NO152605B - Analogifremgangsmaate for fremstilling av terapeutisk aktive 2-pyridyl- og 2-pyrimidylaminobenzoesyrer - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive 2-pyridyl- og 2-pyrimidylaminobenzoesyrer Download PDFInfo
- Publication number
- NO152605B NO152605B NO782707A NO782707A NO152605B NO 152605 B NO152605 B NO 152605B NO 782707 A NO782707 A NO 782707A NO 782707 A NO782707 A NO 782707A NO 152605 B NO152605 B NO 152605B
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- group
- formula
- salts
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- 238000000034 method Methods 0.000 title claims description 10
- -1 2-PYRIDYL Chemical class 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 6
- 239000002253 acid Substances 0.000 title 1
- 150000007513 acids Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 26
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- NNTYAXNEQRSVAQ-UHFFFAOYSA-N 2-(pyrimidin-2-ylamino)benzoic acid Chemical class OC(=O)C1=CC=CC=C1NC1=NC=CC=N1 NNTYAXNEQRSVAQ-UHFFFAOYSA-N 0.000 claims 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000003368 amide group Chemical group 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000003266 anti-allergic effect Effects 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- CZZZABOKJQXEBO-UHFFFAOYSA-N 2,4-dimethylaniline Chemical compound CC1=CC=C(N)C(C)=C1 CZZZABOKJQXEBO-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- YCCFKQJMEAZOEL-UHFFFAOYSA-N [K].[K].OC(=O)C1=CC=C(NC2=NC=CC=C2)C(=C1)C(O)=O Chemical compound [K].[K].OC(=O)C1=CC=C(NC2=NC=CC=C2)C(=C1)C(O)=O YCCFKQJMEAZOEL-UHFFFAOYSA-N 0.000 description 2
- SGXZYXPQUYNQCW-UHFFFAOYSA-N [Na].[Na].N1=C(C=CC=C1)NC1=C(C(=O)O)C=C(C=C1)C1=NN=NN1 Chemical compound [Na].[Na].N1=C(C=CC=C1)NC1=C(C(=O)O)C=C(C=C1)C1=NN=NN1 SGXZYXPQUYNQCW-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000001760 anti-analgesic effect Effects 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000002211 ultraviolet spectrum Methods 0.000 description 2
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 1
- 150000005749 2-halopyridines Chemical class 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 101100295741 Gallus gallus COR4 gene Proteins 0.000 description 1
- 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 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- UDSRZOLOSFWAPY-UHFFFAOYSA-N [Na].N1=C(C=CC=C1)NC1=C(C(=O)O)C=C(C=C1)C#N Chemical compound [Na].N1=C(C=CC=C1)NC1=C(C(=O)O)C=C(C=C1)C#N UDSRZOLOSFWAPY-UHFFFAOYSA-N 0.000 description 1
- BRTGFTYFAJEWOE-UHFFFAOYSA-N [Na].[Na].N1=C(C=CC=C1)NC1=C(C=C(C(=O)O)C=C1)C(=O)O Chemical compound [Na].[Na].N1=C(C=CC=C1)NC1=C(C=C(C(=O)O)C=C1)C(=O)O BRTGFTYFAJEWOE-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000003182 bronchodilatating effect Effects 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000004993 o-toluidines Chemical class 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 239000001120 potassium sulphate Substances 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229930195735 unsaturated hydrocarbon Chemical group 0.000 description 1
- 230000000304 vasodilatating effect Effects 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
-
- 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- 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
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Medicinal Preparation (AREA)
Description
Denne oppfinnelse angår fremstilling av de i kravet definerte forbindelser ved de i kravet angitte fremgangsmåter.
C1~C'4 a-*-kyl- °9 alkoksygrupper kan være lineære eller forgrenede, f.eks. metyl, etyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl og de tilsvarende alkoksygrupper, formyl, acetyl, propionyl og butyryl. ;og R_ betyr fortrinnsvis hydrogen, en påkondensert benzenring eller en karboksylgruppe og også en tetrazol-5-ylrest. Når det gjelder salter med basiske komponenter, er slike først og fremst alkali- eller jordalkalibasr, f.eks. kalium- eller natriumhydroksyd, eller sterke organiske baser, f.eks. lavere alkylaminer, etanolamin, di- eller trietanolamin. ;Forbindelsene ifølge US-patent 1.810.267 inneholder, foruten alkylresten R, bare COOH som substituent. Forbindelsene som fremstilles ifølge foreliggende oppfinnelse inneholder nødvendigvis en COOH-gruppe i 2-stilling i fenylresten og en ytterligere "sur" gruppe (COR4, tetrazolyl eller CN). Dette synes å være vesentlig, eftersom forbindelsene ifølge US-patentet ikke er antiallergisk aktive. Forøvrig er det i patent-skriftet ikke angitt noen konkret terapeutisk virkning. ;Ifølge britisk patent 964.143 inneholder fenylresten bare én karboksygruppe eller et funksjonelt derivat derav. Forbindelsene er heller ikke antiallergisk aktive, men derimot antiinflammatoriske og analgetiske (side 1, linje 29). ;Forbindelsene ifølge britisk patent 1.064.259 (og videreutviklingen 1.162.287) kommer forholdsvis nær forbindelsene fremstilt ifølge oppfinnelsen. Forbindelsene angis å være analgetiske og antiinf lammatoriske (side 1., linje 55-56). Det nevnes intet om antiallergiske virkning. Undersøkelse har vist at f.eks. forbindelsen beskrevet i eksempel VII i patentet (dinatriumsaltet) ikke har noen oral antiallergisk virkning (i et rimelig doseområde, dvs. opptil 100 mg/kg). ;Forbindelsene beskrevet i britisk patent 1.264.798 ;står i et lignende forhold til foreliggende oppfinnelse som angitt for forbindelsene ifølge 1.064.259. Forbindelsene er angitt å være antiinflammatoriske og analgetiske. Det nevnes intet om en (særlig oral) antiallergisk virkning. ;Oksydasjonen ifølge fremgangsmåte a) foretas med sterke oksydasjonsmidler, f.eks. kaliumpermanganat i vandig oppløsning som er bufret med magnesiumsulfat. Reaksjonstemperaturen ligger fortrinnsvis mellom romtemperatur og reaksjonsblandingens koketemperatur. For avspaltning av N-acylgruppen foretas eventuelt påfølgende alkalisk forsepning, f.eks. med kaliumhydroksyd. ;Resten R kan være en alifatisk hydrokarbonrest, særlig en lavere alkylgruppe, f.eks. metyl, eller en umettet hydrokarbonrest, eller også en delvis oksydert hydrokarbonrest, f.eks. en hydrokarbonrest som er substituert med hydroksygrupper, oksogrupper eller halogenatomer.• ;Utgangsstoffene kan fremstilles på i og for seg kjent måte, f.eks. ved omsetning av 2-halogenpyridiner med o-toluidin-derivater og påfølgende acylering. ;For ringåpningen ifølge fremgangsmåte b) kan som basiske stoffer særlig anvendes alkalier, f.eks. natronlut og kalilut, idet reaksjonstemperaturen fortrinnsvis ligger mellom romtemperatur og reaksjonsblandingens koketemperatur. Utgangsstoffene kan fremstilles på i og for seg kjent måte, omtrentlig slik som beskrevet i tysk offentliggjørelsesskrift 25 57 425.8. ;Nitriler kan overføres til de tilsvarende tetrazol-5-yl-forbindelser ved omsetning med natriumazid ifølge fremgangsmåte d). Alkalisk hydrolyse av forbindelse med ester-eller karbamoylgrupper ifølge fremgangsmåte c) kan anvendes for fremstilling av tilsvarende karboksysubstituerte forbind-eiser. Når R^ er acyl, avspaltes den samtidig. ;Utgangsstoffene kan fremstilles ved i og for seg kjente fremgangsmåter. ;De nye forbindelser fremstilt ifølge oppfinnelsen ;er terapeutisk anvendelige. Særlig skal -fremheves deres anti — allergiske virkning. Denne kan anvendes for forebyggelse og behandling av allergiske sykdommer så som astma eller også ;ved høyfeber, conjunctivitt, neslefeber, eksem og atopisk derma-titt. Forbindelsene viser dessuten muskelavslappénde (bronko-dilatorisk) og vasodilatorisk virkning. Når det gjelder den viktigste anvendelse, nemlig astma-forebyggelse, er den fordel i forhold til handelsproduktet dinatriumkromoglykat at de nye forbindelser har en lengre virkningsvarighet og særlig en ;gunstigere oral virkning. ;For anvendelse tilberedes de nye forbindelser på vanlig måte med hjelpe- og bærestoffer til egnede galeniske preparater, f.eks. til kapsler, tabletter, dragéer, oppløsninger, suspensjon-er for oral anvendelse; til aerosoler for pulmonal anvendelse; til sterile, isotoniske, vandige oppløsninger for parenteral anvendelse og til kremer, salver, vann, emulsjoner eller spray-preparater for lokal anvendelse. ;Enkeltdosen er avhengig av indikasjonen, f.eks. av beskaffenheten av den allergiske tilstand. I alminnelighet utgjør dosen pr. kg. kroppsvekt ved pulmonal anvendelse 20 500 \ jg, ved intravenøs anvendelse 0,2 - 10 mg og ved oral av-vendelse 1-50 mg. Nasalt eller okulart anvendes 0,5 - 25 ;mg. ;De følgende eksempler illustrerer fremgangsmåtene ifølge oppfinnelsen. ;UV-spektrene ble oppnådd med et spektralfotometer. ;Hver gang ble 10 - 20 mg av forbindelsen nøye innveid og - når det gjelder forbindelsene merket med <*> efter oppløsning med 10 ml dimetylsulfoksyd - oppløst resp. fortynnet i 0,01 n natronlut. Man valgte de langbølgede absorpsjonsbånd. Absorpsjons-maksimum er angitt som x maks [nm] med de tilhørende molare logaritmiske ekstinksjonskoeffisienter log e.
Eks empel 1
4-( 2- pyridylamino)- isoftalsyre- dikalium
4,8 g N-(2-pyridyl)-2,4-dimetylacetanilid (sm.p. 46-50°C), fremstilt fra 2-klorpyridin og 2,4-dimetylanilin ved 160-170°C og påfølgende acetylering med eddiksyreanhydrid, oppløses sammen med 2,4 g magnesiumsulfat i vann. Til oppløsningen oppvarmet til 30°C settes porsjonsvis 12,64 g kaliumpermanganat. Omrøring foretas i 2 timer ved 80 - 90°C på vannbad, det dannede mangan-dioksyd avsuges i varm tilstand og vaskes med vann. Efter inndampning av oppløsningen til et volum på 50 ml, fortynnes den med 50 ml etanol, og det utfelte kaliumsulfat avsuges. Den alko-
holisk-vandige oppløsning inndampes i vakuum, og residuet bringes til krystallisasjon med etanol/eter. 1 g av det således erholdte N-acetyl-N-(2-pyridyl)-4-amino-isoftalsyredikalium kokes i 2 timer med 0,4 g kaliumhydroksyd i 10 ml vann under tilbakeløpskjøling, og residuet utgnis med etanol/eter. 4-(2-pyridylamino)-isoftalsyre-dikalium (karakterisert ved NMR-spektrum) utkrystalliserer.
Smeltepunkt >200°C (dekomp.).
Elementæranalyse:
<C>13<H>8<N>2°4K2 M = 334'4
Eksempel 2
4-( 2- pyridylamino)- isoftalsyre- dinatrium
C02Na
<^ ^) NH- <^ ^) C02Na x 2 H20
5,24 g ll-H-ll-okso-pyrido[2,1-b]kinazolin-2-karboksyl-syre-natrium oppvarmes med 20 ml 1 n natronlut i 1 time på vannbad. Det dannes en klar, gul oppløsning. Derefter avdrives vannet azeotropt med kloroform. Krystallene opptas i litt eter, avsuges og tørres i vakuum ved 60°C.
Analyse: C13HgN204Na2 x 2 H20
Eksempel 3 2-( 2- pyridylamino)- 5-( lH- tetrazol- 5- yl)- benzoesyre- dinatrium 8 g ll-H-ll-oksopyrido[2,l-b]-2-(lH-tetrazol-5-yl)-kinazolin oppvarmes i 2 timer med 60,6 ml 1 n natronlut til 70°C. Derefter avdestilleres vannet. Krystallene oppslemmes med litt eter, avsuges og tørres ved 60°C i vakuum. Analyse: C13HgN602Na2 x 3 H20 Eks empel 4 2-"( 2- pyridylamino) - 5- ( lH- tetrazol- 5- yl) - benzoesyre- dinatrium 6,2 g 2-(2-pyridylamino)-5-cyano-benzoesyrenatrium, 1,8 g natriumazid og 1,5 g ammoniumklorid oppvarmes i 60 ml dimetylformamid i 10 timer til 100°C. Efter fraskillelse av uorganiske bestanddeler foretas inndampning, og residuet utgnis med etanol/eter.
På analog måte fremstilles følgende forbindelser (som natriumsalter); UV-spektrene for Na-saltene er angitt:
Claims (1)
- Analogifremgangsmåte for fremstilling av terapeutiskaktive 2-pyridyl- og 2-pyrimidylaminobenzoesyrer med formelenhvorA betyr =CH- eller =N-,betyr hydrogen, C-^-C^ alkyl, en benzenring kondensert tilden heterocykliske ring i dens 5,6-stilling, en eventueltacetylert aminogruppe eller en gruppe -COOH,R2 betyr -CO-R4, tetrazol-5-yl, cyan, eller, hvis R^ betyr -COOH,også hydrogen, C^-C^ alkoksy eller en benzenring som erkondensert til den substituerte fenylgruppe i dens 3,4-stilling,og R^ betyr en hydroksy-, amino-, hydroksylamino-, tetrazol-5-ylamino-gruppe eller en lavere alkoksygruppe,eventuelt i form av indre salter eller salter med basiskekomponenter, karakterisert ved at a) en forbindelse med formelenhvor R er en rest som kan omvandles oksydativt til en COOH-gruppe, oksyderes, og N-acylgruppen avspaltes, eller b) en forbindelse med formelenbehandles med basiske stoffer, eller c) for fremstilling av forbindelser med formel I hvor minst en av restene R^ og R2 betyr en karboksylgruppe, forsepes basisk eller surt en forbindelse med formelenhvor minst en av restene R^' og R2' betyr en (over karbonyl-gruppen til ringen bundet) ester- eller amidgruppe, A har den ovenfor angitte betydning og R^' betyr H eller acyl, eller d) for fremstilling av forbindelser med formel I hvor R2 betyr en tetrazol-5-yl-gruppe, omsettes et tilsvarende nitril med natriumazid,og salter med baser erholdt ved fremgangsmåtene a) til d) omvandles eventuelt til indre salter og/eller indre salter omvandles eventuelt til salter med baser.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772735919 DE2735919A1 (de) | 1977-08-10 | 1977-08-10 | Neue 2-pyridyl- und 2-pyrimidylaminobenzoesaeuren |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO782707L NO782707L (no) | 1979-02-13 |
| NO152605B true NO152605B (no) | 1985-07-15 |
| NO152605C NO152605C (no) | 1985-10-23 |
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ID=6016013
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO782707A NO152605C (no) | 1977-08-10 | 1978-08-09 | Analogifremgangsmaate for fremstilling av terapeutisk aktive 2-pyridyl- og 2-pyrimidylaminobenzoesyrer |
Country Status (32)
| Country | Link |
|---|---|
| US (1) | US4241068A (no) |
| JP (1) | JPS5430177A (no) |
| AT (1) | AT370415B (no) |
| AU (1) | AU520240B2 (no) |
| BE (1) | BE869640A (no) |
| BG (1) | BG30472A1 (no) |
| CA (1) | CA1111037A (no) |
| CH (1) | CH649289A5 (no) |
| CS (1) | CS202506B2 (no) |
| DD (1) | DD140351A5 (no) |
| DE (1) | DE2735919A1 (no) |
| DK (1) | DK148019C (no) |
| ES (5) | ES472143A1 (no) |
| FI (1) | FI71555C (no) |
| FR (1) | FR2400017A1 (no) |
| GB (1) | GB2002764B (no) |
| GR (1) | GR65024B (no) |
| HU (1) | HU179933B (no) |
| IE (1) | IE47228B1 (no) |
| IT (1) | IT1107960B (no) |
| LU (1) | LU80094A1 (no) |
| MX (1) | MX5672E (no) |
| NL (1) | NL7808319A (no) |
| NO (1) | NO152605C (no) |
| NZ (1) | NZ188101A (no) |
| PH (1) | PH19117A (no) |
| PL (2) | PL115778B1 (no) |
| PT (1) | PT68407A (no) |
| SE (1) | SE444170B (no) |
| SU (2) | SU735168A3 (no) |
| YU (1) | YU40832B (no) |
| ZA (1) | ZA784501B (no) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3100516A1 (de) * | 1981-01-10 | 1982-08-12 | C.H. Boehringer Sohn, 6507 Ingelheim | Pyridylaminobenzoesaeuren, ihre herstellung und verwendung |
| FR2533567A1 (fr) * | 1982-09-23 | 1984-03-30 | Ki I Farmakologii | 2-(orthocarboxyphenylamino)-6h-pyrimido (2,1-b)-quinazolone-6 et ses derives, leur procede de preparation et leur application therapeutique |
| US4610991A (en) * | 1983-04-18 | 1986-09-09 | Sterling Drug Inc. | Antihypertensive pyridylaminobenzamide compounds |
| JPS60100559A (ja) * | 1983-11-05 | 1985-06-04 | Morishita Seiyaku Kk | ２−アニリノ−１，６−ジヒドロ−６−オキソ−５−ピリミジンカルボン酸誘導体，その製法及び該化合物を含有する抗アレルギ−剤 |
| US4584379A (en) * | 1985-01-22 | 1986-04-22 | Merrell Dow Pharmaceuticals Inc. | Isoquinoline thromboxane synthetase inhibitors |
| ATE68789T1 (de) * | 1985-10-16 | 1991-11-15 | Merck Frosst Canada Inc | 2-substituierte chinoline. |
| GB9615950D0 (en) * | 1996-07-30 | 1996-09-11 | Univ Warwick | Variable reluctance machines |
| US6022884A (en) | 1997-11-07 | 2000-02-08 | Amgen Inc. | Substituted pyridine compounds and methods of use |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1064259A (en) * | 1963-12-19 | 1967-04-05 | Union Pharma Scient Appl | New derivatives of 2-anilino-nicotinic acid and process for their preparation |
| GB1162287A (en) * | 1967-11-07 | 1969-08-20 | Union Pharma Scient Appl | New Salts of 2-Anilino-Nicotinic Acids |
| GB1264798A (no) * | 1968-07-10 | 1972-02-23 | ||
| ES416847A1 (es) * | 1973-07-12 | 1976-03-01 | Hermes Sa Lab | Procedimiento para la obtencion de derivados del acido ni- cotinico. |
-
1977
- 1977-08-10 DE DE19772735919 patent/DE2735919A1/de active Granted
-
1978
- 1978-06-27 FI FI782039A patent/FI71555C/fi not_active IP Right Cessation
- 1978-07-07 GR GR56729A patent/GR65024B/el unknown
- 1978-07-28 AT AT0549278A patent/AT370415B/de not_active IP Right Cessation
- 1978-07-28 ES ES472143A patent/ES472143A1/es not_active Expired
- 1978-07-31 PH PH21447A patent/PH19117A/en unknown
- 1978-08-07 MX MX787292U patent/MX5672E/es unknown
- 1978-08-07 CH CH8381/78A patent/CH649289A5/de not_active IP Right Cessation
- 1978-08-08 SU SU782646404A patent/SU735168A3/ru active
- 1978-08-08 BG BG7840623A patent/BG30472A1/xx unknown
- 1978-08-08 LU LU80094A patent/LU80094A1/de unknown
- 1978-08-08 IT IT50642/78A patent/IT1107960B/it active
- 1978-08-08 DD DD78207180A patent/DD140351A5/de unknown
- 1978-08-09 HU HU78BO1727A patent/HU179933B/hu not_active IP Right Cessation
- 1978-08-09 SE SE7808530A patent/SE444170B/sv not_active IP Right Cessation
- 1978-08-09 IE IE1618/78A patent/IE47228B1/en unknown
- 1978-08-09 DK DK351978A patent/DK148019C/da not_active IP Right Cessation
- 1978-08-09 GB GB7832731A patent/GB2002764B/en not_active Expired
- 1978-08-09 ZA ZA784501A patent/ZA784501B/xx unknown
- 1978-08-09 JP JP9626278A patent/JPS5430177A/ja active Granted
- 1978-08-09 CS CS785205A patent/CS202506B2/cs unknown
- 1978-08-09 NO NO782707A patent/NO152605C/no unknown
- 1978-08-09 AU AU38772/78A patent/AU520240B2/en not_active Expired
- 1978-08-09 PL PL1978208942A patent/PL115778B1/pl unknown
- 1978-08-09 PT PT68407A patent/PT68407A/pt unknown
- 1978-08-09 NZ NZ188101A patent/NZ188101A/xx unknown
- 1978-08-09 PL PL1978215270A patent/PL115889B1/pl unknown
- 1978-08-09 CA CA308,978A patent/CA1111037A/en not_active Expired
- 1978-08-09 YU YU1916/78A patent/YU40832B/xx unknown
- 1978-08-09 BE BE78189801A patent/BE869640A/xx not_active IP Right Cessation
- 1978-08-09 NL NL787808319A patent/NL7808319A/xx not_active Application Discontinuation
- 1978-08-10 FR FR7823617A patent/FR2400017A1/fr active Granted
- 1978-11-28 ES ES475456A patent/ES475456A1/es not_active Expired
- 1978-11-28 ES ES475457A patent/ES475457A1/es not_active Expired
-
1979
- 1979-05-16 ES ES480623A patent/ES480623A1/es not_active Expired
- 1979-05-16 ES ES480622A patent/ES480622A1/es not_active Expired
- 1979-05-21 SU SU792765447A patent/SU886743A3/ru active
- 1979-08-07 US US06/064,355 patent/US4241068A/en not_active Expired - Lifetime
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