alguyl (C ^ -C;), fluorine, chlorine, bromine, trifluoromethyl, cyano, alkoxy (C1- -O- [CH2] x-CfH (2f + 1.g) Fg, where x, f and g are defined as above, including physiologically effective salts Preference is given to compounds of the formula I, in which R 1 is hydrogen or chlorine, R 2 is hydrogen, alkyl (Ci-Cg), alkoxy (CL-Cg), chloro, trifluoromethyl, hydroxy or benzyloxy, or fluoroalkoxy of the formula O- [CH2] xC £ H (2 £ + 1.g) Fg, with x = 0 and 1, f = 1 - 5 and g = 1 a (2f + l), R3 means hydrogen, alkyl (Cx-C8) , alkoxy (Ci-O, fluoro, chloro, cyano, trifluoromethyl, hydroxy, benzyloxy, or fluoroalkoxy of the formula -0- [CH2] xC £ H (2f + 1_g) Fg, wherein x, f and g are defined as above, R4 means hydrogen, alkoxy, fluorine, chlorine, trifluoromethyl, cyano or fluoroalkoxy of the formula -O- [CH2] xCH (2 £ + 1.g) Fg / where x, f and g are defined as above, and R5 is In addition, compounds of the formula I are preferred, wherein 1 is hydrogen or chlorine, R2 is hydrogen, (Cx-C3) alkoxy, chloro, benzyloxy, fluoroalkoxy with x = 0, f = 1, R3 is hydrogen, alkoxy (C., .- C5), chloro, benzyloxy, R4 is hydrogen, chloro, methoxy, R5 is hydrogen, and those, in which R1 is hydrogen or chloro, R2 is hydrogen, alkoxy, chloro, hydroxy, benzyloxy, R3 is hydrogen, (Cx-C3) alkoxy, fluoro, chloro, hydroxy, benzyloxy, R4 is hydrogen, chlorine, R5 is hydrogen. Particularly preferred are compounds of the formula
E, wherein R1 is hydrogen or chloro, R2 is (C1-C) alkoxy, chloro, benzyloxy, and R3, R4 and Rs are hydrogen, or wherein R1 is hydrogen or chloro, R2 is hydrogen or chloro, and R3 is (C-Cg) alkoxy, chloro, benzyloxy, and R4 and Rs are hydrogen, or wherein R.1 is hydrogen or chloro, R2 and R3 are hydrogen or chloro, R4 is alkoxy, chloro, benzyloxy, and Rs is hydrogen In addition, compounds of the formula I, in which R 1 is hydrogen or chlorine, R 2 is alkoxy (CLC O benzyloxy, and R 3, R 4 and Rs are hydrogen, or in which R es is hydrogen or chlorine, R 2 is hydrogen are particularly preferred. , R3 is (Ci-Cg) alkoxy or benzyloxy, and R 'and R5 are hydrogen, Particularly preferred are compounds of the formula
I, wherein R3- is hydrogen or chloro, R "is alkoxy (-Cj), and R3, R4 and Rs are hydrogen, or wherein R1 is hydrogen or chloro, R2 is hydrogen, R3 is alkoxy (Cx-) C6), and R4 and Rs are hydrogen.
Very particularly, there can be mentioned: N- ((1-chloro-4-hydroxyisoquinolin-3-yl) carbonyl) glycine, N - ((8-chloro-4-hydroxyisoquinolin-3-yl) carbonyl) glycine, N- ( (l-Chloro-4-hydroxy-7- ((2-propyl) oxy) isoquinolin-3-yl) -carbonyl) glycine, N- ((4-hydroxy-7- (2-propyl) oxy) isoquinoline- 3-yl) -carbonyl) glycine. In addition, there was a mission to search for effective inhibitors of prolyl hydroxylase that were selective for the liver. It has now been found that new N- (2-hydroxyethyl) amides of isoquinoline-3-carboxylic acid of the formula la are alcohol prodrugs of the corresponding compounds of the formula I. The prodrug compounds of the formula according to the invention are oxidized in the living organism (in vivo) and in the isolated organ (perfused liver, in vitro) in compounds of the formula I: The conversion of the compounds of the formula I it takes place, preferably, in the liver, whereby selective liver inhibition of prolyl-4-hydroxylase and collagen biosynthesis is achieved. After application of the compounds of formula la, they determine the inhibition of prolyl-4-hydroxylase to be observed in vivo and in vitro, forming the compounds of formula I. These compounds inhibit prolyl-4-hydroxylase and, therefore, lead to an inhibition of collagen biosynthesis. The compounds according to the invention correspond to. the formula
wherein R 1 signifies hydrogen or chlorine, R 2 signifies hydrogen, alkyl (C x -Cg), alkoxy (Ci-Cg), chloro, trifluoromethyl, hydroxy or benzyloxy, which is optionally substituted by substituents of the alkyl (C x -C 5) series, alkoxy (Cx-C5), or fluoroalkoxy of the formula -O- [CH2] x-CfH (2f + 1-g) Fg, with x = 0 and 1, f = 1-5 and g = 1 a (2f + 1 ), R3 means hydrogen, alkyl (Cx-Ca), alkoxy (Cx-C8), fluorine, chlorine, cyano, trifluoromethyl, hydroxy or benzyloxy, which is optionally substituted by substituents of the alkyl (Cx-C3) series, (Cx-C5) alkoxy, or fluoroalkoxy of the formula -O- [CH2] xC £ H (2f + 1-g) Fg, wherein x, f and g are defined as above, R4 and R5 mean hydrogen, alkyl (Cx) -C5), fluorine, chlorine, bromine, trifluoromethyl, cyano, (Cx-C5) alkoxy or fluoroalkoxy of the formula -O- [CH2] x-CfH (2f + 1-g) Fg, wherein x, f and g are defined as before, including the physiologically effective salts. Preference is given to compounds of the formula la, in which R 1 is chlorine, R 2 and R 3 are hydrogen or (C x C 4) alkoxy, and R 4 and R 5 are hydrogen. Particularly preferred are compounds of the formula la, wherein R 1 signifies hydrogen or chlorine, R 2 signifies alkoxy, and R 3, R 4 and Rs signify hydrogen, or in which R 1 signifies hydrogen or chlorine, R 2 signifies hydrogen, R 3 signifies (C 1 -C 6) alkoxy ), and R4 and Rs mean hydrogen. Very particularly, it can be mentioned: N- (2-hydroxyethyl) amide of l-chloro-4-hydroxy-7- ((2-pro-pil) oxy) isoquinoline-3-carboxylic acid. The invention also encompasses salts of the compounds of the general formulas I and la. The formation of salts with basic reagents can be effected once or twice in the acid groups of the compounds of the formulas I and, ie in the radicals R1, R2, R3, R4 and R5 and / or in the acidic phenolic OH group, in particular in the phenolic OH group. Reagents which are to be used are, for example, alco-holates, hydroxides, carbonates, hydrogen carbonates, hydro-genophosphates and / or metalloorganyls of the alkali and alkaline earth elements, elements of the 3rd and 4th or main group of the Periodic System and the elements of the transition metals, eimines, optionally 1 to 3 times substituted with hydroxyalkyl (Cx-C8), alkoxy (LC-alkyl (Cx-C8), phenyl, benzyl or alkyl (Cx-Ca), which may be substituted 1 to 3 times with hydroxy or alkoxy (-C -C, for example, trometan (Tris buffer), 2-aminoethanol, 3-aminopropanol, hydroxylamine, im-imethylhydroxylamine, 2-methoxy-ethylamine, 3-ethoxypropaneamine, and amino acids and derivatives of basic amino acids such as amino acid esters, histidine, arginine and lysine and their derivatives, as well as drugs containing a basic group such as, for example, amiloride, verapamil and beta-blockers The invention also encompasses prodrugs to the compounds of the formula (I) which determine an inhibition of collagen biosynthesis in vivo by the liberation of compounds of the formula I or their salts. Finally, the invention also encompasses prodrugs that determine in vivo, by releasing compounds of the formula I or their salts, an inhibitory effect on prolyl-4-hydroxylase. Prodrug groups are chemical groups which, in vivo, are converted to the carboxylate group of the compounds of the formula I and / or can be separated by the N atom of the amide and / or can be transformed into a quinoline ring. The prodrug groups that come into consideration are known to the person skilled in the art. In particular, the following groupings of prodrugs can be mentioned: for the carboxylate group, ester, amide, hydroxymethyl and aldehyde groups and their derivatives, for the N-atom of the quinoline, N-oxides and N-alkyl derivatives. The invention relates to the use of compounds of the formula I, as well as to the physiologically compatible salts for the inhibition of collagen biosynthesis. The invention relates to the use of compounds of the formula I, as well as the physiologically compatible salts, for the inhibition of prolyl-4-hydroxylase. In addition, the invention relates to the use of compounds of the formula I, as well as the physiologically compatible salts, for the preparation of a medicament against fibrotic diseases. In addition, the invention relates to the use of compounds of the formula I, as well as the physiologically compatible salts, for the preparation of a medicament against fibrotic diseases of the liver, kidneys, lungs and skin. Finally, the invention relates to the compounds of the formula I for use as medicaments. In particular, the invention relates to the compounds of the formula I for use as fibrosuppressants. In addition, the invention relates to the use of compounds of the formula la as well as the physiologically compatible salts for the preparation of a medicament against fibrotic diseases of the liver. Compounds of formulas I or 4-mercapto are likewise effective inhibitors of prolyl-4-hydroxylase. The corresponding 3-mercapto-pyridine-2-carboxylic acid amides are known from EP-A 0 661 269 (HOE 93 / F 437K). In addition, the invention relates to a process for the preparation of compounds of the general formula I. The preparation of the compounds of the formula I is carried out
li) by reacting quinoline-2-carboxylic acids of the formula II with the aminoesters of the formula III to give the amidoesters of the formula IV, in which R is H, alkyl of 1 to 8 carbon atoms and benzyl l.ii ) releasing the compounds of the formula I from their esters of the formula IV
The 4-hydroxy group of the compound of the formula II can, in this case, also be protected. Suitable protective groups (GP = protecting groups) such as are usual for the person skilled in the art are, in particular, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, alkyl, methoxymethyl (MOM), methylthio, benzyloxymethyl (BOM). , t-butyloxyethyl, 2-methoxyethoxymethyl (MEM) and tetrahydropyranyl (THP). Other protecting groups and the conditions of their dissociation (transformation of compounds of the formula V into compounds of the formula I) are described by Theodoro W. Greene, Peter G.M. Wuts, in Protective Groups in Organic Synthesis, second edition 1991, John Wiley, Chapters 2 and 3, pages 10 to 174. Suitable procedures for the formation of amides (reaction li) are the methods of carboxyl activation and condensation reactions Known by the Chemistry of Peptides. As reagents for the activation of carboxylic acids, substances known to those skilled in the art such as thionyl chloride, oxalyl chloride, pivaloyl chloride, chloroformic acid ester derivatives or N, '-carbonyldiimidazole may be used. The activated derivatives of the compounds of the formula II are reacted in situ, after the preparation, with the amide derivatives of the formula III. A suitable condensing agent is, for example, the combination of N, '-dicyclohexylcarbodiimide, 1-hydroxy-1H-benzotriazole, (benzotriazol-1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (PyBOP) and N-ethylmorpholine. Suitable solvents are dichloromethane, tetrachloromethane, butyl acetate, ethyl acetate, toluene, tetrahydrofuran, dimethoxyethane, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, nitromethane and / or pyridine. Substituted 4-cixyloxysiqiixDlin-3-carbaxylysic acids or their esters of formulas II (in which R is H, alkyl of from 1 to 8 carbides and -benzyl and Ilb) are accessible from the corresponding esters of the 4-Mdrcß-l (2H) -isa acid irDlcn-3-ca? ± c? idle of the fórrtula V
(V) (Ha)
H2 / P catalyst reduction
The esters of 4-hydroxy-l (2H) -isoquinolone-3-carboxylic acid of the formula V can be prepared according to the following methods:
By reaction of phthalic acid anhydrides with esters of isocyanoacetic acid / DBU and the isomerization under acidic conditions of the isolated 1,3-oxazoles as described in M. Suzuki et al., Synthesis 1978, 461 and K. Nunami, M Suzuki Chem. Pharm. Bull. 27, 1373 (1979),
By the reaction by transposition, catalyzed by alcoholates, of phthalimidoacetates of formula VI to give hydroxyisoquinolone esters (Gabriel-Colman transposition reaction) as described, for example, in L.R. Caswell, P.C. Atkinson, J. Heterocycl. Chem. 1966, 328; ibid, 1968, 865; ibid, 1973, 407.
/ \ p- \ For the preparation of the compounds of the formula la, the compounds of the formulas Ha or IIb are reacted with 2-aminoethanol. The compounds of the formula I and the are inhibitors of prolyl-4-hydroxylase. Inhibition of this enzyme was determined as described by Kaule and Günzler in Anal. Biochem. 184, 291 to 297 (1990).
Use n ° CI5"[μmol] 1 0, 12 2 1,90 3 0,79 4 0,57 5 0, 70 6 2,02 7 1,34 8 0, 62 9 2,30 10 3, 60 11 0, 66 12 0, 65 13 9.30 14 0.35 15 0, 66
The compounds of the formulas I and that according to the invention also possess valuable pharmacological properties and in particular show an antifibrotic activity. The antifibrotic activity can be determined in the model of hepatic fibrosis induced by carbon tetrachloride. For this, rats are treated twice a week with CC14 (1 ml / kg) - dissolved in olive oil -. The test substance is administered daily, possibly even twice a day per os or intraperitoneally - dissolved in a suitable compatible solvent -. The magnitude of liver fibrosis is determined histologically and the collagen portion in the liver is analyzed by determination with hydroxyproline - as described by Kivirikko et al. (Anal. 'Biochem. 19, 249 et seq. (1967)) -. The activity of fibrogenesis can be determined by radioimmunological determination of collagen fragments and procollagen peptides in the serum. The compounds according to the invention are active in this model in a concentration of
1 to 100 mg- / kg.
Control animals: In direct comparison with untreated animals, the hydroxyproline content of the liver increased by 200% by treatment with carbon tetrachloride after 4 weeks (application twice a week). The measurement of the inhibition of hydroxyproline formation by the test substances was referred to this level.
Application of the substance: In this case, the test animals were treated during
2 weeks only with carbon tetrachloride and then, for the next 2 weeks, with carbon tetrachloride and test substance. The test substances were applied intraperitoneally 2 times a day in the total amount indicated.
Results:
Substance in-Dosage Inhibition of sayo of example [mg / kg] formation of (number of animals) hydroxyproline
1 20 (15) - 55%
9 20 (15) - 67% 40 (15) - 65% 100 (24) - 58% 100 * (14) - 71%
19 40 (13) -39% * oral application
The activity of fibrogenesis can be determined by radioimmunological determination of the N-terminal propeptide of type III collagen or of the N- or C-terminal cross-linking domains of type IV collagen (collagen 7s or collagen NCx type IV) in the serum. For this purpose, the concentrations of hydroxyproline, procollagen-peptide III, collagen 7s and NC collagen type IV were measured in the liver of a) untreated rats (controls) b) rats given carbon tetrachloride, (CC14 controls c) rats to which CC14 was first administered and then a compound according to the invention (this test method is described by Rouiller, C, experimentally toxic injury of the liver, in The Liver, C. Rouiller, vol.2, 5. 335 to 476, New York, Academic Press, 1964). In addition, an activity of the compounds according to the invention can be detected in the following systems.
Inhibitory effect of prolyl-4-hydroxylase inhibitors in liver perfusions / combined enzyme assays:
The tissue of the liver selectively transforms inactive inhibitors into inhibitory substances of prolyl-4-hydroxylase with inhibitory activity, the effect of which is mainly displayed in this organ. In order to investigate the inhibitory effect of active proinhibitors of this type, the "compounds were used in perfusion experiments in the liver isolated from rats." The inhibitory effect was then measured in a prolyl-4-hydroxylase assay.
Method: Wistar male non-fasting rats of 200-300 g body weight (Hoe: WISKf (SPF71)) were drugged with pentobarbi-tal (5 mg / 100 g body weight i.p.). After cannulation of the portal vein, the liver was washed for 3 min with 100 ml of heparinized sodium chloride solution (5 IU / ml) of 37 ° C. The fluid left the liver through the vena cava to which an incision had been made. The organ was then removed, the perfusion apparatus was placed and perfused by recirculating it for 2 hours with 100 ml of medium at a flow rate of 30 ml / min. For the perfusion, Krebs-Ringer buffer with bovine erythrocytes was used. For this, the cattle blood was mixed in the slaughterhouse with a citrate solution 1: 1 immediately after the extraction. This mixture was centrifuged for 10 min at 6000 rpm and the supernatant was removed. This process was repeated once with sodium chloride solution and twice with Krebs-Ringer buffer. The final perfusion solution contained 33.3% of the erythrocyte pellet and 66.7% Krebs-Ringer buffer (Schimassek, H. Biochem. Z. 336 (1963) 460-467).
Composition of the solutions used: Citrate solution: Glucose monohydrate 22.6 g Trisodium citrate 4.0 g Citric acid 5.5 g NaCl 4, 2 g up to 1000 ml with distilled water
Buffer Krebs - -Ringer: NaCl 8, 0 g KCl 0, 2 g NaHC03 1.0 g NaH2P04 «H20 0, 1 g CaCl2 0.2 g MgCl2V« 6H20 o,? g Bovine serum albumin 16 g to 898 ml of distilled water, pH 7.4
Perfusion device (Ryoo, H. and Tarver, H. P. S.E. B.M. 128 (1968) 760-772): the central element of the apparatus is a thermostatted cylinder with a removable plate for the deposit of the organ. The outlet hose is extended and its lower end is connected to a peristaltic pump. Before the return of the perfused material to the organ bath, it is passed through a glass spiral that serves as a heat exchanger, which keeps the temperature at 37 ° C constant. On the cylinder floor, the perfusate is gasified with 70 ml of a mixture of C02 / 02 (5: 95%) per minute. In order to avoid foam formation, 14 μl of 0.1% Genapol® PF-10 solution is added per ml of perfusion solution. Samples for analysis are removed from the perfusate at a point prior to entry into the perfused organ.
Treatment: The test substances were added to the perfusion solution at time t = 0 and 60 min in concentrations of in each case 100 or 50 μg / ml. After a perfusion duration of 120 min, a sample was extracted from the perfusion solution for analysis.
Enzyme assay: The inhibitory activity of metabolites that resulted during infusion for two hours in the liver was determined in an in vitro assay of prolyl-4-hydroxylase. The enzyme is purified, as described in the literature, from 14-day-old chicken embryos (Tuder an, L., Kuutti-Savolainen, ER and Kivirikko, KI, Eur. J. Biochem. '52 (1975) 9-16, Kedersha, NL and Berg, RA, Kollagen Rei Res. 1 (1981) 345-353). The enzymatic assay is carried out according to Kaule and Günzler (Kaule G. and Günzler, V., Anal. Biochem 184 (1990) 291-297). The dose-effect curves were obtained by means of dilution series, starting from the undiluted perfusion solution.
Results:
Example n Inhibition of prolyl-4-hydroxylase, IC50 (μM) Comparative substance of Example n ° After perfusion
19 1 10, 5 20 2 16. 6 21 3 7, 5 22 4 6, 4 23 21, 7
Inhibition of hepatic prolyl-4-hydroxylase in vivo:
This model serves for the detection of acute inhibition of prolyl-4-hydroxylase in vivo. For this purpose, the test substance or the corresponding vehicle (intraperitoneally, intravenously, per os) is applied to rats of both sexes (healthy or with induced hepatic fibrosis) and, after administration of the substance, it is administered via intraperitoneal 14C-L-proline (250 μCi / kg body weight). Then an intraperitoneal application of 14C-L-proline (250 μCi / kg body weight) is carried out again. Finally, the animals are bled to death under narcosis with pentobarbital and the liver is removed. The purification of the hepatic collagen by digestion with pepsin and the fractional precipitation with ammonium sulphate were carried out according to published protocols (Ref. 1.2). The purified liver collagen was hydrolyzed and the content of l4C-hydroxyproline and 14C-proline was determined by amino acid analysis by ion exchange chromatography. An inhibition of prolyl-4-hydroxylase results from a decrease in the ratio 14 C-hydroxyproline / [14 C-hydroxypro-line + 14 C-proline]. 2,2 '-dipyridyl is used as the reference substance. (Ref 1: Chojkier, M. 1986. Hepatocyte collagen production in vivo in normal rats, J. Clin Invest. 78: 333-339 and Ref. 2: Ogata I., et al., 1991. Minor contribution of hepatocytes to collagen production in normal and early fibrotic livers, Hepatology 14: 361-367).
Inhibition of prolyl-4-hydroxylase in cell cultures:
For the assay of prolyl-4-hydroxylase inhibiting substances in cell cultures the following cell types are used: normal human skin fibroblasts (Normal human fibroblasts, NHDF) and primary liver fat cells from rats (fat storing cells, Ref. 2). For this, the cells are grown in the presence of inhibitory substances. At the same time, the collagen synthesized again at this time is metabolically labeled with 4-3H-L-proline and x4C-proline. The influence of the test substances on the degree of hydroxylation of the collagen is then determined in a manner corresponding to the method of Chojkier et al (Ref. 3). 2,2'-di-pyridyl is used as the reference substance. 1 .: Blomhoff, R., Berg T. 1990. Isolation and cultivation of rat liver stellate cells. Methods Enzymol.
190: 59-71 and 2 .: Chojkier, M., Peterkofsky, B., Bateman. , J. 1980. A new method for determining the extent of proline hydroxylation by measuring changes in the ratio of [4-3H]: [14C] proline in collagenase digests. Anal. Biochem. 108: 385-393). In the chronic treatment for up to 6 weeks of male rats (Fischer F344, Sprague Dawley, istar) with the compound of Example 9, (N- ((l-chloro-4-hydroxyisoquinolin-3-yl) -carbonyl) glycine, dissolved in water / NaHCO3, administration of 2 times 25 mg / kg ip / day) no steatosis of the liver could be detected . The compounds of the formulas I and I can find application as medicaments in the form of pharmaceutical preparations which they optionally contain with pharmaceutically compatible carriers. The compounds may find application as curative agents, for example in the form of pharmaceutical preparations containing these compounds in admixture with a carrier, organic or inorganic, pharmaceutically suitable for enteral, percutaneous or parenteral administration such as for example water, gum arabic, gelatin, lactose, starch, magnesium stearate, talcum, vegetable oils, polyalkylene glycols, petroleum jelly, etc. For this purpose, they can be administered orally in doses of 0.1 to 25 mg / kg / day, preferably 1 to 5.0 mg / kg / day, or parenterally in doses of 0.01 to 5 mg / kg / day, preferably 0.01 to 2.5 mg / kg / day, in particular 0.5 to 1.0 mg / kg / day. The dosage can also be increased in severe cases. However, in many cases smaller doses are also sufficient. These data refer to an adult person of approximately 75 kg of weight. In the examples described below, the compounds of the formula I according to the invention are designated N- ((isoquinolin-3-yl) carbonyl) glycines. The designation N- (carboxymethyl) amides of substituted isoquinoline-3-carboxylic acid (glycinamides of isoquinoline-3-carboxylic acid) is likewise possible.
Examples
Example 1: tT- ((1-chloro-4-hydroxy-1 - ((2-propyl) oxy) isoquinolin-3-yl) -carbonyl) glycine
a) 4- (2-propyloxy) phthalic acid diethyl ester
54 g of 4-hydroxyphthalic acid were esterified for 4 h under reflux in 1.2 l of ethanol and 25 ml of concentrated sulfuric acid. 60 g (0.252 mol) of diethyl ester were obtained, which was then stirred for
min at 80 ° C in 250 ml of N, N-dimethylacetamide with 37.3 g (0.27 mol) of powdered potassium carbonate. At 40 ° C, 25.7 ml (0.26 mol) of 2-propyl iodide were added dropwise and stirred for 90 min at 100 ° C. After cooling, it was concentrated in vacuo, the residue in water was diluted with 2N hydrochloric acid to pH 7 and extracted twice with ethyl acetate. After drying over magnesium sulfate and concentration, 65 g of an oily crude product were obtained.
b) 4- (2-propyloxy) phthalic acid
65 g of the preceding diester were added at 20 ° C in 400 ml of 3N ethanolic KOH and stirred for 1 h at 45 ° C. The precipitated K salt was filtered with suction, dissolved in water, brought to pH 1 under cooling with concentrated aqueous hydrochloric acid and extracted twice with ethyl acetate. After drying and concentration of the organic phase, 44 g of the title compound, m.p. 116-118 ° C.
c) 4- ((2-propyloxy) phthaloyl) amino-acetic acid
44 g (0.2 mol) of the preceding dicarboxylic acid were stirred for 1 h at a bath temperature of 200 ° C in an open flask in 250 ml of Dowtherm with 16 g (0.2 mol) of glycine. After cooling, 800 ml of petroleum ether was mixed, the precipitated resin was taken up in 400 ml of saturated sodium bicarbonate solution, extracted twice with ethyl acetate, the aqueous phase was brought to pH 1 with hydrochloric acid. aqueous 2N, extracted twice with dichloromethane and the organic phase was dried and concentrated. 47 g of product were obtained, m.p. 120-122 ° C.
d) 4- ((2-p? -opyloxy) phthaloyl) -i -acetic acid (1-butyl) ester
47 g of the preceding product were stirred for 1 h at reflux in 600 ml of 1-butanol with 9 ml of concentrated sulfuric acid. After cooling, it was concentrated in vacuo. The residue was dissolved in 300 ml of ethyl acetate, this solution was shaken with aqueous sodium bicarbonate solution, the organic phase was dried, concentrated and the residue (54 g) was chromatographed on silica gel with ethyl acetate. n-heptane (1: 5). 42.4 g of product, m.p. 83-85 ° C.
e) 4-Hydroxy-7- (2-propyloxy) -1 (2H) -isoquinolone-3-carboxylic acid (1-butyl) ester (A) and 4-hydroxy acid (1-butyl) ester -6- (2-propyloxy) -1 (2H) -isoquinone-3-carboxylic acid (B)
Under a nitrogen atmosphere, 3.2 g were dissolved
(140 millimoles) of sodium at 60-80 ° C with stirring in 350 ml of 1-butanol. At 20 ° C, 22.3 g (70 mmol) of the preceding compound were then added and stirred for 45 min at 95 ° C. The reaction solution was stained from colorless to black and then green. After cooling, the solution was added with stirring in 300 ml of 2N hydrochloric acid, filtered with suction and the residue was treated with 150 ml of diethyl ether. 11.5 g of the product (B), m.p. 168-170 ° C. 1.2 g of product A were obtained from the mother liquor. The butanol phase was dried, concentrated in vacuo and the residue obtained was crystallized with diethyl ether. "5.2 g of product A were obtained, mp 118-123 ° C. A differentiation of isomers A and B is also achieved in CCD with ethyl acetate on silica gel: A: Rf about 0.5, B : Rf about 0.35.
£) L-chloro-4-hydroxy-7- (2-propyloxy) isoquinoline-3-carboxylic acid (1-butyl) ester
12 g of the above compound were heated to boiling for 30 min in 120 ml of phosphorus oxychloride. After work-up and chromatography with ethyl acetate / heptane (1: 5) on silica gel: 7.3 g of product, m.p. 60-62 ° C.
g-) l-Clors-4-hydroxy-7- (2-propyloxy) isoquinoline-3-carboxylic acid
3.7 g (11 mmol) of the preceding ester were heated at reflux for 1 h in 150 ml of 2N sodium hydroxide solution / ethanol (1: 1). It was concentrated in vacuo, acidified, mixed with tetrahydrofuran until the solution became clear, concentrated in vacuo and 3.0 g of precipitated product, m.p. 139-141 ° C.
h) Ester N- ((1-chloro-4-hydroxy-7- (2-propyloxy) isoquinolin-3-yl) carbonyl) glycine- (1-pentylco)
4.8 g (17 mmol) of the above isoquinolinecarboxylic acid were mixed in 600 ml of dichloromethane with 8.9 ml (70 millimoles) of N-ethylmorpholine (NEM), 6.3 g (20 millimoles) of glycine ester (1 mmol). -pentyl) -tosylate, 2.7 g (20 mmol) of 1-hydroxy-lH-benzotriazole (HOBT) and 8.5 g (20 mmol) of methyl-p-toluenesulfonate of N-cyclohexyl-N '- (2 -morpholinoethyl) -carbodiimide (CMC) and stirred for 8 days at 20 ° C. It was then concentrated in vacuo, the residue was dissolved in ethyl acetate and extracted with aqueous sodium bicarbonate solution. The ethyl acetate phase was shaken with 2N aqueous hydrochloric acid, then with water, dried and concentrated. 3.5 g of product, m.p. 70-72 ° C. After treatment with petroleum ether, m.p. 73-75 ° C.
i) The compound of the statement was obtained with follows:
4.6 g (11 mmol) of the above glycine ester were stirred for 1 h in 100 ml of 1.5N methanolic sodium hydroxide solution, a thick precipitate being formed after 15 min. It was then concentrated in vacuo, the residue was dissolved in water, shaken once with diethyl ether, clarified with activated charcoal and acidified under cooling with aqueous hydrochloric acid. 3.5 g of the colorless product, m.p. 207- -208 ° C.
Example 2 N- ((L-Chloro-4-hydroxy-6- ((2-propyl) oxy) isoquinolin-3-yl) car-bonyl) glycine
a) L-chloro-4-hydroxy-6- (2-propyloxy) isoquinoline-3-carboxylic acid ester (1-butyl)
2.0 g of compound B of Example le) were reacted, analogously to lf), with phosphorus oxychloride.
After chromatography with heptane / ethyl acetate (4: 1) on silica gel, 1.5 g of product, m.p. 116-118 ° C (in petroleum ether).
b) l-Chloro-4-hydroxy-6- (2-propyloxy) isoquinoline-3-carboxylic acid
3.3 g of the preceding ester were similarly saponified to Example lg). 2.8 g of product were obtained, m.p. 186-188 ° C (in aqueous hydrochloric acid / tetrahydrofuran).
c) Ester N- ((1-chloro-4-hydroxy-6- (2-propyloxy) isoquinolin-3-yl) carbonyl) glycine- (1-pentyl)
2.8 g (10 mmol) of the preceding carboxylic acid were reacted, analogously to Example lh), for 48 h with 3.2 g (10 mmol) of glycine- (1-phenyl) -tosylate ester, 6 ml. (40 millimoles) of NEM, 1.35 g (10 millimoles) of HOBT and 42.4 g (10 millimoles) of CMC. 1.33 g of product, m.p. 75-77 ° C (in petroleum ether).
d) The title compound was obtained by saponifying 0.45 g of the above glycine ester at 20 ° C in 50 ml of 1.5 N methanolic sodium hydroxide solution. After concentration, the product was crystallized after mixing with acid aqueous hydrochloric. 0.37 g of product, m.p. 223-225 ° C.
The compounds of the following Examples 3 to 8 were obtained analogously to Examples 1 or 2.
Example 3 N- ((1-Chloro-4-hydroxy-7-methoxyisoquinolin-3-yl) carbonyl) glycine a) (1-Butyl) ester of 4-methoxyphthaloyliminoacetic acid P.f. 63-64 ° C (in petroleum ether)
b) 4-Hydroxy-7-methoxy-1 (2H) -isoquinolone-3-carboxylic acid ester (1-butyl) P.f. 125-127CC (in diethyl ether). Content, approx. 90%
c) 1-Butyl ester of l-chloro-4-hydroxy-7-methoxyisoquinoline-3-carboxylic acid P.f. 112 ° C (in petroleum ether)
d) L-chloro-4-hydroxy-7-methoxyisoquinoline-3-carboxylic acid P.f. 185 ° C (in aqueous hydrochloric acid, tetrahydrofuran)
e) Ester N- ((l-chloro-4-hydroxy-7-methoxyisoquinolin-3-yl) -carbonyl) glycine- (1-pentyl) P.f. 93-94 ° C (in petroleum ether)
f) The compound of the statement was obtained by saponification of the preceding glycine ester. P.f. 231 ° C (in aqueous hydrochloric acid / tetrahydrofuran).
Example 4 N- ((1-chloro-4-hydroxy-6-methoxyisoquinolin-3-yl) carbonyl) glycine
a) Ester (1-butyl) of 4-hydroxy-6-methoxy-1 (2H) -isoquinolone-3-carboxylic acid P.f. 193-195 ° C (in aqueous hydrochloric acid / 1-butanol)
b) Ester (1-butyl) of l-chloro-4-hydroxy-6-methoxyisoquinoline-3-carboxylic acid P.f. 114-116 ° C (in petroleum ether)
c) L-chloro-4-hydroxy-6-methoxyisoquinoline-3-carboxylic acid P.f. 174-176 ° C (in aqueous hydrochloric acid / tetrahydrofuran)
d) Ester N- ((1-chloro-4-hydroxy-6-methoxyisoquinolin-3-yl) -carbonyl) glycine- (1-pentyl) P.f. 109-111 ° C (in petroleum ether).
e) The compound of the statement was obtained by saponification of the previous glycine ester. P.f. 212-214 ° C (in aqueous hydrochloric acid / tetrahydrofuran).
Example 5 N- ((7- ((l-butyl) oxy) -1-chloro-4-hydroxy-isoquinolin-3-yl) carbonyl) glycine
a) 4- (1-Butyloxy) phthalic acid
fci) 4- ((1-Butyloxy) phthaloylimino) acetic acid
c) 4- ((1-Butyloxy) phthaloylimino) acetic acid ester (1-butxlxo)
d) 7- (1-Butyloxy) -4-hydroxy-1 (2H) -isoquinolone-3-carboxylic acid ester (1-butyl). 133-135 ° C (in n-heptane / ethyl acetate (3: 2))
e) 7- (1-Butyloxy) -l-chloro-4-hydroxyisoquinoline-3-carboxylic acid ester (1-butyl)
f) 7- (1-Butyloxy) -l-chloro-4-hydroxyisoquinoline-3-carboxylic acid P.f. 140-142 CC (in aqueous hydrochloric acid / tetrahydrofuran)
g) Ester N- ((7- (1-butyloxy) -l-chloro-4-hydroxyisoquinolin-3-yl) carbonyl) glycin- (1-butyl) P.f. 78-80 ° C (in petroleum ether)
h) The compound of the statement was obtained from the saponification of the previous glycine ester. P.f. 158-160 ° C (in ethyl acetate).
Example 6 N- ((6- ((1-Butyl) oxy) -l-chloro-4-hydroxy-isoquinolin-3-yl) -carbonyl) glycine
a) 6- (1-Butyloxy) -4-hydroxy-1 (2H) -isoquinolone-2-carboxylic acid ester (1-butyl) P.f. 160-162 ° C (in n-heptane / ethyl acetate (1: 1))
b) 6- (1-Butyloxy) -l-chloro-4-hydroxyisoquinoline-3-carboxylic acid ester (1-butxylic acid) P.f. 76-78 ° C (in n-heptane / ethyl acetate (1: 1))
c) 6- (1-Butyloxy) -l-chloro-4-hydroxyisoquinoline-3-carboxylic acid P.f. 112-113 ° C (in tetrahydrofuran / ethanol)
d) Ester N- ((6- (1-butyloxy) -l-chloro-4-hydroxy-isoquinolin-3-yl) carbonyl) glycinbenzyl ester
e) Compound of the statement P.f. 182-184 ° C (in aqueous hydrochloric acid / tetrahydrofuran).
Example 7 N- ((6-benzyloxy-1-chloro-4-hydroxy-isoquinolin-3-yl) carbo-nil) glycine
a) Ester (1-butxylic) of 4-benzyloxy-aloyliminoacetic acid P.f. 59-61 ° C (in n-heptane / ethyl acetate (1: 1))
b) 6-Benzyloxy-4-hydroxy-1 (2H) -isoquinolone-3-carboxylic acid ester (1-butyl) P.f. 193 - 195 ° C (in butanol / ethyl acetate)
c) 6-Benzyloxy-l-chloro-4-hydroxy-isoquinoline-3-carboxylic acid ester (1-butyl)
d) 6-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid P.f. 203 - 205 ° C (in aqueous hydrochloric acid / tetrahydrofuran)
e) Ester N- ((6-benzyloxy-l-chloro-4-hydroxyisoquinolin-3-xl) carbonyl) glxcxn-ethyl P.f. 124 - 127 ° C (in diisopropyl ether)
f) Compound of the statement P.f. 210-211 ° C (in diethyl ether).
Example 8 N- ((7-benzyloxy-l-chloro-4-hydroxy-isoquinolin-3-yl) carbonyl) glycine
a) 7-benzyloxy-4-hydroxy-K2H) -isoquinolone-3-carboxylic acid ester (1-butyl)
b) 7-Benzyloxy-l-chloro-4-hx-d-sisisoisoquinoline-3-carboxylic acid ester (1-butyl) P.f. 115-117 ° C (in petroleum ether) c) 7-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid P.f. 166-168 ° C (in aqueous hydrochloric acid / tetrahydrofuran)
d) Ester N- ((7-benzyloxy-l-chloro-4-hydroxyisoquinolin-3-yl) carbonyl) glycine- (1-pentyl) P.f. 121 - 123 ° C (in diisopropyl ether)
6 > ) Compound of the statement P.f. 194-196CC (in aqueous hydrochloric acid / tetrahydrofuran).
Example 9 Nf- ((l-chloro-4-hydroxyisoquinolin-3-yl) carbonyl) glycine
a.) Methyl ester of l-chloro-4-hydroxyisoquinoline-3-carboxylic acid
2.84 g (13 mmol) of 4-hydroxy-1 (2H) -isoquinolone-3-carboxylic acid methyl ester (prepared as described in M. Suzuki, Synthesis 1978, 461) were stirred for 3 h 70 ° C in 25 ml of phosphorus oxychloride. After cooling, it was added to 500 ml of ice / water, the precipitate was filtered with suction the next morning and dried at 70 ° C in the IR irradiator. 2.96 g of product, m.p. 168 ° C.
b) L-chloro-4-hydroxyisoquinoline-3-carboxylic acid
41.0 g (0.17 mmol) of the preceding ester were stirred for 5 h at 90 ° C in 500 ml of ethanol and 500 ml of 2N aqueous sodium hydroxide solution. After acidification with aqueous hydrochloric acid to pH 2, 38.9 g of product, m.p. 192 ° C (with decomposition).
c) Ester N- ((l-chloro-4-hydroxyisoquinolin-3-yl) carbonyl) -glycimethyl ester
1.12 g (5.0 mmol) of the preceding carboxylic acid and 0.63 g (5.0 mmol) of glycinemethyl ester hydrochloride were mixed in anhydrous dichloromethane with 0.7 ml of triethylamine, 2.60 g of hexafluorophosphate of (benzotriazol-1-yloxy) -tripyrrolidinophosphonium (PyBOP) and 1.7 ml of ethyldiisopropylamine and were stirred for 3 h at 20 ° C. After filtering off the undissolved material, it was washed three times with water, the organic phase was dried, concentrated and the residue was purified with dichloromethane on silica gel. 0.72 g of product, m.p. 129 ° C.
d) The title compound was obtained by stirring for 2 h at 20 ° C 14.1 g (4-8.1, millimoles) of the preceding ester in 100 ml of tetrahydrofuran dissolved with 100 ml of 1N sodium hydroxide solution. in vacuo, diluted with water, extracted three times with dichloromethane, the aqueous phase was brought to pH 3 with concentrated hydrochloric acid and the precipitated product was filtered off with suction and dried. 12.38 g of product were obtained, m.p. 213 ° C (with decomposition).
Example 10 N- ((1, 6,7-trichloro-4-hydroxyisoquinolin-3-yl) carbonyl) glycine (obtained analogously to M. Suzuki et al., Synthesis 1978, 461 or K. Nunami, M. Suzuki, Chem. Pharm. Bull 27, 1373 (1979))
a) 6,7-Dichloro-4-hydroxy-l (2H) -isoquinolone-3-carboxylic acid methyl ester P.f. 295 ° C (with decomposition, in methanol)
b) 1, 6, 7-Trichloro-4-hydroxyisoquinoline-3-carboxylic acid methyl ester, P.f. 246 - 248 ° C (in water)
c) 1, 6,7-trichloro-4-hydroxyisoquinoline-3-carboxylic acid P.f. 200 ° C (with decomposition, in aqueous hydrochloric acid / tetrahydrofuran)
d) Ester N- ((1, 6, 7-trichloro-4-hydroxy-isoquinolin-3-yl) -carbonyl) glycine- (1-butyl) mp. 156 - 158 ° C (in diisopropyl ether)
e) Compound of the statement P.f. 295 ° C (with decomposition, in aqueous hydrochloric acid).
Example 11 Kr- ((8-chloro-4-hydroxyisoquinolin-3-yl) carbonyl) glycine
a) 8-Chloro-4-hydroxyisoquinoline-3-carboxylic acid P.f. 209 ° C (in aqueous hydrochloric acid)
b) Ester N- ((8-chloro-4-hydroxyisoquinolin-3-yl) carbonyl) -glycine-methyl P.f. 103 ° C (in ethyl acetate / n-heptane (1: 1))
c) Compound of the statement P.f. 232 ° C (in water).
Example 12 N- ((4-hydroxy-8-methoxyisoquinolin-3-yl) carbonyl) glycine
a) 4-Hydroxy-8-methoxyisoquinoline-3-carboxylic acid P.f. 217 ° C (in aqueous hydrochloric acid)
b) Compound of the statement P.f. 168 ° C (in water).
EXAMPLE 13 N- ((7- ((1-Butyl) oxy) -4-hydroxyisoquinolin-3-yl) carbonyl) gli-ciña
a) 7- (1-Butyloxy) -4-hydroxyisoquinolin-3-yl) carboxylic acid ester (1-butyl)
The compound of Example 5e) was first hydrogenated in tetrahydrofuran with Pd and hydrogen. A complete reaction is achieved in methanol plus 5% formic acid with Pd / C; oily gross product.
b) 7- (1-Butyloxy) -4-hydroxyisoquinoline-3-carboxylic acid P.f. 180 ° C (with decomposition, in aqueous hydrochloric acid / tetrahydrofuran)
c) Ester N- ((7- ((1-butyl) oxy) -4-hydroxyisoquinolin-3-yl) -carbonyl) glycine- (1-butyl) Oily crude product
d) Compound of the statement P.f. 151-153 ° C (in aqueous hydrochloric acid).
Example 14 N- ((6- ((1-Butyl) oxy) -4-hydroxyisoquinolin-3-yl) carbonyl) glycine
he) 6- (1-Butyloxy) -4-hydroxyisoquinoline-3-carboxylic acid (1-butyl) ester was obtained by hydrogenation of the compound of Example 6b); oily gross product.
b) 6- (1-Butyloxy) -4-hydroxyisoquinoline-3-carboxylic acid P.f. 185-187 ° C (in aqueous hydrochloric acid / tetrahydrofuran)
c) Ester N- ((6- (1-butyloxy) -4-hydroxyisoquinolin-3-yl) -carbonyl) glycindobenzyl P.f. 98-100 ° C (in n-heptane / ethyl acetate (l: l))
d) The compound of the statement was obtained by hydrogenation of the preceding benzyl ester. P.f. 199-200 ° C (in petroleum ether).
EXAMPLE 15 N- ((4-hydroxy-7- ((2-propyl) oxy) isoquinolin-3-yl) carbonyl glycine
Analogously to the compound of Example 1, the compounds of Examples 16 to 18 can be obtained.
Example 16 N- ((4-hydroxy-7- (3 -pentyloxy) isoquinolin-3-yl) carbonyl) glycine
Example 17 N- ((4-Hydroxy-7-trifluoromethoxy-isoquinolin-3-yl) carbonyl) glycine
Example 18 N- ((7-difluoromethoxy-4-hydroxyisoquinolin-3-yl) carbsnyl) glycine
EXAMPLE 19 l- Chloro-4-hydroxy-7- (2-pro-piloxy) isoquinoline-3-carboxylic acid N- (2-hydroxyethyl) -amide 0,3 g of the compound of Example lf) were stirred in 5 ml of 2-aminoethanol for 1 h at 85 ° C. It was then mixed with 30 ml of water, adjusted to pH 1 with semi-concentrated aqueous hydrochloric acid, under cooling, extracted twice with ethyl acetate, dried, concentrated and the residue was crystallized with a little diisopropylether. Petroleum ether (1: 1). 0.21 g of the title compound, m.p. 102 - 104 ° C.
EXAMPLE 20 L-Chloro-4-hydroxy-6- (2-pro-plyoxy) isoquinoline-3-carboxylic acid N'- (2-hydrostyethyl) amide
The title compound was prepared starting from compound 2a) and 2-aminoethanol, analogously to Example 19. P.f. 155 - 156 ° C (in petroleum ether).
EXAMPLE 21 l- Chloro-4-hydroxy-7-methoxyisoquinoline-3-carboxylic acid N- (2-hydroxyethyl) amide
The title compound was prepared starting from compound 3c) and 2-aminoethanol, analogously to Example 19. P.f. 165 - 167 ° C (in diisopropyl ether).
Example 22 1-Chloro-4-hydroxy-6-methoxyisoquinoline-3-carboxylic acid N- (2-hydroxyethyl) amide
The title compound was prepared starting from compound 4a) and 2-aminoethanol, analogously to Example 19. P.f. 117 - 119 ° C (in diisopropyl ether).
Example 23 N- (2-hydroxyethyl) amide of 7- (1-butyloxy) -l-chloro-4-hydroxyisoquinoline-3-carboxylic acid
The title compound was prepared starting from compound 5e) and 2-aminoethanol, analogously to Example 19. P.f. 118-120 ° C (in diisopropyl ether).
Claims (2)
- CLAIMS Compounds of the formula I wherein R3 signifies hydrogen or chlorine, R: signifies hydrogen, alkyl (Cx-Ca), alkoxy (Cx-C8), chloro, trifluoromethyl, hydroxy or benzyloxy, which is optionally substituted with substituents of the alkyl series (Cx-C5) , (Cx-C3) alkoxy, or fluoroalkoxy of the formula -O- [CH2] x-CfH (2 £ + 1-g) Fg, with x = 0 and 1, f = 1-5 and g = 1 a (2f + l), R3 means hydrogen, alkyl (Cx-Ca), alkoxy (Cx-C8), fluorine, chlorine, cyano, trifluoromethyl, hydroxy or benzyloxy, which is optionally substituted with substituents of the alkyl (Cx-C5) series, (Cx-C5) alkoxy, or fluoroalkoxy of the formula -0- [CH2] xC £ H (2 £ + 1-g) Fg, wherein x, f and g are defined as above, R4 and R5 mean hydrogen, alkyl (Cx) -C5), fluorine, chlorine, bromine, trifluoromethyl, cyano, (Cx-C3) alkoxy or fluoroalkoxy of the formula -0- [CH2] x-CfH (2 £ + xg) Fg, where x, f and g are defined as before, including the physiologically effective salts.
- 2. Compounds of the formula I according to claim 1, wherein R1 is hydrogen or chloro, R2 is hydrogen, alkyl (Cx-Ca), alkoxy (Cx-C8), chloro, trifluoromethyl, hydroxy, benzyloxy, or fluoroalkoxy of the formula -O- [CH2] x-CfH (2f + xg) Fg, with x = 0 and 1, f = 1 - 5 and g = 1 a (2f + l), R3 means hydrogen, alkyl (Cx-Ca) , (Cx-C8) alkoxy, fluoro, chloro, cyano, trifluoromethyl, hydroxy, benzyloxy, or fluoroalkoxy of the formula -0- [CH2] xC £ H (2 £ + 1-g, Fg, where x, f and g are defined as above, R4 signifies hydrogen, (Cx-Ca) alkoxy, fluoro, chloro, trifluoromethyl, cyano, or fluoroalkoxy of the formula -0- [CH2] x-CfH (2 £ + xg) Fg, wherein x, f and g are defined as above, and R5 is hydrogen 3. Compounds of the formula I according to claim 1 or 2, wherein R1 is hydrogen or chloro, R2 is hydrogen, (Cx-C5) alkoxy, chloro, benzyloxy, fluoroalkoxy with x = 0, f = 1, R3 is hydrogen, alkoxy (Cx-C3), chlorine, benzyloxy, R4 is hydrogen, chlorine, toxi, R5 is hydrogen 4. Compounds of the formula I according to claim 1 or 2, wherein R1 is hydrogen or chloro, R2 is hydrogen, (Cx-C8) alkoxy, chloro, hydroxy, benzyloxy, R3 is hydrogen, (Cx-C8) alkoxy, fluoro, chloro, hydroxy, benzyloxy, R4 is hydrogen, chloro, R5 is hydrogen. 5. Compounds of the formula I according to claim 1 or 2, wherein "R1 is hydrogen or chloro, R2 is (Cx-Ca) alkoxy, chloro, benzyloxy, and R3, R4 and R5 are hydrogen. of the formula I according to claim 1 or 2, wherein R1 is hydrogen or chloro, R2 is hydrogen or chloro, R3 is (Cx-C8) alkoxy, chloro, benzyloxy, and R4 and Rs are hydrogen- 7.- Compounds of the formula I according to claim 1 or 2, wherein R1 is hydrogen or chloro, R2 and R3 are hydrogen or chloro, R4 is (Cx-C3) alkoxy, chloro, benzyloxy, and Rs is hydrogen. The formula I according to claim 1 or 2, wherein R 1 is hydrogen or chlorine, R 2 is (C x C 6) alkoxy or benzyloxy, R 3, R 4 and R s are hydrogen 9. - Compounds of the formula I according to claim 1 or 2, wherein R1 is hydrogen or chloro, R2 is hydrogen, R3 is (Cx-C6) alkoxy or benzyloxy, and R4 and Rs are hydrogen 10. Compounds of the formula I according to claim 1 or 2, wherein R1 is hydrogen or chloro, R2 is (Cx-C3) alkoxy, and R3, R4 and R5 are hydrogen. 11. Compounds of the formula I according to claim 1 or 2, wherein R1 is hydrogen or chloro, R2 is hydrogen, R3 is (Cx-C6) alkoxy, and R4 and R5 are hydrogen. 12.- N- ((1-chloro-4-hydroxyisoquinolin-3-yl) carbonyl) glycine, N - ((8-chloro-4-hydroxyisoquinol-3-yl) carbonyl) glycine, N- ((1-chloro -4-hydroxy-7- ((2-propyl) oxy) isoquinolin-3-yl) carbonyl) glycine, N - ((4-hydroxy-7- (2-propyl) oxy) isoquinolin-3-yl) - carbonyl) glycine. 13. - Compounds of the formula wherein R 1 signifies hydrogen or chlorine, R 2 signifies hydrogen, (C x -C 8) alkyl, (C x C 8) alkoxy, chloro, trifluoromethyl, hydroxy or benzyloxy, which is optionally substituted with substituents of the alkyl (C x -C 3) series, (Cx-C3) alkoxy, or fluoroalkoxy of the formula -0- [CH2] xC £ H (2 £ + xg) Fg, with x = 0 and 1, f = 1-5 and g = 1 a (2f + l ), R3 signifies hydrogen, alkyl (Cx-Ca), alkoxy (Cx-C8), fluorine, chlorine, cyano, trifluoromethyl, hydroxy or benzyloxy, which is optionally substituted by substituents of the series alkyl (Cx-C3), alkoxy ( Cx-C5), or fluoroalkoxy of the formula -0- [CH2] xC £ H (2 £ + xg) Fg, wherein x, f and g are defined as above, R4 and R5 signify hydrogen, alkyl (Cx-C3), fluorine, chlorine, bromine, trifluoromethyl, cyano, (Cx-C5) alkoxy or fluoroalkoxy of the formula -0- [CH2] xC £ H (2 £ + 1-g) Fg, wherein x, f and g are defined as above , including physiologically effective salts. 14. Compounds of the formula according to claim 1, wherein R "is chlorine, R2 and R3 are hydrogen or (Cx-C4) alkoxy, and R4 and R5 are hydrogen 15. - Compounds of the formula la according to Claim 13, wherein R means hydrogen or chlorine, R 2 signifies alkoxy (C x -Ce), and R 3, R 4 and R 5 signify hydrogen 16. Compounds of the formula la according to claim 13, wherein R 1 signifies hydrogen or chlorine, R: 'signifies hydrogen, R-' signifies alkoxy (Cx-C6), and R * and R5 signify hydrogen 17.- N- (2-hydroxyethyl) amide of l-chloro-4-hydroxy-7- ( (2-propyl) oxy) isoquinoline-3-carboxylic acid 18. - Process for the preparation of compounds of the general formula I according to claims 1 to 12, characterized in that li) quinoline-2-carboxylic acids of the formula II are reacted with the amino acids of the formula III to give the amidoesters of the formula IV, in which R is H, alkyl of 1 to 8 carbon atoms and benzyl iii) the compounds of the formula I are released from their esters of the formula IV. 19. - Process for the preparation of the compounds of the formula la according to claims 13 to 17, characterized in that the compounds of the formula lia, in which R is H, alkyl of 1 to 8 carbon atoms and benzyl, (lia) they are reacted with 2-aminoethanol. 20. Compounds according to claims 1 to 17, for use in the inhibition of collagen biosynthesis. 21. - Compounds according to claims 1 to 17, for the use for the inhibition of prolyl-4-hydroxylase. 22. Compounds according to claims 1 to 17, for use as fibrosuppressants. 23. Use according to claims 1 to 17, for the preparation of a medicament against fibrotic diseases. 24. Use according to claims 13 to 17, for the preparation of a medicament against fibrotic diseases of the liver. 25. Compounds according to claims 13 to 17, for use in the inhibition of collagen biosynthesis in the liver. 26. Compounds according to claims 1 to 17, for the preparation of a medicament against fibrotic diseases of the liver, kidneys, lungs and skin. 27. Compounds according to claims 13 to 17, for the preparation of a medicament against fibrotic diseases of the liver. 28. Medication containing compounds according to claims 1 to 17.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19746287.1 | 1997-10-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA98008644A true MXPA98008644A (en) | 1999-05-31 |
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