CA1115709A - 5-substituted-hydroxy picolinic acid derivatives - Google Patents
5-substituted-hydroxy picolinic acid derivativesInfo
- Publication number
- CA1115709A CA1115709A CA323,912A CA323912A CA1115709A CA 1115709 A CA1115709 A CA 1115709A CA 323912 A CA323912 A CA 323912A CA 1115709 A CA1115709 A CA 1115709A
- Authority
- CA
- Canada
- Prior art keywords
- group
- formula
- same
- represented
- picolinic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- -1 5-substituted-hydroxy picolinic acid Chemical class 0.000 title claims abstract description 85
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 54
- 229940081066 picolinic acid Drugs 0.000 claims abstract description 39
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 26
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 claims abstract description 25
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 21
- 125000003277 amino group Chemical group 0.000 claims abstract description 19
- 125000005843 halogen group Chemical group 0.000 claims abstract description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 11
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 10
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 8
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 8
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 4
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 80
- 238000000034 method Methods 0.000 claims description 44
- 230000008569 process Effects 0.000 claims description 42
- 239000002253 acid Substances 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 28
- DHLUJPLHLZJUBW-UHFFFAOYSA-N 6-methylpyridin-3-ol Chemical compound CC1=CC=C(O)C=N1 DHLUJPLHLZJUBW-UHFFFAOYSA-N 0.000 claims description 26
- PEHSSTUGJUBZBI-UHFFFAOYSA-N indan-5-ol Chemical compound OC1=CC=C2CCCC2=C1 PEHSSTUGJUBZBI-UHFFFAOYSA-N 0.000 claims description 20
- 230000001590 oxidative effect Effects 0.000 claims description 15
- 239000007800 oxidant agent Substances 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 13
- NESFDGDRYVANBC-UHFFFAOYSA-N 6-(hydroxymethyl)pyridin-3-ol Chemical compound OCC1=CC=C(O)C=N1 NESFDGDRYVANBC-UHFFFAOYSA-N 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- RXHAQWAUXWKINY-UHFFFAOYSA-N 5-(4-chlorophenoxy)pyridine-2-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC=C1OC1=CC=C(Cl)C=C1 RXHAQWAUXWKINY-UHFFFAOYSA-N 0.000 claims description 11
- 150000004820 halides Chemical class 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 8
- 229910052751 metal Chemical class 0.000 claims description 8
- 239000002184 metal Chemical class 0.000 claims description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 8
- NPAUPKKDRMTHSQ-UHFFFAOYSA-N 5-(4-chlorobutoxy)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(OCCCCCl)C=N1 NPAUPKKDRMTHSQ-UHFFFAOYSA-N 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 239000012954 diazonium Substances 0.000 claims description 7
- YQGKMQPCIMTPCB-UHFFFAOYSA-N 5-(3-chloropropoxy)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(OCCCCl)C=N1 YQGKMQPCIMTPCB-UHFFFAOYSA-N 0.000 claims description 6
- CHBNFEFUVKGTPY-UHFFFAOYSA-N 5-(2-chlorophenoxy)pyridine-2-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC=C1OC1=CC=CC=C1Cl CHBNFEFUVKGTPY-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 150000001989 diazonium salts Chemical class 0.000 claims description 5
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 4
- QBELEDRHMPMKHP-UHFFFAOYSA-N 1-bromo-2-chlorobenzene Chemical compound ClC1=CC=CC=C1Br QBELEDRHMPMKHP-UHFFFAOYSA-N 0.000 claims description 4
- KTHFMMUXNXWKNS-UHFFFAOYSA-N 5-[2-(trifluoromethyl)phenoxy]pyridine-2-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC=C1OC1=CC=CC=C1C(F)(F)F KTHFMMUXNXWKNS-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 235000010288 sodium nitrite Nutrition 0.000 claims description 4
- IQHWLPUHSVSHMK-UHFFFAOYSA-N 2-methyl-5-[4-(trifluoromethyl)phenoxy]pyridine Chemical compound C1=NC(C)=CC=C1OC1=CC=C(C(F)(F)F)C=C1 IQHWLPUHSVSHMK-UHFFFAOYSA-N 0.000 claims description 3
- WHVGGUIIUQHOAL-UHFFFAOYSA-N 5-(2-chlorophenoxy)-2-methylpyridine Chemical compound C1=NC(C)=CC=C1OC1=CC=CC=C1Cl WHVGGUIIUQHOAL-UHFFFAOYSA-N 0.000 claims description 3
- LKLOIBKLYSDLFY-UHFFFAOYSA-N 5-(4-chlorophenoxy)-2-methylpyridine Chemical compound C1=NC(C)=CC=C1OC1=CC=C(Cl)C=C1 LKLOIBKLYSDLFY-UHFFFAOYSA-N 0.000 claims description 3
- OMYLZYZQGXVCJW-UHFFFAOYSA-N 5-(5,5,5-trifluoropentoxy)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(OCCCCC(F)(F)F)C=N1 OMYLZYZQGXVCJW-UHFFFAOYSA-N 0.000 claims description 3
- JXPYTHDXGAGHBU-UHFFFAOYSA-N 5-[4-(trifluoromethyl)phenoxy]pyridine-2-carboxylic acid Chemical compound C1=NC(C(=O)O)=CC=C1OC1=CC=C(C(F)(F)F)C=C1 JXPYTHDXGAGHBU-UHFFFAOYSA-N 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- YWWIVAPTDUGCDE-UHFFFAOYSA-N [5-(3-chloropropoxy)pyridin-2-yl]methanol Chemical compound OCC1=CC=C(OCCCCl)C=N1 YWWIVAPTDUGCDE-UHFFFAOYSA-N 0.000 claims description 3
- GPNKLWSGOAVQBZ-UHFFFAOYSA-N [5-(4-chlorobutoxy)pyridin-2-yl]methanol Chemical compound OCC1=CC=C(OCCCCCl)C=N1 GPNKLWSGOAVQBZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003377 acid catalyst Substances 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 150000005171 halobenzenes Chemical class 0.000 claims description 3
- 125000004436 sodium atom Chemical group 0.000 claims description 3
- YHRUOJUYPBUZOS-UHFFFAOYSA-N 1,3-dichloropropane Chemical compound ClCCCCl YHRUOJUYPBUZOS-UHFFFAOYSA-N 0.000 claims description 2
- KJDRSWPQXHESDQ-UHFFFAOYSA-N 1,4-dichlorobutane Chemical compound ClCCCCCl KJDRSWPQXHESDQ-UHFFFAOYSA-N 0.000 claims description 2
- XLQSXGGDTHANLN-UHFFFAOYSA-N 1-bromo-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(Br)C=C1 XLQSXGGDTHANLN-UHFFFAOYSA-N 0.000 claims description 2
- BEQKYEJRVRVZNZ-UHFFFAOYSA-N 5-bromo-1,1,1-trifluoropentane Chemical compound FC(F)(F)CCCCBr BEQKYEJRVRVZNZ-UHFFFAOYSA-N 0.000 claims description 2
- VZNBOUOHGXQJTK-UHFFFAOYSA-N [5-(5,5,5-trifluoropentoxy)pyridin-2-yl]methanol Chemical compound OCC1=CC=C(OCCCCC(F)(F)F)C=N1 VZNBOUOHGXQJTK-UHFFFAOYSA-N 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical group [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- XJVQMUUYJXFBDH-UHFFFAOYSA-N 2-methyl-5-[2-(trifluoromethyl)phenoxy]pyridine Chemical compound FC(C1=C(OC=2C=CC(=NC2)C)C=CC=C1)(F)F XJVQMUUYJXFBDH-UHFFFAOYSA-N 0.000 claims 2
- RWXUNIMBRXGNEP-UHFFFAOYSA-N 1-bromo-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1Br RWXUNIMBRXGNEP-UHFFFAOYSA-N 0.000 claims 1
- DBCAQXHNJOFNGC-UHFFFAOYSA-N 4-bromo-1,1,1-trifluorobutane Chemical compound FC(F)(F)CCCBr DBCAQXHNJOFNGC-UHFFFAOYSA-N 0.000 claims 1
- CKVQQDUSKCAIDZ-UHFFFAOYSA-N 5-(4,4,4-trifluorobutoxy)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(OCCCC(F)(F)F)C=N1 CKVQQDUSKCAIDZ-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 29
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 abstract description 18
- 229940030600 antihypertensive agent Drugs 0.000 abstract description 10
- 239000002220 antihypertensive agent Substances 0.000 abstract description 10
- 230000003276 anti-hypertensive effect Effects 0.000 abstract description 8
- 125000004442 acylamino group Chemical group 0.000 abstract description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract description 5
- 125000002431 aminoalkoxy group Chemical group 0.000 abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 5
- 239000011734 sodium Substances 0.000 abstract description 5
- 239000004411 aluminium Substances 0.000 abstract description 2
- 239000011591 potassium Substances 0.000 abstract description 2
- 229910052700 potassium Inorganic materials 0.000 abstract description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 abstract 1
- 239000011575 calcium Substances 0.000 abstract 1
- 229910052791 calcium Inorganic materials 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 78
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical group OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 42
- 239000000243 solution Substances 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 35
- 239000013078 crystal Substances 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 23
- 238000002844 melting Methods 0.000 description 22
- 238000000921 elemental analysis Methods 0.000 description 20
- 230000008018 melting Effects 0.000 description 20
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 235000011167 hydrochloric acid Nutrition 0.000 description 18
- 229960000443 hydrochloric acid Drugs 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 17
- 239000000725 suspension Substances 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- 238000007254 oxidation reaction Methods 0.000 description 15
- 230000003647 oxidation Effects 0.000 description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- DGMPVYSXXIOGJY-UHFFFAOYSA-N Fusaric acid Chemical compound CCCCC1=CC=C(C(O)=O)N=C1 DGMPVYSXXIOGJY-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 11
- 239000012286 potassium permanganate Substances 0.000 description 11
- 230000035484 reaction time Effects 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 10
- 229940093499 ethyl acetate Drugs 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 230000036772 blood pressure Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 5
- 159000000007 calcium salts Chemical class 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 229910001873 dinitrogen Inorganic materials 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 235000001968 nicotinic acid Nutrition 0.000 description 5
- 239000011664 nicotinic acid Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 150000002989 phenols Chemical class 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 238000010531 catalytic reduction reaction Methods 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- XXOUHKWIQVEQIH-UHFFFAOYSA-N 5-butoxypyridine-2-carboxylic acid Chemical compound CCCCOC1=CC=C(C(O)=O)N=C1 XXOUHKWIQVEQIH-UHFFFAOYSA-N 0.000 description 3
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 3
- 239000005751 Copper oxide Substances 0.000 description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 229910000431 copper oxide Inorganic materials 0.000 description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 3
- 229940045803 cuprous chloride Drugs 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- OCYOPQMIQQOESK-UHFFFAOYSA-N 5-[2-(trifluoromethyl)phenoxy]pyridine-2-carboxamide Chemical compound C1=NC(C(=O)N)=CC=C1OC1=CC=CC=C1C(F)(F)F OCYOPQMIQQOESK-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
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- 150000003462 sulfoxides Chemical class 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
Abstract
ABSTRACT OF THE DISCLOSURE
5-Substituted picolinic acid derivatives represented by the formula (I):
(I) wherein Rl represents a straight or branched chain halogen-substituted alkyl group having 2 to 6 carbon atoms or a substituted phenyl group having the formula - wherein R3 and R4, which may be the same or different, each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group, an N-alkyl-substituted amino group, an acylamino group, an acetyl group, an acyloxy group, a hydroxy group or a halogen-substituted alkyl group or R3 and R4, when taken together, represent a polymethylene chain; and R2 represents an -OM group wherein M
represents a hydrogen, sodium, potassium, calcium, aluminium or magnesium atom, a straight or branched chain or cyclic alkoxy group having 1 to 6 carbon atoms, an aminoalkoxy group, a phenoxy group, a.substituted phenoxy group, a 5-indanyloxy?
group, an acyloxyalkyloxy group having the formula wherein R5 represents a hydrogen atom or a methyl group and R6 represents a lower alkyl group having 1 to 6 carbon atoms, a phenyl group or a substituted phenyl group, or an amino group represented by the formula wherein R7 and R8, which may be the same or different, each represents a hydrogen atom, a lower alkyl group, or a phenyl group which are useful as anti-hypertensive agents, a process for preparing the above 5-substituted picolinic acid derivatives, and anti-hyper-tensive compositions containing the same.
5-Indanyl ester of 5-alkoxy-picolinic acid represented by the formula (A): .
5-Substituted picolinic acid derivatives represented by the formula (I):
(I) wherein Rl represents a straight or branched chain halogen-substituted alkyl group having 2 to 6 carbon atoms or a substituted phenyl group having the formula - wherein R3 and R4, which may be the same or different, each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group, an N-alkyl-substituted amino group, an acylamino group, an acetyl group, an acyloxy group, a hydroxy group or a halogen-substituted alkyl group or R3 and R4, when taken together, represent a polymethylene chain; and R2 represents an -OM group wherein M
represents a hydrogen, sodium, potassium, calcium, aluminium or magnesium atom, a straight or branched chain or cyclic alkoxy group having 1 to 6 carbon atoms, an aminoalkoxy group, a phenoxy group, a.substituted phenoxy group, a 5-indanyloxy?
group, an acyloxyalkyloxy group having the formula wherein R5 represents a hydrogen atom or a methyl group and R6 represents a lower alkyl group having 1 to 6 carbon atoms, a phenyl group or a substituted phenyl group, or an amino group represented by the formula wherein R7 and R8, which may be the same or different, each represents a hydrogen atom, a lower alkyl group, or a phenyl group which are useful as anti-hypertensive agents, a process for preparing the above 5-substituted picolinic acid derivatives, and anti-hyper-tensive compositions containing the same.
5-Indanyl ester of 5-alkoxy-picolinic acid represented by the formula (A): .
Description
1~15709 (`
Field of the Invention This invention relates to new and useful 5-substituted picolinic acids and salts thereof, 5-substituted picolinic esters and 5-substituted picolinic acid amides, to a process for preparing the same, and to pharmaceutical compositions containing the same.
This invention relates to new and useful compounds, 5-indanyl ester of 5-alkoxy-picolinic acid, to a process for preparing the same, and to pharmaceutical compositions containing the same.
Description of the Prior Art It is known that hypertension o~ten includes apoplexy, heart trouble, etc., which necessitates extensive research for new and useful anti-hypertensives.
Fusaric acid (5-n-butylpicolinic acid) is known to be .,, useful as an anti-hypertensive agent as disclosed in Jap. J.
Pharmacol., Vol. 25, 188 ~1975~, however, fusaric acid has a butyl group at the 5-position of the picolinic acid moiety and has a low LD50 value. As a result, an improved anti-hypertensive agent is desired.
British Patent 1,502,055 discloses that 3-substituted-
Field of the Invention This invention relates to new and useful 5-substituted picolinic acids and salts thereof, 5-substituted picolinic esters and 5-substituted picolinic acid amides, to a process for preparing the same, and to pharmaceutical compositions containing the same.
This invention relates to new and useful compounds, 5-indanyl ester of 5-alkoxy-picolinic acid, to a process for preparing the same, and to pharmaceutical compositions containing the same.
Description of the Prior Art It is known that hypertension o~ten includes apoplexy, heart trouble, etc., which necessitates extensive research for new and useful anti-hypertensives.
Fusaric acid (5-n-butylpicolinic acid) is known to be .,, useful as an anti-hypertensive agent as disclosed in Jap. J.
Pharmacol., Vol. 25, 188 ~1975~, however, fusaric acid has a butyl group at the 5-position of the picolinic acid moiety and has a low LD50 value. As a result, an improved anti-hypertensive agent is desired.
British Patent 1,502,055 discloses that 3-substituted-
2(IH)-pyridone-6-carboxylic acid can be used as an anti-hypertensive agent but the anti~hypertensive activity ~i.e., maximum depression in blood pressure) thereof is poor and an ..;
; improvement is desired.
The inventors have already synthesized 5-alkoxy-: picolinic acids and evaluated them as anti-hypertensive agents as reported in Canadian Patent Application No. 287,913 tcorresponding to U.S. Patent No. 4,189,489~.
.,. ~
. ' .
~:`'' . .
., . . ..
~.~157~9 1 It has now been found that the compounds of the present invention exhibit anti-hypertensive activity equal or superior to 5-alkoxypicolinic acids of the Canadian Patent Application No. 287,913 and have lower toxicity than 5-alkoxypicolinic acids of the Canadian Patent Application No. 287,913 and, therefore, the compounds of the present invention are use~ul compounds for the treatment of hyper-tension.
;i SUMMARY OF THE INVENTION
; 10 It is a principal object of the present invention to provide a novel group of anti-hypertensive agents.
It is another object of the present invention to provide a novel group of anti-hypertensive agents which are less toxic than 5-alkoxypicolinic acids but equal to or superior to "
5-alkoxypicolinic acids in their anti-hypertensive activity.
Still another object of the present invention is to provide novel processes for producing these anti-hypertensive agents.
Accordingly, the present invention provides 5-` 20 substituted picolinic acid derivatives represented by theformula (I):
,i? J~ ORl R2~C ~ (I) ":. :
:; wherein Rl represents a straight or branched chain halogen-" substituted alkyl group having 2 to 6 carbon atoms or a substituted phenyl group of the formula ~ wherein R3 and R4, which may be the same or different, each represents a :"~ .
, ` .Afl . . --, 11~57~
1 hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group, an N-alkyl-substituted amino group, an acylamino group, an acetyl group, an acyloxy group, a hydroxyl group or a halogen-substituted alkyl group, or R3 and R4, when taken together, represent a polymethylene chain; and R2 represents an -OM chain wherein M
represents a hydrogen atom, a sodium atom, a potassium atom, a calcium atom, analuminium atom or a magnesium atom, a straight or branched chain or cyclic alkoxy group having l to 6 carbon atoms, an aminoalkoxy group, a phenoxy group, a 5-indanyloxy group, an acyloxyalkyloxy group having the formula -O-CHOCOR6 wherein R5 represents a hydrogen atom or a methyl group and R6 represents a lower alkyl group having l to 6 carbon atoms, a phenyl group or a substituted phenyl group, or an amino group represented by the formula -N whereLn R7 ,. R8 and R8, which may be the same or different, each represents a hydrogen atom, a lower alkyl group or a phenyl group.
DETAILED DESCRIPTION OF THE INVENTION
In the formula (I), Rl represents a straight or branched chain halogen-substituted alkyl group having 2 to 6 carbon atoms (such as a 4-chlorobutyl group, a 4-bromobutyl group, a 3-chloropropyl group, a 5,5,5-trifluoropentyl group, .
a 4,4,4-trifluorobutyl group, a 3,4-dibromobutyl group, a 5-chloro-3-methyl-pentyl group, etc.); or a substituted phenyl ... .
~ ~ R3 group having the formula ~ R wherein R3 and R4, which may be the same or diJferent, each repre~ents a hydrogen atom, a ., .
': :
lilS7~9 1 halogen atom (such as chlorine, bromine, fluorine, etc.), a lower alkyl group having 1 to 3 carbon atoms (such as a methyl group, an ethyl group, a propyl group, etc.), a lower alkoxy group having 1 to 3 carbon atoms (such as a methoxy group, an ethoxy group, a propoxy group, etc.), a nitro group, an amino group, an N-alkyl-substituted amino group wherein the alkyl moiety has 1 to 3 carbon atoms (such as a dimethylamino group, a diethylamino group, etc.), an acylamino group having 2 to 4 ; carbon atoms (such as an acetamido group, a propionylamino group, etc.), an acetyl group, an acyloxy group having 2 to 4 , carbon atoms (such as an acetoxy group, a propionyloxy group, etc.)c a hydroxy group or a halogen-substituted alkyl group having 1 to 3 carbon atoms (such as a trifluoromethyl group, etc.), or R3 and R4, when taken together, represent a poly-methylene chain having 3 to 5 carbon atoms (such as trimethylene, etc.).
R2 represents an -OM group wherein M represents a hydrogen atom, a sodium atom, a potassium atom, a calcium atom, an ~u~inium atom or a magnesium atom; a straight or branched chain or cyclic alkoxy group having 1 to 6 carbon atoms (such as a methoxy group, an ethoxy group, a propoxy group, an isobutoxy group, a cyclohexylox~ group, etc.); an aminoalkoxy ~ group having 2 to 5 carbon atoms (such as dimethylaminoethyloxy group, etc.); a phenoxy group (including a phenoxy group substituted as illustrated below for the phenyl group); a 5-indanyloxy group; an acyloxyalkyloxy group having the formula -O-CHOCOR6 wherein R5 represents a hydrogen atom or a methyl group and R6 represents a lower alkyl group having 1 to 6 ;`f~ 30 carbon atoms (such as a methyl group, an ethyl group, a propyl .,~,; ,.
~ -4-.', .
~ ' , l~lS709 1 group, an isobutyl group, a t-butyl group, etc.), a phenyl group,or a substituted phenyl group wherein the substituent includes an alkyl group having 1 to 3 carbon atoms and an alkoxy group having 1 to 3 carbon atoms (such as a p-tolyl group, a p-methoxyphenyl group, a 3,4,5-trimethoxyphenyl group, etc.);
. ~ 7 or an amino group represented by the formula -N wherein R
and R8, which may be the same or different, each represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms (such as a methyl group, an ethyl group, etc.), or a phenyl group.
Compounds represented by the formula (II-a):
I ¦l (II-a) ;HOOc~A~iN~
wherein Rlol represents a straight or branched chain halogen-substituted alkyl group having 2 to 6 carbon atoms, can be ~.
` prepared by reacting a compound represented by the formula (IV):
. ~ OH
.j R N (IV) ... ..
~ wherein Rg represents a methyl group or a hydroxymethyl group, :~: with a halide represented by the formula (V):
~`''':' ' ' "'' RlolX (V) .
wherein Rlol is as defined above and X representS a halogen atom, .~ 30 in an organic solvent such as dimethylformamide, dimethyl :" . .
': .
"~', -S-! ~ , - :
;. ~ : , 1 sulfoxide, dimethylacetamide and the like in the presence of an inorganic base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonatel sodium hydrogencarbonate and the like or an organic base such as triethylaminel N,N-dimethylaniline and the like to obtain a compound represented by the formula (VI):
~ 101 ~ ~ ' Rg N (VI) wherein R9 and Rlol are as defined above.
This substitution reaction takes place selectively at the 5-position hydroxy group, and no reaction of the -CH2OH group or by-production of pyridinium salts is observed under the conditions of the invention. The reaction easily proceeds at a temperature ranging from about 30 to 100C and is completed in a relatively short time such as about 1 to 20 -hours.
The compounds of the formula (II-a) according to this . - . .
invention can be prepared by oxidizing the intermediate of the ~ ~-formula (VIj as described above using an oxidizing agent such as : potassium permanganate, chromic anhydride, selenium dioxide, ~ nitric acid, potassium bichromate and the like in a solvent such ., ~ ~ .
~ as acetone, dioxane, pyridine, hydrous acetone, hydrous t-;, butanol, sulfuric acid and the like. Any impurities by-produced ~d ' during the reaction can easily be removed by solvent extraction, ~-precipitation, crystallization or a like operation. Reaction ;~` conditions for the oxidation vary with kind of the oxidizing ~.,...................................................................... :
~ agent used and Rg group in the compound of the formula (VI).
.~
When R9 group is hydroxymethyl group, the reaction conditions for the oxidation are generally mild. For example, when the compound ' .
~"`; -6-:
~ .
l~lS7Q9 .. .
1 of the formula (VI) having hydroxymethyl group as the Rg group is oxidized with potassium permanganate, about 1 to 2 mols of potassium permanganate per mol of the compound of the formula (VI) is used and the reaction.time and reaction temperature are about 5 to 20C and about 2 to 20 hours, respectively. In the case of oxidizing the compound of the formula (VI) having a methyl group as the Rg group with potassium permanganate,about 2 to 4 mols of potassium permanganate per mol of the compound of the formula (VI) are needed at the reaction temperature of about 80 to 100C and for the reaction time of about 4 to 10 hours. In a case of oxidizing the compound of the formula (VI) having a methyl group as the R9 group with chromic anhydride, about 2.5 to 3.5 mols of chromic anhydride per mol of the compound of the formula (VI) is used in the presence of sulfuric acid at the reaction temperature of about 30 to 70C for the reaction ~ time of about 4 to 10 hours. When selenium dioxide is used as an oxidizing agent, the oxidation reaction is carried out in the presence of pyridine in an amount of about 1.8 to 2.5 mols :~ of selenium dioxide per mol of the compound of the formula (VI) ` 20 at reaction temperature of about 100 to 120C for reaction time of about 5 to 10 hours.
.~ ~ Compounds represented by the formula (II-f?:
R
302 (II-f) .~wherein R302 and R404, which may be the same or different, each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group, . 30 an N-alkyl-substituted amino group, an acylamino group, an ,--7--.
.
i:
ll~S7Q9 .
1 acetyl group, or a halogen-subs-tituted alkyl group, or R302 and R404, when taken together, represent a polymethylene chain can ~ :
be obtained by reacting the compound of the formula (IV) or a metal salt thereof such as a potassium salt,a sodium salt, etc., with a substituted halobenzene derivative represented by the ~.
formula (VII-a): ~
X ~ R302 ~ :
~ R404 (VII-a) wherein R302 and R404 are as defined above and X is a halogen :.
atom, in an organic solvent such as dimethylformamide, dim~thlyacetamide, pyridine,collidine and the like preferably in the presence of a catalyst such as a copper powder, copper oxide, copper chloride and the like to obtain a compound represented by the formula (VIII-b):
Rg~ R404 (VIIl-b) : wherein Rg, R302 and R404 are as defined above. Of the compounds of the formula (VII-a), those wherein at least one of R302 and ~.
~ R404 isa nitro group and the nitro group is positioned at ortho- or para-position of the halogen X may be prepared under mild conditions such as at a reaction temperature of about `
S0 to 100C in a reaction time of about 10 to 15 hours without catalyst.
. The halobenzene derivative of the formula (VII-a) ;
is used in an amount of about 0.9 to 1.2 mols per mol of the 30 compound of the formula (IV). The reaction requires a higher ;
; . -8-.'.
. ~:
.','~- ' .
~1157Q9 1 temperature than in the preparation of the compounds of the formula (II-a) generally ranging from about 90 to 180C and takes a relatively long reaction time to complete such as about 8 to 30 hours. The reaction is usually carried out in a nitrogen stream in order to prevent side reactions such as oxidation and polymerization. In the case of using copper powder as the catalyst, about 5 to 15 wt~ of copper powder per weight of the compound of the formula (IV) is used at a reaction temperature of about 100 to 150C for a reaction time of about 10 to 20 hours. In the case of using copper oxide or copper ~ chloride as the catalyst, about 0.2 to 0.3 mol of copper oxide ; or copper chloride per mol of the compound of the formula (IV) is uSed at a reaction temperature of about 130 to 160C for a reaction time of about 10 to 20 hours. In both cases above, the reaction is carried out in a nitrogen gas stream.
Then, the compound of the formula (VIII-b) is oxidized ;;~ in a solvent such as acetone, dioxane, hydrous acetone, pyridine, water, hydous t-butanol, sulfuric acid and the like using an oxidizing agent such as potassium permanganate, selenium dioxide, chromic anhydride, nitric acid, potassium bichromate and the -~ like, thereby to obtain the compound of the formula (II-f).
- The oxidation conditions for this reaction are the same as those for the oxidation of the compound of the formula (VI) obtained above.
Of the compounds of the formula (VIII-b), those wherein at least one of R302 and R404 is a nitro group may be prepared under the conditions employed in the preparation of the compounds of the formula (II-a) since the reaction reagent ,~ ,. .
of the formula (VII-a) is active.
Among the compounds of the formula (II-f), those _9_ ~"
i .., . ~ , .ix,.
. ... .
, lllS7Q9 1 wherein at least one of R302 and R404 is a nitro group can be subjected to reduction using tin or stannic chloric in hydro-chloric acid or an iron powder in hydrochloric acid or catalytic reduction in an alcohol, a dioxane, a hydrous alcohol, an ammoniacal alcohol or an ammoniacal hydrous alcohol in the presence of a catalyst such as platinum oxide, palladium, Raney nickel and the like to obtain a compound represented by the formula (II-h) having at least one amino group on the phenoxy moiety: -HOOC ~ ~ ~405 ~ h) wherein R405 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group, an ~
: N-alkyl-substituted amino group, an acylamino group, an acetyl .
group or a halogen-substituted alkyl group. In the case of using stannic chloride or iron powder as the reducing agent, about 3 mols of stannic chloride or 2.5 to 5 atoms of iron ~;~ 20 powder per mol of the compound o the formula (II-f) is used ..
under acidic conditions, generally in hydrochloric acid, at a reaction temperature of room temperature (about 15C to about ~, ., ~ 30C) to about 70C for a reaction time of about 5 to 20 hours~
f~
~: In the case of catalytic reduction, the catalys~ ~such as platinum oxide, palladium, Raney nickel) is used in an amount ~: :
of about 5 to 10 wt% based on the compound of the formula (II-f) and the catalytic reduction is carried out in neutral or alkaline condition at room temperature (about 15C to about ~ 30C) and atmospheric pressure for a reaction time of about 2 " '4 ~. 30 to 5 hours.
., .
j .`~ `. --10--.''~.' ' :
~ ' '` .
,: .
-- lllS7~9 1 When the above-described catalytic reduction is carried out in an acid anhydride or a mixed solvent of an acid anhydride and an organic acid constituting the same, a compound represented by the formula (II-i) containing an acylamino substituent:
~ NHCORlo (II-i) wherein Rlo represents a lower alkyl group and R405 is the same as defined above is obtained.
The compounds of the formula (II-h) may also be easily prepared by hydrolyzing the compound of the formula (II-i) as described above with an acid or an alkali, followed by deacylation.
The compound of the formula (II-h) as obtained above i8 dissolved in an aqueous solution containing a mineral acid such as hydrochloric acid, sulfuric acid, hydrobromic acid and the ~r~
like, and sodium nitrite is added thereto under ice-cooling to - 20 form a diazonium salt of the compound (II-h). The diazotization is usually carried out in the presence of acid such as hydrochloric acid, sulfuric acid or hydrobronic acid using i sodium nitrite (NaN02) in an amount of about 1 to 1.2 mols per mol of the compound of the formula (II-h) at a reaction ~; temperature of O to 10C. The resulting diazonium salt can be chlorinated or brominated by treating with cuprous chloride hydrochloric acid or cuprous bromid/hydrobromic acid, iodinated by adding potassium iodide or fluorinated by adding fluoroboric acid and heating the resulting diazonium fluoroborate, thereby to obtain a compound represented by the formula (II-j) having ... . . .
: -.
',` --11-, ~:
, ...... .
....
::
...
,f,',' ' ~, ' ' . ' '' ` ' ~ ', ` , " ' lllS709 .
at least one halogen atom on the phenoxy moiety:
HOOC ~ ~ R406 (II~
wherein X represents a halogen atom and R406 represents a .
hydrogen atom, a halogen atom, a lower alkyl group, a lower ~ :
alkoxy group, an N-alkyl-substituted -amino group, an acylamino group, an acetyl group or a halogen-substituted alkyl group. :;
Compounds represented by the formula (II-k) having at least one hydroxy group on the phenoxy ring:
~ ~ R (II-k~
; HOO N
wherein R4 is the same as defined above, can easily be prepared ~i by dealkoxylation of the compound of the formula (II-f) in a hydrohalogenic acid under heating or by treating the diazonium alt of the compound (II-H~ with an aqueous dilute acid.
Compounds represented by the formula (VIII): -~ ~ ~VIII) wherein R3, R4 and Rg axe the same as defined above, which are intermediates for the compounds represented by the formula (II-b):
,,.~ ~;
~;~ ~ R4 (II-b) .~` HOOC N
~t wherein R3 and R4 are the same as defined above, may also be ~ obtained by the following process:
`:.. 30 ., :
.
.: . . , , ~.
.': .
.. .
,, . . , , ~ - ~ . .
1 That is, the compounds of the formula (II-b) can be prepared by reacting a compound represented by the formula (IX):
,~X ' ' :' Rg N (IX) wherein X represents a halogen atom and Rg is as defined above, with a substituted phenol represented by the ormula ~X-a):
;.
HO~ 302 .
404 (X-a) wherein R302 and R404 are the same as defined above. The reaction proceeds under the same conditions as described in the $
condensation reaction between the compound of the formula (IU) and the compound of the formula (VII-a).
The 5-substituted picolinic acids as above obtained can easily be converted to pharmaceutically acceptable salts thereof such as calcium salts, sodium salts, aluminium salts, magnesium salts and potassium salts.
This invention provides a process for preparing a .~ .
5-substituted picolinio acid ester or amide represented by the formula (III):
i~,,j ~ : , 201 ~ ORl (III) .
. ~i, , ~
wherein Rl represents a straight or branched chain halogen-substituted alkyl group having 2 to 6 carbon atoms or a substituted phenyl group represented by the formula ~ 3 ,. ,. :, ~'`' .
~lS7~9 .
1 wherein R3 and R4 are defined as above; and R201 represents a straight or branched chain or cyclic alkoxy group having 1 to -~
6 carbon atoms, an aminoalkoxy group, a phenoxy group, a sub- -stituted phenoxy group, a 5-indanyloxy group, an acyloxy- ~-: `
alkyloxy group represented by the formula -O-CHOCOR6 wherein R5 and R6 are defined as above, or an amino group represented by the formula -N \ wherein R7 and R8 are defined as above, R8 ~ :
which comprises: -(i) reacting a 5-substituted picolinic acid or a ;~
metal salt thereof represented by the formula (II-g):
~ 102 (II-g) MOOC~ N
wherein R102 represents a straight or branched chain halogen-substituted alkyl group (containing a halogen atom such as ~:
chlorine, bromine,iodine and fluorine) or a substituted phenyl : :
~ R302 . -~`
s:: group represented by the formula ~ R404 wherein R302 and ~: R404 are defined as above; and M represents a hydrogen atom or a metal atom (such as sodium, potassium, calciumj aluminium :
and magnesium), with one of an aliphatic alcohol having 1 to ~ . 6 carbon atoms, 5-indanol, phenol, substituted phenols and .~` amineslrepresented by the formula (XI):
;; / R7 --.
~ R (XI) .,. . :
.~.` 30 ~, . . .
i~ -14-'~ `', '' ' ' ' ' ., :
"~. :
1 wherein R7 and R8 are defined as above, in the presence of an acid catalyst or a condensation agent; or (ii) reacting a 5-substitute~ picolinic acid or a metal salt of the formula (II-g) with an ac~loxyalkyl halide represented by the formula (XII):
: I (XII) X--CHOCOR6 ~
wherein R5 and R6 are as deined above, and X represents a halogen atom, in the presence of a base. .
More specifically, of the compounds having the formula (III) according to the present invention, lower alkyl ~ esters such as methyl, ethyl, propyl and isobutyl esters and ;
~` the like can easily be obtained by reacting a 5-substituted picolinic acid represented by the formula (II): ~
: ~ 1 (II) ~ ~ .
. MOOC N . .
:i.l wherein Rl and M are as defined above, with the corresponding ;~ aliphatic alcohoI having 1 to 6 carbon atoms in the presence of an acid catalyst such as hydrochloric acid, sulfuric acid, p-toiuenesulfonic acid and the like at a temperature of from 40C to 100C.
5-Indanyl esters, phenyl esters and substituted phenyl esters having the formula (III) can be obtained by ~ :
reacting the 5-substituted picolinic acid f the formula (II) ~'i.`. with S-indanol, phenyl or substituted phenol (such.as p-ethylphenyl, p-methylphenol, o-methylphenol and the like), ~ ., .
.u respectively, in an organic solvent such as chlorororm, dioxane, dimethylformamide, pyridine and the like in the presence of a `.;. 30 condensation agent such as dicyclohexylcarbodiimide and the like.
;~ ." '.
~,,' , , . 15 :'~.,,'. .
'`,.'' '~ , 57Qg 1 Acyloxyalkyl esters of the 5-substituted picolinic acid such as acetoxymethyl es~ers, pivaloyloxymethyl esters, ~-pivaloyloxyethyl esters, ~-benzoyloxyethyl esters, ~-(isovaleroyloxy)ethyl esters, ~-(3,4,5-trimethoxybenzoloxy)- :
ethyl esters and the like can be prepared by reacting the 5-substituted picolinic acid of the formula (II) with an acyloxyalkyl halide represented by the formula (XII) in a solvent such as dimethylformamide, dimethyl sulfoxide and the like in the presence of a base such as pyridine, triethylamine and the like in an amount of about 1 to 1.5 mols per mol of 5-substituted picolinic acid of the formula (II). The reac-tion is performed at a temperature of from -20 to 80C for a ;
period of from 4 to 20 hours.
Alternatively, the compound of the formula ~III) can be prepared by reacting an acid halide of a 5-substituted picolinic acid represented by the formula (XIII):
~: ~ ORl .
XOC (XIII) wherein Rl is the same as defined above and X represents a halogen atom, which is obtained by reacting a 5-substituted .: picolinic acid represented by the formula ~II) with an acid . halogenating reagent,.with one of an aliphatic alcohol having 1 to 6 carbon atoms, 5-indanol, phenol, substituted phenols, . . , amines represented by the formula (XI) and acyloxyalkanols represented by the formula (XIV):
(XIV) ,`., HO--CHOCOR6 wherein R5 and R6 are the same as defined above, in the presence of a base.
, ., . .
",,, . . .
r . .
. .
' 1 5-Indanyl esters, phenyl esters and substituted phenyl esters can be obtained by reacting the acid halide of the formula (XIII) with 5-indanol, phenyl and a substituted phenol, respectively, in pyridine or in the presence of a base such as triethylamine, N,N-dimethylaniline and the like in an organic solvent such as methylene chloride, ethyl ether, -f dimethylformamide, dioxane and the like. Both reactions are conducted at a temperature ranging from -10 to 5~C for a period of from 2 to 10 hours.
The acyloxyalkyl esters may also be obtained by reacting the acid halide of the formula (XIII) with an acyloxyalkanol of the formula (XIV) in an organic solvent such as methylene chloride, chloroform, dioxane, dimethylformamide and ~ the like in the presence of a base such as triethylamine and the ; like or in pyridine. In this case, the reaction temperature ranges from -30 to 50C and the reaction time ranges from 1 to 10 hours.
~` Amide derivatives of the 5-substituted picolinic f acid can be prepared by reacting the 5-substituted picolinic 20 acid of the formula (II) with an amine of the formula (XI) in f ; an organic solvent in the presence of a condensation agent such ~-~ as dicyclohexylcarbodiimide and the like or by reacting an ' acid halide of a 5-substituted picolinic acid of the formula , .
` (XIII) with an amine of the formula (XI) in a solvent such as ~;~ methylene chloride, ethyl ether, chloroform, dioxane and the like.
~mide derivatives of the formula (III-b):
NOC ~ ORl (III-b) . y ~ -17-:' .;
.: .
lllS7~9 1 wherein Rl is as defined above and R7 and R8 may be the same or different and represent a hydrogen atom, a lower alkyl group, or a phenyl group, may also be prepared by reacting the 5-substituted picolinic ester of the formula ~ a):
~OR
~ (III-a) , wherein Rl is as defined above and R202 represents a straight, branched or cyclic alkoxy group having 1 to 6 carbon atoms, an aminoalkoxy group, a phenoxy group, a substituted phenoxy group, a 5-indanyloxy group or an acyloxyalkyloxy group-having f~ 1 5 the formula -O-CHOCOR6 wherein R5 represents a hydrogen atom or ~` a methyl group and R6 represents a lower alkyl group having 1 ;~ to 6 carbon atoms, a phenyl group or a substituted phenyl group, S with an amine of the formula (XI) with or without an appropriate solvent.
This invention also provides an anti-hypertensive composition containing, as an active ingredient, a therepeu- -~
20 tically effective amount of at least one 5-substituted picolinic ~, acid derivative having the formula (I) described above.
.;. - :, In one embodiment of this invention, this invention provides 5-indanyl ester of 5-alkoxy-picolinic acid represented by the formula (A): -.
RaO ~ _ COO ~ (A) wherein Ra represents an alkyl group having 1 to 6 carbon atoms.
The term "alkyl group having 1 to 6 carbon atoms" as 30 used herein for Ra includes straight or branched chain alkyl ~,,.,,~ .
, . . .:
~, ..
. ' ~ .
.;, .
.
i:,~^
ll~S7Q9 .
1 groups and specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
In another embodiment of this invention, this invention provides a process for preparing a 5-indanyl ester of 5-alkoxy-picolinic acid represented by the formula (A):
R O~ ~ ~ (A) wherein Ra represents an alkyl group having 1 to 6 carbon atoms;
which comprises reacting a 5-alkoxy-picolinic acid or metal salt thereof represented by the formula (B): -RaO ~
(B) N COOM
~ wherein Ra is as described above and M is a hydrogen atom or "~
a metal atom, with a 5-hydroxyindane (i.e., ~ ), in an organic solvent (such as dimethylformamide, dimethylsulfoxide and the like) in the presence of a base (such as pyridine, ~ .
triethylamine, etc.), with a suitable reaction temperature ranging ~bout 0C to about 40C and the reaction time generally ranging from about 3 to 10 hours.
Also, an additional embodiment of this invention provides a process for preparing a 5-indanyl ester of 5-alkoxy-picolinic acid represented by the formula (A):
, ~ C00 ~ (A) .~, , --1 9--: ', , ....................................................... .
11~57~9 1 wherein Ra represents an alkyl group having l to 6 carbon atoms;
which comprises reacting an acid halide of 5-alkoxy-picolinic acid represented by the formula ~C):
RaO
~ (C) ~ N "~`COX
wherein Ra is as described above and X represents a halogen atom, with 5-hydroxyindane, in an organic solvent (such as chloroform, methylene chloride, dimethylformamide, dioxane, etc.) in the presence of a base (such as pyridine, triethylamine, etc.), with a suitable reaction temperature ranging from about -10C to about 40C and the reaction time generally ranging from about 3 hours to about lO hours.
~ The above synthesis will be illustrated in greater ~
; detail by reference to the following Examples which should not ~-be considered as limiting the present invention. Unless -otherwise indicated, all percents, parts, ratios and the like are by weight.
.:
4.86 g of a potassium salt of 5-hydroxy-2-hydroxy-methylpyridine was suspended in 80 mQ of dimethylformamide, and 5.7 g of tetramethylene chloride and l g of potassium carbonate were added to the suspension, followed by sbirring at 70C for 15 hours to effect the reaction. The reaction~ ;
mixture was concentrated to dryness, and to the residue were .... .
added 150 mQ each of ethyl acetate and water to form two layers.
The ethyl acetate layer was separated and dried with anhydrous sodium sulfate, immediately followed by concentration to obtain $ .::
5.4 g of a syrup of 5-(4-chlorobutoxy)-2-hydroxymethylpyridine.
The unreacted materials were found to remain in the aqueous ,' ,~
~ layer.
., . ~ .
;, -20-:,, ~, '' ' , ~' , , 11~5709 4.1 g of the thus-obtained product was dissolved in a mixed solvent of 35 mQ of t-butanol and 12 mQ of water, and 30 mQ of an aqueous solution containing 3.5 g of potassium permanganate was added dropwise thereto for 1 hour. The reaction was further continued at a temperature of 5 to 10C for 2 hours while stirring. The reaction mixture was filtrated, and the filter cake was washed with 50 mQ of a warm 50% aqueous methanol solution (adjusted to a pH of 10 with sodium hydroxide). The filtrate and the washing were combined, the mixture was concen-trated to a volume of about 30 mQ, and the solvent distilled off. The resulting aqueous layer was adjusted to a pH of 1!5 with 5N hydrochloric acid and extracted with 50 mQ of chloroform.
The chloroform layer was dried with anhydrous sodium sulfate and concentrated to a volume of about 3 mQ. 10 mQ of ethanol was then added to the concentrate, and the mixture was allowed to stand at a low temperature, and the product crystallized.
The crystals thus-obtained were separated by filtration to obtain 3.5 g of white crystals of 5-(4-chlorobutoxy)picolinic acid.
Melting Point: 96--97C
..... .
Elemental Analysis for CloH12N3NC
~; C H N 0 CQ
~j ~ Calcd.(%): 52.29 5.23 6.1029.92 15.47 Found (%): 52.18 5.92 6.15 15.32 ~ EXAMPLE 2 ?,,''~ 4.3 g of a potassium salt of 5-hydroxy-2-hydroxy-,....
methylpyridine was suspended in 50 mQ of dimethylsulfoxide, and 4.4 g of 1,3-dichloropropane and 500 mg of potassium carbonate were added to the suspension, followed by stirring at 60C for :~ 30 10 hours to effect the reaction~ The reaction mixture was . ;, .
." j ' ~ , --21--. ~ . . . .
';~' ' :
1~15709 , . . .
t concentrated to dryness, and 100 mQ each of chloroform and water were added to the residue to form two layers. The chloroform layer was separated, dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 4.5 g of a syrup of 5-(3-chloropropoxy)-2-hydroxymethylpyridine.
The thus-obtained product was oxidized in 50 mQ of a 70% aqueous acetone with potassium permanganate in the same manner as described in Example 1 to obtain 3.7 g of white crystals of 5-(3-chloropropoxy)picolinic acid.
Melting Point: 120-121C
Elemental Analysis for C9H10O3NCQ:
C H N O CQ
:.
Calcd.t%): 50.12 4.64 6.50 22.~7 16.47 Found (%): 50.07 4.72 6.58 16.33 .
4.9 g of a potassium salt of 5-hydroxy-2-hydroxy-methylpyridine was suspended in 90 mQ of dimethylformamide, and 6.1 g of 4-bromoni~nbenzene and 0.5 g of potassium carbonate were added to the suspension, and the reaction was effected 20 at 80C for 18 hours. The reaction mixture was immediately concentrated to dryness, and 200 mQ of chloroform and 100 mQ of water were added to the residue to form two iayers. The i chloroform layer was separated, drîed with anhydrous sodium .
sulfate and immediately concentrated to obtain a crystalline ` residue. The resulting residue was recrystallized from chloroform to obtain 5.7 g of crystals of 5-(p-nitrophenoxy)-2-hydroxymethylpyridine having a melting point of 129-130C.
5 g of the thus-obtaîned product was dissolved in ` 150 mQ of acetone, and 80 mQ of an aqueous solution containing
; improvement is desired.
The inventors have already synthesized 5-alkoxy-: picolinic acids and evaluated them as anti-hypertensive agents as reported in Canadian Patent Application No. 287,913 tcorresponding to U.S. Patent No. 4,189,489~.
.,. ~
. ' .
~:`'' . .
., . . ..
~.~157~9 1 It has now been found that the compounds of the present invention exhibit anti-hypertensive activity equal or superior to 5-alkoxypicolinic acids of the Canadian Patent Application No. 287,913 and have lower toxicity than 5-alkoxypicolinic acids of the Canadian Patent Application No. 287,913 and, therefore, the compounds of the present invention are use~ul compounds for the treatment of hyper-tension.
;i SUMMARY OF THE INVENTION
; 10 It is a principal object of the present invention to provide a novel group of anti-hypertensive agents.
It is another object of the present invention to provide a novel group of anti-hypertensive agents which are less toxic than 5-alkoxypicolinic acids but equal to or superior to "
5-alkoxypicolinic acids in their anti-hypertensive activity.
Still another object of the present invention is to provide novel processes for producing these anti-hypertensive agents.
Accordingly, the present invention provides 5-` 20 substituted picolinic acid derivatives represented by theformula (I):
,i? J~ ORl R2~C ~ (I) ":. :
:; wherein Rl represents a straight or branched chain halogen-" substituted alkyl group having 2 to 6 carbon atoms or a substituted phenyl group of the formula ~ wherein R3 and R4, which may be the same or different, each represents a :"~ .
, ` .Afl . . --, 11~57~
1 hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group, an N-alkyl-substituted amino group, an acylamino group, an acetyl group, an acyloxy group, a hydroxyl group or a halogen-substituted alkyl group, or R3 and R4, when taken together, represent a polymethylene chain; and R2 represents an -OM chain wherein M
represents a hydrogen atom, a sodium atom, a potassium atom, a calcium atom, analuminium atom or a magnesium atom, a straight or branched chain or cyclic alkoxy group having l to 6 carbon atoms, an aminoalkoxy group, a phenoxy group, a 5-indanyloxy group, an acyloxyalkyloxy group having the formula -O-CHOCOR6 wherein R5 represents a hydrogen atom or a methyl group and R6 represents a lower alkyl group having l to 6 carbon atoms, a phenyl group or a substituted phenyl group, or an amino group represented by the formula -N whereLn R7 ,. R8 and R8, which may be the same or different, each represents a hydrogen atom, a lower alkyl group or a phenyl group.
DETAILED DESCRIPTION OF THE INVENTION
In the formula (I), Rl represents a straight or branched chain halogen-substituted alkyl group having 2 to 6 carbon atoms (such as a 4-chlorobutyl group, a 4-bromobutyl group, a 3-chloropropyl group, a 5,5,5-trifluoropentyl group, .
a 4,4,4-trifluorobutyl group, a 3,4-dibromobutyl group, a 5-chloro-3-methyl-pentyl group, etc.); or a substituted phenyl ... .
~ ~ R3 group having the formula ~ R wherein R3 and R4, which may be the same or diJferent, each repre~ents a hydrogen atom, a ., .
': :
lilS7~9 1 halogen atom (such as chlorine, bromine, fluorine, etc.), a lower alkyl group having 1 to 3 carbon atoms (such as a methyl group, an ethyl group, a propyl group, etc.), a lower alkoxy group having 1 to 3 carbon atoms (such as a methoxy group, an ethoxy group, a propoxy group, etc.), a nitro group, an amino group, an N-alkyl-substituted amino group wherein the alkyl moiety has 1 to 3 carbon atoms (such as a dimethylamino group, a diethylamino group, etc.), an acylamino group having 2 to 4 ; carbon atoms (such as an acetamido group, a propionylamino group, etc.), an acetyl group, an acyloxy group having 2 to 4 , carbon atoms (such as an acetoxy group, a propionyloxy group, etc.)c a hydroxy group or a halogen-substituted alkyl group having 1 to 3 carbon atoms (such as a trifluoromethyl group, etc.), or R3 and R4, when taken together, represent a poly-methylene chain having 3 to 5 carbon atoms (such as trimethylene, etc.).
R2 represents an -OM group wherein M represents a hydrogen atom, a sodium atom, a potassium atom, a calcium atom, an ~u~inium atom or a magnesium atom; a straight or branched chain or cyclic alkoxy group having 1 to 6 carbon atoms (such as a methoxy group, an ethoxy group, a propoxy group, an isobutoxy group, a cyclohexylox~ group, etc.); an aminoalkoxy ~ group having 2 to 5 carbon atoms (such as dimethylaminoethyloxy group, etc.); a phenoxy group (including a phenoxy group substituted as illustrated below for the phenyl group); a 5-indanyloxy group; an acyloxyalkyloxy group having the formula -O-CHOCOR6 wherein R5 represents a hydrogen atom or a methyl group and R6 represents a lower alkyl group having 1 to 6 ;`f~ 30 carbon atoms (such as a methyl group, an ethyl group, a propyl .,~,; ,.
~ -4-.', .
~ ' , l~lS709 1 group, an isobutyl group, a t-butyl group, etc.), a phenyl group,or a substituted phenyl group wherein the substituent includes an alkyl group having 1 to 3 carbon atoms and an alkoxy group having 1 to 3 carbon atoms (such as a p-tolyl group, a p-methoxyphenyl group, a 3,4,5-trimethoxyphenyl group, etc.);
. ~ 7 or an amino group represented by the formula -N wherein R
and R8, which may be the same or different, each represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms (such as a methyl group, an ethyl group, etc.), or a phenyl group.
Compounds represented by the formula (II-a):
I ¦l (II-a) ;HOOc~A~iN~
wherein Rlol represents a straight or branched chain halogen-substituted alkyl group having 2 to 6 carbon atoms, can be ~.
` prepared by reacting a compound represented by the formula (IV):
. ~ OH
.j R N (IV) ... ..
~ wherein Rg represents a methyl group or a hydroxymethyl group, :~: with a halide represented by the formula (V):
~`''':' ' ' "'' RlolX (V) .
wherein Rlol is as defined above and X representS a halogen atom, .~ 30 in an organic solvent such as dimethylformamide, dimethyl :" . .
': .
"~', -S-! ~ , - :
;. ~ : , 1 sulfoxide, dimethylacetamide and the like in the presence of an inorganic base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonatel sodium hydrogencarbonate and the like or an organic base such as triethylaminel N,N-dimethylaniline and the like to obtain a compound represented by the formula (VI):
~ 101 ~ ~ ' Rg N (VI) wherein R9 and Rlol are as defined above.
This substitution reaction takes place selectively at the 5-position hydroxy group, and no reaction of the -CH2OH group or by-production of pyridinium salts is observed under the conditions of the invention. The reaction easily proceeds at a temperature ranging from about 30 to 100C and is completed in a relatively short time such as about 1 to 20 -hours.
The compounds of the formula (II-a) according to this . - . .
invention can be prepared by oxidizing the intermediate of the ~ ~-formula (VIj as described above using an oxidizing agent such as : potassium permanganate, chromic anhydride, selenium dioxide, ~ nitric acid, potassium bichromate and the like in a solvent such ., ~ ~ .
~ as acetone, dioxane, pyridine, hydrous acetone, hydrous t-;, butanol, sulfuric acid and the like. Any impurities by-produced ~d ' during the reaction can easily be removed by solvent extraction, ~-precipitation, crystallization or a like operation. Reaction ;~` conditions for the oxidation vary with kind of the oxidizing ~.,...................................................................... :
~ agent used and Rg group in the compound of the formula (VI).
.~
When R9 group is hydroxymethyl group, the reaction conditions for the oxidation are generally mild. For example, when the compound ' .
~"`; -6-:
~ .
l~lS7Q9 .. .
1 of the formula (VI) having hydroxymethyl group as the Rg group is oxidized with potassium permanganate, about 1 to 2 mols of potassium permanganate per mol of the compound of the formula (VI) is used and the reaction.time and reaction temperature are about 5 to 20C and about 2 to 20 hours, respectively. In the case of oxidizing the compound of the formula (VI) having a methyl group as the Rg group with potassium permanganate,about 2 to 4 mols of potassium permanganate per mol of the compound of the formula (VI) are needed at the reaction temperature of about 80 to 100C and for the reaction time of about 4 to 10 hours. In a case of oxidizing the compound of the formula (VI) having a methyl group as the R9 group with chromic anhydride, about 2.5 to 3.5 mols of chromic anhydride per mol of the compound of the formula (VI) is used in the presence of sulfuric acid at the reaction temperature of about 30 to 70C for the reaction ~ time of about 4 to 10 hours. When selenium dioxide is used as an oxidizing agent, the oxidation reaction is carried out in the presence of pyridine in an amount of about 1.8 to 2.5 mols :~ of selenium dioxide per mol of the compound of the formula (VI) ` 20 at reaction temperature of about 100 to 120C for reaction time of about 5 to 10 hours.
.~ ~ Compounds represented by the formula (II-f?:
R
302 (II-f) .~wherein R302 and R404, which may be the same or different, each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group, . 30 an N-alkyl-substituted amino group, an acylamino group, an ,--7--.
.
i:
ll~S7Q9 .
1 acetyl group, or a halogen-subs-tituted alkyl group, or R302 and R404, when taken together, represent a polymethylene chain can ~ :
be obtained by reacting the compound of the formula (IV) or a metal salt thereof such as a potassium salt,a sodium salt, etc., with a substituted halobenzene derivative represented by the ~.
formula (VII-a): ~
X ~ R302 ~ :
~ R404 (VII-a) wherein R302 and R404 are as defined above and X is a halogen :.
atom, in an organic solvent such as dimethylformamide, dim~thlyacetamide, pyridine,collidine and the like preferably in the presence of a catalyst such as a copper powder, copper oxide, copper chloride and the like to obtain a compound represented by the formula (VIII-b):
Rg~ R404 (VIIl-b) : wherein Rg, R302 and R404 are as defined above. Of the compounds of the formula (VII-a), those wherein at least one of R302 and ~.
~ R404 isa nitro group and the nitro group is positioned at ortho- or para-position of the halogen X may be prepared under mild conditions such as at a reaction temperature of about `
S0 to 100C in a reaction time of about 10 to 15 hours without catalyst.
. The halobenzene derivative of the formula (VII-a) ;
is used in an amount of about 0.9 to 1.2 mols per mol of the 30 compound of the formula (IV). The reaction requires a higher ;
; . -8-.'.
. ~:
.','~- ' .
~1157Q9 1 temperature than in the preparation of the compounds of the formula (II-a) generally ranging from about 90 to 180C and takes a relatively long reaction time to complete such as about 8 to 30 hours. The reaction is usually carried out in a nitrogen stream in order to prevent side reactions such as oxidation and polymerization. In the case of using copper powder as the catalyst, about 5 to 15 wt~ of copper powder per weight of the compound of the formula (IV) is used at a reaction temperature of about 100 to 150C for a reaction time of about 10 to 20 hours. In the case of using copper oxide or copper ~ chloride as the catalyst, about 0.2 to 0.3 mol of copper oxide ; or copper chloride per mol of the compound of the formula (IV) is uSed at a reaction temperature of about 130 to 160C for a reaction time of about 10 to 20 hours. In both cases above, the reaction is carried out in a nitrogen gas stream.
Then, the compound of the formula (VIII-b) is oxidized ;;~ in a solvent such as acetone, dioxane, hydrous acetone, pyridine, water, hydous t-butanol, sulfuric acid and the like using an oxidizing agent such as potassium permanganate, selenium dioxide, chromic anhydride, nitric acid, potassium bichromate and the -~ like, thereby to obtain the compound of the formula (II-f).
- The oxidation conditions for this reaction are the same as those for the oxidation of the compound of the formula (VI) obtained above.
Of the compounds of the formula (VIII-b), those wherein at least one of R302 and R404 is a nitro group may be prepared under the conditions employed in the preparation of the compounds of the formula (II-a) since the reaction reagent ,~ ,. .
of the formula (VII-a) is active.
Among the compounds of the formula (II-f), those _9_ ~"
i .., . ~ , .ix,.
. ... .
, lllS7Q9 1 wherein at least one of R302 and R404 is a nitro group can be subjected to reduction using tin or stannic chloric in hydro-chloric acid or an iron powder in hydrochloric acid or catalytic reduction in an alcohol, a dioxane, a hydrous alcohol, an ammoniacal alcohol or an ammoniacal hydrous alcohol in the presence of a catalyst such as platinum oxide, palladium, Raney nickel and the like to obtain a compound represented by the formula (II-h) having at least one amino group on the phenoxy moiety: -HOOC ~ ~ ~405 ~ h) wherein R405 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group, an ~
: N-alkyl-substituted amino group, an acylamino group, an acetyl .
group or a halogen-substituted alkyl group. In the case of using stannic chloride or iron powder as the reducing agent, about 3 mols of stannic chloride or 2.5 to 5 atoms of iron ~;~ 20 powder per mol of the compound o the formula (II-f) is used ..
under acidic conditions, generally in hydrochloric acid, at a reaction temperature of room temperature (about 15C to about ~, ., ~ 30C) to about 70C for a reaction time of about 5 to 20 hours~
f~
~: In the case of catalytic reduction, the catalys~ ~such as platinum oxide, palladium, Raney nickel) is used in an amount ~: :
of about 5 to 10 wt% based on the compound of the formula (II-f) and the catalytic reduction is carried out in neutral or alkaline condition at room temperature (about 15C to about ~ 30C) and atmospheric pressure for a reaction time of about 2 " '4 ~. 30 to 5 hours.
., .
j .`~ `. --10--.''~.' ' :
~ ' '` .
,: .
-- lllS7~9 1 When the above-described catalytic reduction is carried out in an acid anhydride or a mixed solvent of an acid anhydride and an organic acid constituting the same, a compound represented by the formula (II-i) containing an acylamino substituent:
~ NHCORlo (II-i) wherein Rlo represents a lower alkyl group and R405 is the same as defined above is obtained.
The compounds of the formula (II-h) may also be easily prepared by hydrolyzing the compound of the formula (II-i) as described above with an acid or an alkali, followed by deacylation.
The compound of the formula (II-h) as obtained above i8 dissolved in an aqueous solution containing a mineral acid such as hydrochloric acid, sulfuric acid, hydrobromic acid and the ~r~
like, and sodium nitrite is added thereto under ice-cooling to - 20 form a diazonium salt of the compound (II-h). The diazotization is usually carried out in the presence of acid such as hydrochloric acid, sulfuric acid or hydrobronic acid using i sodium nitrite (NaN02) in an amount of about 1 to 1.2 mols per mol of the compound of the formula (II-h) at a reaction ~; temperature of O to 10C. The resulting diazonium salt can be chlorinated or brominated by treating with cuprous chloride hydrochloric acid or cuprous bromid/hydrobromic acid, iodinated by adding potassium iodide or fluorinated by adding fluoroboric acid and heating the resulting diazonium fluoroborate, thereby to obtain a compound represented by the formula (II-j) having ... . . .
: -.
',` --11-, ~:
, ...... .
....
::
...
,f,',' ' ~, ' ' . ' '' ` ' ~ ', ` , " ' lllS709 .
at least one halogen atom on the phenoxy moiety:
HOOC ~ ~ R406 (II~
wherein X represents a halogen atom and R406 represents a .
hydrogen atom, a halogen atom, a lower alkyl group, a lower ~ :
alkoxy group, an N-alkyl-substituted -amino group, an acylamino group, an acetyl group or a halogen-substituted alkyl group. :;
Compounds represented by the formula (II-k) having at least one hydroxy group on the phenoxy ring:
~ ~ R (II-k~
; HOO N
wherein R4 is the same as defined above, can easily be prepared ~i by dealkoxylation of the compound of the formula (II-f) in a hydrohalogenic acid under heating or by treating the diazonium alt of the compound (II-H~ with an aqueous dilute acid.
Compounds represented by the formula (VIII): -~ ~ ~VIII) wherein R3, R4 and Rg axe the same as defined above, which are intermediates for the compounds represented by the formula (II-b):
,,.~ ~;
~;~ ~ R4 (II-b) .~` HOOC N
~t wherein R3 and R4 are the same as defined above, may also be ~ obtained by the following process:
`:.. 30 ., :
.
.: . . , , ~.
.': .
.. .
,, . . , , ~ - ~ . .
1 That is, the compounds of the formula (II-b) can be prepared by reacting a compound represented by the formula (IX):
,~X ' ' :' Rg N (IX) wherein X represents a halogen atom and Rg is as defined above, with a substituted phenol represented by the ormula ~X-a):
;.
HO~ 302 .
404 (X-a) wherein R302 and R404 are the same as defined above. The reaction proceeds under the same conditions as described in the $
condensation reaction between the compound of the formula (IU) and the compound of the formula (VII-a).
The 5-substituted picolinic acids as above obtained can easily be converted to pharmaceutically acceptable salts thereof such as calcium salts, sodium salts, aluminium salts, magnesium salts and potassium salts.
This invention provides a process for preparing a .~ .
5-substituted picolinio acid ester or amide represented by the formula (III):
i~,,j ~ : , 201 ~ ORl (III) .
. ~i, , ~
wherein Rl represents a straight or branched chain halogen-substituted alkyl group having 2 to 6 carbon atoms or a substituted phenyl group represented by the formula ~ 3 ,. ,. :, ~'`' .
~lS7~9 .
1 wherein R3 and R4 are defined as above; and R201 represents a straight or branched chain or cyclic alkoxy group having 1 to -~
6 carbon atoms, an aminoalkoxy group, a phenoxy group, a sub- -stituted phenoxy group, a 5-indanyloxy group, an acyloxy- ~-: `
alkyloxy group represented by the formula -O-CHOCOR6 wherein R5 and R6 are defined as above, or an amino group represented by the formula -N \ wherein R7 and R8 are defined as above, R8 ~ :
which comprises: -(i) reacting a 5-substituted picolinic acid or a ;~
metal salt thereof represented by the formula (II-g):
~ 102 (II-g) MOOC~ N
wherein R102 represents a straight or branched chain halogen-substituted alkyl group (containing a halogen atom such as ~:
chlorine, bromine,iodine and fluorine) or a substituted phenyl : :
~ R302 . -~`
s:: group represented by the formula ~ R404 wherein R302 and ~: R404 are defined as above; and M represents a hydrogen atom or a metal atom (such as sodium, potassium, calciumj aluminium :
and magnesium), with one of an aliphatic alcohol having 1 to ~ . 6 carbon atoms, 5-indanol, phenol, substituted phenols and .~` amineslrepresented by the formula (XI):
;; / R7 --.
~ R (XI) .,. . :
.~.` 30 ~, . . .
i~ -14-'~ `', '' ' ' ' ' ., :
"~. :
1 wherein R7 and R8 are defined as above, in the presence of an acid catalyst or a condensation agent; or (ii) reacting a 5-substitute~ picolinic acid or a metal salt of the formula (II-g) with an ac~loxyalkyl halide represented by the formula (XII):
: I (XII) X--CHOCOR6 ~
wherein R5 and R6 are as deined above, and X represents a halogen atom, in the presence of a base. .
More specifically, of the compounds having the formula (III) according to the present invention, lower alkyl ~ esters such as methyl, ethyl, propyl and isobutyl esters and ;
~` the like can easily be obtained by reacting a 5-substituted picolinic acid represented by the formula (II): ~
: ~ 1 (II) ~ ~ .
. MOOC N . .
:i.l wherein Rl and M are as defined above, with the corresponding ;~ aliphatic alcohoI having 1 to 6 carbon atoms in the presence of an acid catalyst such as hydrochloric acid, sulfuric acid, p-toiuenesulfonic acid and the like at a temperature of from 40C to 100C.
5-Indanyl esters, phenyl esters and substituted phenyl esters having the formula (III) can be obtained by ~ :
reacting the 5-substituted picolinic acid f the formula (II) ~'i.`. with S-indanol, phenyl or substituted phenol (such.as p-ethylphenyl, p-methylphenol, o-methylphenol and the like), ~ ., .
.u respectively, in an organic solvent such as chlorororm, dioxane, dimethylformamide, pyridine and the like in the presence of a `.;. 30 condensation agent such as dicyclohexylcarbodiimide and the like.
;~ ." '.
~,,' , , . 15 :'~.,,'. .
'`,.'' '~ , 57Qg 1 Acyloxyalkyl esters of the 5-substituted picolinic acid such as acetoxymethyl es~ers, pivaloyloxymethyl esters, ~-pivaloyloxyethyl esters, ~-benzoyloxyethyl esters, ~-(isovaleroyloxy)ethyl esters, ~-(3,4,5-trimethoxybenzoloxy)- :
ethyl esters and the like can be prepared by reacting the 5-substituted picolinic acid of the formula (II) with an acyloxyalkyl halide represented by the formula (XII) in a solvent such as dimethylformamide, dimethyl sulfoxide and the like in the presence of a base such as pyridine, triethylamine and the like in an amount of about 1 to 1.5 mols per mol of 5-substituted picolinic acid of the formula (II). The reac-tion is performed at a temperature of from -20 to 80C for a ;
period of from 4 to 20 hours.
Alternatively, the compound of the formula ~III) can be prepared by reacting an acid halide of a 5-substituted picolinic acid represented by the formula (XIII):
~: ~ ORl .
XOC (XIII) wherein Rl is the same as defined above and X represents a halogen atom, which is obtained by reacting a 5-substituted .: picolinic acid represented by the formula ~II) with an acid . halogenating reagent,.with one of an aliphatic alcohol having 1 to 6 carbon atoms, 5-indanol, phenol, substituted phenols, . . , amines represented by the formula (XI) and acyloxyalkanols represented by the formula (XIV):
(XIV) ,`., HO--CHOCOR6 wherein R5 and R6 are the same as defined above, in the presence of a base.
, ., . .
",,, . . .
r . .
. .
' 1 5-Indanyl esters, phenyl esters and substituted phenyl esters can be obtained by reacting the acid halide of the formula (XIII) with 5-indanol, phenyl and a substituted phenol, respectively, in pyridine or in the presence of a base such as triethylamine, N,N-dimethylaniline and the like in an organic solvent such as methylene chloride, ethyl ether, -f dimethylformamide, dioxane and the like. Both reactions are conducted at a temperature ranging from -10 to 5~C for a period of from 2 to 10 hours.
The acyloxyalkyl esters may also be obtained by reacting the acid halide of the formula (XIII) with an acyloxyalkanol of the formula (XIV) in an organic solvent such as methylene chloride, chloroform, dioxane, dimethylformamide and ~ the like in the presence of a base such as triethylamine and the ; like or in pyridine. In this case, the reaction temperature ranges from -30 to 50C and the reaction time ranges from 1 to 10 hours.
~` Amide derivatives of the 5-substituted picolinic f acid can be prepared by reacting the 5-substituted picolinic 20 acid of the formula (II) with an amine of the formula (XI) in f ; an organic solvent in the presence of a condensation agent such ~-~ as dicyclohexylcarbodiimide and the like or by reacting an ' acid halide of a 5-substituted picolinic acid of the formula , .
` (XIII) with an amine of the formula (XI) in a solvent such as ~;~ methylene chloride, ethyl ether, chloroform, dioxane and the like.
~mide derivatives of the formula (III-b):
NOC ~ ORl (III-b) . y ~ -17-:' .;
.: .
lllS7~9 1 wherein Rl is as defined above and R7 and R8 may be the same or different and represent a hydrogen atom, a lower alkyl group, or a phenyl group, may also be prepared by reacting the 5-substituted picolinic ester of the formula ~ a):
~OR
~ (III-a) , wherein Rl is as defined above and R202 represents a straight, branched or cyclic alkoxy group having 1 to 6 carbon atoms, an aminoalkoxy group, a phenoxy group, a substituted phenoxy group, a 5-indanyloxy group or an acyloxyalkyloxy group-having f~ 1 5 the formula -O-CHOCOR6 wherein R5 represents a hydrogen atom or ~` a methyl group and R6 represents a lower alkyl group having 1 ;~ to 6 carbon atoms, a phenyl group or a substituted phenyl group, S with an amine of the formula (XI) with or without an appropriate solvent.
This invention also provides an anti-hypertensive composition containing, as an active ingredient, a therepeu- -~
20 tically effective amount of at least one 5-substituted picolinic ~, acid derivative having the formula (I) described above.
.;. - :, In one embodiment of this invention, this invention provides 5-indanyl ester of 5-alkoxy-picolinic acid represented by the formula (A): -.
RaO ~ _ COO ~ (A) wherein Ra represents an alkyl group having 1 to 6 carbon atoms.
The term "alkyl group having 1 to 6 carbon atoms" as 30 used herein for Ra includes straight or branched chain alkyl ~,,.,,~ .
, . . .:
~, ..
. ' ~ .
.;, .
.
i:,~^
ll~S7Q9 .
1 groups and specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
In another embodiment of this invention, this invention provides a process for preparing a 5-indanyl ester of 5-alkoxy-picolinic acid represented by the formula (A):
R O~ ~ ~ (A) wherein Ra represents an alkyl group having 1 to 6 carbon atoms;
which comprises reacting a 5-alkoxy-picolinic acid or metal salt thereof represented by the formula (B): -RaO ~
(B) N COOM
~ wherein Ra is as described above and M is a hydrogen atom or "~
a metal atom, with a 5-hydroxyindane (i.e., ~ ), in an organic solvent (such as dimethylformamide, dimethylsulfoxide and the like) in the presence of a base (such as pyridine, ~ .
triethylamine, etc.), with a suitable reaction temperature ranging ~bout 0C to about 40C and the reaction time generally ranging from about 3 to 10 hours.
Also, an additional embodiment of this invention provides a process for preparing a 5-indanyl ester of 5-alkoxy-picolinic acid represented by the formula (A):
, ~ C00 ~ (A) .~, , --1 9--: ', , ....................................................... .
11~57~9 1 wherein Ra represents an alkyl group having l to 6 carbon atoms;
which comprises reacting an acid halide of 5-alkoxy-picolinic acid represented by the formula ~C):
RaO
~ (C) ~ N "~`COX
wherein Ra is as described above and X represents a halogen atom, with 5-hydroxyindane, in an organic solvent (such as chloroform, methylene chloride, dimethylformamide, dioxane, etc.) in the presence of a base (such as pyridine, triethylamine, etc.), with a suitable reaction temperature ranging from about -10C to about 40C and the reaction time generally ranging from about 3 hours to about lO hours.
~ The above synthesis will be illustrated in greater ~
; detail by reference to the following Examples which should not ~-be considered as limiting the present invention. Unless -otherwise indicated, all percents, parts, ratios and the like are by weight.
.:
4.86 g of a potassium salt of 5-hydroxy-2-hydroxy-methylpyridine was suspended in 80 mQ of dimethylformamide, and 5.7 g of tetramethylene chloride and l g of potassium carbonate were added to the suspension, followed by sbirring at 70C for 15 hours to effect the reaction. The reaction~ ;
mixture was concentrated to dryness, and to the residue were .... .
added 150 mQ each of ethyl acetate and water to form two layers.
The ethyl acetate layer was separated and dried with anhydrous sodium sulfate, immediately followed by concentration to obtain $ .::
5.4 g of a syrup of 5-(4-chlorobutoxy)-2-hydroxymethylpyridine.
The unreacted materials were found to remain in the aqueous ,' ,~
~ layer.
., . ~ .
;, -20-:,, ~, '' ' , ~' , , 11~5709 4.1 g of the thus-obtained product was dissolved in a mixed solvent of 35 mQ of t-butanol and 12 mQ of water, and 30 mQ of an aqueous solution containing 3.5 g of potassium permanganate was added dropwise thereto for 1 hour. The reaction was further continued at a temperature of 5 to 10C for 2 hours while stirring. The reaction mixture was filtrated, and the filter cake was washed with 50 mQ of a warm 50% aqueous methanol solution (adjusted to a pH of 10 with sodium hydroxide). The filtrate and the washing were combined, the mixture was concen-trated to a volume of about 30 mQ, and the solvent distilled off. The resulting aqueous layer was adjusted to a pH of 1!5 with 5N hydrochloric acid and extracted with 50 mQ of chloroform.
The chloroform layer was dried with anhydrous sodium sulfate and concentrated to a volume of about 3 mQ. 10 mQ of ethanol was then added to the concentrate, and the mixture was allowed to stand at a low temperature, and the product crystallized.
The crystals thus-obtained were separated by filtration to obtain 3.5 g of white crystals of 5-(4-chlorobutoxy)picolinic acid.
Melting Point: 96--97C
..... .
Elemental Analysis for CloH12N3NC
~; C H N 0 CQ
~j ~ Calcd.(%): 52.29 5.23 6.1029.92 15.47 Found (%): 52.18 5.92 6.15 15.32 ~ EXAMPLE 2 ?,,''~ 4.3 g of a potassium salt of 5-hydroxy-2-hydroxy-,....
methylpyridine was suspended in 50 mQ of dimethylsulfoxide, and 4.4 g of 1,3-dichloropropane and 500 mg of potassium carbonate were added to the suspension, followed by stirring at 60C for :~ 30 10 hours to effect the reaction~ The reaction mixture was . ;, .
." j ' ~ , --21--. ~ . . . .
';~' ' :
1~15709 , . . .
t concentrated to dryness, and 100 mQ each of chloroform and water were added to the residue to form two layers. The chloroform layer was separated, dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 4.5 g of a syrup of 5-(3-chloropropoxy)-2-hydroxymethylpyridine.
The thus-obtained product was oxidized in 50 mQ of a 70% aqueous acetone with potassium permanganate in the same manner as described in Example 1 to obtain 3.7 g of white crystals of 5-(3-chloropropoxy)picolinic acid.
Melting Point: 120-121C
Elemental Analysis for C9H10O3NCQ:
C H N O CQ
:.
Calcd.t%): 50.12 4.64 6.50 22.~7 16.47 Found (%): 50.07 4.72 6.58 16.33 .
4.9 g of a potassium salt of 5-hydroxy-2-hydroxy-methylpyridine was suspended in 90 mQ of dimethylformamide, and 6.1 g of 4-bromoni~nbenzene and 0.5 g of potassium carbonate were added to the suspension, and the reaction was effected 20 at 80C for 18 hours. The reaction mixture was immediately concentrated to dryness, and 200 mQ of chloroform and 100 mQ of water were added to the residue to form two iayers. The i chloroform layer was separated, drîed with anhydrous sodium .
sulfate and immediately concentrated to obtain a crystalline ` residue. The resulting residue was recrystallized from chloroform to obtain 5.7 g of crystals of 5-(p-nitrophenoxy)-2-hydroxymethylpyridine having a melting point of 129-130C.
5 g of the thus-obtaîned product was dissolved in ` 150 mQ of acetone, and 80 mQ of an aqueous solution containing
3.8 g of potassium permanganate was added dropwise to the .,;
:, .
., 1~15709 1 solution over a 1 hour period. The reaction was further continued at room temperature for 3 hours, and the reaction mixture was filtered. The filter cake was washed with 80 mQ of a warm 50% aqueous methanol (adjusted to a pH of 10 with sodium hydroxide). The filtrate and the washing were combined, concentrated to a volume of about 40 mQ, adjusted to a pH of 1.5 with 5N hydrochloric acid and extracted wi~h 100 mQ of chloroform. The extract was dried with anhydrous sodium sulfate, concentrated to a volume of about 30 mQ and allowed to stand at a low temperature to crystallize the product. The thus-formed crystals were separated by filtration to obtain
:, .
., 1~15709 1 solution over a 1 hour period. The reaction was further continued at room temperature for 3 hours, and the reaction mixture was filtered. The filter cake was washed with 80 mQ of a warm 50% aqueous methanol (adjusted to a pH of 10 with sodium hydroxide). The filtrate and the washing were combined, concentrated to a volume of about 40 mQ, adjusted to a pH of 1.5 with 5N hydrochloric acid and extracted wi~h 100 mQ of chloroform. The extract was dried with anhydrous sodium sulfate, concentrated to a volume of about 30 mQ and allowed to stand at a low temperature to crystallize the product. The thus-formed crystals were separated by filtration to obtain
4.2 g of crystals of 5-(p-nitrophenyl)picolinic acid.-Melting Point: 188-189C
s Elemental Analysis for C12H8O5N2:
C H N O
, Calcd.(~): 55.38 3.08 10.77 30.77 Found (%~: 55.47 3.12 10.68 7.35 g of a potassium salt of 5-hydroxy-2-methyl-pyridine was suspended in 20 mQ of dimethylformamide, and 9.6 g of bromochlorobenzene and 800 mg of a copper powder were added to the suspension. The reaction was effected at a temperature of 120C for a period of 18 hours in a nitrogen stream while stirring. After allowing the reaction mixture to
s Elemental Analysis for C12H8O5N2:
C H N O
, Calcd.(~): 55.38 3.08 10.77 30.77 Found (%~: 55.47 3.12 10.68 7.35 g of a potassium salt of 5-hydroxy-2-methyl-pyridine was suspended in 20 mQ of dimethylformamide, and 9.6 g of bromochlorobenzene and 800 mg of a copper powder were added to the suspension. The reaction was effected at a temperature of 120C for a period of 18 hours in a nitrogen stream while stirring. After allowing the reaction mixture to
5 `;
i cool, the reaction mixture was diluted with 50 mQ of methanol and then filtered. The filtrate was immediately concentrated ; to dryness, and 200 mQ of chloroform and loO mQ of water were .:
1~ added to the dried material, and the mixture adjusted to a pH j ~`~' ~ !, of g with 5N sodium hydroxide. The insoluble matter was again , " i h,~' 30 separated by filtration. The resulting chloroform layer was . ~ , .
.
:
, ~ '' - :`, : .~' ,.
1:1157Q9 1 dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 8.2 g of oily 5-(p-chlorophenoxy)-2-methylpyridine. Gas chromatoyraphy revealed that the thus-obtained product contained no 5-(p-bromophenoxy)-2-methylpyridine.
4.7 g of the above product was dissolved in 25 mQ of pyridine, and 4.5 g of selenium dioxide was added to the solution, followed by stirring at 120C for 12 hours to effect oxidation. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The concentrate was dissolved in 200 mQ of chloroform and then washed successively with 100 mQ of an aqueous hydrochloric acid solution at pH 2 and 50 mQ of water. The chloroform layer was dried with anhydrous sodium sulfate and immediately concentrated to crystallize the product, which were then recrystallized from ethanol to obtain 4.2 g of crystals of 5-~p--chlorophenoxy)picolinlc acid.
Melting Point: 158-159.5C
Elemental Analysis for C12H8O3NCQ:
C H N O CQ
Calcd.(~): 57.72 3.21 5.61 19.24 14.23 Found (%): 57.63 3.26 5.53 14.19 ., .
2.0 g of the 5-(p-chlorophenox~)-2-methylpyridine as obtaîned in Example 4 was suspended in 60 mQ of water, and a 1.53 g portion of potassium permanganate was added four times to the suspension while stirring at 100C over a 10 hour period to effect oxidation. The reaction mixture was filtered, and the filter cake washed with 30 mQ of warm water. The filtrate and the washin~ were combined, adjusted to a pH of 9.5 with 5N
. ~ .
sodium hydroxide and washed with 30 mQ of chloroform. The aqueous layer was adjusted to a pH of 1.5 with a 5N aqueous , ` ~ .
;;, -:' , '~
11157~19 hydrochloric acid solution, extracted with 50 m~ of chloroform.The chloroform layer was worked up in the same manner as described in Example 4 to obtain 1.2 g of crystals of 5-~p-chlorophenoxy)picolinic acid.
7.4 g of a potassium salt of 5-hydroxy-2-methyl-pyridine, 8.5 g of p-bromotoluene and 500 mg of a copper powder were suspended in 25 mQ of dimethylformamide, and the mixture was allowed to react in a nitrogen gas stream at 130C
for 14 hours under stirring. The reaction mixture was dlluted with 70 mQ of methanol and filtered. The filtrate was immediately concentrated, and to the residue was added 150 mQ
of chloroform. The mixture was washed with 100 mQ of a O.OlN
aqueous sodium hydroxide solution, whereby the unreacted 5-hydroxy-2-methylpyridine shifted to the aqueous layer. The ; chloroform layer was washed with water, dried with anhydrous sodium sulfate and immediately dried to obtain 8.9 g of oily ~-5-(p-methylphenoxy)-2-methylpyridine.
4 g of the thus-obtained product was dissolved in ~o 20 mQ of pyridine, and 4.3 g of selenium dioxide was added , .
;~ thereto, followed by stirring at 120C for lS hours to effect Xj oxidation. The reaction mixture was worked up in the same manner as described in Example 4 to obtain 3.1 g of crystals of 5-(p-methylphènoxy)picolinic acid.
~ ~ Melting Point: 165-166C --`' Elemental AnalySiS for C13HllO3N:
;~ C H N O
, ~ .
"t' Calcd.(~): 68.12 4.80 6.11 20.96 , . , Found (%): 68.17 4.72 6.19 ., ., , .~ - .
', :
. .
' . ' : . ~.' ': .
s7Q9 2.84 g of a potassium salt of 5-hydroxy-2-methyl-pyridine, 4.7 g of p-dibromobenzene and 400 mg of cuprous oxide were suspended in 10 m of dimethylacetamide, and the ;~
mixture was allowed to react in a nitrogen gas stream at 150C
for 15 hours. The reaction mixture was diluted with 30 mQ of methanol and then filtered. The filtrate was immediately dried, and the residue was taken into 100 mQ of chloroform and washed successively with a 3% aqueous sodium carbonate solution ~ 10 and 50 mQ of water. The chloroform layer was dried with ; anhydrous sodium sulfate and immediately concentrated to dryness to obtain 2.1 g of oily 5-(p-bromophenoxy)-2-methyl-; pyridine.
2.0 g of the thus-obtained product-was then subjected to oxidation in pyridine with selenium dioxide in the same manner as described in Example 6 to obtain 1.4 g of crystals of 5-!~
(p-bromophenoxy)picolinic acid.
;, Melting Point: 139-141C ;
~ Elemental Analysis for C12H803NBr:
,' 20 C H N 0 Br Calcd.(%): 49.00 2.72 4.76 16.33 27.19 , ~ .
Found (%): 49.13 2.64 4.81 26.83 ... ~
2.2 g of the 5-(p-nitrophenoxy)picolinic acid as obtained in Example 3 was added to a solution of 6.1 g of stannous chloride in 16.2 mQ of concentrated hydrochloric acid ~' cooled at 5C, followed by stirring at room temperature for 16 hours. The resulting crystalline precipitate was separated by filtration and dissolved in 12 mQ of warm water. To the . ~
~ 30 immediately solidified crystals was added 12 mQ of water, and ~''.'`'' ' . '.
.
-~
.: . , :.
11157~9 1 the resulting suspension was filtered. The resulting crude crystals were washed with 25 mQ of water, recrys~allized from 75 mQ of a mixed solvent system of concentrated hydrochloric acid/ethanol (3:5 by volume), washed with 15 mQ of ethanol and dried under reduced pressure to obtain 1.0 g of colorless crystals of 5-(p-aminophenoxy)picolinic acid dihydrochloride.
Melting Point: 221-230C (decomposition) Elemental Analysis for C12Hl N O 2HCQ:
C H N O CQ
; 10 Calcd.(~): 47.52 3.96 9.2415.84 23.43 Found (%): 47.61 3.72 9.36 23.40 1.4 g of the 5~(p-aminophenoxy)picolinic acid dihydrochloride as obtained in Example 8 was suspended in 22 mQ
of concentrated hydrochloric acid, and 3 mQ of an aqueous solution containing 828 mg of sodium nitrite was added dropwise ~ to the suspension over a period of 1 hour under ice-cooling.
;~ 5.4 mQ of an aqueous solution containing 760 mg of sodium metabisulfite and 480 mg of sodium hydroxide was added to 11 mQ of a warm aqueous solution containing 3.4 g of copper sulfate pentahydrate and 2.9 g of sodium chloride to prepare a ' cuprous chloride solution. The cuprous chloride solution was added to the diazonium salt solution as above obtained to form ~i a solution, and 15 mQ of concentrated hydrochloric acid was ~hen added to the resulting solution, followed by stirring at 10C for 2 hours and then at room temperature for 16 hours to effect the reaction. The reaction mixture was diluted with 50 mQ of water, adjusted to a pH of 1.5 with 5N sodium hydroxide and extracted with 100 mQ of chloroform. The extract was dried with anhydrous sodium sulfate, concentrated to a volume of about '':' ' .'~ .
~i~S7Q9 . .
1 10 m~ and allowed to stand at 3C to form crystals, which were then separated by filtration to obtain 0.91 g of crystals of 5-(p-chlorophenoxy)picolinic acid.
3.68 g of a potassium salt of 5-hydroxy-2-methyl-pyridine was suspended in 10 mQ of dimethylformamide, and 5.65 g of m-bromobenzotrifluoride and 300 mg of copper powders were added to the suspension, followed by allowing the mixture to react in a nitrogen stream at 120C for 15 hours while -~
; 10 stirring. After cooling, the reaction mixture was diluted with ,.~
40 m~ of acetone and filtered. The filtrate was im~ediately ,, :
dried to solidify, and 100 mQ of chloroform and 50 mQ of water were added thereto. The mlxture was adjusted to a pH of 9 with 5N sodium hydroxide, and any insoluble matter was again ,~ separated by filtration. The resulting chloroform layer was ;~ dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 4.1 g of oily 5-(m-trifluoromethylphenoxy)-2-methylpyridine.
The thus-obtained product was subjected to oxidation in pyridine using selenlum dioxide in the same manner as described in Example 4. The product was crystallized from 20 :',`1 ~
~- mQ of ethyl acetate to obtain 2.7 g o crystals of 5-(m-trifluoromethylphenoxy)picolinic acid.
Melting Point: 151-152C
Elemental Analysis for C13H803NF3:
~ C H N
; Calcd.(~):55.12 2.83 4.95 Found (%):53.68 2.72 4.79 ~'."
`~ 30 3 g of a potassium salt of 5-hydroxy-2-methylpyridine, : ~ .
.
, ..
:~"''.', `
. .
.
,; .
. . .. :. ::
~1~57Q9 .
1 3.83 g of m-bromochlorobenzene and 200 mg of a copper powder were suspended in 8 mQ of dimethylformamide, followed by allowing the mixture to react in a nitrogen gas stream at 130C
for 13 hours while stirring. The reaction mixture was diluted with 40 mQ of ethanol and filtered. The filtrate was immediately concentrated, and 80 mQ of chloroform was added to the residue.
The mixture was washed with a O.OlN aqueous sodium hydroxide solution. The chloroform layer was washed with water, dried with anhydouus sodium sulfate and dried to solidify to obtain 2.96 g of oily 5-(m-chlorophenoxy)-2-methylpyridine.
The thus, obtained product was subjected to oxidation A, '"t:~
using potassium permanganate in the same manner as described in Example 5 to obtain 1.43 g of crystals of 5-(m-chlorophenoxy)-/ picolinic acid.
; Melting Point: 138-139C
. j . .
Elemental Analy~is for C12H8O3NCQ:
C H N CQ
-~ Calcd.t%): 57.72 3.21 5.61 14.23 Found (~): 57.58 3.29 5.38 13.82 ,~ 2Q EXAMPLE 12 ;~ 4 g of a potassium salt of 5-hydroxy-2-methyl-pyridine was suspended in 10 mQ of dimethylacetamide, and 5.1 g of p-methOxybromobenzene and 450 mg of a copper powder were added to the suspension, followed by allowing the mixture to ~; react in a nitrogen stream at 140C for 14 hours. The reaction mixture was diluted with 50 mQ of methanol and filtered, and the filtrate was immediately dried to a solid. 100 mQ of ethyl -acetate was added to the résidue, and the mixture was washed ~` with 50 mQ of an aqueous sodium hydroxide solution at pH 9.
The ethyl acetate layer was washed with water, dried with ~`'`~,', ' .
.. ~
j,,.
. ~,, .
:-." . . ,; , ~ .
11~;57Q9 1 anhydrous sodium sulfate and immediately dried to obtain 3.9 g of oily 5-(p-methoxyphenoxy)-2-methylpyridine.
The thus-obtained product was subjected to oxidation in pyridine with selenium dioxide in the same manner as described in Example 4 to obtain 1.8 g of crystals of 5-(p-methoxyphenoxy)picolinic acid.
Melting Point: 170 172C
Elemental Analysis for C13HllO4N:
C H N ~ -Calcd.(%): 63.67 4.49 5.71 Found (~): 63.25 4.62 5.76 , 4 g of a potassium salt of 5-hydroxy-2-methylpyridine, ;i 5.2 g of o-bromochlorobenzene and 250 mg of a copper powder were suspended i~ 10 mQ of dimethylformamide, and tbe mixture was allowed to react in a nitrogen gas stream at 115C for 23 " hours under stirring. The reaction mixture was diluted with ~; 70 mQ of methanol and filtered. The filtrate was dried to a L
solid, and 120 mQ of chloroform was added to the residue. The mixture was washed with 70 mQ of an aqueous sodium hydroxide solution at pH of 9. The solvent layer was washed with water, dried with anhydrous sodium sulfate and immediately dried to obtain 2.8 g of oily 5-(o-chlorophenoxy)-2-methylpyridine.
~he thus-obtained product was subjected to oxidation i in pyridine with selenium dioxide in the same manner as described in Example 4 to obtain 1~82 g of crystals of 5-(o-chlorophenoxy)picolinic ccid.
Melting Point: 178-179C
- Elemental Analysis for Cl2H8o3NcQ:
C H N CQ
Calcd.(~): 57.72 3.21 5.61 14.23 Found (%): 57.67 3.15 5.73 13.82 .`''' , ~ -30-, . . .
~;, ~1~57~9 4 g of a potassium salt of 5-hydroxy-2-methyl-pyridine was suspended in 10 mQ of dimethylformamide, and
i cool, the reaction mixture was diluted with 50 mQ of methanol and then filtered. The filtrate was immediately concentrated ; to dryness, and 200 mQ of chloroform and loO mQ of water were .:
1~ added to the dried material, and the mixture adjusted to a pH j ~`~' ~ !, of g with 5N sodium hydroxide. The insoluble matter was again , " i h,~' 30 separated by filtration. The resulting chloroform layer was . ~ , .
.
:
, ~ '' - :`, : .~' ,.
1:1157Q9 1 dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 8.2 g of oily 5-(p-chlorophenoxy)-2-methylpyridine. Gas chromatoyraphy revealed that the thus-obtained product contained no 5-(p-bromophenoxy)-2-methylpyridine.
4.7 g of the above product was dissolved in 25 mQ of pyridine, and 4.5 g of selenium dioxide was added to the solution, followed by stirring at 120C for 12 hours to effect oxidation. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The concentrate was dissolved in 200 mQ of chloroform and then washed successively with 100 mQ of an aqueous hydrochloric acid solution at pH 2 and 50 mQ of water. The chloroform layer was dried with anhydrous sodium sulfate and immediately concentrated to crystallize the product, which were then recrystallized from ethanol to obtain 4.2 g of crystals of 5-~p--chlorophenoxy)picolinlc acid.
Melting Point: 158-159.5C
Elemental Analysis for C12H8O3NCQ:
C H N O CQ
Calcd.(~): 57.72 3.21 5.61 19.24 14.23 Found (%): 57.63 3.26 5.53 14.19 ., .
2.0 g of the 5-(p-chlorophenox~)-2-methylpyridine as obtaîned in Example 4 was suspended in 60 mQ of water, and a 1.53 g portion of potassium permanganate was added four times to the suspension while stirring at 100C over a 10 hour period to effect oxidation. The reaction mixture was filtered, and the filter cake washed with 30 mQ of warm water. The filtrate and the washin~ were combined, adjusted to a pH of 9.5 with 5N
. ~ .
sodium hydroxide and washed with 30 mQ of chloroform. The aqueous layer was adjusted to a pH of 1.5 with a 5N aqueous , ` ~ .
;;, -:' , '~
11157~19 hydrochloric acid solution, extracted with 50 m~ of chloroform.The chloroform layer was worked up in the same manner as described in Example 4 to obtain 1.2 g of crystals of 5-~p-chlorophenoxy)picolinic acid.
7.4 g of a potassium salt of 5-hydroxy-2-methyl-pyridine, 8.5 g of p-bromotoluene and 500 mg of a copper powder were suspended in 25 mQ of dimethylformamide, and the mixture was allowed to react in a nitrogen gas stream at 130C
for 14 hours under stirring. The reaction mixture was dlluted with 70 mQ of methanol and filtered. The filtrate was immediately concentrated, and to the residue was added 150 mQ
of chloroform. The mixture was washed with 100 mQ of a O.OlN
aqueous sodium hydroxide solution, whereby the unreacted 5-hydroxy-2-methylpyridine shifted to the aqueous layer. The ; chloroform layer was washed with water, dried with anhydrous sodium sulfate and immediately dried to obtain 8.9 g of oily ~-5-(p-methylphenoxy)-2-methylpyridine.
4 g of the thus-obtained product was dissolved in ~o 20 mQ of pyridine, and 4.3 g of selenium dioxide was added , .
;~ thereto, followed by stirring at 120C for lS hours to effect Xj oxidation. The reaction mixture was worked up in the same manner as described in Example 4 to obtain 3.1 g of crystals of 5-(p-methylphènoxy)picolinic acid.
~ ~ Melting Point: 165-166C --`' Elemental AnalySiS for C13HllO3N:
;~ C H N O
, ~ .
"t' Calcd.(~): 68.12 4.80 6.11 20.96 , . , Found (%): 68.17 4.72 6.19 ., ., , .~ - .
', :
. .
' . ' : . ~.' ': .
s7Q9 2.84 g of a potassium salt of 5-hydroxy-2-methyl-pyridine, 4.7 g of p-dibromobenzene and 400 mg of cuprous oxide were suspended in 10 m of dimethylacetamide, and the ;~
mixture was allowed to react in a nitrogen gas stream at 150C
for 15 hours. The reaction mixture was diluted with 30 mQ of methanol and then filtered. The filtrate was immediately dried, and the residue was taken into 100 mQ of chloroform and washed successively with a 3% aqueous sodium carbonate solution ~ 10 and 50 mQ of water. The chloroform layer was dried with ; anhydrous sodium sulfate and immediately concentrated to dryness to obtain 2.1 g of oily 5-(p-bromophenoxy)-2-methyl-; pyridine.
2.0 g of the thus-obtained product-was then subjected to oxidation in pyridine with selenium dioxide in the same manner as described in Example 6 to obtain 1.4 g of crystals of 5-!~
(p-bromophenoxy)picolinic acid.
;, Melting Point: 139-141C ;
~ Elemental Analysis for C12H803NBr:
,' 20 C H N 0 Br Calcd.(%): 49.00 2.72 4.76 16.33 27.19 , ~ .
Found (%): 49.13 2.64 4.81 26.83 ... ~
2.2 g of the 5-(p-nitrophenoxy)picolinic acid as obtained in Example 3 was added to a solution of 6.1 g of stannous chloride in 16.2 mQ of concentrated hydrochloric acid ~' cooled at 5C, followed by stirring at room temperature for 16 hours. The resulting crystalline precipitate was separated by filtration and dissolved in 12 mQ of warm water. To the . ~
~ 30 immediately solidified crystals was added 12 mQ of water, and ~''.'`'' ' . '.
.
-~
.: . , :.
11157~9 1 the resulting suspension was filtered. The resulting crude crystals were washed with 25 mQ of water, recrys~allized from 75 mQ of a mixed solvent system of concentrated hydrochloric acid/ethanol (3:5 by volume), washed with 15 mQ of ethanol and dried under reduced pressure to obtain 1.0 g of colorless crystals of 5-(p-aminophenoxy)picolinic acid dihydrochloride.
Melting Point: 221-230C (decomposition) Elemental Analysis for C12Hl N O 2HCQ:
C H N O CQ
; 10 Calcd.(~): 47.52 3.96 9.2415.84 23.43 Found (%): 47.61 3.72 9.36 23.40 1.4 g of the 5~(p-aminophenoxy)picolinic acid dihydrochloride as obtained in Example 8 was suspended in 22 mQ
of concentrated hydrochloric acid, and 3 mQ of an aqueous solution containing 828 mg of sodium nitrite was added dropwise ~ to the suspension over a period of 1 hour under ice-cooling.
;~ 5.4 mQ of an aqueous solution containing 760 mg of sodium metabisulfite and 480 mg of sodium hydroxide was added to 11 mQ of a warm aqueous solution containing 3.4 g of copper sulfate pentahydrate and 2.9 g of sodium chloride to prepare a ' cuprous chloride solution. The cuprous chloride solution was added to the diazonium salt solution as above obtained to form ~i a solution, and 15 mQ of concentrated hydrochloric acid was ~hen added to the resulting solution, followed by stirring at 10C for 2 hours and then at room temperature for 16 hours to effect the reaction. The reaction mixture was diluted with 50 mQ of water, adjusted to a pH of 1.5 with 5N sodium hydroxide and extracted with 100 mQ of chloroform. The extract was dried with anhydrous sodium sulfate, concentrated to a volume of about '':' ' .'~ .
~i~S7Q9 . .
1 10 m~ and allowed to stand at 3C to form crystals, which were then separated by filtration to obtain 0.91 g of crystals of 5-(p-chlorophenoxy)picolinic acid.
3.68 g of a potassium salt of 5-hydroxy-2-methyl-pyridine was suspended in 10 mQ of dimethylformamide, and 5.65 g of m-bromobenzotrifluoride and 300 mg of copper powders were added to the suspension, followed by allowing the mixture to react in a nitrogen stream at 120C for 15 hours while -~
; 10 stirring. After cooling, the reaction mixture was diluted with ,.~
40 m~ of acetone and filtered. The filtrate was im~ediately ,, :
dried to solidify, and 100 mQ of chloroform and 50 mQ of water were added thereto. The mlxture was adjusted to a pH of 9 with 5N sodium hydroxide, and any insoluble matter was again ,~ separated by filtration. The resulting chloroform layer was ;~ dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 4.1 g of oily 5-(m-trifluoromethylphenoxy)-2-methylpyridine.
The thus-obtained product was subjected to oxidation in pyridine using selenlum dioxide in the same manner as described in Example 4. The product was crystallized from 20 :',`1 ~
~- mQ of ethyl acetate to obtain 2.7 g o crystals of 5-(m-trifluoromethylphenoxy)picolinic acid.
Melting Point: 151-152C
Elemental Analysis for C13H803NF3:
~ C H N
; Calcd.(~):55.12 2.83 4.95 Found (%):53.68 2.72 4.79 ~'."
`~ 30 3 g of a potassium salt of 5-hydroxy-2-methylpyridine, : ~ .
.
, ..
:~"''.', `
. .
.
,; .
. . .. :. ::
~1~57Q9 .
1 3.83 g of m-bromochlorobenzene and 200 mg of a copper powder were suspended in 8 mQ of dimethylformamide, followed by allowing the mixture to react in a nitrogen gas stream at 130C
for 13 hours while stirring. The reaction mixture was diluted with 40 mQ of ethanol and filtered. The filtrate was immediately concentrated, and 80 mQ of chloroform was added to the residue.
The mixture was washed with a O.OlN aqueous sodium hydroxide solution. The chloroform layer was washed with water, dried with anhydouus sodium sulfate and dried to solidify to obtain 2.96 g of oily 5-(m-chlorophenoxy)-2-methylpyridine.
The thus, obtained product was subjected to oxidation A, '"t:~
using potassium permanganate in the same manner as described in Example 5 to obtain 1.43 g of crystals of 5-(m-chlorophenoxy)-/ picolinic acid.
; Melting Point: 138-139C
. j . .
Elemental Analy~is for C12H8O3NCQ:
C H N CQ
-~ Calcd.t%): 57.72 3.21 5.61 14.23 Found (~): 57.58 3.29 5.38 13.82 ,~ 2Q EXAMPLE 12 ;~ 4 g of a potassium salt of 5-hydroxy-2-methyl-pyridine was suspended in 10 mQ of dimethylacetamide, and 5.1 g of p-methOxybromobenzene and 450 mg of a copper powder were added to the suspension, followed by allowing the mixture to ~; react in a nitrogen stream at 140C for 14 hours. The reaction mixture was diluted with 50 mQ of methanol and filtered, and the filtrate was immediately dried to a solid. 100 mQ of ethyl -acetate was added to the résidue, and the mixture was washed ~` with 50 mQ of an aqueous sodium hydroxide solution at pH 9.
The ethyl acetate layer was washed with water, dried with ~`'`~,', ' .
.. ~
j,,.
. ~,, .
:-." . . ,; , ~ .
11~;57Q9 1 anhydrous sodium sulfate and immediately dried to obtain 3.9 g of oily 5-(p-methoxyphenoxy)-2-methylpyridine.
The thus-obtained product was subjected to oxidation in pyridine with selenium dioxide in the same manner as described in Example 4 to obtain 1.8 g of crystals of 5-(p-methoxyphenoxy)picolinic acid.
Melting Point: 170 172C
Elemental Analysis for C13HllO4N:
C H N ~ -Calcd.(%): 63.67 4.49 5.71 Found (~): 63.25 4.62 5.76 , 4 g of a potassium salt of 5-hydroxy-2-methylpyridine, ;i 5.2 g of o-bromochlorobenzene and 250 mg of a copper powder were suspended i~ 10 mQ of dimethylformamide, and tbe mixture was allowed to react in a nitrogen gas stream at 115C for 23 " hours under stirring. The reaction mixture was diluted with ~; 70 mQ of methanol and filtered. The filtrate was dried to a L
solid, and 120 mQ of chloroform was added to the residue. The mixture was washed with 70 mQ of an aqueous sodium hydroxide solution at pH of 9. The solvent layer was washed with water, dried with anhydrous sodium sulfate and immediately dried to obtain 2.8 g of oily 5-(o-chlorophenoxy)-2-methylpyridine.
~he thus-obtained product was subjected to oxidation i in pyridine with selenium dioxide in the same manner as described in Example 4 to obtain 1~82 g of crystals of 5-(o-chlorophenoxy)picolinic ccid.
Melting Point: 178-179C
- Elemental Analysis for Cl2H8o3NcQ:
C H N CQ
Calcd.(~): 57.72 3.21 5.61 14.23 Found (%): 57.67 3.15 5.73 13.82 .`''' , ~ -30-, . . .
~;, ~1~57~9 4 g of a potassium salt of 5-hydroxy-2-methyl-pyridine was suspended in 10 mQ of dimethylformamide, and
6.15 g of p-bromobenzotrifluoride and 500 mg of a copper powder were added to the suspension, followed by stirring in a nitrogen ; stream at 125C for 18 hours to effect the reaction. The reaction mixture was allowed to cool, diluted with 50 mQ of ;
methanol and then filtered. The filtrate was immediately dried to a solid, and 150 mQ of chloroform and 100 mQ of water were added to the residue. The resulting mixture was adjusted to a pH of 9.5 with 5N sodium hydroxide-and any insoluble matter again separated by filtration. The chloroform layer was dried `~
with anhydrous sodium sulfate and immediately concentrated to ,, " dryness to obtain 5.6 g of oily 5-(p-trifluoromethylphenoxy)-2-methylpyridine.
The thus-obtained product was subjected to oxidation ; ~
' in pyridine with selenium dioxide in the same manner as described in Example 4 to obtain 3.8 g of crystals of 5-(p-trifluoromethyl-phenoxy)picolinic acid.
, .. ..
;~ 20 Melting Point: 150-151C
:
Elemental Analysis for C13H8O3NF3:
;~ C H N
;1~ Calcd.(%): 55.12 2.83 4.95 Found (%): 54.63 3.02 4.81 0.8 g of sodium hydroxide was added to a suspension .~ - ,. .
` of 4.63 g of 5-(3-chloropropoxy)picolinic acid in 180 mQ of water, followed by stirring to obtain an aqueous solution of !
the sodium salt of 5-(3-chloropropoxy)picolinic acid. Ta this '~ 30 solution was added 20 mQ of an aqueous solution containing 1.8 g ~ -31 . . .
~ ' ' , ' ~, , .- .
. . , ~, .. : ~ .
11~57~9 ,, . ", 1 of calcium acetate monohydrate to form a white precipitate.
The thus-formed precipitate was separated by filtration, washed with water and dried over phosphorus pentoxide to obtain 4.7 g of a calcium salt of 5-(3-chloropropoxy)picolinic acid as white powder.
Melting Point: above 220C
Elemental Analysis for CgHl0o3NcQ 1/2Ca:
C H N CQ
Calcd.(%): 45.86 4.25 5.94 15.07 Found (%): 44.72 4.31 5.73 14.25 8.15 g of a potassium salt of 5-hydroxy-2-hydroxy-methylpyridine was suspended in 120 mQ of dimethylformamide, and 10.5 g of 1,1,1-trifluoro-5-bromopentane was added to the ; suspension, followed by stirring at 65C for 18 hours to effect the reaction. The reaction mixture was immediately concentrated to dryness, and 200 mQ each of chloroform and water were added to the residue to form two layers. The chloroform layer was washed with water, dried with anhydrous sodium sulfate and immediately ddred to obtain 12.83 g of a syrup of 5-(5,5,5-trifluoropentyloxy)-2-hydroxymethylpyridine.
- 12.73 g of the thus-obtained product was dissolved in 150 mQ of a mixed solvent system of t-butanol-water (3:1 by volume), and 110 mQ of an aqueous solution containing 9.4 g of potassiurn permanganate was added dropwise thereto under ice-; cooling over a period of 1.5 hours. The reaction mixture was further stirred at 10 to 20C for an additional 2 hour -`
period and filtered. The filter cake was washed with 150 mQ of a warm 50% aque~us methanol (adjusted to a pH 10 with sodium hydroxide). The filtrate and the washlng were combined, .
: . .
;'' '' .
l~ls7~a 1 concentrated to a volume of about 100 mQ, adjusted to a pH of 1.5 with a 5N aqueous hydrochloric acid solution and extracted with 200 mQ of chlorof~rm. The chloroform layer was dried with anhydrous sodium sulfate, concentrated to a volume of about 20 mQ, mixed with 30 mQ of ethanol and allowed to stand at a low temperature to form crystals, which were separated by filtration to obtain 9.1 g of white crystals of 5-(5,5,5-trifluoropentyloxy)picolinic acid.
Melting Point: 99-101C
10 Elemental Analysis for CllH12NO3F3:
C H N O F
Calcd.(%): 50.19 4.56 5.32 18.25 21.67 ; Found (%): 49.92 4.67 5.19 5 g of 5-(4-chlorobutoxy)picolinic acid was suspended in 30 mQ of benzene, and 14 mQ of thionyl chloride was added to the suspension, ~ollowed by heat-refluxing for 3 hours. The reaction mixture was immediately concentrated to dryness, and 20 mQ of benzene was added to the residue. The mixture was again dried to solidify to remove the by-produced hydrogen -~ chloride and sulfurous acid gas, thereby preparing an acid chloride of 5-(4-chlorobutoxy)picolinic acid (hydrochloride).
The resulting acid chloride was dissolved in 40 mQ of benzene, and the solution was added dropwise to 40 mQ of a benzene ~ solution containing 2~81 g of 5-hydroxyindane and 10.5 mQ of i- triethylamine u~er ice-cooling over aperiod of 15 minutes while ` stirring. The reaction was further continued at 5 to 10C for !~l 2 hours and then at room temperature for 2 hours. The reaction `j~t~ mixture was dried to solidify, andthe residue was taken into 200 mQ of chloroform. The mixture was washed successively with i ' :
- 11157~9 ~
1 50 mQ each of an aqueous hydrochloric acid solution at a pH o~
3, an aqueous alkali solution at a pH of 9 and distilled water.
The chloroform layer was dried with anhydrous sodium sulfate, concentrated to dryness and recrystallized from a mixed solvent of ethyl ether and hexane to obtain 5.6 g of crystals of a 5-indanyl ester of 5~(4-chlorobutoxy)picolinic acid.
Melting Point: 62-63C
Elemental Analysis,for ClgH20NO3C :
C H N CQ
.
Calcd.(%): 65.99 5.79 4.05 10.27 Found (%): 65.28 5.83 3.97 10.56 1.5 g of 5-(p-chlorophenoxy)picolinic acid was dissolved in 40 mQ of dried ethanol, and 0.15 mQ of concentrated sulfuric acid was added to the solution, followed by heat-refluxing for 6 hours. The reaction mixture was neutralized with sodium hydrogencarbonate and concentrated to dryness. The ,: :
~' residue was dissolved in 50 mQ of chloroform and washed with i~
~ 30 mQ of water~ The chloroform layer was decolored with a '~ 20 small amount of carbon powder, immediately dried to solidify, dissolved in diethyl ether and allowed to stand at a low ` temperature to form crystals. The thus-formed crystals were , separated by filtration to obtain 1.62 g of white crystals of an ethyl ester of 5-(p-chlorophenoxy)picolinic acid.
:
Melting Point: 75-76C
Elemental Analysis for C14H12NO3C :
C H N CQ
^ Calcd.(%):60.54 4.325.05 12.79 Found (~):60.42 4.515.13 13.02 i 30 ~ -, .,~ ' . .
~ ' .
11~57~)9 14 mQ of 28~ aqueous ammonia was added to 30 m~ of a chloroform solution containing 2.37 g of the acid chloride of 5-(o-trifluoromethylphenoxy)picolinic acid (hydrochloride), and the resulting mixture was vigorously stirred for 2 hours.
The aqueous layer was removed, and the chloroform layer was washed with two 20 mQ portions of water, dried with anhydrous sodium sulfate and concentrated to dryness to obtain a crystal-line residue. Recrystallization from a mixed solvent system of ethanol-diethyl ether afforded 2.1 g of white crystals of 5-(o-trifluoromethylphenoxy)picolinic acid amide.
Melting Point: 137-138C -~
Elemental Analysis for C15H12NO3F3:
C H N F ~;
Calcd.(%): 57.88 3.86 4.50 18.33 -Found (%): 57.69 3.92 4.~1 1 g of 5-(p-chlorophenoxy)picolinic acid was dissolved in 20 mQ of dimethylformamide, and 1.22 g of -zo pivaloyloxyethyl chloride and 1.12 mQ of triethylamine were added to the solution, followed by stirring at room temperature for 20 hours. 3 mQ of ice-water was added to the reaction mixture, and the mixture was allowed to stand for 1 hour, '~ followed by concentration to dryness. 70 mQ of ethyl acetate was added to the residue, and the mixture was washed succes-sively with 40 mQ each of an aqueous hydrochloric acid solution at pH 3, a 5% aqueous sodium bicarbonate and water. The ethyl acetate layer was dried with anhydrcussodium sulfate, dried to solidify and dissolved in 5 mQ of diethyl ether. 10 mQ of hexane was added to the solution, followed by allowing the _35_ ' .
; , .
:
~1~57~)9 1 mixture to stand at a low temperature to crystallize the product. The thus-formed crystals ~ere separated by filtration to obtain 1.2 g of white crystals of an ~-pivaloyloxyethyl ester of 5-(p-chlorophenoxy)picolinic acid.
Melting Point: 120-122C
Elemental Analysis for C18H20NO5CQ:
C H N CQ
Calcd.(%): 59.10 5.473.83 9.71 Found (%): 59.02 5.533.78 10.02 10 m of a dichloromethane solution containing the acid chloride of 5(o-chlorophenoxy)picolinic acid (hydrochloride) ; was added dropwise to 20 mQ of a dichloromethane solution containing 0.43 g of 5-hydroxyindane and 1.6 mQ of triethylamine under ice-cooling while stirring over a period of 5 minutes.
The reaction was continued at 0 to 5C for 1 hour and then at room temperature for 2 hours. The reaction product was dried ~;
to solidify and further worked up in the same manner as described in Example 17 to obtain 1.32 g of white crystals of `~ 20 an indanyl ester of 5-(o-chlorophenoxy)picolinic acid.
Melting Point: 100-102C
Elemental Analysis for C21H16NO3CQ:
; C_ H N CQ
~` Calcd.(%): 68.95 4.38 3.83 9.71 ' ~,~ Found ~%): 68.82 4.41 3.95 9.86 1.3 g of the ethyl ester of ~(p-chlorophenoxy)-picolinic acid was dissolved in 6 mQ of acetone, and 15 mQ of 28% aqueous ammonia was added to the solution, followed by allowing the mixture to stand at room temperature for 23 hours.
, .`',~ , .
., - .`' ` `
~ " ~
~ lilS7(~9 1 The reaction mixture was cooled, and the precipitated crystals were separated by filtration and recrystallized from a mixed solvent of ethanol-diethyl ether to obtain 1.1 g of crystals -~
of 5-(p-chlorophenoxy)picolinic acid amide. -Melting Point: 173-174C
Elemental Analysis for C12HgN202CQ:
C H N CQ
Calcd.(%): 57.95 3.6311.27 14.29 Found (%): 58.02 3.7111.25 14.18 EXAMPLE A
3 g of 5-n-butyloxy-picolinic acid was suspended 30 mQ of benzene and 8 mQ of thionyl chloride was added to the ~ suspension followed by stirring the mixture at 70C for 3 ; hours. The resulting solution was then concentrated to dryness.
10 mQ of benzene was then added to the residue and the resulting solution was concentrated to dryness. The addition of benzene y (10 mQ) and the concentration to dryness was further repeated two times so as to remove hydrogen chloride and sulfur dioxide ; ;~
~ by-produced and, thereby, the acid chloride of 5-n-butyloxy-,~ 20 picolinic acid (hydro~hloride) was obtained. The acid chloride thus-obtained was dissolved in 20 mQ of benzene and, then, the 3 resulting solution was added dropwise to a solution of 2.1 g of 5-hydroxyindane, 7.7 mQ of triethylamine and 30 mQ of benzene for 10 minutes under cooling with ice-water while stirring~
The solution was stirred for 1.5 hours at 5-10C and further stirred for 4 hours at room temperature to complete the reaction.
.. ~ .
The reaction solution was then concentrated to dryness. 100 mQ -, of ethyl acetate was then added to the residue and the resulting solution was washed with 50 mQ of cooled (at 5C) hydrochloric ` 30 acid solution (pH 2), 50 mQ of alkaline aqueous solution of `` ' ~, i -37-~. .
: . . .
! ~
1 sodium bicarbonate (pH 9) and 50 mQ of water, respectively.
The ethyl acetate solution was dried over anhydrous sodium sulfate, and, then, concentrated to dryness to obtain a crystallize residue. Recrystallization from diethylether- -hexane provided 4.5 g of crystals of the 5-indanyl ester of 5-n-butvloxy-picolinic acid.
Melting Point: 58-59C
Elemental Analysis for ClgH2lNO3:
C H N
Calcd.(~): 73.31 6.75 ~.50 ;
Found (%): 73.28 6.86 4.35 In clinical use, the compounds of this invention may be administered orally in the form of tablets, capsules or dry syrups usually employed as vehicles. The compounds may also be administered in the form of a subcutaneous injection. In this case, derivatives having an increased water solubility, e.g.
a dimethylaminoethyl ester of 5-(4-chlorobutoxy)picolinic acid hydrochloride, are suitably used.
The compounds of this invention can be used as the sole active agent or can be used in combination with one or more other physiologically active agents, particularly diuretic anti-hypertensive agents.
A dosage amount of the compounds of this invention is about 200 to about 500 mg in one or two doses per day.
The composition of this Example is a tablet. A
granulation was prepared of:
Lactose 65 parts Corn Starch30 parts Polyvinyl pyrrolidone 5 parts WaterA sufficient quantity .
1 , The granulation was dried and screened. The follow-ing ingredients were then mixed well together and compressed into tablets weighing 250 mg and containing 100 mg of the calcium salt.
Calcium 5-(4-chlorobutoxy)picolinate 100 g Lactose granulation 97.5 g Magnesium Stearate 2.5 g ~-The composition of this Example is a capsule. The following ingredients were blended and then introduced into standard clear gelatin capsules.
Calcium 5-(5,5,5-trifluoropentyloxy)picolinate 100 g ' '`
Lactose 98 g Magnesium Stearate 2 g The resulting capsules contained 100 mg of the calcium salt per dosage unit.
All the compounds of this invention represented by -; , the formula (I) above exhibit an anti-hypertensive activity by oral or nonoral administration and can be regarded as useful , pharmaceutical agents as illustrated in the Examples 25 and 26 given below.
Each of the compounds of the invention as indicated below was suspended in a 5% aqueous gum arabic solution and the suspension was administered orally (100 mg/kg) to groups consisting of three spontaneously hypertensive rats (18-23 weeks old; blood pressure before administration: 170-190 mmHg).
' Blood pressure changes were determined according to a Direct Blood Pressure Measuring Method and the results obtained ar,e shown in Table 1 below.
1 Each of the test compounds was administered intra-peritoneally to male mice (ICR strain, 5 week old) and LD50 value was observed 1 week after administration, and the results of acute toxicity are also shown in Table 1 below. -~
Maximum Acute Depression ChemicalToxicity n Test Compound Formula (Ln50) Pressure (mg/kg) (%) Fusaric Acid CloH13 2 75-100 15.8 ~ -s-n-Butoxy-picolinic C10 13 3 100-150 16.6 5-(4-Chlorobutoxy)- Clo 12 3 150-200 23.0 picolinic Acid 5-(3-Chloropropoxy)- CgHloNO3CQ 150-200 18.2 ~
picolinic Acid -s~(p-chlorophenoxy)- C12H8 3 150-200 28.3 picolinic Acid s-(p-MethylPhenXY)~ C13HllN 3 200-300 17 0 picolinic Acid 5-(p-Aminophenoxy)- C12 10 2 3 8.3 picolinic Acid 2HCQ
Dihydrochloride 20 5-(m-Trifluoromethyl- C13H8NO F500-600 - 20.8 phenoxy)picolinic 3 3 Acia 5-(p-Bromophenoxy)- C12H8N 3150-200 27.5 picolinic Acid 5-(p-Methoxyphenoxy)- C13H lN 4500-600 14~2 picolinic Acld 5-(m-Chlorophenoxy)- C12H8NO3CQ 300-400 16.7 picolinic Acid 5-(o-Chlorophenoxy)- C12H8NO3CQ 150-200 30.1 picolinic Acid 5-(p-Acetylphenoxy)- C14HllNO4 400-500 17.3 picolinic Acid s-(p-Trifluoromethyl- C13H8N 3 3 2Q0-250 29.3 phenoxy)picolinic Acid .
1 Table 1 - cont'd Maximum Depression Acute in Chemical ToxicityBlood Test Compound Formula 50Pressure 5-(2,4-Dimethyl- C14H13N3 250-300 16.9 phenoxy)picolinic Acid 5-(o-Trifluoro- C13 8 3 3 150-200 27.6 methylphenoxy)-picolinic Acid 5-(2,4-Dimethoxy- C14H13 5 19.2 phenoxy)picolinic Acid lO 5-(p-Nitrophenoxy)- C12H8N2 5 500-600 15.1 picolinic Acid 5-(2,6-Dichloro- C12H7NO3cQ2 150-200 23.7 phenoxy)picolinic Acid 5-(2,4-Ditrifluoro- C14H7NO3F6 200-250 25.5 methylphenoxy)-picolinic Acid 5-(2,4-Dichloro- C12H7NO3cQ2 150-200 24.6 phenoxy)picolinic Acid 5-(5,5,5-Trifluoro- CllHl2NO3F3 150-200 28.7 pentyloxy)picolinic Acid Calcium Salt of 5-(4- CloHllNO3CQ- 800-1000 22.8 Chlorobutoxy)picolinic 1/2Ca Aci Calcium Salt of 5-(p- C12H7NO3CQ 350 400 23.5 Chlorophenoxy)- 1/2C
picolinic Acid Calcium Salt of 5- CllHllNO3F3 800-900 26.9 (5,5,5-Trifluoro- 1/2Ca pentyloxy)picolinic Acid Each of the compounds of the invention as indicated below was s~spended in a 5% aqueous gum arabic solution and the suspension was administered orally to groups consisting of three spontaneously hypertensive rats (17-23 week old; blood .. ~1~9 -1 pressure before administration: 170-190 mmHg~. Blood pressure changes were determined according to a Tail Cuff Method and the results obtained are shown in Table 2 below.
Maximum Depression in Blood Test Compound Dose Pressure (mg/kg) (%) ;
Indanyl Ester of 5-(4-Chlorobutoxy)- 100 26.3 picolinic Acid 5-(4-Chlorobutoxy)picolinic Acid 100 21.5 Amide Ethyl Ester of 5-(p-Chlorophenoxy)- 100 23.3 picolinic Acid Indanyl Ester of 5-(p-Chlorophenoxy)- 100 27.5 picolinic Acid ~ Pivaloyloxyethyl Ester of 5-(p- 100 21.8 Chlorophenoxy)picolinic Acid 5-(p-Chlorophenoxy)picolinic Acid 100 23.7 Amide Indanyl Ester of 5-~o-trifluoro- 100 26.3 ~-methylphenoxy)picolinic Acid 5-(o-Trifluoromethylphenoxy)picolinic 10020.7 ~ Acid Amide Indanyl Ester of 5-(-Chlorophenoxy)- 100 29.0 ; picolinic Acid 5-(o-Chlorophenoxy)picolinic Acid 100 19.6 Amide The oral LD50 f free acids according to the present invention was 900 mg/kg for 5-(4-chlorobutoxy)picolinic acid ; and 400 to 600 mg/kg for 5-(p-chlorophenoxy)picolinic aCid, 5-(o-chlorophenoxy)picolinic acid and 5-(o-trifluoromethyl-phenoxy)picolinic acid. On the other hand, the oral LD50 f the indanyl esters, acyloxyalkyl esters and amide derivatives Of the present invention were improved, for example, 1600-1800 1 m~/kg for the indanyl ester of 5-(4-chlorobutoxy)picolinic acid, 700-800 mg/kg for the indanyl ester of 5-(p-chlorophenoxy)-picolinic acid, 900-1,000 mg/kg for the ~-pivaloyloxyethyl ester of 5-(p-chlorophenoxy)picolinic acid, 1,500-1,600 mg/kg for 5-(4-chlorobutoxy)picolinic acid amide and 950 mg/kg for 5-(o-trifluoromethylphenoxy)picolinic acid amide.
All the compounds of this invention represented by -the formula (A) above exhibit a long-lasting antihypertensive activity by oral administration and can be regarded as useful `
lO pharmaceutical agents as illustrated in the Reference Example ~;
hereinafter.
EXAMPLE B
Each of the compounds indicated below was suspended in a 5% aqueous gum arabi~ solution containing-2~ Tween 80, an~ the suspension was administered orally to groups of spontaneously hypertensive rats (15-20 weeks old; 3 rats per group; blood pressure before administration: 175-190 mmHg). Arterial blood pressure of concious SHR was recorded from the caudal artery via a pressure transducer (NIHON KOHDEN MP-24T) on a polygraph 20 (NIHON KOHDEN RM-85). ' The results obtained are shown in the table below.
Maximum Depression in Blood Test Compound DoSe Pressure ~ (mg/kg) (%) 5-Indanyl Ester of 5-n- 100 21.8 Butyloxy-picolinic Acid Fusaric Acid* (control) 100 10.5 * ~ C4H9 HOOC N
57~g 1 The oral LD50 of the fusaric acid (control~ was 180 mg/kg and the oral LD50 of free 5-alkoxy-picolinic acids, such as 5-n-propyloxy-picolinic acid and 5-n-butyloxy-picolinic acid, was 300-500 mg/kg. On the other hand, the oral LD50 of the esters of 5-alkoxy-picolinic acid of the present invention were improved, for example 800-1,000 mg/kg for the indanyl ester.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and ~ :
modifications can be made therein without departing from the spirit and scope thereof.
~.
methanol and then filtered. The filtrate was immediately dried to a solid, and 150 mQ of chloroform and 100 mQ of water were added to the residue. The resulting mixture was adjusted to a pH of 9.5 with 5N sodium hydroxide-and any insoluble matter again separated by filtration. The chloroform layer was dried `~
with anhydrous sodium sulfate and immediately concentrated to ,, " dryness to obtain 5.6 g of oily 5-(p-trifluoromethylphenoxy)-2-methylpyridine.
The thus-obtained product was subjected to oxidation ; ~
' in pyridine with selenium dioxide in the same manner as described in Example 4 to obtain 3.8 g of crystals of 5-(p-trifluoromethyl-phenoxy)picolinic acid.
, .. ..
;~ 20 Melting Point: 150-151C
:
Elemental Analysis for C13H8O3NF3:
;~ C H N
;1~ Calcd.(%): 55.12 2.83 4.95 Found (%): 54.63 3.02 4.81 0.8 g of sodium hydroxide was added to a suspension .~ - ,. .
` of 4.63 g of 5-(3-chloropropoxy)picolinic acid in 180 mQ of water, followed by stirring to obtain an aqueous solution of !
the sodium salt of 5-(3-chloropropoxy)picolinic acid. Ta this '~ 30 solution was added 20 mQ of an aqueous solution containing 1.8 g ~ -31 . . .
~ ' ' , ' ~, , .- .
. . , ~, .. : ~ .
11~57~9 ,, . ", 1 of calcium acetate monohydrate to form a white precipitate.
The thus-formed precipitate was separated by filtration, washed with water and dried over phosphorus pentoxide to obtain 4.7 g of a calcium salt of 5-(3-chloropropoxy)picolinic acid as white powder.
Melting Point: above 220C
Elemental Analysis for CgHl0o3NcQ 1/2Ca:
C H N CQ
Calcd.(%): 45.86 4.25 5.94 15.07 Found (%): 44.72 4.31 5.73 14.25 8.15 g of a potassium salt of 5-hydroxy-2-hydroxy-methylpyridine was suspended in 120 mQ of dimethylformamide, and 10.5 g of 1,1,1-trifluoro-5-bromopentane was added to the ; suspension, followed by stirring at 65C for 18 hours to effect the reaction. The reaction mixture was immediately concentrated to dryness, and 200 mQ each of chloroform and water were added to the residue to form two layers. The chloroform layer was washed with water, dried with anhydrous sodium sulfate and immediately ddred to obtain 12.83 g of a syrup of 5-(5,5,5-trifluoropentyloxy)-2-hydroxymethylpyridine.
- 12.73 g of the thus-obtained product was dissolved in 150 mQ of a mixed solvent system of t-butanol-water (3:1 by volume), and 110 mQ of an aqueous solution containing 9.4 g of potassiurn permanganate was added dropwise thereto under ice-; cooling over a period of 1.5 hours. The reaction mixture was further stirred at 10 to 20C for an additional 2 hour -`
period and filtered. The filter cake was washed with 150 mQ of a warm 50% aque~us methanol (adjusted to a pH 10 with sodium hydroxide). The filtrate and the washlng were combined, .
: . .
;'' '' .
l~ls7~a 1 concentrated to a volume of about 100 mQ, adjusted to a pH of 1.5 with a 5N aqueous hydrochloric acid solution and extracted with 200 mQ of chlorof~rm. The chloroform layer was dried with anhydrous sodium sulfate, concentrated to a volume of about 20 mQ, mixed with 30 mQ of ethanol and allowed to stand at a low temperature to form crystals, which were separated by filtration to obtain 9.1 g of white crystals of 5-(5,5,5-trifluoropentyloxy)picolinic acid.
Melting Point: 99-101C
10 Elemental Analysis for CllH12NO3F3:
C H N O F
Calcd.(%): 50.19 4.56 5.32 18.25 21.67 ; Found (%): 49.92 4.67 5.19 5 g of 5-(4-chlorobutoxy)picolinic acid was suspended in 30 mQ of benzene, and 14 mQ of thionyl chloride was added to the suspension, ~ollowed by heat-refluxing for 3 hours. The reaction mixture was immediately concentrated to dryness, and 20 mQ of benzene was added to the residue. The mixture was again dried to solidify to remove the by-produced hydrogen -~ chloride and sulfurous acid gas, thereby preparing an acid chloride of 5-(4-chlorobutoxy)picolinic acid (hydrochloride).
The resulting acid chloride was dissolved in 40 mQ of benzene, and the solution was added dropwise to 40 mQ of a benzene ~ solution containing 2~81 g of 5-hydroxyindane and 10.5 mQ of i- triethylamine u~er ice-cooling over aperiod of 15 minutes while ` stirring. The reaction was further continued at 5 to 10C for !~l 2 hours and then at room temperature for 2 hours. The reaction `j~t~ mixture was dried to solidify, andthe residue was taken into 200 mQ of chloroform. The mixture was washed successively with i ' :
- 11157~9 ~
1 50 mQ each of an aqueous hydrochloric acid solution at a pH o~
3, an aqueous alkali solution at a pH of 9 and distilled water.
The chloroform layer was dried with anhydrous sodium sulfate, concentrated to dryness and recrystallized from a mixed solvent of ethyl ether and hexane to obtain 5.6 g of crystals of a 5-indanyl ester of 5~(4-chlorobutoxy)picolinic acid.
Melting Point: 62-63C
Elemental Analysis,for ClgH20NO3C :
C H N CQ
.
Calcd.(%): 65.99 5.79 4.05 10.27 Found (%): 65.28 5.83 3.97 10.56 1.5 g of 5-(p-chlorophenoxy)picolinic acid was dissolved in 40 mQ of dried ethanol, and 0.15 mQ of concentrated sulfuric acid was added to the solution, followed by heat-refluxing for 6 hours. The reaction mixture was neutralized with sodium hydrogencarbonate and concentrated to dryness. The ,: :
~' residue was dissolved in 50 mQ of chloroform and washed with i~
~ 30 mQ of water~ The chloroform layer was decolored with a '~ 20 small amount of carbon powder, immediately dried to solidify, dissolved in diethyl ether and allowed to stand at a low ` temperature to form crystals. The thus-formed crystals were , separated by filtration to obtain 1.62 g of white crystals of an ethyl ester of 5-(p-chlorophenoxy)picolinic acid.
:
Melting Point: 75-76C
Elemental Analysis for C14H12NO3C :
C H N CQ
^ Calcd.(%):60.54 4.325.05 12.79 Found (~):60.42 4.515.13 13.02 i 30 ~ -, .,~ ' . .
~ ' .
11~57~)9 14 mQ of 28~ aqueous ammonia was added to 30 m~ of a chloroform solution containing 2.37 g of the acid chloride of 5-(o-trifluoromethylphenoxy)picolinic acid (hydrochloride), and the resulting mixture was vigorously stirred for 2 hours.
The aqueous layer was removed, and the chloroform layer was washed with two 20 mQ portions of water, dried with anhydrous sodium sulfate and concentrated to dryness to obtain a crystal-line residue. Recrystallization from a mixed solvent system of ethanol-diethyl ether afforded 2.1 g of white crystals of 5-(o-trifluoromethylphenoxy)picolinic acid amide.
Melting Point: 137-138C -~
Elemental Analysis for C15H12NO3F3:
C H N F ~;
Calcd.(%): 57.88 3.86 4.50 18.33 -Found (%): 57.69 3.92 4.~1 1 g of 5-(p-chlorophenoxy)picolinic acid was dissolved in 20 mQ of dimethylformamide, and 1.22 g of -zo pivaloyloxyethyl chloride and 1.12 mQ of triethylamine were added to the solution, followed by stirring at room temperature for 20 hours. 3 mQ of ice-water was added to the reaction mixture, and the mixture was allowed to stand for 1 hour, '~ followed by concentration to dryness. 70 mQ of ethyl acetate was added to the residue, and the mixture was washed succes-sively with 40 mQ each of an aqueous hydrochloric acid solution at pH 3, a 5% aqueous sodium bicarbonate and water. The ethyl acetate layer was dried with anhydrcussodium sulfate, dried to solidify and dissolved in 5 mQ of diethyl ether. 10 mQ of hexane was added to the solution, followed by allowing the _35_ ' .
; , .
:
~1~57~)9 1 mixture to stand at a low temperature to crystallize the product. The thus-formed crystals ~ere separated by filtration to obtain 1.2 g of white crystals of an ~-pivaloyloxyethyl ester of 5-(p-chlorophenoxy)picolinic acid.
Melting Point: 120-122C
Elemental Analysis for C18H20NO5CQ:
C H N CQ
Calcd.(%): 59.10 5.473.83 9.71 Found (%): 59.02 5.533.78 10.02 10 m of a dichloromethane solution containing the acid chloride of 5(o-chlorophenoxy)picolinic acid (hydrochloride) ; was added dropwise to 20 mQ of a dichloromethane solution containing 0.43 g of 5-hydroxyindane and 1.6 mQ of triethylamine under ice-cooling while stirring over a period of 5 minutes.
The reaction was continued at 0 to 5C for 1 hour and then at room temperature for 2 hours. The reaction product was dried ~;
to solidify and further worked up in the same manner as described in Example 17 to obtain 1.32 g of white crystals of `~ 20 an indanyl ester of 5-(o-chlorophenoxy)picolinic acid.
Melting Point: 100-102C
Elemental Analysis for C21H16NO3CQ:
; C_ H N CQ
~` Calcd.(%): 68.95 4.38 3.83 9.71 ' ~,~ Found ~%): 68.82 4.41 3.95 9.86 1.3 g of the ethyl ester of ~(p-chlorophenoxy)-picolinic acid was dissolved in 6 mQ of acetone, and 15 mQ of 28% aqueous ammonia was added to the solution, followed by allowing the mixture to stand at room temperature for 23 hours.
, .`',~ , .
., - .`' ` `
~ " ~
~ lilS7(~9 1 The reaction mixture was cooled, and the precipitated crystals were separated by filtration and recrystallized from a mixed solvent of ethanol-diethyl ether to obtain 1.1 g of crystals -~
of 5-(p-chlorophenoxy)picolinic acid amide. -Melting Point: 173-174C
Elemental Analysis for C12HgN202CQ:
C H N CQ
Calcd.(%): 57.95 3.6311.27 14.29 Found (%): 58.02 3.7111.25 14.18 EXAMPLE A
3 g of 5-n-butyloxy-picolinic acid was suspended 30 mQ of benzene and 8 mQ of thionyl chloride was added to the ~ suspension followed by stirring the mixture at 70C for 3 ; hours. The resulting solution was then concentrated to dryness.
10 mQ of benzene was then added to the residue and the resulting solution was concentrated to dryness. The addition of benzene y (10 mQ) and the concentration to dryness was further repeated two times so as to remove hydrogen chloride and sulfur dioxide ; ;~
~ by-produced and, thereby, the acid chloride of 5-n-butyloxy-,~ 20 picolinic acid (hydro~hloride) was obtained. The acid chloride thus-obtained was dissolved in 20 mQ of benzene and, then, the 3 resulting solution was added dropwise to a solution of 2.1 g of 5-hydroxyindane, 7.7 mQ of triethylamine and 30 mQ of benzene for 10 minutes under cooling with ice-water while stirring~
The solution was stirred for 1.5 hours at 5-10C and further stirred for 4 hours at room temperature to complete the reaction.
.. ~ .
The reaction solution was then concentrated to dryness. 100 mQ -, of ethyl acetate was then added to the residue and the resulting solution was washed with 50 mQ of cooled (at 5C) hydrochloric ` 30 acid solution (pH 2), 50 mQ of alkaline aqueous solution of `` ' ~, i -37-~. .
: . . .
! ~
1 sodium bicarbonate (pH 9) and 50 mQ of water, respectively.
The ethyl acetate solution was dried over anhydrous sodium sulfate, and, then, concentrated to dryness to obtain a crystallize residue. Recrystallization from diethylether- -hexane provided 4.5 g of crystals of the 5-indanyl ester of 5-n-butvloxy-picolinic acid.
Melting Point: 58-59C
Elemental Analysis for ClgH2lNO3:
C H N
Calcd.(~): 73.31 6.75 ~.50 ;
Found (%): 73.28 6.86 4.35 In clinical use, the compounds of this invention may be administered orally in the form of tablets, capsules or dry syrups usually employed as vehicles. The compounds may also be administered in the form of a subcutaneous injection. In this case, derivatives having an increased water solubility, e.g.
a dimethylaminoethyl ester of 5-(4-chlorobutoxy)picolinic acid hydrochloride, are suitably used.
The compounds of this invention can be used as the sole active agent or can be used in combination with one or more other physiologically active agents, particularly diuretic anti-hypertensive agents.
A dosage amount of the compounds of this invention is about 200 to about 500 mg in one or two doses per day.
The composition of this Example is a tablet. A
granulation was prepared of:
Lactose 65 parts Corn Starch30 parts Polyvinyl pyrrolidone 5 parts WaterA sufficient quantity .
1 , The granulation was dried and screened. The follow-ing ingredients were then mixed well together and compressed into tablets weighing 250 mg and containing 100 mg of the calcium salt.
Calcium 5-(4-chlorobutoxy)picolinate 100 g Lactose granulation 97.5 g Magnesium Stearate 2.5 g ~-The composition of this Example is a capsule. The following ingredients were blended and then introduced into standard clear gelatin capsules.
Calcium 5-(5,5,5-trifluoropentyloxy)picolinate 100 g ' '`
Lactose 98 g Magnesium Stearate 2 g The resulting capsules contained 100 mg of the calcium salt per dosage unit.
All the compounds of this invention represented by -; , the formula (I) above exhibit an anti-hypertensive activity by oral or nonoral administration and can be regarded as useful , pharmaceutical agents as illustrated in the Examples 25 and 26 given below.
Each of the compounds of the invention as indicated below was suspended in a 5% aqueous gum arabic solution and the suspension was administered orally (100 mg/kg) to groups consisting of three spontaneously hypertensive rats (18-23 weeks old; blood pressure before administration: 170-190 mmHg).
' Blood pressure changes were determined according to a Direct Blood Pressure Measuring Method and the results obtained ar,e shown in Table 1 below.
1 Each of the test compounds was administered intra-peritoneally to male mice (ICR strain, 5 week old) and LD50 value was observed 1 week after administration, and the results of acute toxicity are also shown in Table 1 below. -~
Maximum Acute Depression ChemicalToxicity n Test Compound Formula (Ln50) Pressure (mg/kg) (%) Fusaric Acid CloH13 2 75-100 15.8 ~ -s-n-Butoxy-picolinic C10 13 3 100-150 16.6 5-(4-Chlorobutoxy)- Clo 12 3 150-200 23.0 picolinic Acid 5-(3-Chloropropoxy)- CgHloNO3CQ 150-200 18.2 ~
picolinic Acid -s~(p-chlorophenoxy)- C12H8 3 150-200 28.3 picolinic Acid s-(p-MethylPhenXY)~ C13HllN 3 200-300 17 0 picolinic Acid 5-(p-Aminophenoxy)- C12 10 2 3 8.3 picolinic Acid 2HCQ
Dihydrochloride 20 5-(m-Trifluoromethyl- C13H8NO F500-600 - 20.8 phenoxy)picolinic 3 3 Acia 5-(p-Bromophenoxy)- C12H8N 3150-200 27.5 picolinic Acid 5-(p-Methoxyphenoxy)- C13H lN 4500-600 14~2 picolinic Acld 5-(m-Chlorophenoxy)- C12H8NO3CQ 300-400 16.7 picolinic Acid 5-(o-Chlorophenoxy)- C12H8NO3CQ 150-200 30.1 picolinic Acid 5-(p-Acetylphenoxy)- C14HllNO4 400-500 17.3 picolinic Acid s-(p-Trifluoromethyl- C13H8N 3 3 2Q0-250 29.3 phenoxy)picolinic Acid .
1 Table 1 - cont'd Maximum Depression Acute in Chemical ToxicityBlood Test Compound Formula 50Pressure 5-(2,4-Dimethyl- C14H13N3 250-300 16.9 phenoxy)picolinic Acid 5-(o-Trifluoro- C13 8 3 3 150-200 27.6 methylphenoxy)-picolinic Acid 5-(2,4-Dimethoxy- C14H13 5 19.2 phenoxy)picolinic Acid lO 5-(p-Nitrophenoxy)- C12H8N2 5 500-600 15.1 picolinic Acid 5-(2,6-Dichloro- C12H7NO3cQ2 150-200 23.7 phenoxy)picolinic Acid 5-(2,4-Ditrifluoro- C14H7NO3F6 200-250 25.5 methylphenoxy)-picolinic Acid 5-(2,4-Dichloro- C12H7NO3cQ2 150-200 24.6 phenoxy)picolinic Acid 5-(5,5,5-Trifluoro- CllHl2NO3F3 150-200 28.7 pentyloxy)picolinic Acid Calcium Salt of 5-(4- CloHllNO3CQ- 800-1000 22.8 Chlorobutoxy)picolinic 1/2Ca Aci Calcium Salt of 5-(p- C12H7NO3CQ 350 400 23.5 Chlorophenoxy)- 1/2C
picolinic Acid Calcium Salt of 5- CllHllNO3F3 800-900 26.9 (5,5,5-Trifluoro- 1/2Ca pentyloxy)picolinic Acid Each of the compounds of the invention as indicated below was s~spended in a 5% aqueous gum arabic solution and the suspension was administered orally to groups consisting of three spontaneously hypertensive rats (17-23 week old; blood .. ~1~9 -1 pressure before administration: 170-190 mmHg~. Blood pressure changes were determined according to a Tail Cuff Method and the results obtained are shown in Table 2 below.
Maximum Depression in Blood Test Compound Dose Pressure (mg/kg) (%) ;
Indanyl Ester of 5-(4-Chlorobutoxy)- 100 26.3 picolinic Acid 5-(4-Chlorobutoxy)picolinic Acid 100 21.5 Amide Ethyl Ester of 5-(p-Chlorophenoxy)- 100 23.3 picolinic Acid Indanyl Ester of 5-(p-Chlorophenoxy)- 100 27.5 picolinic Acid ~ Pivaloyloxyethyl Ester of 5-(p- 100 21.8 Chlorophenoxy)picolinic Acid 5-(p-Chlorophenoxy)picolinic Acid 100 23.7 Amide Indanyl Ester of 5-~o-trifluoro- 100 26.3 ~-methylphenoxy)picolinic Acid 5-(o-Trifluoromethylphenoxy)picolinic 10020.7 ~ Acid Amide Indanyl Ester of 5-(-Chlorophenoxy)- 100 29.0 ; picolinic Acid 5-(o-Chlorophenoxy)picolinic Acid 100 19.6 Amide The oral LD50 f free acids according to the present invention was 900 mg/kg for 5-(4-chlorobutoxy)picolinic acid ; and 400 to 600 mg/kg for 5-(p-chlorophenoxy)picolinic aCid, 5-(o-chlorophenoxy)picolinic acid and 5-(o-trifluoromethyl-phenoxy)picolinic acid. On the other hand, the oral LD50 f the indanyl esters, acyloxyalkyl esters and amide derivatives Of the present invention were improved, for example, 1600-1800 1 m~/kg for the indanyl ester of 5-(4-chlorobutoxy)picolinic acid, 700-800 mg/kg for the indanyl ester of 5-(p-chlorophenoxy)-picolinic acid, 900-1,000 mg/kg for the ~-pivaloyloxyethyl ester of 5-(p-chlorophenoxy)picolinic acid, 1,500-1,600 mg/kg for 5-(4-chlorobutoxy)picolinic acid amide and 950 mg/kg for 5-(o-trifluoromethylphenoxy)picolinic acid amide.
All the compounds of this invention represented by -the formula (A) above exhibit a long-lasting antihypertensive activity by oral administration and can be regarded as useful `
lO pharmaceutical agents as illustrated in the Reference Example ~;
hereinafter.
EXAMPLE B
Each of the compounds indicated below was suspended in a 5% aqueous gum arabi~ solution containing-2~ Tween 80, an~ the suspension was administered orally to groups of spontaneously hypertensive rats (15-20 weeks old; 3 rats per group; blood pressure before administration: 175-190 mmHg). Arterial blood pressure of concious SHR was recorded from the caudal artery via a pressure transducer (NIHON KOHDEN MP-24T) on a polygraph 20 (NIHON KOHDEN RM-85). ' The results obtained are shown in the table below.
Maximum Depression in Blood Test Compound DoSe Pressure ~ (mg/kg) (%) 5-Indanyl Ester of 5-n- 100 21.8 Butyloxy-picolinic Acid Fusaric Acid* (control) 100 10.5 * ~ C4H9 HOOC N
57~g 1 The oral LD50 of the fusaric acid (control~ was 180 mg/kg and the oral LD50 of free 5-alkoxy-picolinic acids, such as 5-n-propyloxy-picolinic acid and 5-n-butyloxy-picolinic acid, was 300-500 mg/kg. On the other hand, the oral LD50 of the esters of 5-alkoxy-picolinic acid of the present invention were improved, for example 800-1,000 mg/kg for the indanyl ester.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and ~ :
modifications can be made therein without departing from the spirit and scope thereof.
~.
Claims (22)
- Claim 1 cintinued...
wherein R1,R7 and R8 are the same as defined above, which comprises the steps of:
(i) preparing a 5-substituted picolinic ester represented by the formula (III-a):
(III-a) wherein R1 is the same as defined above, and R202 represents a straight or branched chain or a cyclic alkoxy group having 1 to 6 carbon atoms, a 5-indanyloxy group or an acyloxy-alkyloxy group having the formula wherein R5 and R601 are the same as defined above, according to a process selected from the group of processes consisting of the processes of parts F and G, and (ii) reacting the esters produced in step H(i) with an amine represented by the formula (XI):
(XI) wherein R7 and R8 are the same as defined above. - 2. 5-Substituted pivolinic acids, salts, esters and acid amides thereof represented by the formula (I) as defined in claim 1 wherein R1 and R2 are the same as defined in claim1 when prepared by a process as claimed in claim 1 or an obvious chemical equivalent.
3. A process for preparing 5-substituted picolinic acids and salts thereof represented by the formula (II): - Claim 3 continued...
(II) wherein R1 and M are the same as defined in claim 1 comprising a process selected from the group of processes consisting of the processes of parts A, B, C, D and E of claim 1. - 4. 5-Substituted picolinic acids and the salts thereof represented by the formula (II) as defined in claim 2 wherein R1 and M are the same as defined in claim 1 when prepared by a process as claimed in claim 2 or an obvious chemical equivalent.
- 5. A process for preparing compounds represented by the formula (III) as defined in claim 1 wherein R1 and R201 are the same as defined in claim 1 comprising a process selected from the group of processes consisting of the processes of parts F, G and H of claim 1.
- 6. Compounds represented by the formula (III) as defined in claim 1 wherein R1 and R201 are the same as defined in claim 1 when prepared by the process of claim 5 or an obvious chemical equivalent.
- 7. A process for preparing 5-(4-chlorobutoxy)picolinic acid and salts thereof comprising the process of part A of claim 1 including:
reacting 5-hydroxy-2-hydroxymethylpyridine with tetramethylene chloride to produce 5-(4-chlorobutoxy)-2 hydroxymethylpyridine, and oxidizing the 5-(4-chlorobutoxy)-2-hydroxymethylpyridine with an oxidizing agent. - 8. 5-(4-Chlorobutoxy)picolinic acid and salts thereof when prepared by the process of claim 7 or an obvious chemical equivalent.
- 9. A process for preparing 5-(3-chloropropoxy)picolinic acid and salts thereof comprising the process of part A of claim 1 including:
reacting-5-hydroxy-2-hydroxymethylpyridine with 1,3-dichloropropane to produce 5-(3-chloropropoxy)-2-hydroxymethyl-pyridine, and oxidizing the 5-(3-chloropropoxy)-2-hydroxymethylpyridine with an oxidizing agent. - 10. 5-(3-Chloropropoxy)picolinic acid and salts thereof when prepared by the process of claim 8 or an obvious chemical equivalent.
- 11. A process for preparing 5-(5,5,5-trifluoropentyloxy)-picolinic acid and salts thereof comprising the process of part A of claim 1 including:
reacting 5-hydroxy-2-hydroxymethylpyridine with 1,1,1-trifluoro-5-bromopentane to produce 5-(5,5,5-trifluoropentyloxy)-2-hydromethylpyridine, and oxidizing the 5-(5,5,5-trifluoropentyloxy)-2-hydroxymethyl-pyridine with an oxidizing agent. - 12. 5-(5,5,5-Trifluoropentyloxy)picolinic acid and salts thereof when prepared by the process of claim 11 or an obvious chemical equivalent.
13. A process for preparing 5-(p-chlorophenoxy)picolinic acid and salts thereof comprising the process of part B of claim 1 including: - Claim 13 continued....
reacting 5-hydroxy-2-methylpyridine with bromochlorobenzene to produce 5-(p-chlorophenoxy)-2-methylpyridine, and oxidizing the 5-(p-chlorophenoxy)-2-methylpyridine with an oxidizing agent. - 14. 5-(p-Chlorophenoxy)picolinic acid and salts thereof when prepared by the process of claim 13 or an obvious chemical equivalent.
- 15. A process for preparing 5-(o-chlorophenoxy)picolinic acid and salts thereof comprising the process of part B of claim 1 including:
reacting 5-hydroxy-2-methylpyridine with o-bromochlorobenzene to produce 5-(o-chlorophenoxy)-2-methylpyridine, and oxidizing the 5-(o-chlorophenoxy)-2-methylpyridine with an oxidizing agent. - 16. 5-(o-Chlorophenoxy)picolinic acid and salts thereof when prepared by the process of claim 15 or an obvious chemical equivalent.
- 17. A process for preparing 5-(p-trifluoromethylphenoxy)-picolinic acid and salts thereof comprising the process of part B of claim 1 including:
reacting 5-hydroxy-2-methylpyridine and p-bromobenzo-trifluoride to produce 5-(p-trifluoromethylphenoxy)-2-methyl-pyridine, and oxidizing the 5-(p-trifluoromethylphenoxy)-2-methylpyridine with an oxidizing agent. - 18. 5-(p-Trifluoromethylphenoxy)picolinic acid and salts thereof when prepared by the process of claim 17 or an obvious chemical equivalent.
- 19. A process for producing 5-(o-trifluoromethylphenoxy)-picolinic acid and salts thereof comprising the process of part B of claim 1 including:
reacting 5-hydroxy-2-methylpyridine with o-bromobenzo-trifluoride to produce 5-(o-trifluoromethylphenoxy)-2-methyl-pyridine, and oxidizing the 5-(o-trifluoromethylphenoxy)-2-methylpyridine with an oxidizing agent. - 20. 5-(o-Trifluoromethylphenoxy)picolinic acid and salts thereof when prepared by the process of claim 19 or an obvious chemical equivalent.
- 21. A process for producing 5-(4,4,4,-trifluorobutoxy)-picolinic acid and salts thereof comprising the process of part A of claim 1 including:
reacting 5-hydroxy-2-hydroxymethylpyridine with 1,1,1-trifluoro-4-bromobutane to produce 5-(4,4,4-trifluorobutoxy)-2-hydromethylpyridine, and oxidizing the 5-(4,4,4,-trifluorobutoxy)-2-hydromethyl-pyridine with an oxidizing agent. - 22. 5-(4,4,4-Trifluorobutoxy)picolinic acid and salts thereof when prepared by the process of claim 19 or an obvious chemical equivalent.
1. A process for preparing 5-substituted picolinic acids and the salts, esters and acid amides thereof represented by the formula (I):
(I) wherein Rl represents a straight or branched chain halogen-substituted alkyl group having 2 to 6 carbon atoms or a phenyl group of the formula wherein R3 and R4, which may be the same or different, each represents a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxy group having 1 to 3 carbon atoms, a nitro group, an amino group, an acetyl group, or a halogen-substituted alkyl group having 1 to 3 carbon atoms; and R2 represents an -OM
group wherein M represents a hydrogen atom, a sodium atom, a potassium atom, a calcium atom, an aluminium atom or a magnesium atom, a straight or branched chain or cyclic alkoxy group having 1 to 6 carbon atoms, a 5-indanyloxy group, an acyloxy alkoxy group of the formula wherein R5 represents a hydrogen atom or a methyl group and R6 represents a lower alkyl group having 1 to 6 carbon atoms, or an amino group represented by the formula wherein R7 and R8, which may be the same or different, each represents a hydrogen atom, a lower alkyl group or a phenyl group, which comprises a process selected from the group of processes comprising:
Claim 1 continued....
(A) a process for preparing 5-substituted picolinic acids represented by the formula (II-a):
(II-a) wherein R101 represents a straight or branched chain halogen-substituted alkyl group having 2 to 6 carbon atoms, which comprises reacting a compound represented by the formula (IV):
(IV) wherein R9 represents a methyl group or a hydroxymethyl group, with a halide represented by the formula (V):
R101X (V) wherein R101 is the same as defined above and X represents a halogen atom, to obtain a compound represented by the formula (VI):
(VI) wherein R9 and R101 are the same as defined above, and oxidizing the compound of the formula (VI) with an oxidizing agent;
(B) a process for preparing a 5-substituted picolinic acid represented by the formula (II-b):
(II-b) wherein R3 and R4 are the same as defined above, which comprises reacting a compound represented by the formula (IV) as defined above, wherein R9 is the same as defined above, with a Claim 1 continued....
halobenzene derivative represented by the formula (VII):
(VII) wherein R3, R4 and X are the same as defined above, to obtain a compound represented by the formula (VIII):
(VIII) wherein R3, R4 and R9 are the same as defined above, and then oxidizing the compound of the formula (VIII) with an oxidizing agent;
(C) a process for preparing a compound represented by the formula (II-c):
(II-c) .
wherein R401 represents a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxy group having 1 to 3 carbon atoms, an amino group, an acetyl group, or a halogen-substituted alkyl group having 1 to 3 carbon atoms, which comprises the steps of:
(i) preparing, according to the process of part B above, a compound represented by the formula (II-b) as defined above wherein R3 and R4 are the same as defined above and at least one of R3 and R4 is a nitro group, and Claim 1 continued....
(ii) reducing the product of step (C)(i);
(D) a process for preparing a compound represented by the formula (II-d):
(II-d) wherein X is the same as defined above and R402 represents a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxy group having 1 to 3 carbon atoms, an acetyl group, or a halogen-substituted alkyl group having 1 to 3 carbon atoms, which comprises the process of part C above further including diazotizing the compound represented by formula (II-c) as defined above wherein R401 is as defined above, with sodium nitrite to obtain a diazonium salt and substituting the diazonium salt with a halogen atom;
(E) a process for preparing a 5-substituted picolinic acid represented by the formula (II-e):
.
(II-e) wherein R301 and R403, which may be the same or diferent,each represents a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxy group having 1 to 3 carbon atoms, a nitro group, an amino group, an acetyl group or a halogen-substituted alkyl group having 1 to 3 carbon atoms, which com-prises reacting a compound represented by the formula (IX):
(IX) Claim 1 continued...
wherein R9 and X are the same as defined above, with a phenol represented by the formula (X):
(X) wherein R301 and R403 are as defined above, to obtain a compound represented by the formula (VIII-a):
(VIII-a) wherein R301, R403 and R9 are the same as defined above, and then oxidizing the compound of the formula (VIII-a) with an oxidizing agent;
(F) a process for preparing a 5-substituted picolinic acid ester or amide represented by the formula (III):
(III) wherein R1 is the same as defined above and R201 represents a straight or branched chain or cyclic alkoxy group having 1 to 6 carbon atoms, a 5-indanyloxy group, an acyloxyalkyloxy group represented by the formula wherein R5 and R6 are the same as defined above, which comprises:
preparing a 5-substituted picolinic acid or a metal salt thereof represented by the formula (II):
(II) Claim 1 continued.....
wherein M and R1 are the same as defined above, according to a process selected from the group of processes consisting of the processes of parts A, B, C, D and E above, followed by reacting the resultant acid or metal salt thereof of the formula (II), (i) with an aliphatic alcohol having 1 to 6 carbon atoms, 5-indanol or an amine having the formula (XI):
(XI) wherein R7 and R8 are the same as defined above, in the presence of an acid catalyst or a condensation agent, or (ii) with an acyloxyalkyl halide represented by the formula (XII-a):
(XII-a) wherein X and R5 are the same as defined above and R601 represents a lower alkyl group having 1 to 6 carbon atoms, in the presence of a base;
(G) a process for preparing a 5-substituted picolinic acid ester or amide represented by the formula (III):
(III) wherein R1 and R201 are the same as defined above, which comprises the steps of:
(i) preparing an acid represented by the formula (XX):
Claim 1 continued...
(XX) wherein R1 is the same as defined above, according to a process selected from the group of processes consisting of the pro-cesses of parts A, B, C, D and E above, (ii) preparing an acid halide represented by the formula (XIII):
(XIII) wherein R1 and X are the same as defined above, by reacting the acid produced in step G(i) with an acid halogenating reagent,and (iii) reacting the acid halide produced in step G(ii) with an aliphatic alcohol having 1 to 6 carbon atoms, 5-indanol, an amine of the formula (XI):
(XI) .
wherein R7 and R8 are the same as defined above, or acyloxy-alkanols having the formula (XIV):
(XIV) wherein R5 and R6 are the same as defined above, in the presence of a base; and (H) a process for preparing a 5-substituted picolinic acid amide represented by the formula (III-b):
(III-b)
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP32967/78 | 1978-03-24 | ||
JP3296678A JPS54125680A (en) | 1978-03-24 | 1978-03-24 | 5-alkoxypicolinic acid ester, its preparation, and hypotensive agent containing the same |
JP32966/78 | 1978-03-24 | ||
JP3296778A JPS54125681A (en) | 1978-03-24 | 1978-03-24 | 5-substituted picolinic acid, its preparation, and hypotensive agent containing the same |
JP80485/78 | 1978-07-04 | ||
JP8048578A JPS559002A (en) | 1978-07-04 | 1978-07-04 | 5-substituted picolinic acid derivative, its preparation and hypotensive agent containing the same |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1115709A true CA1115709A (en) | 1982-01-05 |
Family
ID=27287919
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA323,912A Expired CA1115709A (en) | 1978-03-24 | 1979-03-21 | 5-substituted-hydroxy picolinic acid derivatives |
Country Status (9)
Country | Link |
---|---|
CA (1) | CA1115709A (en) |
CH (1) | CH637941A5 (en) |
DE (1) | DE2911492C2 (en) |
ES (1) | ES478918A1 (en) |
FR (1) | FR2422639A1 (en) |
GB (1) | GB2018753B (en) |
IT (1) | IT1115064B (en) |
NL (1) | NL178251C (en) |
SE (1) | SE446863B (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5344572A (en) * | 1976-09-30 | 1978-04-21 | Meiji Seika Kaisha Ltd | 5-alkoxy-picolic acid, its preparation and hypotensives containing the same |
-
1979
- 1979-03-21 CA CA323,912A patent/CA1115709A/en not_active Expired
- 1979-03-22 CH CH268779A patent/CH637941A5/en not_active IP Right Cessation
- 1979-03-22 IT IT48451/79A patent/IT1115064B/en active
- 1979-03-23 GB GB7910324A patent/GB2018753B/en not_active Expired
- 1979-03-23 DE DE2911492A patent/DE2911492C2/en not_active Expired
- 1979-03-23 SE SE7902665A patent/SE446863B/en not_active IP Right Cessation
- 1979-03-23 NL NLAANVRAGE7902306,A patent/NL178251C/en not_active IP Right Cessation
- 1979-03-23 ES ES478918A patent/ES478918A1/en not_active Expired
- 1979-03-23 FR FR7907345A patent/FR2422639A1/en active Granted
Also Published As
Publication number | Publication date |
---|---|
IT7948451A0 (en) | 1979-03-22 |
GB2018753B (en) | 1982-08-25 |
IT1115064B (en) | 1986-02-03 |
DE2911492C2 (en) | 1983-05-05 |
FR2422639A1 (en) | 1979-11-09 |
NL7902306A (en) | 1979-09-26 |
SE7902665L (en) | 1979-09-25 |
NL178251C (en) | 1986-02-17 |
CH637941A5 (en) | 1983-08-31 |
ES478918A1 (en) | 1979-12-16 |
SE446863B (en) | 1986-10-13 |
GB2018753A (en) | 1979-10-24 |
DE2911492A1 (en) | 1979-09-27 |
FR2422639B1 (en) | 1983-05-20 |
NL178251B (en) | 1985-09-16 |
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