NO178859B - Pyridine-2,4- and 2,5-dicarboxylic acid diamides and the use of the same, as well as drugs based on these compounds - Google Patents
Pyridine-2,4- and 2,5-dicarboxylic acid diamides and the use of the same, as well as drugs based on these compounds Download PDFInfo
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- NO178859B NO178859B NO921025A NO921025A NO178859B NO 178859 B NO178859 B NO 178859B NO 921025 A NO921025 A NO 921025A NO 921025 A NO921025 A NO 921025A NO 178859 B NO178859 B NO 178859B
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- pyridine
- compounds
- dicarboxylic acid
- collagen
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 20
- 239000003814 drug Substances 0.000 title claims description 10
- 229940079593 drug Drugs 0.000 title claims description 4
- 229920001436 collagen Polymers 0.000 claims description 12
- 102000008186 Collagen Human genes 0.000 claims description 10
- 108010035532 Collagen Proteins 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- -1 hydroxy, carboxyl Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000004060 metabolic process Effects 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 102000004079 Prolyl Hydroxylases Human genes 0.000 abstract description 11
- 108010043005 Prolyl Hydroxylases Proteins 0.000 abstract description 11
- 102000008490 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Human genes 0.000 abstract description 7
- 108010020504 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Proteins 0.000 abstract description 7
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 229960003444 immunosuppressant agent Drugs 0.000 abstract description 3
- 239000003018 immunosuppressive agent Substances 0.000 abstract description 3
- 150000001408 amides Chemical class 0.000 abstract description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 8
- 230000008014 freezing Effects 0.000 description 7
- 238000007710 freezing Methods 0.000 description 7
- 239000000969 carrier Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 5
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000013543 active substance Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 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 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000036570 collagen biosynthesis Effects 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000000829 suppository 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
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- ABKKZPBEHVFPTE-UHFFFAOYSA-N 2-n,4-n-bis(3-propan-2-yloxypropyl)pyridine-2,4-dicarboxamide Chemical compound CC(C)OCCCNC(=O)C1=CC=NC(C(=O)NCCCOC(C)C)=C1 ABKKZPBEHVFPTE-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 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
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 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
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 231100000644 Toxic injury Toxicity 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical class N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000002775 capsule Substances 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
- 239000003026 cod liver oil Substances 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 150000001470 diamides Chemical class 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 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
- 239000013583 drug formulation Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 235000011187 glycerol Nutrition 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
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000004072 lung Anatomy 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
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- OOXOXZVOZIURRD-UHFFFAOYSA-N pyridine-2,4-dicarboxamide Chemical class NC(=O)C1=CC=NC(C(N)=O)=C1 OOXOXZVOZIURRD-UHFFFAOYSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 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
- C07D213/81—Amides; Imides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Transplantation (AREA)
- Gastroenterology & Hepatology (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Medicinal Preparation (AREA)
- Photoreceptors In Electrophotography (AREA)
- Hydrogenated Pyridines (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Forbindelser som hemmer prolin- og lysinhydroksylase, bevirker en meget selektiv hemming av kollagenbiosyntesen ved påvirkning av kollagenspesifikke hydroksyleringsreaksjoner. I deres forløp blir proteinbundet protein eller lysin hydroksy-lert ved enzymet prolin- henholdsvis lysinhydroksylase. Blir denne reaksjonen undertrykket ved hemming, så oppstår et ikke-funksjonsdyktig, underhydroksylert kollagenmolekyl, som kan bli avgitt fra cellen bare i mindre mengde til det ekstracellulære rom. Det underhydroksylerte kollagenet kan dessuten ikke bli innbygget i kollagenmatriksen og blir meget lett proteolytisk nedbrutt. Som følge av denne effekten forringes den samlede mengden med ekstracellulært opplagret kollagen. Compounds that inhibit proline and lysine hydroxylase cause a highly selective inhibition of collagen biosynthesis by influencing collagen-specific hydroxylation reactions. In their course, protein-bound protein or lysine is hydroxylated by the enzyme proline or lysine hydroxylase. If this reaction is suppressed by inhibition, then a non-functional, underhydroxylated collagen molecule is produced, which can be released from the cell only in small quantities into the extracellular space. Furthermore, the underhydroxylated collagen cannot be incorporated into the collagen matrix and is very easily proteolytically degraded. As a result of this effect, the total amount of extracellularly stored collagen deteriorates.
Det er kjent at hemming av prolinhydroksylase ved kjente hemmere som a ,oc' -dipyridyl fører til en hemming av Clq-biosyntese av makrofager (W. Muller et al. , FEBS Lett. 90 It is known that inhibition of proline hydroxylase by known inhibitors such as a,oc'-dipyridyl leads to an inhibition of Clq biosynthesis by macrophages (W. Muller et al., FEBS Lett. 90
(1978), 218; Immunbiology 155 (1978) 47). Det fører til et utfall i klassisk veg av komplimentaktivering. Hemmere av prolinhydroksylase virker derfor også som immunsuppressiva, f.eks. ved immunkomplekssykdommer. (1978), 218; Immunobiology 155 (1978) 47). This leads to an outcome in the classical way of compliment activation. Inhibitors of proline hydroxylase therefore also act as immunosuppressants, e.g. in immune complex diseases.
Det er kjent at prolinhydroksylase blir effektivt hemmet med pyrridin-2,4 og —2,5-dikarboksylsyre (K. Mayama et al., Eur. J. Biochem. 138 (1984) 239-245). Disse forbindelsene er i cellekultur fremfor alt bare virksomme i meget høye konsen-trasjoner (Tschank, G. et al., Biochem. J. 238 (1987) 625-633). It is known that proline hydroxylase is effectively inhibited by pyridine-2,4 and -2,5-dicarboxylic acid (K. Mayama et al., Eur. J. Biochem. 138 (1984) 239-245). These compounds are above all only effective in cell culture in very high concentrations (Tschank, G. et al., Biochem. J. 238 (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. DE-A 34 32 094 describes pyridine-2,4- and -2,5-dicarboxylic acid diesters with 1-6 C atoms in the ester alkyl part as drugs for inhibiting proline and lysine hydroxylase.
Disse lav-alkylerte diesterene har imidlertid den ulempen at de raskt blir spaltet i organismen og foreligger ikke i tilstrekkelig høy konsentrasjon på deres virkeområde i cellen og er dermed mindre egnet for en eventuell administrering som legemiddel. However, these low-alkylated diesters have the disadvantage that they are quickly broken down in the organism and are not present in a sufficiently high concentration in their area of action in the cell and are thus less suitable for possible administration as medicine.
DE-A 37 03 959, DE-A 37 03 962 og DE-A 37 03 936 beskriver i generell form blandede ester/amider, høyere alkylerte diestere og diamider av pyridin-2,4- og -2,5-dikarboksylsyre, som hemmer kollagenbiosyntesen i dyremodell. DE-A 37 03 959, DE-A 37 03 962 and DE-A 37 03 936 describe in general form mixed ester/amides, higher alkylated diesters and diamides of pyridine-2,4- and -2,5-dicarboxylic acid, which inhibits collagen biosynthesis in an animal model.
Således blir det i DE-A 37 03 959 blant annet beskrevet syntese av N,N'-bis(2-metoksymetyl)-pyridin-2,4-dikarboksylsyrediamid og N,N'-bis(3-isopropoksypropyl)-pyridin-2,4-dikarboksylsyrediamid. Thus, DE-A 37 03 959 describes, among other things, the synthesis of N,N'-bis(2-methoxymethyl)-pyridine-2,4-dicarboxylic acid diamide and N,N'-bis(3-isopropoxypropyl)-pyridine-2 ,4-dicarboxylic acid diamide.
I tysk patentsøknad 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 )-pyr i din-2 ,4-dikarboksylsyrediamid. Den tyske patentsøknad P 3924093.2 foreslår nye N.N'-bis(alkoksyalkyl)-pyridin-2,4-dikarboksylsyrediamider. In German patent application P 38 26 471.4 and P 38 28 140.6, an improved method for the production of N,N'-bis(2-methoxyethyl)-pyr in din-2,4-dicarboxylic acid diamide is proposed. The German patent application P 3924093.2 proposes new N.N'-bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides.
Det var derfor aktuelt å løse oppgaven ved å finne forbindelser som på en mye bedre måte er egnet til hemming av prolin- og lysinhydroksylase. Oppgaven ble løst ved pyrridin-2,4 og 2,5-dikarboksylsyrediamider med formel I It was therefore relevant to solve the task by finding compounds that are much better suited to inhibiting proline and lysine hydroxylase. The task was solved with pyridine-2,4 and 2,5-dicarboxylic acid diamides with formula I
der there
R<1> betyr C^-C^-alkyl, som kan være usubstituert eller substituert med R<1> means C₁-C₁-alkyl, which may be unsubstituted or substituted with
hydroksy, karboksyl, alkoksy, fenylalkoksykarbonyl, der alkylresten inneholder 1-4 C-atomer, hydroxy, carboxyl, alkoxy, phenyl alkoxycarbonyl, where the alkyl residue contains 1-4 C atoms,
og and
R<2> betyr hydrogen eller R<1>, der R<*> og R<2> er identiske eller forskjellige, ;eller der restene R<*> og R<2> sammen med nitrogen danner en rest med formel R<2> means hydrogen or R<1>, where R<*> and R<2> are identical or different, or where the residues R<*> and R<2> together with nitrogen form a residue of formula
så vel som fysiologisk godtagbare salter. as well as physiologically acceptable salts.
Videre angår oppfinnelsen forbindelser med formel I til anvendelse som legemiddel. Dessuten angår oppfinnelsen anvendelse av forbindelser med formel I for fremstilling av et preparat til påvirkning av stoff-skifte ved kollagen og kollagenlignende stoffer, henholdsvis biosyntese av Clq. Hemmere av prolylhydroksylase er egnede verktøy i terapi av sykdommer, der opplagring av kollagener bidrar utslagsgivende til sykdomsbilde. Til dette hører blant annet fibroser i lunge, lever og hud (skleroderma), så vel som atherosklerose. Furthermore, the invention relates to compounds of formula I for use as medicine. Furthermore, the invention relates to the use of compounds of formula I for the production of a preparation for influencing the metabolism of collagen and collagen-like substances, respectively biosynthesis of Clq. Inhibitors of prolyl hydroxylase are suitable tools in the therapy of diseases, where the storage of collagens contributes decisively to the disease picture. This includes fibrosis in the lungs, liver and skin (scleroderma), as well as atherosclerosis.
Den utelukkende i posisjon 4, hhv. 5 i amidgruppen sub-stituerte pyridin-2,4- og 2,5-dikarboksylsyrediamid med generell formel I viser sammenlignet med den i posisjon 5 også med karboksylsyreamidgruppen substituert pyridin-2,4-dikarboksylsyrediamider fra DE-A-3 707 429, og sammenlignet med den i begge amidgruppene substituert pyridin-2,4- og -2,5-dikarboksylsyrediamid i DE-A-37 039 59, en vesentlig og overraskende forbedret virksomhet ved hemming av prolin- og lysinhydroksylase i dyreforsøk. It exclusively in position 4, respectively 5 in the amide group substituted pyridine-2,4- and 2,5-dicarboxylic acid diamide of general formula I shows compared to that in position 5 also with the carboxylic acid amide group substituted pyridine-2,4-dicarboxylic acid diamides from DE-A-3 707 429, and compared to the pyridine-2,4- and -2,5-dicarboxylic acid diamide substituted in both amide groups in DE-A-37 039 59, a significantly and surprisingly improved activity in inhibiting proline and lysine hydroxylase in animal experiments.
Forbindelsene med formel I ifølge oppfinnelsen besitter verdifulle farmakologiske egenskaper og viser spesiell virksomhet som hemmer av prolin- og lysinhydroksylase, som fibrosuppressivum og immunsuppressivum. The compounds of formula I according to the invention possess valuable pharmacological properties and show special activity as inhibitors of proline and lysine hydroxylase, as fibrosuppressants and immunosuppressants.
Aktiviteten til fibrogenase kan bli bestemt ved radioimmuno-logisk bestemmelse av N-terminale propeptider i kollagen type-III eller N- hhv. C-terminale tverrbindingsdomener av kollagener type-IV (7s-kollagen hhv. type-IV-kollagen-NC-L) i serum. The activity of fibrogenase can be determined by radioimmuno-logical determination of N-terminal propeptides in collagen type-III or N-, respectively. C-terminal cross-linking domains of collagens type-IV (7s-collagen or type-IV-collagen-NC-L) in serum.
Til dette formål blir hydroksyprolin-, prokollagen-III-peptid-, 7s-kollagen- og type-IV-kollagen-NC^-konsentrasjon målt i lever av To this end, hydroxyproline, procollagen-III peptide, 7s-collagen and type-IV-collagen-NC^ concentration is measured in liver by
a) ubehandlede rotter (kontroller) a) untreated rats (controls)
b) rotter, som har blitt administrert med karbontetraklorid (CCl4-kontroll) c) rotter som først har blitt administrert med CCI4 og deretter en forbindelse ifølge oppfinnelsen (denne b) rats which have been administered with carbon tetrachloride (CCl4 control) c) rats which have been administered first with CCI4 and then a compound according to the invention (this
testmetoden er beskrevet av Rouiller, C, Experimental toxic injury of the liver; in The Liver, C. Rouiller, Vol. 2, s. 335-476, New York, Academic Press, 1964). the test method is described by Rouiller, C, Experimental toxic injury of the liver; in The Liver, C. Rouiller, Vol. 2, pp. 335-476, New York, Academic Press, 1964).
På grunn av disse farmakologiske egenskapene er forbindelsene ifølge oppfinnelsen egnet til behandling av forstyrrelser i stoffskifte til kollagen og kollagenlignende stoffer, hhv. til behandling av forstyrrelser i biosyntese av Clq. Due to these pharmacological properties, the compounds according to the invention are suitable for the treatment of disturbances in the metabolism of collagen and collagen-like substances, respectively. for the treatment of disturbances in the biosynthesis of Clq.
Oppfinnelsen angår således videre anvendelse av forbindelsen med formel I ifølge oppfinnelsen, så vel som deres fysiologisk godtagbare salter ved behandling av de ovenfor nevnte stoffskifteforstyrrelsene. The invention thus further relates to the use of the compound of formula I according to the invention, as well as their physiologically acceptable salts in the treatment of the above-mentioned metabolic disorders.
Forbindelsene kan bli anvendt alene eller blandet med fysiologisk godtagbare hjelpe- eller baererstof f er som legemidler. De kan til dette formål bli anvendt i orale doser fra 0,01-25,0 mg/kg/dag, fortrinnsvis 0,01-5,0 mg/kg/dag eller parenteralt i doser fra 0,001-5 mg/kg/dag, fortrinnsvis 0,001-2,5 mg/kg/dag, særlig 0,005-1,0 mg/kg/dag. Doseringene kan i vanskelige tilfeller også bli forhøyet. I mange tilfeller er det imidlertid tilstrekkelig også med lavere doser. Disse angivelsene viser til en voksen person på ca. 75 kg kroppsvekt. The compounds can be used alone or mixed with physiologically acceptable excipients or carriers as pharmaceuticals. They can be used for this purpose in oral doses from 0.01-25.0 mg/kg/day, preferably 0.01-5.0 mg/kg/day or parenterally in doses from 0.001-5 mg/kg/day , preferably 0.001-2.5 mg/kg/day, especially 0.005-1.0 mg/kg/day. The dosages can also be increased in difficult cases. In many cases, however, lower doses are also sufficient. These specifications refer to an adult person of approx. 75 kg body weight.
Oppfinnelsen omfatter videre anvendelse av forbindelsene ifølge oppfinnelsen ved fremstilling av legemidler, som kan bli anvendt til behandling og profylakse av de foranstående nevnte stoffskifteforstyrrelsene. The invention further comprises the use of the compounds according to the invention in the preparation of pharmaceuticals, which can be used for the treatment and prophylaxis of the metabolic disorders mentioned above.
En videre gjenstand ved oppfinnelsen er legemidler, som inneholder en eller flere forbindelser ifølge oppfinnelsen med formel I og/eller deres fysiologisk godtagbare salter. A further object of the invention are pharmaceuticals, which contain one or more compounds according to the invention with formula I and/or their physiologically acceptable salts.
Legemidlene blir fremstilt på i og for seg kjente måter som er enkle for en person med kunnskap innenfor fagområdet. Som legemidler blir de farmakologisk virksomme forbindelsene ifølge oppfinnelsen (= virkestoff) anvendt enten slik de er eller fortrinnsvis i kombinasjon med egnede farmasøytiske hjelpe- eller bærestoffer i form av tabletter, dragéer, kapsler, suppositorier, emulsjoner, suspensjoner eller oppløsninger, der virkestoffinnholdet utgjør inntil 95$, fortrinnsvis mellom 10 og 75$. The medicines are produced in known ways which are easy for a person with knowledge in the field. As pharmaceuticals, the pharmacologically active compounds according to the invention (= active substance) are used either as they are or preferably in combination with suitable pharmaceutical excipients or carriers in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions, where the active substance content is up to 95$, preferably between 10 and 75$.
Egnede hjelpe- hhv. bærestoffer til de ønskede legemiddel-formuleringene er f.eks. ved siden av oppløsningsmidler, geldannere, suppositoriegrunnlag, tabletthjelpestoffer og andre virkestoffbærere også antioksidanter, dispergerings-midler, emulgatorer, skummidler, smakskorrigerere, konser-veringsmidler, oppløsningsformidlere og fargestoffer. Suitable auxiliary or carriers for the desired drug formulations are e.g. in addition to solvents, gel formers, suppository bases, tablet excipients and other active substance carriers, also antioxidants, dispersants, emulsifiers, foaming agents, flavor correctors, preservatives, solubilizers and dyes.
Virkestoffene kan bli anvendt oralt, parenteralt eller rektalt. The active substances can be used orally, parenterally or rectally.
De aktive forbindelsene blir blandet med de dertil egnede tilsatsstoffene som bærestoffer, stabilisatorer eller inerte fortynningsmidler og brakt med vanlige metoder til egnede administreringsformer, som tabletter, dragéer, stikkapsler, vandige alkoholiske eller oljeaktige suspensjoner eller vandige eller oljeaktige oppløsninger. Som inerte bærestoffer kan det f.eks. bli anvendt gummi arabicum, magnesia, magnesiumkarbonat, kaliumfosfat, melkesukker, glukose eller stivelse, spesielt maisstivelse. The active compounds are mixed with the appropriate additives such as carriers, stabilizers or inert diluents and brought by usual methods into suitable administration forms, such as tablets, dragees, suppositories, aqueous alcoholic or oily suspensions or aqueous or oily solutions. As inert carriers, it can e.g. be used gum arabic, magnesia, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch.
Videre kan tilberedningen foregå både som tørr- og også som fuktgranulat. Som oljeaktige bærestoffer eller oppløsnings-midler- er det f.eks. aktuelt med plante- eller animalske oljer, som solsikkeolje eller levertran. Furthermore, the preparation can take place both as dry and also as moist granules. As oily carriers or solvents, there are e.g. applicable with vegetable or animal oils, such as sunflower oil or cod liver oil.
Til subkutan eller intravenøs anvendelse blir de aktive forbindelsene eventuelt anvendt med de egnede substansene som oppløsningsformidlere, emulgatorer eller ytterligere hjelpestoffer i oppløsning, suspensjon eller emulsjon. Som oppløsningsmiddel er det f.eks. aktuelt med fysiologisk koksaltoppløsning eller alkoholer, f.eks. etanol, propanol, glyserin, ved siden av sukkeroppløsninger som glukose- eller mannittoppløsninger, eller også en blanding av de forskjellige nevnte oppløsningsmidlene. For subcutaneous or intravenous use, the active compounds are optionally used with the appropriate substances such as dissolution agents, emulsifiers or further auxiliaries in solution, suspension or emulsion. As a solvent, there is e.g. applicable with physiological saline solution or alcohols, e.g. ethanol, propanol, glycerine, next to sugar solutions such as glucose or mannitol solutions, or also a mixture of the various solvents mentioned.
I det etterfølgende blir oppfinnelsen nærmere forklart ved hjelp av eksempler. In what follows, the invention is explained in more detail by means of examples.
Generell beskrivelse av fremstilling av forbindelsene. General description of the preparation of the compounds.
1 mmol pyridin-4-karboksylsyreamid-2-karboksylsyremetylester (IV) blir oppløst i 30 ml mettet metanolisk ammoniakkopp-løsning og omrørt i 2 timer ved romtemperatur. Oppløsningen blir inndampet og resten omrørt med diisopropyleter og suget av. 1 mmol of pyridine-4-carboxylic acid amide-2-carboxylic acid methyl ester (IV) is dissolved in 30 ml of saturated methanolic ammonia solution and stirred for 2 hours at room temperature. The solution is evaporated and the residue stirred with diisopropyl ether and suctioned off.
Eksempel 1 Example 1
Pyridin-4-karboksylsyre-etylamid-2-karboksylsyreamid. Pyridine-4-carboxylic acid-ethylamide-2-carboxylic acid amide.
Frysepunkt: 197"C. Freezing point: 197"C.
Eksempel 2 Example 2
Pyridin-4-karboksylsyre-N-morfolinamid-2-karboksylsyreamid Frysepunkt: 128°C. Pyridine-4-carboxylic acid-N-morpholinamide-2-carboxylic acid amide Freezing point: 128°C.
Eksempel 3 Example 3
Pyridin-4-karboksylsyre-dietylamid-2-karboksylsyreamid Pyridine-4-carboxylic acid-diethylamide-2-carboxylic acid amide
Olje, MS = 222 (M + H<+>) molmasse C11H15N302 (221) Oil, MS = 222 (M + H<+>) molar mass C11H15N302 (221)
Eksempel 4 Example 4
Pyr idin-4-karboksyl syre-(2-metoksyetyl)-amid-2-karboksyl-syreamid. Pyridine-4-carboxylic acid-(2-methoxyethyl)-amide-2-carboxylic acid amide.
Frysepunkt: 116-120°C Freezing point: 116-120°C
Eksempel 5 Example 5
Pyr i din-5-karboksyl syre - (3-metoksypropyl )-amid-2-karboksyl-syreamid Pyr in din-5-carboxylic acid - (3-methoxypropyl)-amide-2-carboxylic acid amide
Frysepunkt: 149°C Freezing point: 149°C
Eksempel 6 Example 6
Pyr i d i n - 4 -karboksyl syre-(3-hydroksypropyl)-amid-2-karboksyl-syreamid Pyridine-4-carboxylic acid-(3-hydroxypropyl)-amide-2-carboxylic acid amide
Frysepunkt: 154-156°C Freezing point: 154-156°C
Eksempel 7 Example 7
Pyridin-4-karboksylsyre-(alanyl)-amld-2-karboksylsyreamid Frysepunkt: 124 - 125°C Pyridine-4-carboxylic acid-(alanyl)-amld-2-carboxylic acid amide Freezing point: 124 - 125°C
Eksempel 8 Example 8
Pyr i din-4-karboksyl syre - ( 0-benzyl al anyl)-amid-2-karboksyl-syreamid. Pyr in din-4-carboxylic acid - (O-benzyl al anyl)-amide-2-carboxylic acid amide.
Frysepunkt: 138-140°C. Freezing point: 138-140°C.
Claims (3)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4108824 | 1991-03-18 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO921025D0 NO921025D0 (en) | 1992-03-17 |
| NO921025L NO921025L (en) | 1992-09-21 |
| NO178859B true NO178859B (en) | 1996-03-11 |
| NO178859C NO178859C (en) | 1996-06-19 |
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| NO921025A NO178859C (en) | 1991-03-18 | 1992-03-17 | Pyridine-2,4- and 2,5-dicarboxylic acid diamides and the use of the same, as well as drugs based on these compounds |
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| EP (1) | EP0504799B1 (en) |
| JP (1) | JP3121428B2 (en) |
| KR (1) | KR100243959B1 (en) |
| AT (1) | ATE154929T1 (en) |
| AU (1) | AU645668B2 (en) |
| CA (1) | CA2063177A1 (en) |
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| DE (1) | DE59208651D1 (en) |
| DK (1) | DK0504799T3 (en) |
| ES (1) | ES2104758T3 (en) |
| FI (1) | FI101701B (en) |
| GR (1) | GR3024309T3 (en) |
| HR (1) | HRP940835A2 (en) |
| HU (1) | HU217809B (en) |
| IE (1) | IE920843A1 (en) |
| IL (1) | IL101257A (en) |
| MX (1) | MX9201156A (en) |
| NO (1) | NO178859C (en) |
| NZ (1) | NZ241968A (en) |
| TW (1) | TW199147B (en) |
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| ZA (1) | ZA921945B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3703959A1 (en) * | 1987-02-10 | 1988-08-18 | Hoechst Ag | PYRIDINE-2,4- AND 2,5-DICARBONIC ACID AMIDES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
| ATE113036T1 (en) * | 1988-08-04 | 1994-11-15 | Hoechst Ag | IMPROVED PROCESS FOR THE PRODUCTION OF N,N-BIS(ALKOXYALKYL)-PYRIDINE-2,4-DICARBONIC DIAMIDES. |
| DE3924093A1 (en) * | 1989-07-20 | 1991-02-07 | Hoechst Ag | N, N'-BIS (ALKOXY-ALKYL) -PYRIDINE-2,4-DICARBONESAUREDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE3928144A1 (en) * | 1989-08-25 | 1991-02-28 | Hoechst Ag | CYCLIC PYRIDINE-2,4- AND -2,5-DICARBONIC ACIDEDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE3938805A1 (en) * | 1989-11-23 | 1991-05-29 | Hoechst Ag | PYRIDINE-2,4- AND 2,5-DICARBONIC ACID DIAMOND, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE4030999A1 (en) * | 1990-10-01 | 1992-04-09 | Hoechst Ag | 4- OR 5-SUBSTITUTED PYRIDINE-2-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
-
1991
- 1991-09-20 TW TW080107458A patent/TW199147B/zh active
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1992
- 1992-03-12 YU YU24692A patent/YU48156B/en unknown
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- 1992-03-17 KR KR1019920004320A patent/KR100243959B1/en not_active IP Right Cessation
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- 1992-03-17 AU AU12967/92A patent/AU645668B2/en not_active Ceased
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- 1992-03-17 MX MX9201156A patent/MX9201156A/en unknown
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- 1992-03-17 CZ CS92803A patent/CZ282298B6/en unknown
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