NO180446B - 2,4- og 2,5-bis-tetrazolylpyridiner og deres anvendelse som legemiddel - Google Patents
2,4- og 2,5-bis-tetrazolylpyridiner og deres anvendelse som legemiddel Download PDFInfo
- Publication number
- NO180446B NO180446B NO920462A NO920462A NO180446B NO 180446 B NO180446 B NO 180446B NO 920462 A NO920462 A NO 920462A NO 920462 A NO920462 A NO 920462A NO 180446 B NO180446 B NO 180446B
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- Prior art keywords
- bis
- pyridine
- hydroxylase
- collagen
- proline
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- BOHMMCZTSDZIBJ-UHFFFAOYSA-N 2,5-bis(2h-tetrazol-5-yl)pyridine Chemical class C1=CC(C=2NN=NN=2)=NC=C1C1=NN=NN1 BOHMMCZTSDZIBJ-UHFFFAOYSA-N 0.000 title abstract description 9
- 239000003814 drug Substances 0.000 title description 6
- 229940079593 drug Drugs 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 102000004079 Prolyl Hydroxylases Human genes 0.000 abstract description 16
- 108010043005 Prolyl Hydroxylases Proteins 0.000 abstract description 16
- 102000008490 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Human genes 0.000 abstract description 8
- 108010020504 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Proteins 0.000 abstract description 8
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 230000036570 collagen biosynthesis Effects 0.000 abstract description 3
- 229920001436 collagen Polymers 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 102000008186 Collagen Human genes 0.000 description 5
- 108010035532 Collagen Proteins 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 4
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- VGLDXXCENJFTCG-UHFFFAOYSA-N 2,4-bis(2h-tetrazol-5-yl)pyridine Chemical compound N=1C=CC(C=2NN=NN=2)=CC=1C1=NN=NN1 VGLDXXCENJFTCG-UHFFFAOYSA-N 0.000 description 3
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- -1 3-isopropoxypropyl Chemical group 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 102000004266 Collagen Type IV Human genes 0.000 description 2
- 108010042086 Collagen Type IV Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- YXHPFSCDWSLLRT-UHFFFAOYSA-N pyridine-2,5-dicarbonitrile Chemical compound N#CC1=CC=C(C#N)N=C1 YXHPFSCDWSLLRT-UHFFFAOYSA-N 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- HORQAOAYAYGIBM-UHFFFAOYSA-N 2,4-dinitrophenylhydrazine Chemical compound NNC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O HORQAOAYAYGIBM-UHFFFAOYSA-N 0.000 description 1
- JUCNGMPTCXPMNB-UHFFFAOYSA-N 2-n,4-n-bis(2-methoxyethyl)pyridine-2,4-dicarboxamide Chemical compound COCCNC(=O)C1=CC=NC(C(=O)NCCOC)=C1 JUCNGMPTCXPMNB-UHFFFAOYSA-N 0.000 description 1
- QQWLSYUKOSYBRH-UHFFFAOYSA-N 2-n,5-n-bis(2-methoxyethyl)pyridine-2,5-dicarboxamide Chemical compound COCCNC(=O)C1=CC=C(C(=O)NCCOC)N=C1 QQWLSYUKOSYBRH-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 102000001187 Collagen Type III Human genes 0.000 description 1
- 108010069502 Collagen Type III Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 244000165918 Eucalyptus papuana Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 208000024781 Immune Complex disease Diseases 0.000 description 1
- LEIKGVHQTKHOLM-IUCAKERBSA-N Pro-Pro-Gly Chemical compound OC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 LEIKGVHQTKHOLM-IUCAKERBSA-N 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 231100000644 Toxic injury Toxicity 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000003837 chick embryo Anatomy 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 150000001470 diamides Chemical class 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- LVPMIMZXDYBCDF-UHFFFAOYSA-N isocinchomeronic acid Chemical class OC(=O)C1=CC=C(C(O)=O)N=C1 LVPMIMZXDYBCDF-UHFFFAOYSA-N 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000010773 plant oil Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Transplantation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Forbindelser som hemmer enzymene prolin- og lysinhydroksylase, bevirker en meget selektiv hemming av kollagenbio-syntesen ved påvirkning av den kollagenspesifikke hydroksyle-ringsreaksjonen. I dette forløpet blir proteinbundet prolin eller lysin hydroksylert ved enzymene prolin- hhv. lysinhydroksylase. Blir denne reaksjonen bundet ved hemming, så oppstår et ikke-funksjonsdyktig, underhydroksylert kollagen-molekyl, som fra cellene bare kan bli avgitt i mindre mengder til det ekstracellulære rom. Det underhydroksylerte kollagen kan dessuten ikke bli bygget inn i kollagenmatriks og blir meget lett proteolyttisk nedbrutt. Som følge av denne effekt forringes den samlede mengden av ekstracellulær opplagret kollagen.
Det er kjent at hemming av prolinhydroksylase ved kjente hemmere som a ,a'-dipyridyl fører til en hemming av Clq-biosyntese av makrofager (W. Muller et al., FEBS Lett. 90
(1978), 218; Immunbiology 155 (1978), 47). Dette er et resultat av den klassiske veien for komplementaktivering. Hemmere av prolinhydroksylase virker derfor også som immunsuppressiva, f.eks. ved immunkomplekssykdommer.
Det er kjent at enzymet prolinhydroksylase effektivt blir hemmet ved pyridin-2,4- og -2,5-dikarboksylsyre (K. Majamaa et al., Eur.J.Biochem. 138 (1984) 239-245). Disse forbindelsene er virksomme i cellekulturen fremfor alt bare i meget høy konsentrasjon som hemmestoffer (Tschank, G. et al., Biochem.J.248 (1987) 625-633).
I DE-A 34 32 094 blir det beskrevet pyridin-2,4- og -2,5-dikarboksylsyrediester med 1-6 C-atomer i esteralkyldelen som legemiddel for hemming av prolin- og lysinhydroksylase.
Disse lav-alkylerte diestrene har imidlertid den ulempen at de raskt blir spaltet i organismen til syrer og lykkes ikke i tilstrekkelig høy konsentrasjon på sitt virkeområde i cellen og egner seg dermed mindre for en eventuell administrering som legemiddel.
DE-A 37 03 959, DE-A 37 03 962 og DE-A 37 03 963 beskriver i generelle former blandede ester/amider, høyere alkylerte diestere og diamider av pyridin-2,4- og -2,5-dikarboksylsyre, som virksomt hemmer kollagenbiosyntese i dyremodell. Således blir det i DE-A 37 03 959 blant annet, beskrevet syntese av N,N'-bis(2-metoksyetyl)-pyridin-2,5-dikarboksylsyrediamid og N , N ' -b i s(3-i sopropoksypropyl)-pyridin-2,4-dikarboksylsyrediamid.
I de tyske patentsøknadene P 38 26 471.4 og P 38 28 140.6 blir det foreslått en forbedret fremgangsmåte for fremstilling av N,N'-bis(2-metoksyetyl)-pyridin-2,4-dikarboksylsyrediamid.
Tysk patentsøknad P 38 26 093.2 foreslår nye N,N'-bis(al-koksyalkyl)-pyridin-2,4-dikarboksylsyrediamid.
Tysk patentsøknad P 40 01 002.3 beskriver anvendelse av pyridin-2,4- og 2 ,5-dikarboksylsyredi-(nitroksyakyl)amid for fremstilling av prolin- og lysinhydroksylasehemmende legemiddel.
Både pyrid-in-2 ,4- og -2 ,5-dikarboksylsyrediamid (Hirakata et al., J. pharm. Soc. Japan 77 (1957) 219 og Hår ing et al., Heiv. 37 (1954) 147, 153), og også pyridin-2,4- og -2,5-dikarboksylsyredihydrazid (Itai et al., Bl. nation, hyg. Labor. Tokyo, 74 (1956) 115, 117 og Shinohara et al., Chem. High Polymers, Japan, 15 (1958) 839) er allerede kjent som tuberkulosemiddel.
I JP 53/28175 (78/28175) blir det beskrevet N,N'-bis(2-nitroksyetyl)pyridin-2,4- og 2,5-dikarboksylsyreamid som substanser med vasodilatorisk virkning.
Tysk patentsøknad P 40 20 570.3 beskriver anvendelse av 2,4-og 2,5-substituerte pyridin-N-oksider til fremstilling av prolin- og lysinhydroksylasehemmende legemidler.
Det er nå overraskende funnet at 2,4- og 2,5-bis-tetrazolylpyridin med den nedenfor angitte generelle formel I så vel som deres fysiologisk godtagbare salter virksomt hemmer lysin- og prolinhydroksylase i dyremodell.
Foreliggende oppfinnelse angår 2,4- og 2,5-bis-tetrazolylpyridin forbindelser med generell formel I
der A betyr
og R betyr E.
Forbindelsene i oppfinnelsen kan fremstilles på i og for seg kjent måte ved at man omsetter en forbindelse med formel II
med NaN3 og NH4CI i et egnet organisk oppløsningsmiddel.
Forbindelsen med formel I ifølge oppfinnelsen besitter verdifulle farmakologiske egenskaper og viser spesiell virksomhet som hemmer av prolin- og lysinhydroksylase som fibrosuppressivum og immunsuppressivum.
Aktiviteten til fibrogenase kan bli bestemt ved radioimmuno-logisk bestemmelse av N-terminale propeptider til kollagen type-III eller N- hhv. C-terminale tverrbindingsdomener til kollagen type-IV (7s-kollagen hhv. type-IV-kollagen-NC^) i serum.
Til dette formål blir hydroksyprolin-, prokollagen-III-peptid-, 7s-kollagen- og type-IV-kollagen-NC^-konsentrasjon målt i
a) ubehandlede rotter (kontroll)
b) rotter som har blitt administrert med karbontetraklorid (CCl4-kontroll) c) rotter som først har blitt administrert med CCI4 og deretter med en forbindelse ifølge oppfinnelsen (denne
testmetoden er beskrevet av Roullier, C, experimental toxic injury of the liver; in The Liver C. Roullier, Vol. 2, S. 335-476, New York, Academic Press, 1964).
Forbindelsen med formel I kan finne anvendelse som medika-menter i form av farmasøytiske preparater, som eventuelt er inneholdt sammen med godtagbare farmasøytiske bærere. Forbindelsene kan finne anvendelse som helningsmidler, f.eks. i form av farmasøytiske preparater, der disse forbindelsene er inneholdt i blanding med en til enteral, perkutan eller parenteral anvendelse i egnet farmasøytisk, organisk eller uorganisk bærer, som f.eks. vann, gummi arabicum, gelatin, melkesukker, stivelse, magnesiumstearat, talkum, planteolje, polyalkylenglykol, vaselin osv.
Egnede hjelpe- hhv. bærestoffer for de ønskede legemiddelfor-muleringene er f.eks. ved siden av oppløsningsmidler, bindere, suppositorgrunnleggere, tabletthjelpestoffer og andre virkestoffer også antioksidanter, dispergeringsmidler, emulgatorer, avskummere, smakskorrigerere, konserveringsmid-ler, oppløsninsformidlere eller fargestoffer.
Virkestoffene kan bli anvendt oralt, parenteralt eller rektalt.
De aktive forbindelsene blir blandet med de egnede til-setningsstoffene som bærestoffer, stabilisatorer eller inerte fortynningsmidler og brakt via vanlige metoder i egnet administreringsform, som tabletter, drageer, stikkapsler, vandige alkoholiske eller oljeaktige suspensjoner eller vandige eller oljeaktige oppløsninger.
Som inerte bærestoffer kan f.eks. det bli anvendt gummi arabicum, magnesia, magnesiumkarbonat, kaliumfosfat, melkesukker, glukose eller stivelse, særlig maisstivelse. Tilberedningene kan foregå både som tørr- og også som fuktgranulat. Som oljeaktige bærestoffer og oppløsningsmidler er det f.eks. aktuelt med plante eller animalske oljer, som solsikkeolje eller levertran.
I det følgende blir oppfinnelsen nærmere forklart ved hjelp av eksempler.
2,4-bis-(tetrazol-5-yl)-pyridin (1)
En blanding med 100 g 2,5-dicyanopyridin, 122,8 g NaN3 og 12,8 g NH4C1 ble oppvarmet i 910 ml absolutt DMF i løpet av 36 timer til 80-100°C. Den dannede beige krystallmassen ble blandet med 500 ml H2O og deretter surgjort under omrøring og isavkjøling med kons. HC1 til pE 1. Den dannede massen ble suget av, resten oppløst og filtrert i ca. 1 1 2N NaOH-oppløsning under omrøring. Etter fornyet surgjøring til pH 1 med kons. HC1 ble det igjen suget av og resten tørket i vakuum ved 50°C. Man fikk 165,0 g (9956), beige krystaller, frysepunkt 265-267°C (spaltning).
<1->H-NMR (60 MHz, DMS0-d6)
5=8,1 (dd, J=6Hz, J'=2Hz, 1H) , 8,8 (s, 1E), 9,0 (d, J=5Ez, 1H), 7-10 (bs, 2H) ppm.
C7E6N9
Beregnet 216
Funnet 216 (M<+> + E<+>)
2,5-bis-(tetrazol-5-yl)-pyridin (2)
230 mg 2,5-dicyanopyridin, 283 mg NaN3 og 36 mg NE4C1 ble suspendert i 3 ml absolutt DMF og omrørt i 16 timer ved 80-100°C. Etter avkjøling ble det fortynnet med E20, filtrert over amberlit IR-120 (E<+->form) og etterspylt med EgO. Filtratet ble inndampet i vakuum: 348 mg (91$), 2 fargeløse krystaller, frysepunkt >200°C.
<i>H-NMR (60 MHz, DMS0-d6)
§=5,5-8,0 (bs), 8,6 (m, 2H), 9,5 (s, 1H) ppm.
C7E6N9
Beregnet 216
Funnet 216 (M<+> + H<+>)
Sammenligningsforsøk
Analyse av prolyl 4-hydroksylaseaktivitet
Prolyl-4-hydroksylase ble renset fra kylling embryoer i henhold til standard prosedyrer (1,2). Enzymet ble inkubert i 40 minutter ved 37°C i et volum på 50 pl inneholdende 0,04 M Tris/ECl, pE 7,5, 0,05 mM FeS04, 100.000 dpm (0,1 mM) 2-oksc-CS-l^Clglutarat, 20 pg syntetisk peptid (Pro-Pro-Gly » 1 mM askorbat, 20 pg katalase, 0,5 mM ditiotreitol, og 100 pg bovint serumalbumin. Etter inkuberingsperioden, ble 25 pl av en oppløsning inneholdende 20 mM av både ikke-merket succinat og 2-oksoglutarat (tjener som bærersubstanser) tilsatt, og 2-oksoglutaratet ble utfelt med 25 pl 0,16 M 2,4-dinitrofenyl-hydrazin i 30 % HCIO4 i henhold til en standard prosedyre (3). Radioaktiviteten i supernatanten består av succinat som ble generert fra 2-oksoglutarat ved prolyl 4-hydroksylase og som er korrelert med enzymaktivitet.
Resultater
Forbindelsene 2,4-bis-(5-tetrazolyl) pyridin og 2,5-bis-(5-tetrazolyl) pyridin ble anvendt som hemmere i det beskrevne testsystem. Kj verdier ble bestemt i Lineweaver-Burk kinetiske eksperimenter i henhold til en standard prosedyre (3). Det som ble oppnådd ble sammenlignet med verdier oppnådd med referansesubstansene 2,4- og 2,5-pyridin dikarboksylsyrer (4).
Begge isomerene av den nylig oppdagede klasse av prolyl 4-hydroksylasehemmere, dvs. 2,4- og 2,5-bis-(5-tetrazolyl) pyridin viste seg å være mer potente hemmere av prolyl 4-hydroksylaseaktivitet enn de respektive dikarboksylatene.
Referanser
1) Tuderman L., Kuutti ER og Kivirikko K. (1975 ) Eur. J.
Biochem 52, 9-16.
2) Kedersha NL og Berg RA. (1981) Collagen Relat. Res. 1, 345-353. 3) Kaule G. og Gtinzler V. (1990) Analyt. Biochem. 184, 291-297. 4) Majamaa K. , Hanauske-Abel HM, Gtinzler V. og Kivirikko K.
(1984) Eur. J. Biochem. 138, 239-245.
Claims (1)
1.
Forbindelse, karakterisert ved generell formel I
der A betyr og R betyr H.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4103372 | 1991-02-05 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO920462D0 NO920462D0 (no) | 1992-02-04 |
| NO920462L NO920462L (no) | 1992-08-06 |
| NO180446B true NO180446B (no) | 1997-01-13 |
| NO180446C NO180446C (no) | 1997-04-23 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO920462A NO180446C (no) | 1991-02-05 | 1992-02-04 | 2,4- og 2,5-bis-tetrazolylpyridiner og deres anvendelse som legemiddel |
Country Status (23)
| Country | Link |
|---|---|
| US (2) | US5482953A (no) |
| EP (1) | EP0498334B1 (no) |
| JP (1) | JPH0559041A (no) |
| KR (1) | KR100214797B1 (no) |
| AT (1) | ATE193288T1 (no) |
| AU (1) | AU650511B2 (no) |
| CA (1) | CA2060622A1 (no) |
| CZ (1) | CZ283006B6 (no) |
| DE (1) | DE59209838D1 (no) |
| DK (1) | DK0498334T3 (no) |
| ES (1) | ES2146581T3 (no) |
| FI (1) | FI103117B (no) |
| GR (1) | GR3033536T3 (no) |
| HR (1) | HRP940840B1 (no) |
| HU (1) | HUT61295A (no) |
| IE (1) | IE920368A1 (no) |
| IL (1) | IL100860A (no) |
| MX (1) | MX9200492A (no) |
| NO (1) | NO180446C (no) |
| NZ (1) | NZ241505A (no) |
| PT (1) | PT498334E (no) |
| YU (1) | YU9492A (no) |
| ZA (1) | ZA92788B (no) |
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| CZ305460B6 (cs) * | 2013-05-06 | 2015-10-07 | Contipro Biotech S.R.O. | Způsob přípravy esteru 2-oxoglutarátu, přípravek obsahující ester 2-oxoglutarát a jeho použití |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3432094A1 (de) * | 1984-08-31 | 1986-03-06 | Hoechst Ag, 6230 Frankfurt | Ester der pyridin-2,4- und -2,5- dicarbonsaeure als arzneimittel zur inhibierung der prolin- und lysinhydroxylase |
| DE3703963A1 (de) * | 1987-02-10 | 1988-08-18 | Hoechst Ag | Pyridin-2,4- und 2,,5-dicarbonsaeure-derivate, verfahren zu ihrer herstellung, verwendung derselben, sowie arzneimittel auf basis dieser verbindungen |
| DE3703962A1 (de) * | 1987-02-10 | 1988-08-18 | Hoechst Ag | Pyridin-2,4- und 2,5-dicarbonsaeure-derivate, verfahren zu ihrer herstellung, verwendung derselben sowie arzneimittel auf basis dieser verbindungen |
| US5238948A (en) * | 1987-02-10 | 1993-08-24 | Hoechst Aktiengesellschaft | Pyridine-2,4- and -2,5-dicarboxylic acid derivatives and medicaments based on these compounds |
| DE3703959A1 (de) * | 1987-02-10 | 1988-08-18 | Hoechst Ag | Pyridin-2,4- und 2,5-dicarbonsaeureamide, verfahren zu ihrer herstellung, verwendung derselben sowie arzneimittel auf basis dieser verbindungen |
| EP0353668B1 (de) * | 1988-08-04 | 1994-10-19 | Hoechst Aktiengesellschaft | Verbessertes Verfahren zur Herstellung von N,N-Bis(alkoxyalkyl)-pyridin -2,4-dicarbonsäurediamiden |
| JPH02178263A (ja) * | 1988-12-27 | 1990-07-11 | Kaken Pharmaceut Co Ltd | アザアズレン誘導体、その製造法およびそれを有効成分とする抗アレルギー剤および抗炎症剤 |
| DE3924093A1 (de) * | 1989-07-20 | 1991-02-07 | Hoechst Ag | N,n'-bis(alkoxy-alkyl)-pyridin-2,4-dicarbonsaeurediamide, verfahren zu deren herstellung sowie deren verwendung |
| FR2655801B1 (fr) * | 1989-12-08 | 1992-03-13 | Charbonnages De France | Procede et dispositif de transmission de signaux video en milieu confine. |
| ZA91291B (en) * | 1990-01-16 | 1991-09-25 | Hoechst Ag | Di(nitroxyalkyl)amides of pyridine-2,4-and-2,5-dicarboxylic acids,a process for the preparation thereof,and the use thereof |
| DE4020570A1 (de) * | 1990-06-28 | 1992-01-02 | Hoechst Ag | 2,4- und 2,5-substituierte pyridin-n-oxide, verfahren zu deren herstellung sowie deren verwendung |
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