NZ616045B2 - Fe(iii) complexes for the treatment and prophylaxis of iron deficiency symptoms and iron deficiency anaemias - Google Patents
Fe(iii) complexes for the treatment and prophylaxis of iron deficiency symptoms and iron deficiency anaemias Download PDFInfo
- Publication number
- NZ616045B2 NZ616045B2 NZ616045A NZ61604512A NZ616045B2 NZ 616045 B2 NZ616045 B2 NZ 616045B2 NZ 616045 A NZ616045 A NZ 616045A NZ 61604512 A NZ61604512 A NZ 61604512A NZ 616045 B2 NZ616045 B2 NZ 616045B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- iron
- group
- iron deficiency
- alkyl
- defined above
- Prior art date
Links
- VTLYFUHAOXGGBS-UHFFFAOYSA-N fe3+ Chemical class [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 206010022972 Iron deficiency anaemia Diseases 0.000 title claims description 54
- 206010022971 Iron deficiency Diseases 0.000 title claims description 17
- 206010022970 Iron deficiency Diseases 0.000 title claims description 17
- 230000000069 prophylaxis Effects 0.000 title claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 261
- 229910052742 iron Inorganic materials 0.000 claims abstract description 117
- 230000027455 binding Effects 0.000 claims abstract description 43
- 239000003446 ligand Substances 0.000 claims abstract description 43
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- -1 oxabutylene group Chemical group 0.000 claims description 184
- 150000001875 compounds Chemical class 0.000 claims description 119
- 239000000203 mixture Substances 0.000 claims description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 32
- 239000007787 solid Substances 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 239000011780 sodium chloride Substances 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000005842 heteroatoms Chemical group 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 14
- 208000007502 Anemia Diseases 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 239000003826 tablet Substances 0.000 claims description 8
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 7
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 7
- 239000002775 capsule Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- 230000037227 Blood Loss Effects 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 239000000969 carrier Substances 0.000 claims description 5
- 235000005911 diet Nutrition 0.000 claims description 5
- 235000013305 food Nutrition 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 206010021972 Inflammatory bowel disease Diseases 0.000 claims description 4
- 206010039073 Rheumatoid arthritis Diseases 0.000 claims description 4
- 125000005418 aryl aryl group Chemical group 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 125000004986 diarylamino group Chemical group 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- 208000008032 Gastrointestinal Hemorrhage Diseases 0.000 claims description 3
- 208000002287 Hemorrhoids Diseases 0.000 claims description 3
- 206010061598 Immunodeficiency Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 208000005793 Restless Legs Syndrome Diseases 0.000 claims description 3
- 206010068760 Ulcers Diseases 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000004947 alkyl aryl amino group Chemical group 0.000 claims description 3
- 230000003925 brain function Effects 0.000 claims description 3
- 201000009030 carcinoma Diseases 0.000 claims description 3
- 230000001684 chronic Effects 0.000 claims description 3
- 230000001149 cognitive Effects 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 230000000378 dietary Effects 0.000 claims description 3
- 239000008298 dragée Substances 0.000 claims description 3
- 239000002662 enteric coated tablet Substances 0.000 claims description 3
- 200000000018 inflammatory disease Diseases 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 210000004914 menses Anatomy 0.000 claims description 3
- 230000005906 menstruation Effects 0.000 claims description 3
- 239000006187 pill Substances 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 230000002459 sustained Effects 0.000 claims description 3
- 230000001960 triggered Effects 0.000 claims description 3
- 231100000397 ulcer Toxicity 0.000 claims description 3
- 206010018388 Glossodynia Diseases 0.000 claims description 2
- 206010019233 Headache Diseases 0.000 claims description 2
- 206010022998 Irritability Diseases 0.000 claims description 2
- 210000003734 Kidney Anatomy 0.000 claims description 2
- 206010024642 Listless Diseases 0.000 claims description 2
- 206010027175 Memory impairment Diseases 0.000 claims description 2
- 241001482237 Pica Species 0.000 claims description 2
- 210000000952 Spleen Anatomy 0.000 claims description 2
- 206010042727 Swollen tongue Diseases 0.000 claims description 2
- 208000001871 Tachycardia Diseases 0.000 claims description 2
- OVSIZNMTLNQPQX-UHFFFAOYSA-N [Fe+3].OC1=NC=CC=[N+]1[O-] Chemical compound [Fe+3].OC1=NC=CC=[N+]1[O-] OVSIZNMTLNQPQX-UHFFFAOYSA-N 0.000 claims description 2
- 230000001133 acceleration Effects 0.000 claims description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 2
- 235000019789 appetite Nutrition 0.000 claims description 2
- 230000036528 appetite Effects 0.000 claims description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 230000000973 chemotherapeutic Effects 0.000 claims description 2
- 230000003001 depressive Effects 0.000 claims description 2
- 201000009910 diseases by infectious agent Diseases 0.000 claims description 2
- 239000010408 film Substances 0.000 claims description 2
- 230000002496 gastric Effects 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 231100000869 headache Toxicity 0.000 claims description 2
- 230000036651 mood Effects 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 3
- 206010007559 Cardiac failure congestive Diseases 0.000 claims 2
- 201000006233 congestive heart failure Diseases 0.000 claims 2
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 claims 2
- 208000001458 Chronic Renal Insufficiency Diseases 0.000 claims 1
- 206010038444 Renal failure chronic Diseases 0.000 claims 1
- 229940035295 Ting Drugs 0.000 claims 1
- 125000002877 alkyl aryl group Chemical group 0.000 claims 1
- 201000000522 chronic kidney disease Diseases 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 21
- 238000005755 formation reaction Methods 0.000 abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 6
- 231100000486 side effect Toxicity 0.000 abstract description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract description 4
- 108009000578 Oxidative Stress Proteins 0.000 abstract description 4
- 230000036542 oxidative stress Effects 0.000 abstract description 4
- 239000003642 reactive oxygen metabolite Substances 0.000 abstract 2
- CWYNVVGOOAEACU-UHFFFAOYSA-N fe2+ Chemical class [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- 230000001988 toxicity Effects 0.000 abstract 1
- 231100000419 toxicity Toxicity 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 81
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 81
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 64
- 239000000047 product Substances 0.000 description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 32
- 239000000126 substance Substances 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 238000004458 analytical method Methods 0.000 description 20
- 239000012043 crude product Substances 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 19
- ONOZITMVLMAPDB-UHFFFAOYSA-N OC1=NC=CC=[N+]1[O-] Chemical compound OC1=NC=CC=[N+]1[O-] ONOZITMVLMAPDB-UHFFFAOYSA-N 0.000 description 18
- 238000001035 drying Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- VSNHCAURESNICA-UHFFFAOYSA-N hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 14
- 230000000875 corresponding Effects 0.000 description 13
- 229960001330 hydroxycarbamide Drugs 0.000 description 13
- 229940027318 hydroxyurea Drugs 0.000 description 13
- 125000000547 substituted alkyl group Chemical group 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000009835 boiling Methods 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 230000002194 synthesizing Effects 0.000 description 12
- 238000001291 vacuum drying Methods 0.000 description 12
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 235000019270 ammonium chloride Nutrition 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 10
- 102000001554 Hemoglobins Human genes 0.000 description 9
- 108010054147 Hemoglobins Proteins 0.000 description 9
- 230000037396 body weight Effects 0.000 description 9
- 239000006227 byproduct Substances 0.000 description 9
- 150000002500 ions Chemical class 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 229910015391 FeC Inorganic materials 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 210000004369 Blood Anatomy 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 150000002505 iron Chemical class 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 210000004027 cells Anatomy 0.000 description 5
- 230000002354 daily Effects 0.000 description 5
- 150000002431 hydrogen Chemical group 0.000 description 5
- 159000000014 iron salts Chemical class 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- IXRIVZOKBPYSPK-UHFFFAOYSA-N phenylmethoxyurea Chemical compound NC(=O)NOCC1=CC=CC=C1 IXRIVZOKBPYSPK-UHFFFAOYSA-N 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 125000003107 substituted aryl group Chemical group 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 210000003743 Erythrocytes Anatomy 0.000 description 4
- 229910015400 FeC13 Inorganic materials 0.000 description 4
- 230000036740 Metabolism Effects 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 230000035786 metabolism Effects 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 150000002829 nitrogen Chemical group 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 125000005415 substituted alkoxy group Chemical group 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 3
- POILWHVDKZOXJZ-ARJAWSKDSA-M (Z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- 102000008857 Ferritin Human genes 0.000 description 3
- 108050000784 Ferritin Proteins 0.000 description 3
- 238000008416 Ferritin Methods 0.000 description 3
- 206010022114 Injury Diseases 0.000 description 3
- LXCFILQKKLGQFO-UHFFFAOYSA-N Methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 3
- 206010033546 Pallor Diseases 0.000 description 3
- 210000002966 Serum Anatomy 0.000 description 3
- 102000004338 Transferrin Human genes 0.000 description 3
- 108090000901 Transferrin Proteins 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000001058 adult Effects 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 125000000473 carbonimidoyl group Chemical group [H]\N=C(/*)* 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 210000001842 enterocyte Anatomy 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 230000001105 regulatory Effects 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000002562 thickening agent Substances 0.000 description 3
- 239000012581 transferrin Substances 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N 2-Pyrrolidone Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- MXKBHIPOOQSROI-UHFFFAOYSA-N 3-bromo-4-tert-butylaniline;hydrochloride Chemical compound Cl.CC(C)(C)C1=CC=C(N)C=C1Br MXKBHIPOOQSROI-UHFFFAOYSA-N 0.000 description 2
- GGOZGYRTNQBSSA-UHFFFAOYSA-N 3-hydroxy-1H-pyridin-2-one Chemical compound OC1=CC=CN=C1O GGOZGYRTNQBSSA-UHFFFAOYSA-N 0.000 description 2
- GSOHKPVFCOWKPU-UHFFFAOYSA-N 3-methylpentane-2,4-dione Chemical compound CC(=O)C(C)C(C)=O GSOHKPVFCOWKPU-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K Aluminium chloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 229940009098 Aspartate Drugs 0.000 description 2
- 206010007554 Cardiac failure Diseases 0.000 description 2
- 210000000170 Cell Membrane Anatomy 0.000 description 2
- MVHVIPHOVHSFOB-UHFFFAOYSA-N Cl.CC1=CC(C)=[N+]([O-])C(O)=N1 Chemical compound Cl.CC1=CC(C)=[N+]([O-])C(O)=N1 MVHVIPHOVHSFOB-UHFFFAOYSA-N 0.000 description 2
- AVFKMZCLKUNYJS-UHFFFAOYSA-N Cl.CCC1=CC=NC(O)=[N+]1[O-] Chemical compound Cl.CCC1=CC=NC(O)=[N+]1[O-] AVFKMZCLKUNYJS-UHFFFAOYSA-N 0.000 description 2
- ZIUSSTSXXLLKKK-HWUZOJPISA-N Curcumin Natural products C1=C(O)C(OC)=CC(\C=C\C(\O)=C/C(=O)/C=C/C=2C=C(OC)C(O)=CC=2)=C1 ZIUSSTSXXLLKKK-HWUZOJPISA-N 0.000 description 2
- YYLLIJHXUHJATK-UHFFFAOYSA-N Cyclohexyl acetate Chemical compound CC(=O)OC1CCCCC1 YYLLIJHXUHJATK-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- CKLJMWTZIZZHCS-UHFFFAOYSA-N DL-aspartic acid Chemical compound OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 2
- 206010018987 Haemorrhage Diseases 0.000 description 2
- 210000003128 Head Anatomy 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K Iron(III) chloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 210000002540 Macrophages Anatomy 0.000 description 2
- GUBGYTABKSRVRQ-YOLKTULGSA-N Maltose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)O[C@H]1CO)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 GUBGYTABKSRVRQ-YOLKTULGSA-N 0.000 description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 2
- 229960003330 Pentetic Acid Drugs 0.000 description 2
- 102100017041 SLC40A1 Human genes 0.000 description 2
- 108091006892 SLC40A1 Proteins 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 210000002784 Stomach Anatomy 0.000 description 2
- 229960004793 Sucrose Drugs 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 125000004429 atoms Chemical group 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000004210 cyclohexylmethyl group Chemical class [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000004851 cyclopentylmethyl group Chemical class C1(CCCC1)C* 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000013681 dietary sucrose Nutrition 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 150000003278 haem Chemical class 0.000 description 2
- 102000018511 hepcidin family Human genes 0.000 description 2
- 108060003558 hepcidin family Proteins 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000004698 iron complex Chemical class 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 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
- 230000002175 menstrual Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000001264 neutralization Effects 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000004430 oxygen atoms Chemical group O* 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000009738 saturating Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-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
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- KNZBHMSRULVCIO-UHFFFAOYSA-N 1,1-dimethoxyhexan-2-one Chemical compound CCCCC(=O)C(OC)OC KNZBHMSRULVCIO-UHFFFAOYSA-N 0.000 description 1
- QVEFWBQLIVFFTH-UHFFFAOYSA-N 1,1-dimethoxypentan-2-one Chemical compound CCCC(=O)C(OC)OC QVEFWBQLIVFFTH-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- MZGRODPRIKETFE-UHFFFAOYSA-N 1-hydroxypyrimidin-2-one Chemical class ON1C=CC=NC1=O MZGRODPRIKETFE-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- OQZGLXOADHKTDN-UHFFFAOYSA-N 1-oxidopyrimidin-1-ium Chemical class [O-][N+]1=CC=CN=C1 OQZGLXOADHKTDN-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- OEKATORRSPXJHE-UHFFFAOYSA-N 2-acetylcyclohexan-1-one Chemical compound CC(=O)C1CCCCC1=O OEKATORRSPXJHE-UHFFFAOYSA-N 0.000 description 1
- OSWDNIFICGLKEE-UHFFFAOYSA-N 2-acetylcyclopentan-1-one Chemical compound CC(=O)C1CCCC1=O OSWDNIFICGLKEE-UHFFFAOYSA-N 0.000 description 1
- 125000005999 2-bromoethyl group Chemical group 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000005924 2-methylpentyloxy group Chemical group 0.000 description 1
- 125000006607 3,3-dimethylbutyloxy group Chemical group 0.000 description 1
- 125000004336 3,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- XGXARWIRPMUVCS-UHFFFAOYSA-N 3-(dimethoxymethyl)pentan-2-one Chemical compound CCC(C(C)=O)C(OC)OC XGXARWIRPMUVCS-UHFFFAOYSA-N 0.000 description 1
- LIPRKYKMVQPYPG-UHFFFAOYSA-N 3-Hydroxy-2H-pyran-2-one Chemical compound OC1=CC=COC1=O LIPRKYKMVQPYPG-UHFFFAOYSA-N 0.000 description 1
- 125000004337 3-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- UCYQBFGYQFAGSO-UHFFFAOYSA-N 3-hydroxy-3H-furan-2-one Chemical compound OC1C=COC1=O UCYQBFGYQFAGSO-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- 125000005925 3-methylpentyloxy group Chemical group 0.000 description 1
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 description 1
- HOCNVUHATLZBNK-UHFFFAOYSA-N 5,6-dimethyl-1H-pyrimidin-2-one;hydrochloride Chemical compound Cl.CC1=CN=C(O)N=C1C HOCNVUHATLZBNK-UHFFFAOYSA-N 0.000 description 1
- MFLKSHVKRZWJRO-UHFFFAOYSA-N 6-ethyl-5-methyl-1H-pyrimidin-2-one Chemical compound CCC=1NC(=O)N=CC=1C MFLKSHVKRZWJRO-UHFFFAOYSA-N 0.000 description 1
- IQBJNNLJWKHORW-UHFFFAOYSA-N 6-tert-butyl-1H-pyrimidin-2-one Chemical compound CC(C)(C)C1=CC=NC(=O)N1 IQBJNNLJWKHORW-UHFFFAOYSA-N 0.000 description 1
- YRKCREAYFQTBPV-UHFFFAOYSA-N Acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 1
- 229940063655 Aluminum stearate Drugs 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 229960000686 Benzalkonium Chloride Drugs 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N Boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 102100006077 CP Human genes 0.000 description 1
- 102100014003 CYBRD1 Human genes 0.000 description 1
- 101710023964 CYBRD1 Proteins 0.000 description 1
- 229960001631 Carbomer Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229940105329 Carboxymethylcellulose Drugs 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 108010075016 Ceruloplasmin Proteins 0.000 description 1
- OSASVXMJTNOKOY-UHFFFAOYSA-N Chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 1
- 229960004926 Chlorobutanol Drugs 0.000 description 1
- VDITWBFYZBPURO-UHFFFAOYSA-N Cl.CC(C)(C)C1=CC=[N+]([O-])C(O)=N1 Chemical compound Cl.CC(C)(C)C1=CC=[N+]([O-])C(O)=N1 VDITWBFYZBPURO-UHFFFAOYSA-N 0.000 description 1
- HBMVJDNPCZXEHV-UHFFFAOYSA-N Cl.CC1=CC=[N+]([O-])C(O)=N1 Chemical compound Cl.CC1=CC=[N+]([O-])C(O)=N1 HBMVJDNPCZXEHV-UHFFFAOYSA-N 0.000 description 1
- HCMCOVCBEMHWPG-UHFFFAOYSA-N Cl.CC1=NC(O)=[N+]([O-])C(C)=C1C Chemical compound Cl.CC1=NC(O)=[N+]([O-])C(C)=C1C HCMCOVCBEMHWPG-UHFFFAOYSA-N 0.000 description 1
- WCXCNEYMWHYIPX-UHFFFAOYSA-N Cl.CC1=NC(O)=[N+]([O-])C(C)=C1Cl Chemical compound Cl.CC1=NC(O)=[N+]([O-])C(C)=C1Cl WCXCNEYMWHYIPX-UHFFFAOYSA-N 0.000 description 1
- KHPJTPYFEZMPNY-UHFFFAOYSA-N Cl.CCC1=C(C)N=C(O)[N+]([O-])=C1C Chemical compound Cl.CCC1=C(C)N=C(O)[N+]([O-])=C1C KHPJTPYFEZMPNY-UHFFFAOYSA-N 0.000 description 1
- DXDWPHIOEDYHKS-UHFFFAOYSA-N Cl.CCC1=CC(CC)=[N+]([O-])C(O)=N1 Chemical compound Cl.CCC1=CC(CC)=[N+]([O-])C(O)=N1 DXDWPHIOEDYHKS-UHFFFAOYSA-N 0.000 description 1
- GGMOPHZOHBHYDY-UHFFFAOYSA-N Cl.CCCC1=CC=NC(O)=[N+]1[O-] Chemical compound Cl.CCCC1=CC=NC(O)=[N+]1[O-] GGMOPHZOHBHYDY-UHFFFAOYSA-N 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 206010011401 Crohn's disease Diseases 0.000 description 1
- 229940109262 Curcumin Drugs 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229960002887 Deanol Drugs 0.000 description 1
- 229940076449 Dexferrum Drugs 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N Diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 229910002553 FeIII Inorganic materials 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 206010019280 Heart failure Diseases 0.000 description 1
- 229960002897 Heparin Drugs 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N Heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 210000003494 Hepatocytes Anatomy 0.000 description 1
- 241000282619 Hylobates lar Species 0.000 description 1
- 206010065973 Iron overload Diseases 0.000 description 1
- 229940096010 Iron polysaccharide Drugs 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L Iron(II) sulfate Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 241000229754 Iva xanthiifolia Species 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 229960004873 LEVOMENTHOL Drugs 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 210000004698 Lymphocytes Anatomy 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229920002521 Macromolecule Polymers 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L Magnesium hydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N Meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 210000004379 Membranes Anatomy 0.000 description 1
- 229940041616 Menthol Drugs 0.000 description 1
- 241001024304 Mino Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 206010028334 Muscle spasms Diseases 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N N-benzyl-1-phenylmethanamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 108060005223 NARF Proteins 0.000 description 1
- 229940100662 Nasal Drops Drugs 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 210000001331 Nose Anatomy 0.000 description 1
- 108020005203 Oxidases Proteins 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 241000164466 Palaemon adspersus Species 0.000 description 1
- 239000004698 Polyethylene (PE) Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 229940093932 Potassium Hydroxide Drugs 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N Potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N Procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010038435 Renal failure Diseases 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 241001000605 Semia Species 0.000 description 1
- 210000003491 Skin Anatomy 0.000 description 1
- 206010040844 Skin exfoliation Diseases 0.000 description 1
- 229960003885 Sodium Benzoate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M Sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- HELHAJAZNSDZJO-UHFFFAOYSA-L Sodium tartrate Chemical compound [Na+].[Na+].[O-]C(=O)C(O)C(O)C([O-])=O HELHAJAZNSDZJO-UHFFFAOYSA-L 0.000 description 1
- 229960002167 Sodium tartrate Drugs 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 208000002903 Thalassemia Diseases 0.000 description 1
- 102000007238 Transferrin Receptors Human genes 0.000 description 1
- 108010033576 Transferrin Receptors Proteins 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical class [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- 229940035081 Venofer Drugs 0.000 description 1
- INLLPKCGLOXCIV-UHFFFAOYSA-N Vinyl bromide Chemical compound BrC=C INLLPKCGLOXCIV-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- QGJJUBXGEPGQPZ-UHFFFAOYSA-N [Fe+3].OC1=NC=CC=N1 Chemical compound [Fe+3].OC1=NC=CC=N1 QGJJUBXGEPGQPZ-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical class [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 231100000319 bleeding Toxicity 0.000 description 1
- 230000000740 bleeding Effects 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 125000005998 bromoethyl group Chemical group 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000001413 cellular Effects 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229920001940 conductive polymer Polymers 0.000 description 1
- 238000010192 crystallographic characterization Methods 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical class C1(CCC1)C* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 230000035618 desquamation Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 1
- 201000008286 diarrhea Diseases 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical class OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 230000002996 emotional Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N ethanolamine Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N ethyl amine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940102709 ferumoxytol Drugs 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical class OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- DGCTVLNZTFDPDJ-UHFFFAOYSA-N heptane-3,5-dione Chemical compound CCC(=O)CC(=O)CC DGCTVLNZTFDPDJ-UHFFFAOYSA-N 0.000 description 1
- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- NDOGLIPWGGRQCO-UHFFFAOYSA-N hexane-2,4-dione Chemical compound CCC(=O)CC(C)=O NDOGLIPWGGRQCO-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- UCNNJGDEJXIUCC-UHFFFAOYSA-L hydroxy(oxo)iron;iron Chemical compound [Fe].O[Fe]=O.O[Fe]=O UCNNJGDEJXIUCC-UHFFFAOYSA-L 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 201000002161 intrahepatic cholestasis of pregnancy Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 235000000396 iron Nutrition 0.000 description 1
- 235000020796 iron status Nutrition 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000003903 lactic acid esters Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000007787 long-term memory Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000002934 lysing Effects 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 235000012254 magnesium hydroxide Nutrition 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000000873 masking Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- XOBKSJJDNFUZPF-UHFFFAOYSA-N methoxyethyl Chemical group CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000005244 neohexyl group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 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
- 230000001590 oxidative Effects 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000001575 pathological Effects 0.000 description 1
- 125000005003 perfluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
- 125000005804 perfluoroheptyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
- 125000005005 perfluorohexyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
- 125000005008 perfluoropentyl group Chemical group FC(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(F)* 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229920001888 polyacrylic acid Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940093956 potassium carbonate Drugs 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000000750 progressive Effects 0.000 description 1
- OEUAEFQARUZYLW-UHFFFAOYSA-N prop-1-en-2-olate Chemical group [CH2+]C([O-])=C OEUAEFQARUZYLW-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical class CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000001172 regenerating Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 150000003902 salicylic acid esters Chemical class 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 230000006403 short-term memory Effects 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003419 tautomerization reaction Methods 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
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- 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
-
- 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
- A61P7/06—Antianaemics
-
- 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
- C07D239/34—One oxygen atom
-
- 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
- C07D239/46—Two or more oxygen, sulphur or 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
Abstract
Disclosed are Fe(III) complexes with bidentate pyrimidine ligands (formula I) and pharmaceutical compositions for use in the treatment and prevention of iron dificency and anaema. In comparison to classical preparations of Fe(II) salts, the complexes have fewer side effects, lower toxicity, low molecular weight, high complex stability and do not lead to free Fe which catalyses the formation of reactive oxygen species that cause oxidative stress. cular weight, high complex stability and do not lead to free Fe which catalyses the formation of reactive oxygen species that cause oxidative stress.
Description
Fe(III) Complexes for the Treatment and Prophylaxis of Iron Defiency Symptoms and Iron
Deficiency as
AH26(9127889_1):SAK
per second). This high regenerative capacity is achieved by
macrophages phagocytizing the ageing erythrocytes, lysing them and
thus recycling the iron thus ed for the iron metabolism. The amount
of iron of about 25 mg required daily for erythropoiesis is thus provided
for the main part.
The daily iron requirement of an adult human is between 0.5 to 1.5 mg
per day, infants and women during pregnancy require 2 to 5 mg of iron
per day. The daily iron loss, e.g. by desquamation of skin and lial
cells, is low; increased iron loss occurs, for example, during menstrual
hemorrhage in women. Generally, blood loss can significantly reduce the
iron level since about 1 mg iron is lost per 2 ml blood. In a healthy
human adult, the normal daily loss of iron of about 1 mg is usually
replaced via the daily food . The iron level is regulated by
I5 absorption, with the absorption rate of the iron present in food being
n 6 and I2 %; in the case of iron deficiency, the absorption rate
is up to 25%. The absorption rate is regulated by the organism
depending on the iron requirement and the size of the iron store. in the
process, the human organism utilizes both divalent as well as trivalent
iron ions. Usually, iron[|||) compounds are dissolved in the stomach at a
sufficiently acid pH value and thus made available for absorption. The
absorption of the iron is carried out in the upper small intestine by
mucosal cells. In the process, ent non-heme iron is first reduced in
the intestinal cell membrane to FeIII) for absorption, for example by
ferric reductase [membrane-bound duodenal cytochrome b), so that it
can then be transported into the inal cells by means of the
transport protein DMTI (divalent metal orter I). In contrast, heme
iron enters the enterocytes through the cell membrane without any
change. In the enterocytes, iron is either stored in ferritin as depot iron,
or discharged into the blood by the ort protein ferroportin.
Hepcidin plays a central role in this process e it is the most
important regulating factor of iron uptake. The divalent iron transported
into the blood by ferroportin is converted into trivalent iron by oxidases
[ceruloplasmin, stin), the trivalent iron then being transported to
the relevant places in the organism by transferrin (see for example
"Balancing acts: lar control of mammalian iron metabolism". M.W.
Hentze, Cell 117,2004,285-297.)
Mammalian organisms are unable to actively discharge iron. The iron
metabolism is ntially controlled by hepcidin via the cellular release
of iron from macrophages, hepatocytes and enterocytes.
In pathological cases, a reduced serum iron level leads to a reduced
hemoglobin level, reduced erythrocyte production and thus to anemia.
External ms of anemias include fatigue, pallor as well as reduced
capacity for concentration. The al symptoms of an anemia include
low serum iron levels [hypoferremia), low hemoglobin , low
crit levels as well as a reduced number of erythrocytes, reduced
i5 locytes and elevated levels of soluble transferrin receptors.
Iron deficiency symptoms or iron anemias are treated by ing iron.
In this case, iron substitution takes place either orally or by intravenous
iron administration. Furthermore, in order to boost ocyte formation,
erythropoietin and other erythropoiesis-stimulating substances can also
be used in the treatment of anemias.
Anemia can often be traced back to malnutrition or low-iron diets or
imbalanced nutritional habits low in iron. Moreover, anemias occur due
to reduced or poor iron absorption, for e because of
ectomies or diseases such as Crohn's disease. Moreover, iron
deficiency can occur as a consequence of increased blood loss, such
as because of an injury, strong menstrual bleeding or blood donation.
Furthermore, an increased iron requirement in the growth phase of
3O adolescents and children as well as in pregnant women is known. Since
iron deficiency not only leads to a reduced erythrocyte formation, but
thereby also to a poor oxygen supply of the organism, which can lead to
the above-mentioned symptoms such as fatigue, pallor, reduced powers
of concentration, and especially in adolescents, to long-term negative
effects on cognitive pment, a highly effective and well tolerated
therapy is of particular interest.
Through using The Fe(lll) complex compounds according To The invenTion,
There is The possibliTy of TredTing iron ency sympToms and iron
deficiency anemias ively by oral opplicaTion wiThouT having To
accepT The large poTenTiaI for side effecTs of The classical preparaTions,
The Fe(|i] iron salTs, such as FeSO4, which is caused by oxidaTive s’rress.
Poor compliance, which ofTen is The reason for The deficienT eliminaTion
of The iron deficiency ion, is Thus avoided.
Prior arT:
A mulTiTude of iron complexes for The TreaTmenT of iron deficiency
ions is known from The prior arT.
A very large proporTion of These complex compounds consisTs of polymer
sTrucTures. MosT of These x compounds are iron-polysaccharide
complex nds [W020081455586, 062546,
WO20040437865, U82003236224, EPi50085). IT is precisely from This area
ThoT There are medicamenTs available on The morkeT (such as MalTofer,
2O Venofer, FeriniecT, Dexferrum, FerumoxyTol).
AnoTher large porTion of The group of The polymer complex compounds is
comprised of The iron-pepTide x compounds (CNiOi 481404,
EP939083, JP02083400].
There are also Fe complex compounds described in The IiTeroTure ThoT
are sTrucTurally derived from macromolecules such as hemoglobin,
phyll, curcumin and heparin (US474670, CNl687089, BiomeTols,
2009,22,7OT-710).
Moreover, low-molecular Fe complex compounds are also described in
The IiTeraTure. A large number of These Fe complex compounds
comprises carboxylic acid and amino acids as ligands. In This case, The
focus is on asparTaTe (U82009035385) and ciTraTe [EP308362] as ligands.
Fe complex compounds containing derivatized phenylalanine groups as
ligands are also described in this context (E82044777).
Hydroxypyrone and ypyridone Fe complex compounds are also
described in the literature [EP159194, EP138420, EP107458). The
corresponding 5-ring systems, the hydroxyfuranone Fe complex
compounds, are also described in y thereto (WO2006037449). l
particular, the hydroxypyridone Fe complex nds, however, have
comparatively low water solubility, making them less suitable, especially
for oral administration. rmore the hydroxypyridone Fe complex
compounds have comparatively low iron utilization.
er, iron-cyclopentadienyl complex nds are also described
in the literature (GB842637).
Furthermore, oxy-4,o-dimethyl-2[1H]-pyrimidone are described in
the literature as Fe(lil) ligands (Bull. Chem. Soc. Jpn., 66, 841 - 841
(1993), and as a possible structure of a corresponding iron[|||) complex
the following structure is specified:
(see also “Reviews On Heteroatom Chemistry", vol. 18., 1998, pages 87
to 118 from the same authors). A characterization of this complex was
only carried out in solution. A solid form of this complex is not disclosed.
Furthermore, the iron complex compounds are not proposed or used as
medicaments, such as especially for the treatment of iron deficiency
ms. The same authors suggest only the use of hexadentate 1-
hydroxy-lH-pyrimidine-2—one compounds as iron sequestering agents for
treatment of iron overload conditions such as semia (J. Org. Chem.
1997, 62, 3618 — 3624). By the administration of hydroxy-pyrimidinone
compounds to the body for the treatment of thalassemia iron might be
removed — so no iron will be ed — as in the treatment of iron
deficiency anemia by administration of iron complex nds in
accordance with the present invention.
J. Am. Chem. Soc. 1985, 107, 6540 — 6546 describes tetradentate i—
hydroxy-TH-pyridineone compounds as ligands and a binuclear iron
complex compound therewith. The possibility to use the ligands for iron
sequestering is mentioned, too. Similarly, lnorganico Chimica Acta, 135
(1987) T45 — 150 discloses the use of oxy-lH-pyridineones as
agents for masking iron.
Iron salts (e.g. iron(|l) sulfate, iron(|l) fumarote, iron(lll) chloride, iron(|l)
aspartate, iron(|l) ate] are another important constituent for the
treatment of iron deficiency symptoms and iron deficiency anemias.
These iron salts are very problematic in that, in part, they are highly
incompatible (up to 50%) in the form of nausea, vomiting, diarrhea and
also obstipation and cramps. Moreover, free iron(|l) ions which catalyze
the formation (inter alia Fenton on) of reactive oxygen s
(ROS) occur during the use of these iron(|l) salts. These ROS cause
damage to DNA, lipids, proteins and ydrates which has far-
reaching effects in cells, tissue and organs. This complex of problems is
known and, in the literature, is largely considered the cause for the high
incompatibility and referred to as oxidative stress.
Therefore, iron(IIIJ-i-hydroxy-lH-pyrimidineone or pyrimidineoI-i-
oxide complex compounds, respectively, have not been described in the
prior art r as a medicament nor in particular for the use in the
treatment and/or for prophylaxis of iron deficiency symptoms and iron
deficiency anemia so far.
According to a first aspect of the present invention there is ed use of
iron(III) pyrimidineoloxide complex compounds or pharmaceutically
acceptable salts thereof, which contain at least one ligand of the formula (I):
AH26(9820323_1):JIN
wherein
the arrows respectively represent a coordinate bond to one or different iron
atoms, and
R1, R2, R3 may be the same or different and are ed from the group
consisting of:
- hydrogen,
- alkyl, which may be substituted with cycloalkyl or with 1 to 3 substituents
selected from the group consisting of
o y,
o aryl, which may be substituted with one or more substituents
selected from
halogen,
hydroxy,
alkyl, as defined above and
alkoxy, as defined below,
o heteroaryl, which may be substituted with one or more
substituents selected from
halogen,
hydroxy,
alkyl, as defined above and
alkoxy, as defined above,
o alkoxy (RO-), with R being alkyl as defined above,
o alkoxycarbonyl (RO-CO-), with R being alkyl as d above,
o acyl,
o halogen,
o amino ( -NH2) or a 5 or ered cyclic amino that may
contain further hetero atoms selected from N, O, S, and which
each may be substituted to form mono- or dialkylamino or
AH26(9820323_1):JIN
mono- or diarylamino, with aryl being aryl or heteroaryl, or
mixed alkylarylamino groups, each with al kyl, aryl or heteroaryl
as defined above,
o aminocarbonyl, derived by adding a yl group to amino or
a 5 or 6-membered cyclic amino, each as defined above, and
o cyano,
- halogen,
- alkoxy, as defined above,
- aryl, as defined above,
- alkoxycarbonyl, as defined above,
- amino, as defined above, and
- aminocarbonyl, as defined above, or
R1 and R2 or R2 and R3 er with the carbon atoms to which they are
bonded, form an optionally substituted saturated or unsaturated 5 - or 6-
membered ring, which may optionally contain one or more heteroatoms for the
manufacture of a medicament medicament for the treatment and prophylaxis
of iron deficiency symptoms and iron deficiency anemias and the symptoms
associated therewith.
ing to a second aspect of the t invention there is provided use of
a composition containing iron(III) complex nds as defined in the first
aspect, in combination with at least one further ment which acts on the
iron metabolism for the preparation of medicaments for the treatment of iron
deficiency anemia.
AH26(9820323_1):JIN
therapeutic success in the treatment of iron ency anemia could be
achieved. ally in comparison to iron salts, the complex
compounds according to the invention ted a faster and higher
utilization. Furthermore, these new systems have significantly reduced
side effects than the classically used iron salts since there is no
noteworthy occurrence of free iron irons in this case. The complex
compounds according to the invention exhibit almost no oxidative stress
since there is no formation of free radicals. Thus, significantly fewer side
effects occur in the case of these complex compounds than in the case
of the Fe salts known from the prior art. The x compounds exhibit
good stability at various pH value ranges. Furthermore, the iron complex
compounds have a very low toxicity and can therefore be administered
in high dosages t side effects. Finally the complex compounds
can be prepared well and are optimally suitable for the ation of
medicaments. in particular for oral administration.
Thus, the subject matter of the invention are iron(|l|)-pyrimidineol-T-
oxide complex compounds or their pharmaceutically acceptable salts
for use as medicaments or synonymous for use in a method for
therapeutic treatment of the human body, respectively.
The iron(|l|)-pyrimidineo|-T-oxide complex compounds as used in
accordance with the present invention particularly include such
nds with comprise the following structural t:
N O
' \
8\Fe
wherein “W" respectively is a substituent saturating the free valence and
the arrows respectively ent coordinate bonds to the iron atom.
Thus. the terms
- “pyrimidineol-l -oxide”,
- “pyrimidineol-i —oxide compounds” or
- idineol-i oxide-“ligands
occording To The invenTion include The corresponding y sTorTing
compounds
o'—N\O):j
OS well as The corresponding deproTonoTed ligonds
N+ , O-——N‘Nj
\N / O/kl
, Tively,
which are presenT in The corresponding ironllll] complex compounds.
FurThermore, ing To The invenTion The oforemenTioned Terms do
noT only comprise The respecTive bose body:
Ho;-—N:’Nj
or The ligand compound resulTing from deproTonoTing The underlying
hydroxy compound
01—NO);/j
, respecTiver
buT as well Their represenToTives subsTiTuTed on The pyrimidine rings,
resulTing from The replocemenT of one or more hydrogen dToms on The
dine ring by other substituents. Accordingly, in context with the
t invention the aforementioned terms refer to the entire class of
“pyrimidine—2-ol-l-oxide” compounds and the deprotonated ligands,
ing their representatives substituted on the pyrimidine ring.
Formally, a (deprotonated) pyrimidineol-l-oxide ligand according to
the present invention carries a negative charge. This means, that in the
case of three s per iron atom, the iron atom formally has the
oxidation state +3. It is clear to the person skilled in the art that the
shown formulas represent only one possible mesomeric formula and that
there are several mesomeric formulas and that delocalisation of the
electrons in the ligands or in the iron complex compound may be
present, respectively, as shown hereinafter tically.
In the iron(lll) pyrimidineol—l-oxide complex compounds according to
the invention, the coordination number of the iron atoms is generally six
(6), with a coordinating atoms generally being arranged octahedrally.
Furthermore, mono- or polynuclear iron(lll) pyrimidineol-l-oxide
complex compounds in which one or more (such as 2, 3 or 4) iron atoms
are present are also comprised according to the ion.
Generally, 1—4 iron atoms and 2—1 0 ligands can be present in the iron(|ll}
pyrimidineol-l-oxide complex compounds. Mononuclear iron[lll)
pyrimidineol-l-oxide complex compounds with at least one preferably
tri-, preferably bidentate dineol-l-oxide ligands are preferred.
Mononuclear iron(lll) dineol-l-oxide complex compounds with
one [1) central iron atom and three (3) pyrimidineol-l-oxide ligands
are particularly preferred.
The iron(|l|) pyrimidineol-l-oxide complex nds are generally
present in neutral form. However, salt like iron(l|l] pyrimidineol-l-oxide
complex compounds are also included, in which the complex has a
ve or negative charge which is compensated, in particular, by
pharmacologically compatible, substantially non-coordinating anions
(such as, in particular, halogenides, such as chloride] or cations [such
as, in particular, alkaline or alkaline-earth metal ions].
The iron[lll) pyrimidineol-l-oxide complex compounds according to
the invention ularly include complex compounds, comprising at
least one, preferably a bidentate pyrimidineol-l-oxide ligand of the
formula
lea/K
if 0
9o\_\Fe
wherein ”WW respectively is a substituent saturating the free valence of
the ligands, which can, as shown above, bond to one or even two
different iron atoms in the sense of bridging.
lron[||l) pyrimidineol-l—oxide complex compounds are red which
exclusively comprise preferably bidentate pyrimidineol-l -oxide ligands
which may be the same or different. Furthermore, iron(lll) pyrimidineol-
l-oxide complex compounds are particularly preferred which exclusively
comprise the same pyrimidineol—l-oxide ligands and very particularly
red are tris[pyrimidineol-l -oxide] |l) nds.
Preferably, the molecular weight of the ive iron [ll|)-pyrimidinol l-
oxide-complex compounds is less than 1000 g / mol, more preferably
less than 850 g / mol, still more preferably less than 700 g / mol (each
determined from the structural formula).
In a ularly preferred embodiment the iron(lll) complex compounds
according to the present invention comprise at least one, preferably
three same or ent, preferably same ligands of the formula (l):
R2 \
R3 3A0
@\ (1)
wherein
the arrows respectively ent a coordinate bond to one or different
iron atoms, and
R1, R2, R3 may be the same or different and are selected from the group
consisting of:
- hydrogen,
- optionally substituted alkyl,
- halogen,
- optionally substituted alkoxy,
- optionally substituted aryl,
- optionally substituted alkoxycarbonyl,
- optionally substituted amino, and
- optionally substituted aminocarbonyl or
R1 and R2 or R2 and R3 together with the carbon atoms to which they are
bonded, form an ally substituted saturated or unsaturated 5- or 6-
membered ring, which may optionally contain one or more heteroatoms,
or pharmaceutically acceptable salts thereof.
The above-mentioned ring formation of the substituents I?1 and R2 or R2
and R3 is schematically shown in the ing formulas:
91 01
A preferred embodiment of the present invention relates to these lron(ll|)
complex compounds containing at least one ligand of the formula [I]:
1 ska
0 \
@\ (I)
wherein
the arrows respectively represent a coordinate bond to one or different
iron atoms, and
R1, R2, R3 may be the same or different and are selected from the group
consisting of:
- hydrogen,
- optionally substituted alkyl,
- halogen,
— ally substituted alkoxy,
- ally substituted aryl,
- optionally substituted alkoxycarbonyl, and
- optionally substituted arbonyl or
R1 and R2 or I?2 and R3 together with the carbon atoms to which they are
bonded, form an optionally substituted saturated or unsaturated 5- or o-
membered ring, which may optionally contain one or more heteroatoms,
or pharmaceutically acceptable salts Thereof.
A preferred embodiment of the t invention relates to these ironilll)
complex compounds containing at least one ligand of the formula (I):
R2 \
R, iii/*0
@\ (I)
wherein the arrows respectively represent a coordinate bond to one or
different iron atoms, and
R1, R2, R3 may be the same or different and are selected from the group
consisting of:
- hydrogen
- optionally substituted alkyl, and
— halogen.
Within the overall context of the invention, optionally substituted alkyl, in
ular for the substituents R1 to R3, preferably includes:
straight-chained or branched alkyl with i to 8, preferably i to 6 carbon
atoms, cycloalkyl with 3 to 8, ably 5 or 6 carbon atoms, or alkyl
with i to 4 carbon atoms, which is substituted with cycloalkyl, wherein
these alkyl groups can be optionally substituted.
The above mentioned alkyl groups can be unsubstituted or substituted,
preferably with i to 3 substituents. These substituents at the alkyl groups
are preferably selected from the group consisting of: hydroxy, ally
tuted aryl, in particular as d below, optionally tuted
heteroaryl, in particular as defined below, optionally substituted alkoxy,
in particular as defined below, optionally substituted alkoxycarbonyl, in
particular as defined below, optionally substituted acyl, in particular as
defined below, halogen, in ular as defined below, optionally
substituted amino, in particular as defined below, optionally substituted
aminocarbonyl, in particular as defined below, and cyano.
Halogen includes here and within to the t of the present invention,
fluorine, chlorine, bromine and iodine, ably fluorine or chlorine.
In the above defined alkyl groups, ally one or more, more
preferably 1 to 3 carbon atoms can furthermore be replaced with
hetero-analogous groups that contain nitrogen, oxygen or sulphur. This
means, in particular, that, for example, one or more, preferably 1 to 3,
still more preferred one (i) ene group (-CH2-) can be replaced in
the alkyl groups by —NH-, -NR4-, -O- or —S-, wherein R4 is optionally
substituted alkyl as d above, preferably C1-C6 alkyl, such as methyl
or ethyl, optionally substituted with i to 3 substituents, such as fluorine,
ne, hydroxy or alkoxy.
Examples of alkyl residues having 1 to 8 carbon atoms include: a methyl
group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl
group, an i-butyl group, a sec-butyl group, a t-butyl group, an n-pentyi
group, an i-pentyi group, a sec-pentyl group, a t-pentyl group, a 2-
methylbutyl group, an n-hexyl group, a i-methylpentyl group, a 2-
methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a
i-ethylbutyl group, a lbutyi group, a 3-ethylbutyl group, a i,i-
dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl
group, a i-ethyI-i-methyipropyl group, an n-heptyl group, a i-
methylhexyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 4-
methyihexyl group, a 5-methylhexyl group, a i-ethylpentyi group, a 2-
ethylpentyl group, a 3-ethylpentyl group, a 4-ethylpentyl group, a i,i-
dimethylpentyl group, a 2,2-dimethylpentyl group, a 3,3-dimethylpentyl
group, a 4,4-dimethylpentyl group, a i-propylbutyl group, an n-octyl
group, a i-methyiheptyl group, a 2-methylheptyl group, a ylheptyl
group, a 4-methylheptyl group, a 5-methylheptyi group, a 6-methylheptyl
group, a l-ethylhexyl group, a 2-ethylhexyl group, a lhexyl group,
a lhexyl group, a 5-ethylhexyl group, a l,l-dimethy|hexyl group, a
2,2—dimethylhexyl group, a methylhexyl group, a 4,4-dimethylhexyl
group, a 5,5-dimethylhexyl group, a l-propylpentyl group, a 2-
propylpentyl group, etc. Those with l to 6 carbon atoms are preferred.
Methyl, ethyl, n-propyl, isopropyl, sec-butyl and n-butyl are most
preferred.
Examples of alkyl groups ed by replacement with one or more
-analogous groups, such as —O—, —S—, —NH— or —N(R4)— are
preferably such groups in which one or more methylene groups (-CH2-)
are replaced with —0— while forming an ether group, such as
methoxymethyl, ethoxymethyl, 2-methoxyethyl etc. Therefore, the
definition of alkyl also includes, for example, alkoxyalkyl groups as
defined below, which are produced from the above-mentioned alkyl
groups by replacement of a methylene group with -O-. If, according to
the invention, alkoxy group are additionally permitted as substituents of
alkyl, several ether groups can also be formed in this manner [such as a
—CH2-O-CH2-OCH3-group]. Thus, according to the invention, polyether
groups are also sed by the definition of alkyl.
Cycloalkyl groups with 3 to 8 carbon atoms preferably include: a
cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a
cyclohexyl group, a cycloheptyl group, a ctyl group, etc. A
cyclopropyl group, a cyclobutyl group, a Cyclopentyl group and a
exyl group are preferred. The Cycloalkyl groups may optionally be
substituted preferably with l to 2 substituents such as hydroxyl or C1-C6
alkoxycarbonyl.
The definition of the optionally substituted alkyl also includes alkyl groups
which are substituted by the above mentioned cycloalkyl groups, such as
ropylmethyl, cyclobutylmethyl, cyclopentylmethyl or
cyclohexylmethyl.
Heterocyclic alkyl groups according to the invention are preferably those
formed by the replacement of methylene with hetero-analogous groups
from lkyl, and include, for example, saturated 5 or ered
heterocyclic residues, which may be ed via a carbon atom or a
nitrogen atom, and which preferably may have i to 3, preferably 2
heteroatoms, especially 0, N, such as tetrahydrofuryl, azetidine-l-yl,
substituted inyl, such as 3-hydroxyazetidin—l-yl, pyrrolidinyl, such as
pyrrolidin-l-yl, substituted pyrrolidinyl, such as oxypyrrolidin-l-yl, 2-
hydroxypyrrolidin-l -yl 2-methoxycarbonylpyrrolidin-l -yl, 2-
ethoxycarbonylpyrrolidin-l -yl, 2-methoxypyrrolidin-l -yl, 2-ethoxypyrrolidin-
l-yl, 3-methoxycarbonylpyrrolidin-l-yl, 3-ethoxycarbonylpyrrolidin-l-yl, 3-
methoxypyrrolidin-l-yl, 3-ethoxypyrrolidine-l-yl, piperidinyl, such as
piperidin-l-yl, piperidinyl, substituted piperidinyl, such as 4-methyl-ipiperidyl
, 4-hydroxy-l-piperidyl, oxy-l-piperidyl, 4-ethoxy-l-
piperidyl, 4-methoxycarbonyI-l-piperidyl, 4-ethoxycarbonyl-l-piperidy|, 4-
carboxy-l-piperidyl, 4-acetyl-l-piperidyl, 4-formyl-l-piperidyl, l-methyl
piperidyl, 4-hydroxy-2,2,6,é-tetramethyl-l-piperidy|, 4-(dimethylamino]-l-
piperidyl, 4-(diethylaminol-l-piperidyl, 4-amino-l-piperidyl, 2-
(hydroxymethyl)-l -piperidyl, 3-(hydroxymethyl)-l idyl, 4-
[hydroxymethyl)-l -piperidyl, 2—hydroxy-l -pi'peridyl, 3-hydroxy-l -piperidy|,
4-hydroxy-l-piperidyl, morpholin-A-yl, substituted morpholinyl, such as
2,6-dimethyl morpholinyl, piperazinyl, such as zin-l-yl,
substituted piperazinyl, such as 4-methylpiperazin-l-yl, 4-ethylpiperazin-
l-yl, 4-ethoxycarbonylpiperazin-i-yl, 4-methoxycarbonylpiperazin-l-yl, or
ydropyranyl, such as tetrahydropyran-A-yl, and which can
optionally be condensated with aromatic rings, and which may
ally be substituted, such as with i to 2 substituents such as
hydroxy, halogen, Cl-Cé-alkyl, etc. The definition of the optionally
substituted alkyl groups thus includes also alkyl groups, which are
substituted by the above-defined heterocyclic groups, such as 3-(l-
dyl)propyl, 3-pyrrolidin-l -ylpropyl, 3-morpholinopropyl, 2-
morpholinoethyl, 2-tetrahydropyranylethyl, 3-tetrahydropyran
ylpropyl, 3-(azetidin-l -yl) propyl etc.
Examples of a linear or branched alkyl group substituted with halogen
and having 1 to 8, preferably 1 to 6 carbon atoms include, in particular:
a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a
methyl group, a dichloromethyl group, a trichloromethyl group, a
bromomethyl group, a dibromomethyi group, a tribromomethyl group, a
l-fluoroethyl group, a i-chloroethyl group, a i-bromoethyl group, a 2-
fluoroethyl group, a roethyl group, a 2-bromoethyl group, a 1,2-
difluoroethyl group, a 1,2-dichloroethyl group, a bromoethyl group,
a 2,2,2-trifluoroethyl group, a heptafluoroethyl group, a l-tluoropropyl
group, a ropropyl group, a l-bromopropyl group, a 2-fluoropropyl
group, a 2-chloropropyl group, a 2-bromopropyl group, a 3-fluoropropyl
group, a 3-chloropropyl group, a 3-bromopropyl group, a 1,2-
difluoropropyl group, a chloropropyl group, a l,2-dibromopropyl
group, a 2,3-difluoropropyl group, a chloropropyl group, a 2,3-
dibromopropyl group, a 3,3,3-trifluoropropyl group, a 2,2,3,3,3-
pentafluoropropyl group, a 2-fluorobutyl group, a 2-chlorobutyi group, a
2-bromobutyl group, a 4-fiuorobutyl group, a 4-chlorobutyl group, a 4-
bromobutyl group, a 4,4,4-trifluorobutyl group, a 2,2,3,3,4,4,4-
heptafluorobutyl group, a perfluorobutyl group, a 2-fluoropentyl group, a
2-chloropentyl group, a 2—bromopentyl group, a 5-fluoropentyl group, a
ropentyl group, a 5-bromopentyl group, a perfluoropentyl group, a
2O 2-fluorohexyl group, a 2-chlorohexyl group, a 2-bromohexyl group, a 6-
fluorohexyl group, a 6-chlorohexyl group, a 6-bromohexyl group, a
perfluorohexyl group, a 2-fluoroheptyl group, a 2-chloroheptyl group, a
2-bromoheptyl group, a 7-fluoroheptyl group, a roheptyl group, a
7-bromoheptyl group, a perfluoroheptyl group, etc..
Examples of an alkyl group substituted with hydroxy include the above-
mentioned alkyl residues, which have i to 3 y residues, such as,
for example hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-
ybutyl, 5-hydroxypentyl, b-hydroxyhexyl.
Optionally substituted aryl preferably includes according to the invention
aromatic hydrocarbon residues with 6 to l4 carbon atoms (with no
hetero atom in the aromatic ring system), for example: phenyl, naphthyl,
phenanthrenyl and anthracenyl. The aforementioned aromatic groups
may be unsubstituted or substituted. In case of substitution, they
preferably preferably have one or more, preferably one (i) or two (2)
substituents, in particular halogen, hydroxy, alkyl, alkoxy, in each case as
explained above or below. A preferred aromatic group is phenyl. A
preferred alkyl substituted with an aromatic group [arylalky|) is benzyl.
Optionally substituted aryl according to the present invention further
includes optionally substituted heteroaryl, that is, heteroaromatic groups,
such as for example: pyridyl, pyridyl-N-oxide, pyrimidyl, zinyl,
pyrazinyl, thienyl, furyl, pyrrolyl, lyl, imidazolyl, thiazolyl, oxazolyl or
isoxazolyl, indolizinyl, indolyl, benzo[b]thienyl, benzo[b]furyl, lyl,
quinolyl, isoquinolyl, naphthyridinyl, qulnazolinyl. 5- or 6-membered
aromatic heterocycles such as, for example pyridyl, pyridyl-N-oxide,
pyrimidyl, pyridazinyl, furyl and thienyl are red. The entioned
heteroaromatic groups may be unsubstituted or substituted. In case of
substitution, they preferably have one or more, preferably one (i) or two
(2] substituents, in particular n, hydroxy, alkyl, alkoxy, in each case
as ned above or below. Preferred examples of an alkyl substituted
with a heteroaromatic group (hetarylalkyl) are methyl, ethyl, or propyl, in
each case substituted with a heteroaromatic group, such as
thienylmethyl, pyridylmethyl etc.
Optionally substituted alkoxy (RO-] is formally derived from the above
mentioned optionally substituted alkyl residues by adding an oxygen
atom and includes in t with the t invention, for e,
linear or branched alkoxy groups with up to 6 carbon atoms, such as a
methoxy group, an ethoxy group, an n-propyloxy group, an i-propyloxy
group, an n-butyloxy group, an loxy group, a sec-butyloxy group, a
t-butyloxy group, an n-pentyloxy group, an i-pentyloxy group, a sec-
pentyloxy group, a t-pentyloxy group, a 2-methylbutoxy group, an n-
hexyloxy group, an i-hexyloxy group, a t-hexyloxy group, a sec-hexyloxy
group, a 2-methylpentyloxy group, a 3-methylpentyloxy group, a l-
ethylbutyloxy group, a 2-ethylbutyloxy group, a l,l-dimethylbutyloxy
group, a 2,2-dimethylbutyloxy group, a 3,3-dimethylbutyloxy group, a l-
ethyl-l-methylpropyloxy group, etc. A methoxy group, an ethoxy group,
an n-propyloxy group, an i-propyloxy group, an n-butyloxy group, an i-
butyloxy group, a sec-butyloxy group, a t-butyloxy group, etc., are
preferred. The alkoxy groups may optionally be substituted, such as with
the above le substituents for alkyl.
Methoxy, ethoxy, n-propoxy, n-butoxy, etc. are red alkoxy.
Optionally substituted alkoxycarbonyl (RO-CO-] groups are ly
derived from the above alkyl groups by adding a - e under
formation of an optionally substituted alkyloxycarbonyl residue. In that
regard reference can be made to the definition of the above-described
alkyl groups. As an alternative optionally substituted alkoxycarbonyl (ROCO-
) groups are derived from the aforementioned alkoxy groups by the
addition of a carbonyl group. Methoxycarbonyl, ethoxycarbonyl, n-
propoxycarbonyl, n-butoxycarbonyl tert.-butoxycarbonyl etc. are
preferred alkoxycarbonyl, which may all be substituted as the above
defined alkyl groups.
Optionally substituted amino according to the invention includes
preferably: amino (-NH2), optionally substituted mono- or dialkylamino
(RHN-, (R)2N), wherein with respect to the definition of optionally
substituted alkyl it can be referenced to the above definition. Further
included are optionally substituted mono- or diarylamino radicals or
mixed optionally substituted alkyl aryl amino radicals, wherein with
respect to the definition of optionally substituted alkyl or aryl nce
can be made to the above tion. Such groups include, for example,
methylamino, dimethylamino, ethylamino, hydroxyethylamino, such as 2-
hydroxyethylamino, lamino, phenylamino, methylphenylamino etc..
Particularly preferred is mino. ally substituted amino further
includes an optionally substituted cyclic amino, such as optionally
substituted 5 or 6-membered cyclic amino that may contain further
hetero atoms such as N, O, S, preferably O. Examples of such cyclic
amino groups include: the above-mentioned nitrogen-containing
heterocyclic groups which are attached via a nitrogen atom, such as
piperidin-i-yl, 4-hydroxy-piperidin-i-yl, hoxycarbonyi)pyrrolidin-i-y|,
idin-l-yl, morpholinyl, etc.
ally substituted amino carbonyl ing to the invention can be
formally derived from ally substituted amino, as explained before,
by adding a carbonyl residue [{R)2N-C[=O)-). Therein optionally
substituted amino preferably includes according to the invention: amino
(-NH2], optionally substituted mono- or dialkylamino (RHN-, (R)2N-] for
which with regard to the definition of optionally tuted alkyl
reference can be made to the above definition. Furthermore included
are optionally substituted mono- or diarylamino groups or mixed
optionally substituted alkylarylamino groups, for which as regards the
definition of optionally substituted alkyl or aryI reference can be made to
the above tions. Such groups include, for example methylamino,
Dimethylamino, ethylamino, hydroxyethylamino, such as 2-
hydroxyethlyamino, Diethylamino, phenylamino, methylphenylamino etc.
Optionally substituted amino further includes an optionally substituted
cyclic amino, such as ally tuted 5 or 6-membered cyclic
amino that may contain further hetero atoms such as N, O, 5, preferably
0. Examples of such cyclic amino groups include the above-mentioned
nitrogen-containing heterocyclic groups bonded through a nitrogen
atom, such as piperidin-l-yl, 4-hydroxy-piperidin-i-y|, 2-
(methoxycarbonyl)pyrrolidin-i-y|, pyrrolidin-i—yl, Morpholinyl etc.
Examples of optionally substituted aminocarbonyl include therefore:
Carbamoyl [HQNC(=O}-), ally substituted mono- or
dialkylaminocarbonyl [RHNC(=O), [R)2NC(=O)-), wherein reference can
be made to the above definition of optionally tuted alkyl.
Furthermore are included optionally substituted mono- or
diarylaminocarbonyl residues or mixed, ally substituted
alkylarylaminocarbonyl es, wherein reference can be made to the
above definitions of optionally substituted alkyl and aryi. Preferred
substituted aminocarbonyl groups comprise up to 14 carbon atoms.
Such groups include for example methylaminocarbonyl,
dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl,
phenylaminocarbonyl, diphenylaminocarbonyl, methylphenylamino-
carbonyl etc.
In a preferred embodiment, R1 and R2 or R2 and R3 form together with the
carbon atoms to which they are ed a 5- or b-membered
carbocyclic ring.
Examples of the aforementioned ring formation of the substituents R1 and
R2 or R2 and R3 as represented schematically by the following formulas:
\N \N
I l
R3 32% 9%
e in particular:
compounds in which R1 and R2 or R2 and R3 together preferably ent
a propylene (-CHQ-CHg-CHQ-l- or a butylene (-CHQ-CHQ-CHz-CHQ-l group, in
which ally one methylene group [-CH2—] tively can be
replaced with —O-, -NH- or —NR4-, wherein R4 is defined as mentioned
above and wherein the groups formed by R1 and R2 or R2 or R3 optionally
can furthermore respectively be substituted by one to three substituents
selected from the group consisting of hydroxy, oxo, C1-C4 alkoxy, amino
and mono- or di-(C1-C4-alkyIJamino.
Exemplary ligands are the following:
\N \“
| to)?» l
R3 @Xo
8\ 9\
wherein R1 and R3 are each as described above.
In another particularly preferred embodiment of iron [Ill] complex
compounds according to the the invention R,, R2, R3 are identical or
different and are selected from the group consisting of hydrogen and
alkyl, with the proviso that at least one, preferably two of the substituents
R1, R2, and R3 are alkyl. Alkyl is preferably as mentioned above,
especially straight-chained or branched, preferably, unsubstituted alkyl
having up to 6, preferably up to 4 carbon atoms. Still more preferred are
iron (III) x compounds n R2 is hydrogen, and R1 and R3 are
each the same or different and are selected from alkyl as mentioned
above.
The ll) x compounds of the formula (ll) are particularly
preferred:
wherein R1, R2 and R3 are each defined as above or preferably as
defined below.
Furthermore, preferably R1, R2 and I?3 are the same or ent and are
selected from:
- hydrogen,
- Ci a|kyl, preferably as presented above,
- halogen, preferably as presented above,
- C3cycloalkyl, preferably as presented above,
- ycloalkyI-Ci yl, preferably as presented above,
- Ci a|i<oxy-Ci a|kyl, preferably as presented above,
— Ci alkoxycarbonyl, ably as presented above,
- Ci mono- or diaikylaminocarbonyl, ably as presented
i5 above,
- aminocarbonyl or carbamoyl [H2NC0-1 respectively,
- hydroxy-Ci aiky|, preferably as presented above, and
- halogen-Ci yl, preferably as presented above.
Particularly ably R], R2 and R3 are the same or different and are
selected from: hydrogen, halogen and Ci-é-alkyl, preferably as
presented above, in particular hydrogen, chlorine, methyl, ethyl and
propyl, in particular i-propyi, butyl, especially tyi. Most preferably,
R1, R2 and R3 are selected from: hydrogen, methyl and ethyl.
In a further embodiment of the invention there are provided the iron (III)-
pyrimidinol i-oxide-compiex compounds in solid form. The term “solid
form“ means here in particular in contrast to the dissolved form, in which
the iron [II|)-pyrimidinoi i-oxide-complex compounds are present
dissolved in a solvent such as water. The term ”solid form” means also
that the iron (|i|)-pyrimidinol T-oxide-compiex compounds at room
temperature [23 °C) are present in solid form. The iron (ll|)-pyrimidin-2—oi
i-oxide-complex nds can be present in an amorphous,
crystalline or partially crystalline form. Also, the iron [|l|)-pyrimidino| i—
complex compounds of the invention may exist as hydrates, in
particular as crystalline hydrates, such as the monohydrate, in particular
as a crystalline monohydrate,
It is clear to the person skilled in the art that the ligands ing to the
invenfion
R3 fik
e9\ 0\
arise from the corresponding pyrimidineol-i -oxide compounds:
R3 $A0H
In the pyrimidineoI—i-oxide compounds there is a keto-enol-
tautomerism, wherein the equilibrium state is determined by various
factors.
R1 R1 R1
RUN“ R
v..— RZPN
EN/Ko 6/ 2|):
R3 R3 N/|\OH v— R3 '7‘ 0
(5 ('3 OH
e e
The ligand is formally obtained by cleavage of a proton from the
ponding pyrimidine-i -oxide compounds:
R1 R1
R2 \ [- H+] R2 \N
l i ———————-> l
69/ 69/ E)
R3 l|\l OH R3 lIl o
o o
e 6
so formally carries a single negative charge.
Furthermore it is clear to a person skilled in the art that the pyrimidine
oI-i-oxide compounds as used according to the present invention can
be drawn by different notations (a, b and c}, but all include the same
issue of the N-oxide.
R1 R1 R1
R2 \ R2 R2 /
N I N NH
R3 fiAOH R3 N’kori R3 \N/KO
l l
9 (a) 0 (b) 0 (c).
The same applies for the corresponding deprotonated form of the
pyrimidineol-i-oxide ligand compounds. Within the scope of the
present invention all tautomeric forms are included, even if only one of
the mesomeric formulas is drawn.
Depending on the substituent R1, R2, R3 they can also participate in the
eric resonance ures in the pyrimidineol-i-oxide . By
way of example, the 4-amino nds can be mentioned. For
example:
All such tautomers are included within the scope of the ion.
Optionally substituted amino preferably is in the position of R1, ie, in the
4-positlon of the pyrimidine ligand.
The iron(||l) pyrimidineoI-oxide complex compounds, in ular such
as of the general a [H] or the corresponding pyrimidineol-i-
oxide ligands, respectively, can be present in the form of various isomers
or tautomers. Isomeric forms include, for example, regioisomers which
differ in the position of the ligands relative to one another, including so-
called optical s that have an image/mirror image relationship to
one another. If asymmetric carbon atoms are present, the ligands can
be present in the form of l isomers which have an image/mirror
image relationship to one another, and include pure enantiomers,
mixtures of the enantiomers, in particular racemates. Enantiomerically
pure ligands can be obtained, as is known to the person skilled in the art,
by optical resolution s, such as reaction with chiral reagents to
form diastereomers, separation of the diastereomers and release of the
enantiomers. Examples of tautomeric nce structures, which are
also included according to the invention have been shown above as an
example.
Furthermore, in particular the following are preferred embodiments of the
invenfion:
(In the t ion, the digits 1-6 in “l-éC” or “1-4” in “1 -4C” or “Cl-
4” etc. in each case signify the number of the carbon atoms of the
subsequent arbon group designations].
R1, R2 and R3 are selected from the group consisting of:
- hydrogen,
- halogen,
- mono- or di(i -6C-a|ky|)amino,
- i—éC-alkyl, (i.e. alkyl with l to 6 carbon atoms),
- 3-6C-cycloalkyl,
- 3-6C-cycloalkyI-l -4C-a|kyl,
- l-4C-alkoxy-i -4C-a|kyl,
- hydroxy-l -4C-a|kyl,
- fluoro-l-4C-alkyl;
or I?1 and R2 together form a propylene (-CHQ-CHz-CH2], butylene [-CHQ-
CH2—CH2-CH2-L azabutylene or oxabutylene group;
or R2 and R3 together form a propylene (-CHz-CHz-CH2-]-, butylene (-CHQ-
CHQ—CHQ-CHQ-l, azabutylene or oxabutylene group
or R1 and R2 together with a carbon atom to which they are bonded,
form an unsaturated ring, which may optionally contain one or more
further hetero atoms,
or R2 and R3 together with a carbon atom to which they are bonded,
form an unsaturated ring, which may optionally contain one or more
further hetero atoms,
or pharmaceutically able salts thereof.
ably, the aforementioned substituent groups are defined as follows:
l-éC-alkyl preferably includes straight-chained or branched alkyl groups
with l to 6 carbon atoms. Examples therefore can be methyl, ethyl, n-
propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl n-pentyl, iso-
pentyl, neo-pentyl, n-hexyl, iso-hexyl and neo-hexyl.
3-6C-Cycloalkyl preferably includes cycloalkyl l to 6 carbon atoms, such
as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
3cycloalkyl-l-4C-alky| preferably includes a l-bC-alkyl group
described above, tuted with a 3-éC-cycloalkyl group described
above. Examples therefor can be a cyclopropylmethyl.
cyclopentylmethyl and cyclohexylmethyl group.
l-3C-alkoxy-carbonyl-l-6C-alky|, preferably es a l-éC-alkyl group
described above, which is linked to a carbonyl group which is t
with a l-3C alkoxy group as a carboxylic acid ester. es therefor
can be methoxycarbonylmethyl, carbonylmethyl,
methoxycarbonylethyl, ethoxycarbonylethyl and
isopropoxycarbonylmethyl.
l-4C-alkoxy preferably includes a l-4C-alkoxy group, in which an oxygen
atom is connected to a straight or branched alkyl chain with 1-4 carbon
atoms. Examples of this group can be methoxy, ethoxy, propoxy and
isobutoxy.
l-4C-alkoxy-l-4C-alkyl preferably includes a l-4C-alkoxy group
described above, which is substituted with a l-4C-alkyl group described
above. Examples of this group can be methoxyethyl, propyl.
methoxypropyl, isobutoxymethyl.
Hydroxy-l-4C-alkyl includes a lkyl group described above, which is
substituted with a hydroxy group. es or can be hydroxyethyl,
hydroxybutyl and hydroxyisopropyl.
Fluoro-l-4C-alkyl includes a l-4C-alkyl group described above, which is
substituted with one to three fluorine atoms. Examples or can by
trifluoromethyl and trifluoroethyl.
Halogen signifies F, Cl, Br, I.
Particularly preferred are:
R1, R2 and R3 are selected from the group consisting of:
- hydrogen,
- halogen,
- l-éC-alkyl,
- l-4C-alkoxy-l-4C-alkyl,
- hydroxy-l -AC-alkyl;
or R1 and R2 together form a propylene (-CHz-CHQ-CHQ), butylen (-CHQ-
CHQ-CHQ-CHz-l, azabutylene or oxabutylene group;
2O or R2 and R3 er form a propylene (-CHz-CH2-CH2), butylene (-CH2-
CH2-CH2-CH2-), azabutylene or oxabutylene group,
or R1 and R2 er with a carbon atom on which they are bonded,
form an rated ring which may optionally contain further hetero
atoms,
or R2 and R3 together with a carbon atom to which they are ,
form an unsaturated ring which may optionally comprise further hetero
atoms.
Particularly preferably:
R1, R2 and R3 are selected from the group consisting of:
- hydrogen,
- i-éC-aikyl;
- i-4C-alkoxy-l-4C-alkyl
or R1 and R2 together form a propylene CHz-CHQ] or butylene
(-CHQ-CHQ-CHz-CHQJ group;
or R2 and R3 together form a ene (-CHz-CHQ-CHQJ or butylene
(-CHQ-CHQ-CHz-CHQ-J group
or R1 and R2 together with a carbon atom to which they are bonded form
an unsaturated ring which may comprise one further nitrogen atom.
or R2 and R3 together with a carbon atom to which they are bonded form
an unsaturated ring which may comprise a further en atom.
Particularly preferred complex compounds of the general formula (II) are
described in the examples.
The ion further relates to a method for the preparation of the
iron(|ll) complex compounds ing to the invention which comprises
the reaction of a pyrimidineol-i-oxide of formula [Ill] with an iron(|||)
salt.
PyrimidinoI-i-oxides as the starting compounds include in particular
those of the formula (III):
R3 WIAOH
6 (m)
wherein R1, R2 and R3 are defined as above, to the tautomeric resonance
structures of which it has been referred to.
es of suitable ironilll) salts e: iron(|||] chloride, iron[i|l)
acetate, iron(lll) sulfate, iron[|l|) e and ll) acetylacetonate,
among which iron(|l|) chloride is preferred.
A preferred method is shown in the following scheme:
R1 R
FeXs 3 V» R3
I e
\N (N) g\ l/OfiD/ERZ
| EDAOH Fe
Base
R 0/ /| R
3 1
('3 (V) X69 o
e \N’e
(Ill) WMRshi /
wherein R,, R2 and R3 are as defined above, X is an anion such as
halogenide, such as chloride, a carboxylate, such as acetate, sulphate,
nitrate and acetylacetonate and base is a common organic or inorganic
base.
in the method according to the invention, preferably 3 eq pyrimidine
ol-i-oxide (ill), using suitable ironilll} salts (IV) (in this case Fe(|l|) chloride,
) e, Fe(|||] sulphate and Feilll) acetylacetonate are particularly
suitable), are reacted under standard conditions to form the
corresponding complexes of the general formula [II]. In this case, the
synthesis is carried out under the pH conditions optimal for complex
2O formation. The optimum pH value is set by adding a base (V); in this
case, the use of sodium hydroxide, sodium carbonate, sodium hydrogen
carbonate, sodium methanolate, potassium hydroxide, potassium
carbonate, potassium hydrogen carbonate or potassium methanolate is
particularly suitable.
The ligands (ill) required for the preparation of the complexes where
prepared according to the following synthesis method (analogue
tetrahedron 1967, 23, 353 — 357). For this purpose, the commercially
available or synthesised l,3—dicarbonyl compounds of the l
formula [N] were reacted under standard conditions with hydroxy urea [V]
to form ligands of the general formula (III). When using unsymmetrical l-
rbonyl compounds in this synthesis, this results almost always in the
occurrence of the corresponding regioisomers , which can be
separated by standard methods which are well known to a person skilled
in the art. For n substitution patterns for R1, R2 and R3 [Illa] can also
ent the main product and, in these cases, then is the synthesis
access to the tive substitution patterns.
R2 R
° °
————»
R1 R3 l169/ 2'169/
acid R3 r]: OH R1 r}: OH
(lV) (Ill) (Illa)
l5 Analogously, it is also possible to use slightly modified synthesis routes for
the preparation of the respective ligands of the general formula (III). l.
e., in the synthesis of Ohkanda et al. (Bull. Chem. Soc. Jpn. 1993, 66,
841 — 847) the benzyl ted urea according to formula [V-Bn) is
cyclized under rd conditions with the respective l,3-dicarbonyl
compounds (IV) to form the corresponding benzyl protected product (lll-
Bn], wherein the subsequent cleavage leads to the desired product (III).
In this alternative synthesis route it comes to the occurrence of (Illa), too.
(iv) (lll-Bn)
Bn = Hz/Pd
(ill)
For ligands in which one or both of the radicals R1 and R3 are hydrogen,
a slightly modified synthesis was carried out. Herein the ponding
protected i,3-dicarbonyl compounds such as for example those of the
general formula (VI) have been reacted similarly with hydroxyurea (V)
under acidic standard conditions. In this case R is preferably methyl or
ethyl.
Herein too, the product ratio of the two forming pyrimidineol-l-oxides
[lllc] and (llld) is controlled by the choice of the ls R1 and R2. The
separation is then performed under standard conditions ar to those
skilled in the art.
)1 OH R
o/R H2N N/ 1 H
R1M3
——___—»<v> l 0
HCI e/ko/ .19/
M) (We) (llld)
In general, the preparation of the pyrimidineoI-oxide (III) can be as
well carried out by other synthesis routes familiar to a d person. Thus,
for example, there is the possibility to react the respective substituted
pyrimidines (Vii) with suitable oxidizing agents, such as hydrogen
peroxide or peroxycarboxylic acids, to form the desired ts of
general formula (III) (e.g. analogous to Can. J. Chem. 1984, 62, 1176 —
1180).
R1 R1
R2 H O R2
| 1 —‘—’Z2 \N
/ or
R3 N OH R3 (r? OH
peroxycarboxylic o
acids 9
(W) (m)
es of the pyrimidineoI-l-oxide starting compounds (III) include
particularly the following:
hll DH
EN”Am
From These nds The ligands of The iron complex compounds
according To The presenT invenTion are derived by simple deproTondTion
CT The hydroxy group.
ceutically acceptable salts of the compounds according to the
invention in which the iron(lll) complex formally s a ve charge
include, for example, salts with le anions, such as carboxylates,
sultonates, sulfates, chlorides, bromides, iodides, phosphates, tartates,
methanesulfonates, hydroxethanesulfonates, ates, maleates,
propionates, fumarates, tulouenesulfonates, benzene sulfonates,
trifluoroacetates, naphthalenedisulfonates-l,5, salicylates, benzoates,
lactates, salts of malic acid, salts of 3-hydroxynaphthoic acid-2,
citrates and acetates.
ceutically acceptable salts of the compounds according to the
invention in which the ll) complex formally carries a negative charge
include, for example, salts with suitable pharmaceutically acceptable
bases, such as, for e, salts with alkaline or alkaline-earth
ides, such as NaOH, KOH, Ca(OH]2, Mg(OH)2 etc., amine
compounds such as ethylamine, diethylamine, triethylamine,
iisopropylamine, ethanolamine, diethanolamine, triethanolamine,
methylglucamine, dicyclohexylamine, dimethylaminoethanol, procaine,
dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine,
N-methylpiperidin, 2-aminomethyI-propanol-(l), 2-aminomethyl-
propandioI-(l,3), 2-aminohydroxyI-methyl-propandioi-[l ,3) [TRIS] etc..
The water-solubility or the solubility in physiological saline solution and
thus, optionally, also the efficacy of the compounds according to the
invention can be significantly influenced by salt formation in general,
specifically by the choice of the counterion.
Preferably, the compounds according to the ion constitute neutral
complex compounds.
Advantageous pharmacological effects:
Surprisingly, the inventors found that the iron(lll) pyrimidineoI-l-oxide
complex compounds which are the subject matter of the present
invention and which are represented, in particular, by the general
structural formula (II), are stable bioavailable iron complexes and
suitable for use as a medicament for the treatment and prophylaxis of
iron deficiency symptoms and iron deficiency anemias the symptoms
occompanying them.
The medicaments containing the compounds ing to the invention
are suitable for use in human and veterinary medicine.
The compounds according to the invention are thus also suitable for
TO preparing a medicament for the treatment of patients ing from
ms of an iron deficiency anemia, such as, for example: e,
listlessness, lack of concentration, low cognitive ency, difficulties in
finding the right words, forgetfulness, unnatural pallor, irritability,
acceleration of heart rate (tachycardia), sore or swollen tongue,
enlarged spleen, desire for strange foods (pica), headaches, lack of
appetite, increased susceptibility to infections or depressive moods.
The ll) complex compounds according to the invention are
rmore suitable for the treatment of iron deficiency anemia in
pregnant women, latent iron deficiency anemia in en and
adolescents, iron deficiency anemia caused by gastrointestinal
abnormalities, iron deficiency anemia due to blood loss, such as
gastrointestinal hemorrhage (e.g. due to ulcers, carcinoma,
hemorrhoids, inflammatory disorders, taking of salicylic acid), iron
deficiency anemia caused by menstruation, iron deficiency anemia
caused by injuries, iron deficiency anemia due to sprue, iron deficiency
anemia due to reduced dietary iron uptake, in particular in selectively
eating children and adolescents, immunodeficiency caused by iron
deficiency anemia, brain function impairment caused by iron deficiency
s, restless leg syndrome caused by iron ency anemias, iron
deficiency anemias in the case of cancer, iron deficiency anemias
caused by chemotherapies, iron deficiency anemias triggered by
inflammation (Al), iron deficiency anemias in the case of congestive
cardiac insufficiency (CHF; tive heart failure), iron deficiency
anemias in the case of c renal insufficiency stage 3-5 (CDK 3-5;
chronic kidney es sTage 3-5), iron deficiency anemias Triggered by
c maTion (ACD), iron deficiency anemias in The case of
rheumatoid arThriTis (RA), iron deficiency anemias in The case of sysTemic
lupus eryThemaTosus [SLE) and iron deficiency anemias in The case of
inflammaTory bowel diseases (IBD).
AdminisTraTion can Take place over a period of several monfhs unTil The
iron sTaTus is improved, which is reflecfed, for e, by The
obin level, Transferrin saTuraTion and The serum ferriTin level of The
TO paTienTs, or unTil The desired emenT of The sTaTe of healTh affecTed
by iron deficiency .
The preparaTion according To The invenTion can be Taken by children,
adolescenTs and adulTs.
The applied compounds according To The invenTion can in This case be
adminisTered boTh orally as well as parenTally. Oral sTraTion is
preferred.
The compounds according To The ion and The aforemenfioned
combinaTions of The compounds according To The invenTion wiTh oTher
acTive subsTances or medicines can Thus be used, in parTicular, for The
preparaTion of medicamenTs for The TreaTmenT of iron deficiency
anemia, such as iron deficiency anemia in pregnanT women, laTenT iron
deficiency anemia in children and adolescenTs, iron ency anemia
caused by gasfroinTesTinal abnormalifies, iron deficiency anemia due To
blood loss, such as gasTroinTesTinal hemorrhage [e.g. due To ulcers,
carcinoma, hemorrhoids, inflammaTory disorders, Taking of aceTylsalicylic
acid), mensTruaTion, injuries, iron deficiency anemia due To sprue, iron
deficiency anemia due To reduced dieTary iron up’rake, in parTicular in
selecTively eaTing children and adolescenTs, immunodeficiency caused
by iron deficiency anemia, brain funcTion impairmenT caused by iron
deficiency anemia, resTless leg syndrome.
The application according to the invention leads to an improvement of
the iron, hemoglobin, ferritin and transferrin levels, which, in particular in
children and adolescents, but also in adults, is accompanied by an
improvement in short-term memory tests (STM), long-term memory tests
(LTM), Ravens' progressive matrices test, in the Wechsler adult
intelligence scale (WAIS) and/or in the emotional coefficient (Baron EQ-i,
YV test, youth version), or to an improvement of the neutrophile level, the
dy levels and/or lymphocyte function.
Furthermore, the present invention relates to pharmaceutical
compositions comprising one or more of the compounds according to
the invention, in particular according to the formula [II], as well as
ally one or more further pharmaceutically effective compounds,
as well as optionally one or more pharmacologically acceptable carriers
and/or auxiliary substances and/or ts. The said pharmaceutical
compositions contain, for e up to 99 weight-% or up to 90
weight-% or up to 80 weight-% of the compounds of the invention, the
remainder being each formed by pharmacologically acceptable carriers
and/or auxiliaries and/or ts.
These are common ceutical carriers, auxiliary substances or
ts. The mentioned pharmaceutical compositions are
suitable, for example, for intravenous, intraperitoneal, intramuscular,
intravaginal, intrabuccal, percutaneous, subcutaneous, mucocutaneous,
oral, rectal, transdermal, topical, intradermal, intragasteral or
intracutaneous application and are provided, for example, in the form of
pills, s, enteric-coated tablets, film tablets, layer tablets, sustained
release formulations for oral, subcutaneous or cutaneous administration
(in particular as a plaster), depot formulations, dragees, itories,
3O gels, solves, syrup, granulafes, suppositories, emulsions, dispersions,
microcapsules, ormulations, nanoformulations, liposomal
formulations, capsules, enteric-coated capsules, powders, inhalation
powders, microcrystalline formulations, inhalation sprays, epipastics,
drops, nose drops, nose sprays, aerosols, ampoules, solutions, juices,
suspensions, on solutions or injection solutions etc.
Preferably, the compounds according to the invention as well as
pharmaceutical compositions ning such compounds are applied
orally, gh other forms, such as parentally, in particUlar
intravenously, are also possible.
For this purpose, the compounds according to the invention are
ably provided in pharmaceutical compositions in the form of pills,
tablets, enteric-coated tablets, film tablets, layer tablets, sustained
e formulations for oral administration, depot formulations, dragees,
granulates, emulsions, dispersions, apsules, microformulations,
nanoformulations, liposomal formulations, capsules, enteric-coated
capsules, powders, microcrystalline formulations, epipastics, drops,
ampoules, solutions, suspensions, infusion solutions or injection solutions.
The compounds according to the invention can be administered in
ceutical compositions which may contain various organic or
inorganic r and/or auxiliary materials as they are customarily used
for pharmaceutical purposes, in particular for solid medicament
formulations, such as, for example, excipients [such as saccharose,
starch, mannitol, sorbitol, lactose, glucose, cellulose, talcum, calcium
phosphate, m carbonate), binding agents (such as cellulose,
methylcellulose, hydroxypropylcellulose, polypropyl pyrrolidone, gelatine,
gum , polyethylene glycol, saccharose, starch), disintegrating
agents (such as starch, hydrolyzed starch, carboxymethylcellulose,
calcium salt of carboxymethylcellulose, hydroxypropyl , sodium
glycol starch, sodium onate, calcium phosphate, m citrate),
lubricants (such as magnesium stearate, talcum, sodium laurylsulfate}, a
flavorant [such as citric acid, menthol, glycin, orange powder),
preserving agents (such as sodium benzoate, sodium bisulfite,
methylparaben, proylparaben), stabilizers ( such as citric acid, sodium
citrate, acetic acid and multicarboxylic acids from the titriplex series,
such as, for example, diethylenetriaminepentaacetic acid [DTPA],
suspending agents (such as methycellulose, nyl pyrrolidone,
aluminum stearate], dispersing agents, diluting agents [such as water,
organic solvents), beeswax, cocoa butter, polyethylene , white
petroldtum, etc.
Liquid medicament formulations, such as solvents, suspensions and gels
usually contain a liquid carrier, such as water and/or pharmaceutically
acceptable organic solvents. Furthermore, such liquid formulations can
also contain pH-adjusting agents, emulsifiers or dispersing agents,
ing agents, preserving , wetting agents, gelatinizing agents
(for example methylcellulose], dyes and/or flavouring agents. The
TO compositions may be isotonic, that is, they can have the same osmotic
pressure as blood. The isotonicity of the composition can be ed by
using sodium chloride and other pharmaceutically acceptable agents,
such as, for example, dextrose, maltose, boric acid, sodium tartrate,
ene glycol and other inorganic or c soluble substances. The
viscosity of the liquid compositions can be adjusted by means of a
pharmaceutically able thickening agent, such as methylcellulose.
Other suitable thickening agents include, for example, xanthan gum,
carboxymethylcellulose, hydroxypropylcellulose, carbomer and the like.
The preferred concentration of the thickening agent will depend on the
agent selected. Pharmaceutically acceptable preserving agents can be
used in order to increase the storage life of the liquid composition.
Benzyl alcohol can be le, even though a plurality of preserving
agents ing, for example, paraben, thlmerosal, chlorobutanol and
benzalkonium chloride can also be used.
The active substance can be administered, for example, with a unit dose
of 0.001 mg/kg to 500 mg/kg body weight, for example i to 4 times a
day. However, the dose can be increased or reduced depending on the
age, weight, condition of the patient, severity of the e or type of
administration.
The designation of the ligands has been carried according to the IUPAC
nomenclature with the program ACD/name, version 12.01 according to
Advanced Chemistry Development Inc.
Abbreviations
s singlet t triplet
a doublet q quartet
dd double doublet m mu lti plet
[broad/superimposed)
L ligand
Starting compounds:
A. Pyrimidineol-l -oxlde hydrochloride
l QIAOH
0.261 mol (19.85 g] hydroxy urea have been dissolved in 390 ml T M HCI
and 0.235 mol [51.77 g) i.i,3.3-tetraethoxypropane were added
se under ice cooling, with the al ature being
maintained at i — 2 °C. The solution was thawed in an ice bath to room
temperature and d over night, then evaporated to dryness. The
residue was suspended with 250 ml of e, the mixture was cooled
in an ice/ethanol bath, the solid filtered off and washed with a little ice-
cold acetone. After drying, 24.5 g of crude product were obtained. The
crude product was recrystallized with 460 ml of methanol from the
boiling heat, cooled in an ice/ethanol bath, filtered off and dried. The
mother liquor was concentrated on a rotary evaporator until again
product started to precipitate, then a second fraction was crystallized
rly. After drying 11.8 g (1. fraction) and 5.9 g (2. fraction) the title
compound were ed.
IR (in substance, cm"): 3114, 3082, 2995, 2935, 2837, 2776,2718, 2467,
1734,1575,1492,1421,1363,1314,1232,1176,1123,1100,1073,911,
861, 773, 733, 689, 574 (2. fraction).
CN-elementary analysis: C, 32.29; N, 18.98 (1. fraction]; C, 32.41; N,
18.98 (2. fraction).
Chloride t: 24.6 % (m/m) (1. fraction], 23.6 % (m/m) (2. fraction)
LC-MS:113[M+H).
1H-NMR (DMSO-dé, 400 MHz]. 8 [ppm] = 9.05 (dd, 1H), 8.55 (dd, 1H), 6.74
(t, 1H).
B. 4-Methylpyrimidineoloxld hydrochloride
0.10 mol (7.61 g] hydroxy urea were dissolved in 150 ml of 1 M HC1 and
0.11 mol [16.15 g, techn. 90 %] of 4,4,-dimethoxybutanone was
added dropwise under ice cooling whereby the internal ature was
maintained at 1 — 3 °C. The solution was thawed in an ice bath to room
temperature and stirred over night, then filtered and evaporated to
dryness. The residue was suspended with 100 ml of acetone, the mixture
was cooled to —18 °C, the solid filtered off and washed with a little ice-
cold acetone. After drying, 10.7 g or crude product were obtained. The
crude product was recrystallized with 1750 ml ethanol from the boiling
heat, cooled in an ice/ethanol bath, filtered off, washed with a little
l and dried [fraction 1]. The mother liquor was concentrated on a
3O rotary evaporator until again product started to precipitate, cool stored
and a second fraction isolated. After , 6.15 g (1. fraction) and 1.86
g (2. fraction) product was obtained. Both fractions were combined and
recrystallized from the boiling heat with 230 mi 90 °/o ethanol (10 %
water] similarly. After drying, 3.75 g (3. fraction) and 2.36 g (4. fraction]
of the title compound were obtained.
IR (in substance, cm"): 3102, 3034, 2926, 2841, 2730, 2657, 2531, 1741,
1650,1602,1581,1518,1456,1374,1302,.1184,1131,1110,1037,977, .
888, 821, 780, 734, 697, 603 (3. fraction].
TO CHN-elementary analysis: C, 37.48; H, 4.33; N, 17.12 (3.Fraktion]; C,
37.12; H, 4.30; N, 17.08 (4. fraction).
LC-MS: 127 (M+H).
1H-NMR (DMSO-db, 400 MHz): 8 [ppm] = 8.97 (d, 1H), 6.73 (d, 1H], 2.49
(s, 3H).
C. 4,6-Dimethylpyrimidlneoloxide hydrochloride
0.40 mol (30.6 g) hydroxy urea was dissolved in 600 ml of 1 M HCI and
0.50 mol (50.06 g] acetyl e were added dropwise under ice
g, maintaining the internal temperature at 1 — 3 °C. The solution
was thawed to room temperature in an ice bath and stirred over night,
then filtered off and evaporated to dryness. The residue was suspended
with 400 ml of acetone, the mixture was cooled to -18 °C, the solid
filtered off and washed with a little ice-cold acetone. After drying, 45,5 g
of crude product were ed. The crude product was recrystallized
with 4.0 I l from the boiling heat, cooled to —18 °C, filtered off
and washed with little ethanol and dried (fraction 1). The mother liquor
was concentrated on a rotary evaporator until product started to
itate again, cool stored and a second fraction isolated. After
drying 26.0 g (1. fraction, purity >98 %) and 11.0 g (2. fraction,
contained 32 % NH4CI as by-product) of the titie compound was
obtained.
IR (in substance, cm"): 3077, 3052, 2938, 2855, 2796, 2521, 1740, 1610,
1564,1509,1423,1368,1316,1215,1163,1141,1089,1049,1026,997,
975, 852, 775, 741, 695, 626, 601 (1. fraction].
CHN-elementary analysis: C, 40.74; H, 5.03; N, 15.78 [1. fraction]; C,
27.75; H, 5.87; N, 18.98 (2. fraction).
Chioride content: 19.9% (m/m) (1. fraction], 33.4% (m/m) (2. fraction)
Lc-Ms: 141 [M+H).
1H-NMR (DMSO-db, 400 MHz): 8 [ppm] = 6.78 (s, 1H]: 2.53 (s, 3H); 2.43 (s,
3H] (1. fraction].
D. 4,6-Dlethylpyrimidlneol 1-oxid hydrochlorlde
N OH
0.19 moi [14.45 g) hydroxy urea were dissolved in 300 ml 1 M HCI, 300 ml
of methanol was added and 0.19 mol [24.35 g) of 3,5-heptandione was
added se under ice cooling, maintaining the internal temperature
at 1-2 °C. The on was thawed to room temperature in an ice bath
and stirred over night, then evaporated to s. The residue was
suspended with 200 ml of acetone, the mixture was cooled to below 0
°C in an ice/ethanol bath, the solid filtered off and washed with a little
ice-cold acetone. After drying, 7.88 g of a product was obtained which
contained 48 % of the title compound and 52 % ammonium de as
by-product.
IR [in substance, cm"): 3116, 3024, 2804, 2687, 2628, 1996, 1746, 1603,
1572, 1512, 1443, 1394, 1297, 1213, 1156, 1082, 1061, 963, 901, 861.
814, 745, 700.
CHN-elementary analysis: C, 22.71; H, 6.94; N, 19.99.
Chloride content: 42.9% (m/m)
LC-MS: 169 (M+H).
1H-NMR (DMSO-dé, 400 MHz): 8 [ppm] = 6.75 (s, 1H), 2.86 (q, 2H], 2.70
(q, 2H), 1.21 (t, 3H), 1.20 (t, 3H).
E. 4-Methyl(2-methylpropyl)pyrimldlne—2-oloxide hydrochloride
E OH
0.20 mol (15.21 9] hydroxy urea were dissolved in 300 ml of M HCI, 300
ml of methanol were added, and 0.20 mol [28.44 g] 6-methyI-2,4-
heptanedione were added dropwise while cooling at —1 2 to —10 °C. The
solution was allowed to warm slowly to room Temperature and stirred over
night, then evaporated to dryness. The e was suspended with 200
ml of acetone, the e cooled to below 0 °C in an ice/ethanol bath,
the solid filtered off and washed with a little ice-cold acetone. After
drying 7.23 g of a product was obtained, which contained 58 % of the
title compound and 42 % of the by-product ammonium chloride.
IR (in substance, cm"): 3106, 3011, 2963, 2576, 1834, 1740, 1604, 1567,
1514, 1467, 1446, 1403, 1371, 1321, 1280, 1234, 1209, 1149, 1104,
1070, 1032, 1010, 915, 861, 820, 774, 750, 712, 680, 644, 615, 580.
CHN-elementary analysis: C, 28.68; H, 6.93; N, 18.33.
Chloride content: 37.6% [m/m]
LC-MS: 183 (M+H].
1H-NMR [DMSO-dé, 400 MHz]: 6 [ppm] = 6.76 (s, 1H), 2.72 (d, 2H), 2.44 (s,
3H], 2.13 (m, 1H), 0.91 (d, 6H]. From the NMR-spectrum was estimated
that the product contained approximately 2 % of the regioisomere 6-
(2-methylpropyl)pyrimidineoloxide hydrochloride.
F. 4.5,6-Trlmethylpyrlmldlneol-T —oxide hydrochlorlde
0.263 mol (20.0 9) hydroxy urea were dissolved in 263 ml 1 M HCl and
0.876 mol (100 g) 3-methyl-2,4-pentanedione (95 %, Alfa Aesar] were
added dropwise under ice cooling. The two-phase-mixture was stirred for
T h at room ature, and then it was extracted twice with 530 ml
ethyl acetate. The combined c phases were dried with sodium
sulphate and concentrated on a rotary evaporator to dryness. 86.6 g 3-
methyl-2,4-pentanedione, depleted with acetyl acetone, were obtained.
0.758 mol [60.84 9) hydroxy urea were dissolved in 500 ml of 2 M HCI
and 200 ml of methanol and 0.758 mol (86.56 g] 3-methyl-2,4-
edione were added. The solution was stirred for i h at 50 °C, and
then concentrated to dryness. The residue was suspended in 80 ml of
acetone, the mixture was cooled to below 0 °C in an ice/ethanol bath,
the solid filtered off, washed with a little ice-cold acetone and dried.
21.7 g of intermediate product were heated to boiling in 150 ml
methanol, hot filtered from insoluble fractions and again evaporated to
dryness. There were obtained 7.05 9 solid (1. fraction] which contained
9.6 % of the title nd and 90 % of the duct ammonium
From the acetone mother liquor further solid precipitated which was
filtered off, washed with a little acetone and dried. 2.50 g of the solid [2.
fraction) contained 82 % of the title compound and T8 % of the by-
product ammonium chloride.
IR (in substance, cm"): 3112, 2997, 2934, 2850, 2796, 2629, 2544, 1734,
1612, 1582, 1513, 1472, 1392, 1373, 1309, 1247, 1215, 1152, 1132,
1093, 1014, 945, 896, 803, 777, 742, 707, 630, 603, 558, 528, 500.
CHN-elementary analysis: C, 36.31; H, 6.16; N, 16.28 (2. fraction).
Chloride t: 25.9% (m/m) [2. fraction]
LC-MS: 155 (M+H).
1H-NMR [DMSO-dé, 400 MHz): 8 [ppm] = 2.56 (s, 3H), 2.47 (s, 3H), 2.05 (s.
3H]. From the NMR-spectrum was estimated that the product contained
approximately 9 % 4,6-dimethylpyrimidine-2—oloxide hydrochloride as
by-product.
G. 5-Chloro-4,6-dlmethylpyrlmldlneoloxide hydrochloride
0.20 mol (15.21 g) hydroxy urea were dissolved in 300 ml of 1 M HCI, 300
ml methanol were added and 0.20 mol (26.91 g) of 3-chloro-2,4-
pentandedione were added dropwise under ice g at 1-2 °C. The
two-phase-mixture was allowed to warm slowly to room temperature and
stirred over night. The clear on was then evaporated to dryness. The
residue was suspended with 200 ml of acetone, the mixture was cooled
to below 0 °C in an ice/ethanol bath, the solid filtered off and washed
with a little ice—cold acetone. The filtrate was trated to dryness,
the residue was suspended in 20 ml of tetrahydrofuran, filtered off,
washed with little ydrofuran and dried. 1.40 g of a product
containing about 53 °/o of the title compound and 47 % of the byproduct
ammonium chloride were obtained.
IR (in substance, cm"): 3115, 2900, 2667, 2516, 1745, 1577, 1505, 1378.
1310,1194,1135, 1102, 1049, 973, 900, 835, 737, 674, 578.
Chloride content: 40.1% [m/m]
LC-MS: 175 (M+H].
1H-NMR [DMSO-dé, 400 MHz): 8 [ppm] = 2.49 (s, 3H), 2.37 (s, 3H).
H. lpyrlmldlneol-T -oxide hydrochlorlde
04—2 OH
T,T-Dimethoxypentanon
(T. Harayama, H. Cho and Y. Inubushi, Chem. Pharm. Bull. 1978, 26.
1201-12l4)
Vk/ko/o
In a multi-neck flask with internal thermometer and KPG-stirrer 0.96 mol
TO [89 g) propionic acid chloride were charged and cooled with a salt/ice
ng mixture. 0.82 mol (110 g) aluminium chloride was added portion
wise and the mixture was stirred vigorously for 10 min and mixed with 50
ml of form. Then, within about i h 0.93 mol (TOO g) vinyl bromide
was added in small portions (maximum internal temperature l4 °C). The
mixture was stirred on ice for l h, and then the reaction mixture was
poured onto 500 g ice and extracted several times with a total of l l of
chloroform. The ed organic phases were washed 4 times with l l
of water, dried with sodium sulphate and the chloroform was distilled off
on a rotary evaporator. The residue was distilled in a rotary evaporator at
80 °C water bath temperature and 16 mbar (head temperature about
47 °C), which resulted in 118 g intermediate product (unstable, storage
-18 °C).
118 g intermediate t were dissolved in 600 ml ous
methanol and cooled on ice. 1.03 mol [55.65 g) natrium methoxid were
dissolved in 360 ml anhydrous methanol and added dropwise within 30
min and the mixture was stirred at room temperature for further 18 h. The
resulting salt was filtered off, washed with a small amount of dry
methanol and the filtrate was concentrated on a rotary evaporator. The
residue was led at a rotary ator at a water bath temperature
of 75 °C and 4 mbar [head temperature 40 — 52 °C). 61.4 g of a product
mixture containing 62 % (m/m] of the title compound sponding to
38 g) were obtained.
1H-NMR (DMSO-db, 400 MHZ]: 8 [ppm] = 4.74 (t, 1H], 3.23 (s, 6H), 2.70 (d,
2H), 2.45 (q, 2H), 0.90 (t, 3H) [title compound, 62% m/m in product
mixture); 8 = 7.69 (d, 1H), 5.61 (d, 1H), 3.69 (s, 3H), 2.48 (q, 2H), 0.96 (t,
3H) ((1E)-l -methoxypent-l -enon, 38% in product mixture].
4-Ethylpyrimidinoloxlde hydrochloride
0.388 mol (25.9 9) y urea were dissolved in 195 ml 2 M HCI, 80 ml
of methanol were added and 0.388 mol (56.7 g) of 1,1-
dimethoxypentane-B-on (62 % content in product mixture) were added
dropwise under cooling with the internal temperature being maintained
at —6 to —7 °C. The solution was thawed to room temperature in an ice
bath and stirred for 1 h, then evaporated until dryness. The residue was
suspended with 100 ml of acetone, the mixture was cooled to below 0
°C in an ice/ethanol bath, the solid filtered off and washed with little ice-
cold acetone. After drying 32.6 g crude product were ed. The
crude product was heated until bOiling with 200 ml ethanol, hot ed
and slowly cooled to —18 °C. The precipitated solid was filtered off,
washed with a little amount of ethanol and dried. 11.7 g of the title
compound were obtained.
IR [in substance, cm”): 3115, 3038, 2936, 2678, 2518, 1753, 1606, 1585.
1516,1465,1403,1381,1301,1229,1184,1134,1109,1053,1002,896,
803, 769, 736, 680, 605, 540, 513, 494, 474.
CHN-elementary analysis: C, 40.72; H, 5.03; N, 15.32.
LC-MS: 141 [M+H).
1H-NMR [DMSO-dé, 400 MHz): 8 [ppm] = 8.92 (d, 1H], 6.70 (d, 1H), 2.73
(q, 2H); 1.19 (t, 3H). From the NMR-spectrum was estimated that the
product contained <3 % of the regioisomere 6—ethylpyrimidineol
oxide hydrochloride.
I. 6-Ethylmethylpyrlmidlneoloxlde hydrochloride
N OH
0.12 mol (9.13 g) hydroxy urea were dissolved in 50 ml 2 M HCI, 20 ml of
methanol were added and 0.10 mol (11.41 g] 2,4-hexanedione were
added dropwise under cooling by approximately —15 °C. Further 30 ml of
water and 10 ml of methanol were added. The two-phase reaction
mixture was allowed to warm up slowly to room temperature and was
stirred at room ature for further 2 h, then ated until dryness.
The residue was suspended with 50 ml of acetone, the mixture was
cooled in an ice/ethanol bath, the solid filtered off and washed with a
little ice—cold acetone. After drying 7.88 g crude product were ed
which were recrystallized from 45 ml ethanol wherefrom first an insoluble
salt compound was hot filtered off and the product was subsequently
recrystallized from the filtrate at —18 °C. 3.0 g product were obtained
which were again recrystallized from 28 ml ethanol. Finally 2.26 g of the
title compound were obtained.
IR (in substance, cm“): 3093, 2997, 2945, 2679, 2555, 1805, 1741, 1601,
1571, 1508, 1435, 1401, 1370, 1327, 1290, 1253, 1213, 1157, 1103,
1049, 903, 849, 811, 766, 742, 701, 669, 626, 607, 582, 512, 494.
LC-MS (m/Z]: 155.7 (M+H).
1H-NMR (DMSO-db, 400 MHz): 5 [ppm] = 6.78 (s, 1H), 2.88 (q, 2H], 2.46 (s,
3H), 1.21 (t, 3H). From the ectrum was estimated that the product
contained imately 6.6 % of the regioisomer I
methylpyrimidineoIoxide hydrochloride.
J. 4-Methyl-6,7-dihydro-5H-cyclopenta[dlpyrimldineoloxide
hydrochloride
1‘ OH
0.20 mol (15.21 9) hydroxy urea was dissolved in 200 ml of 1 M HCI, 200
ml of methanol were added and 0.20 mol (25.23 g) 2-
acetylcyclopentanone were added dropwise, 1 r hour stirred and
then the solution was evaporated at the rotary evaporator until dryness.
The residue was suspended with 100 ml of acetone, the solid filtered off
and washed with acetone. After drying 12.41 g crude product 1 were
obtained which were solubilised in the g heat with 1200 ml
isopropanol and hot filtered. The filtrate was evaporated until dryness
and 8.49 g crude product 2 were obtained. This was lised in the
boiling heat in 200 ml of ethanol and 200 ml of tetrahydrofuran were
added. The precipitated solid was filtered off and dried. 5.63 g of a
product were obtained which contained 91.5 % of the title nd
and 8.5 % ammonium chloride.
1R (in substance, cm"): 3133, 3042, 2841, 2751, 2480, 1730, 1613, 1590.
1493, 1404, 1374, 1314, 1289, 1221, 1134, 1062, 1044, 1020, 972, 938,
894, 868, 822, 740, 707, 637, 575, 552, 525, 509.
LC-MS [m/z): 167.5 [M+H].
ementary analysis: C, 43.93; H, 6.07; N, 13.41.
Chloride content: 21.7% (m/m]
lH-NMR [DMSO-dé, 400 MHz): 8 [ppm] = 3.22 (t, 2H), 2.82 (t, 2H), 2.42 (s,
3H), 2.13 (quintett, 2H). From the MNR-spectrum was estimated that the
product contained approximately 6 % of the regioisomere 4-methyI-6,7-
dihydro-5H-cyc|openta[d]pyrimidineoIoxide hydrochloride.
K. 4-MethyI-5,6,7,8-tetrahydrochinazolineoIoxlde hydrochlorlde
N OH
0.08 mol (6.08 9] y urea were dissolved in 40 ml of 2 M HCI, 40 ml
of ol were added and 0.08 mol (11.21 g) 2-acetylcyclohexanone
were added dropwise under cooling at approximately —1 5 °C, stirred one
further hour and Thereby warmed up to 20 °C. This was carried out six
times in total. The combined on mixtures were then evaporated at
the rotary evaporator. The residue was suspended with acetone, the solid
filtered off and washed with acetone. After drying 36.97 g crude product
1 were obtained which were suspended with 250 mi ethanol and hot
filtered. The filtrate was evaporated until s and 20.87 g crude
product 2 were obtained. This was solubilised in the g heat in 500
ml of ethanol, hot filtered, and the filtrate was combined with 800 ml
tetrahydrofuran. The precipitated solid was filtered off and dried. 14.3 g
of a product were ed which contained 87 % of the title compound
and 13 % ammonium chloride.
IR [in substance, cm"): 3135, 3044, 2937, 2875, 2805, 2706, 2426, 1743,
1572, 1501, 1443, 1403, 1345, 1288, 1260, 1235, 1150, 1122, 1086,
1041, 908, 883, 824, 740, 707, 669, 643, 605, 546, 514.
CHN-elementary analysis: C, 43.63; H, 6.08; N, 14.66.
Chloride content: 22.2% (m/m)
iH-NMR (DMSO-dé, 400 MHz): 8 [ppm] = 2.76 (m, 2H), 2.53 (s, 3H), 2.49
(m, 2H], 1.70 (m, 4H). From the NMR-spectrum was estimated that the
product contained approximately 5 % of the regioisomere 4-methyl-
,6,7,8-tetrahydrochinazolinoloxide hydrochloride.
L. panyl)pyr|mldlneoloxlde hydrochloride
lN/AOH
0.187 mol (14.22 g) hydroxy urea were dissolved in 200 ml of 1 M HCI
and 0.187 mol [30 g) 1,1—dimethoxymethylpentaneon (E.E. Royals
and K.C. Brannock, J. Am Chem. Soc. 1953, 75, 2050-2053) were added
dropwise under cooling, with the al temperature being maintained
at 0 — 1 °C. The two-phase mixture was thawed to room temperature in
an ice bath and stirred for 12 h, then evaporated until dryness. The
residue was suspended with 100 ml acetone, the mixture was cooled in
an ice/ethanol bath, the solid filtered off and washed with a little ice-
cold acetone. After drying 15.79 g crude product 1 were obtained.
11.04 g of crude t 1 were heated until boiling with 141 ml ethanol
and precipitated solid was filtered off after cooling. The filtrate was
again evaporated until dryness and 8.49 g crude product 2 were
obtained which were heated until boiling in 80 ml ethanol and hot
ed. The filtrate was cooled down slowly to room temperature and
over night down to —18 °C. The precipitated solid was filtered off and
after drying 2.18 g of the title compound were obtained.
IR (in substance, cm"): 2971, 2585, 1815, 1748, 1598, 1572, 1513, 1463,
1390, 1305, 1230, 1186, 1163, 1132, 1049, 986, 934, 901, 815, 773,
749, 719, 681, 616, 582, 518, 498, 484, 478.
CHN-elementary is: C. 43.54; H, 6.10; N, 14.50
LC-MS (m/z): 155.5 (M+H).
1H-NMR [DMSO-dé, 400 MHz): 8 [ppm] = 8.88 (d, 1H), 6.68 (d, 1H), 3.02
[heptett, 1H); 1.20 (d, 6H)
M. 4-Ethylmethylpyrimidineol 1-oxlde hydrochlorlde
1N)OH
Various mother liquors from recrystallization from the synthesis of the
regioisomer 6-ethyImethyl-pyrimidineol 1-oxide hydrochloride
[Example 1) were combined and ated to dryness. In total 22.14
grams of this product mixture, containing about 50% of the title
compound, were heated in 140 ml of l to boiling, ed hot and
evaporated to dryness. 20.96 g of the residue was recrystallized from 90
ml of l, in doing so first 0.82 g of an insoluble fraction were
separated in the heat, and then it was slowly cooled down from the
boiling point to -18 °C. 17.25 g of a precipitate were then recrystallized
accordingly from 150 ml of ethanol / 70 ml of tetrahydrofuran, whereby
6.05 g of a solid predominantly containing 6-ethylmethyI-pyrimidine
oi 1-oxide hydrochloride was separated. The filtrate was trated to
dryness and 9.53 g of the residue were recrystallized from 180 ml of
isopropanol. 7.57 g of a product mixture were obtained (63%
enrichment) and recrystallized several times from isopropanol in a
2O corresponding manner. y there were obtained 0.69 g of the title
compound.
IR (neat, cm"): 3077, 2853, 2685, 2550, 1745, 1608, 1568, 1514, 1461,
1416,1370,1323,1304,1249,1211,1160,1142,1104,1069,1028,994,
936,887, 849, 767, 746, 707, 685, 625, 599, 567, 525, 500.
LC—MS [m / z): 155 (M + H).
1H-NMR (DMSO-dé, 400 MHz): 6 [ppm] = 6.83 (s, 1H), 2.70 (q, 2H), 2.55 (s,
3H), 1.20 (t, 3H). From the NMR spectrum it was estimated that the
product contained approximately 13% of the regioisomer 6—ethyl
-pyrimidinol 1-oxide hydrochloride.
N. 4-tert-Butylpyrimidineol 1-oxlde hydrochlorlde
The synthesis of the precursor 1,1-dimethoxy-4 ,4-dimethylpentaneone
was performed in y to E.E. Royals and K.C. Brannock (J. Am. Chem
Soc. 1953, 75, 2050-2053], wherein a mixture of about 20% of the
desired precursor and 80% of the byproduct 1-methoxy-4,4—
dimethylpent-l-en-S-one was obtained. To 32.8 g of this mixture were
added 33.9 mmol (5.63 g) N-benzyloxy urea, 51 ml of methanol, 1.7 ml
of water and 4.06 ml of sulfuric acid [analogous to M. Yamaguchi et al.,
J. Inorg. Biochemistry 2006, 100, 260-269). It was stirred at room
temperature with portionwise addition of in total 153 mmol (25 g] N-
benzyloxy urea for 5 h, untii N-benzyloxy urea could be detected in the
reaction mixture (TLC hexane / ethyl acetate 2/1, 1% acetic acid]. The
reaction mixture was evaporated to dryness, the residue taken up in
water / romethane, the s phase was adjusted to pH 9.3 with
saturated sodium carbonate solution and extracted three times with
dichloromethane. The ed organic phases were washed with
2O water, dried over sodium sulfate and evaporated to dryness. 51.8 g of a
crude product were obtained which was chromatographed with
cyclohexane / ethyl acetate over silica gel. 46.4 mmol (12.0 g) purified
intermediate product were obtained, which was dissolved in 240 ml of
methanol and hydrogenated with 0.93 g of 10% Pd / C for 3.5 h with
hydrogen. It was filtered over Celite, the filtrate was added with 50 mi of
1 M HCI and ated to dryness. The crude product was suspended in
100 ml of water, ed off from ble constituents and the filtrate
was concentrated. After drying, 8.15 g [39.8 mmol, 5.0% yield over three
steps) of the title compound were obtained.
lR (neat, cm“): 2850, 2482, 1758, 1505, 1555, 1517, 1494, 1457, 1389,
1377,1310,1254,1190,1118,1085,887,828,751,730,703
1H-NMR (DMSO-db, 400 MHz]: 5 [ppm] = 8.55 (d, 1H), 5.51 (d, 1H), 1.27
(s, 9H]
0. 5,6-Dimethylpyrlmidineol i-oxlde hydrochlorlde
The synthesis of the precursor 4,4-dimethoxymethylbutanone was
performed in analogy to E.E. Royals and K.C. Brannock (J. Am. Chem.,
1953, 75, 2050-2053) and d a mixture of 58% of the desired
precursor, 24% of the byproduct 1,1-dimethoxy-pentanone and about
18% elimination t. 102 g of this mixture (0.405 mol of 4,4-
dimethoxymethylbutanone) were ved in 30 ml of methanol
and added dropwise to 0.698 mol of N-hydroxyurea in 400 ml of 2M HCI,
while the internal temperature was ined at -10 to -4 °C. The
solution was thawed to room temperature, stirred for 1 h, and then
evaporated to dryness. The e was slurried with 200 ml of acetone,
the solid filtered off and washed with little ice-cold acetone. After drying,
the crude product was heated with 150 ml of ethanol to boiling, filtered
hot, concentrated to 50 ml and cooled to -18 ° C. The precipitated solid
was filtered off, washed with little ethanol and dried. 20 g of this solid
was again recrystallized from 100 ml of ethanol, and finally 10 g (12%
yield) of the title compound were obtained (content of 85% the title
compound and 13% ammonium chloride].
IR (neat, cm"): 2569, 2539, 1726, 1628, 1589, 1503, 1453, 1378, 1336,
1255, 1220, 1157, 1141, 1120, 1021, 919, 828, 755, 734, 713
1H-NMR (DMSO-dé, 400 MHz]: 6 [ppm] = 8.98 (s, 1H); 2.50 [5, 3H]; 2.08 (s,
3H)
P. 6—n-Propylpyrimidlneol 1-oxlde hydrochlorlde
N OH
The synthesis of the precursor 1,1 -dimethoxyhexaneone was performed
in analogy to E.E. Royals and K.C. Brannock (J. Am. Chem. Soc. 1953,
75, 2050-2053) and yielded a mixture of 75% of the desired precursor,
13% of the byproduct 3-(dimethoxymethyl) pentanone and about 12%
of elimination products. 29.2 g of this mixture [0.137 mol 1,1-
dlmethoxyhexane-B-one) were mixed with 0.164 moles (27.3 g) N-
benzyloxy urea, added with 150 ml of methanol and 20 ml of sulfuric
acid [analogous to M. Yamaguchi et al., J. Inorg. Biochemistry 2006,
100, 260-269). The mixture was stirred at room temperature, then further
0.0164 mmol (2.73 g) of N-benzyloxy urea were added and it was heated
for 1 h at 50 ° C. The mixture was evaporated to dryness, the residue was
taken up in water / dichloromethane, the aqueous phase was adjusted to
pH 11 with saturated sodium ate solution and extracted three
times with dichloromethane. The combined organic phases were washed
with water, dried over ium e and ated to dryness.
2O There were obtained 40.3 g of a crude product which was
chromatographed with cyclohexane / ethyl acetate over silica gel. 0.026
mol (6.3 g) of the ed intermediate were ved in TOO ml of
methanol and hydrogenated with 0.53 g of 10% Pd / C for 0.5 h with
hydrogen. It was filtered off through Celite, the filtrate was concentrated
to 50 ml added with 50 ml of 1 M HC1 and evaporated to dryness. The
crude product was recrystallized from 50 ml of 2-propanol and 200 ml of
diethyl ether. 3.46 g [18.2 mmol, 13% yield over 2 steps) of the title
compound were obtained.
1R (neat, cm"): 2591, 2536, 2477, 1770, 1736, 1608, 1580, 1311, 1194,
3O 1185, 1130, 1115, 1082, 1001, 904, 892, 823, 787, 736, 680
1H-NMR dé, 400 MHz): 5 [ppm] = 8.98 (d, 1H), 6.75 (d, 1H), 2.74
(t, 2H), 1.69 [hextett, 2H), 0.93 (t, 3H)
Iron com lex com ounds exam les
Example 1
Tris-(pyrimidineoloxlde)-lron(|ll) complex
I: O
C)/we\o/k/
N/KN/o
114 mmol [16.93 g] pyrimidineoIoxide hydrochloride were ved
in 150 ml of water and 38 mmol [10.27 g] FeC|3*6H20 ved in 15 ml
water were added. The solution was adjusted to pH 6.3 with
approximately 90 ml 2 M NaOH and stirred for 0.5 h. The product was
filtered off, washed with water and dried in a vacuum drying oven at 50
°C. 14.2 g of the title compound were obtained.
1R (in substance, cm"): 3082, 3054, 1596, 1506, 1431, 1366, 1278, 1197,
1136, 1108, 1055, 907, 798, 765, 613, 554, 513.
CHN-elementary analysis: C, 35.77; H, 2.78; N, 20.23.
ESI-MS: 278.3 [FeL2+); 390.4 (M+H+); 412.4 (M+Na+).
Fe-content: 13.61% [m/m]
Example 2
Trls-(4-methylpyrlmldineol-oxlde)-lron(lll) complex
'N/k.
°\./°‘" \
NKN/o
21 mmol (3.76 9, approximately 90 % purity) 4-methylpyrimidineol
oxide hydrochloride were dissolved in 15 ml water and 7.0 mmol (1.89 g)
FeCla*6H20 ved in 5 ml water were added. The solution was
adjusted to pH 5.85 with imately 44 ml 1 M NaOH and stirred for
0.5 h. The product was filtered off, washed with water and dried in a
vacuum drying oven at 50 °C. 3.03 g of the title compound were
obtained.
1R (in substance, cm"): 3400, 3074, 1602, 1545, 1503, 1425, 1378, 1339,
1249, 1201, 1145, 1110, 1032, 954, 805, 762, 645, 600.
CHN-elementary analysis: C, 38.42; H, 4.10; N, 18.11.
ESI-MS: 306.4 [FeL2+); 432.4 [M+H+).
Fe-content: 12.15% [m/m]
Tris-(4,6-dlmethylpyrlmidineolox|de)-iron(ll|) complex
120 mmol (21.19 g] 4,6-dimethylpyrimidineoloxide hydrochloride
were dissolved in 15 ml of water and 40 mmol (10.81 g) 6H20
dissolved in 10 ml water were added. The solution was adjusted to pH
.90 with approximately 238 ml 1 M NdOH and stirred for 0.5 h. The
product was filtered off, washed with water and dried in a vacuum drying
oven at 50 °C. 18.66 g of the title compound were obtained.
IR (in substance, cm"): 3596, 3441, 3077, 1604, 1551, 1511, 1441, 1393,
1380, 1360, 1320, 1153, 1097, 1029, 875, 856, 798, 651, 564, 524, 486.
CHN-elementory onolysis: C, 44.27; H, 4.22; N, 17.35.
ESI-MS: 334.4 [FeL2+); 474.5 (M+H+]; 496.6 (M+No+).
Fe-content: 11.33% [m/m]
No melting point, at about 230 ° C exothermic decomposition stdrts.
Tris-(4,6-diethylpyrlmldlneoloxide)-lron(lll) complex
o>1<l$
14 mmol [6.1 9, approximately 48 % purity, 52 % ammonium chloride]
4,6-diethylpyrimidineoloxide hydrochloride were dissolved in 15 ml
water and 4.67 mmol [1.26 g] FeC|3*6HQO dissolved in 2 ml water were
added. The solution was adjusted to pH 5.85 with 27.7 ml 1 M NaOH and
stirred for 0.5 h. The product was filtered off, washed with water and
dried at 50°C in a vacuum drying oven. 2.57 g of the title nd
were obtained.
IR (in substance, cm"): 3593, 3378, 3087, 2969, 2934, 2880, 1602, 1549.
1510, 1460, 1406, 1328, 1255, 1235, 1146, 1108, 1073, 1027, 964, 903,
863, 807, 764, 701, 672, 645, 619, 578, 522.
CHN-elementary analysis: C, 49.23; H, 6.03; N, 14.43.
Fe-content: 10.05 % [m/m]
Example 5
Tris-(4-methyl(2-methylpropyl)pyrlmld|noloxide)-iron(lll) complex
mmol (5.74 g, imately 58 % purity, 42 % ammonium chloride]
4-methyl(2-methylpropyllpyrimidineoloxide hydrochloride were
dissolved in 25 ml water and 5.0 mmol (1.35 g] FeC13*6HQO ved in 2
ml water were added. The solution was adjusted to pH 5.88 with 29.2 ml
1 M NaOH and stirred for 0.5 h. The product was filtered off, washed with
water and dried in a vacuum drying oven at 50 °C. There was obtained
3.00 of the title compound.
IR (in substance, cm“): 2959, 2929, 2872, 1598, 1549, 1513, 1462, 1434,
1400, 1355, 1289, 1233, 1151, 1122, 1102, 1034, 990, 928, 879, 853,
799, 769, 701, 648, 606, 575.
CHN-elementary analysis: C, 53.71; H, 6.40; N, 13.92.
Fe-content: 9.29% [m/m]
Example 6
Trls-(4,5,6-trlmethylpyrlmldlneoloxide)-iron(ll|) complex
.2 mmol (2.38 9, approximately 82 °/o purity, 18 % um
chloride) trimethylpyrimidineoloxide hydrochloride were
dissolved in 5 ml water and 3.4 mmol (0.93 g) FeC|3*6H2O dissolved in 1
ml water were added. The solution was adjusted to pH 6.04 with 19 ml 1
M NaOH and stirred for 0.5 h. The product was filtered off, washed with
water and dried in a vacuum drying oven at 50 °C. There were obtained
1.72 g of the title compound.
IR (in substance, cm"): 3424, 2925, 1593, 1510, 1439, 1377, 1234, 1188,
1160, 1109,'999, 935, 869, 803, 763, 720, 657, 613, 561.
CHN-elementory analysis: C, 45.43; H, 5.80; N, 14.12.
Fe-content: 10.68% [m/m]
Example 7
Trls-(5-chloro-4,6-dimethylpyrlmldineoloxlde)-lron(lll) complex
6.73 mmol [3.8 9, approximately 37 % purity, 63 % ammonium chloride)
and 0.77 mmol (0.31 9, imately 53 % , 47 % ammonium
chloride) 5-chloro-4,6-dimethylpyrimidineoloxide hydrochloride
were dissolved in 25 ml of water and 2.5 mmol (0.68 g] FeC13*6H20
dissolved in 2 ml water were added. The solution was adjusted to pH 5.96
with 14.8 ml 1 M NaOH and stirred for 0.5 h. The product was filtered off,
washed with water and dried in a vacuum drying oven at 50 °C. There
was obtained 1.37 g of the title compound.
IR (in substance, cm"): 2929, 2363, 1688, 1589, 1509, 1431, 1390, 1375,
1196, 1169, 1092, 1016, 968, 847, 759, 694, 667, 553.
CHN-elementary analysis: C, 37.01; H, 2.83; N, 14.47.
Fe-content: 9.88% [m/m]
Example 8
Trls-(4-ethylpyrlmidineoloxlde)-lron(lll) complex
63 mmol (11.13 g] 4-ethylpyrimidineoIoxide hydrochloride were
dissolved in 20 ml water and 21 mmol (5.68 g) FeC|3*6H20 dissolved in 5
ml water were added. The solution was adjusted to pH 6.17 with 125.6 mi
1 M NaOH and stirred for 0.5 h. The t was filtered off, washed with
water and dried in a vacuum drying oven at 50 °C. There was obtained
9.52 g of the title compound.
IR (in substance, cm"): 3083, 2974, 2936, 2876, 1596, 1543, 1511, 1460,
1428, 1313, 1249, 1194, 1143, 1107, 1079, 1056, 991, 948, 811, 770,
748, 696, 639, 598, 531, 502.
CHN-elementary analysis: C, 44.67; H, 4.52; N, 17.36.
Fe-content: 11.40% [m/m]
Example 9
Tris-(6-ethylmethylpyrlmIdIn-2—o|oxlde)-Iron(|ll) x
I .2»
3) 0‘
\/ / N \ Fe
\ )l\ /
0 N
11.4 mmol (2.17 g) 6-ethyImethylpyrimidineoloxide hydrochlorid
were dissolved in 5 ml water and 3.8 mmol (1.03 g] FeC13*6H20 dissolved
in 2 ml water were added. The solution was ed to pH 6.3 with 22.7
ml 1 M NaOH and stirred for 0.5 h. The product was filtered off, washed
with water and dried in a vacuum drying oven at 50 °C. There was
obtained 1.89 g of the title compound.
IR (in substance, cm“): 3515, 3080, 2974, 2938, 1598, 1550, 1516, 1461,
1427, 1401, 1317, 1257, 1229, 1149, 1104, 1060, 1035, 985, 918, 851,
813, 768, 681, 651, 557, 522.
CHN-elementary analysis: C, 47.48; H, 5.44; N, 15.81.
Fe-content: r0.32% [m/m]
Chloride-content: 0.0% [m/m]
Example 10
Tris-(4—methyl-6,7-dihydro-5H-cyclopenta[d]pyrlmldInoloxide)-Iron(lll)
complex
21 mmol (4.73 g) yI-6,7-dihydro-5H-cyclopenta[d]pyrimidineol—
1-oxide hydrochlorid (content approximately 90 %) were dissolved in 30
ml water and 7.0 mmol (1.89 g] FeC13*6H20 dissolved in 5 ml water were
added. The solution was ed to pH 5.96 with 41.6 ml 1 M NaOH and
stirred for 0.5 h. The product was filtered off, washed with water and
dried in a vacuum drying oven at 50 °C. There was obtained 3.8 g of the
title compound.
1R (in substance, cm"): 2918, 2361, 2326, 1599, 1571, 1499, 1429, 1382,
1359, 1311, 1279, 1232, 1208, 1173, 1100, 1067, 1043, 1013, 970, 945.
904, 881, 836, 761, 733, 663, 566, 528, 499.
CHN-elementary analysis: C, 50.36; H. 4.98; N, 14.88.
Fe-content: 9.71% [m/m]
Chloride-content: 1.05% [m/m]
Example 1 1
4-methyl-5.6.7,8-tetrohydrochlnozollne—2-oloxide)-iron(lll) complex
55 mmol (14.3 g) 4-methyl-5,6,7,8-tetrohydrochindzolineoIoxide
hydrochloride were dissolved in 30 ml water and 18.3 mmol [4.95 g]
FeCI3*6H20 dissolved in 5 ml woter were added. The solution was
adjusted to pH 6.19 with 110.7 ml 1 M NdOH and stirred for 0.5 h. The
product was filtered off, washed with water and dried in or vacuum drying
oven at 50 °C. There was obtained 10.7 g of the title nd.
IR (in substance, cm"): 2932, 2859, 1586, 1510, 1446, 1421, 1377, 1348,
1308, 1267, 1229, 1189, 1168, 1100, 1079, 1057, 1030, 969, 889, 846,
824, 762, 704, 654, 614, 571, 507.
CHN-elementory dnolysis: C, 53.25; H, 5.49; N, 13.76.
Fe-content: 9.03% [m/m]
Chloride-content: 0.0% [m/m]
Example 12
Trls-(4-propdneyl)pyrlmldlneoloxlde)-|ron(lll) complex
9.76 mmol (1.86 g] 4-(propdneyl)pyrimidineoloxide hlorid
were dissolved in 5 ml water and 3.25 mmol (0.88 g) FeC|3*6H20
dissolved in 2 ml water were added. The solution was adjusted lo pH 6.04
wilh 18.5 ml 1 M NdOH and stirred for 0.5 h. The producl was filtered off,
washed with water and dried in d vacuum drying oven at 50 °C. There
was obtained 1.64 g of The title compound.
IR (in substance, cm“): 3071, 2965, 2930, 2871, 1594, 1540, 1510, 1467,
1428, 1373, 1309, 1239, 1204, 1152, 1132, 1108, 1049, 970, 931, 881,
834, 809, 777, 733, 712, 645, 599, 552, 514.
CHN-elemenldry onolysis: C, 47.53; H, 5.01; N, 15.84.
Fe-conleni: 10.86% [m/m] (ICP)
Chloride-content: 0.60% [m/m]
Example 13
Trls-(4-elhylmelhylpyrlmldlneol 1-oxlde)-lron(lll) complex
3.51 mmol (0.69 g] of 4-ethylmethylpyrimidineol 1-oxide
hydrochloride were dissolved in 3 ml water and 1.17 mmol [0,316 g)
FeCI3 * 6H20 were added. The solution was adjusted to pH 6.37 with
6.975 ml of 1 M NdOH and stirred further for 0.5 h. The product was
filtered off, washed with water and dried at 50 °C in CI vacuum oven. This
gave 0.63 g (92% Fe-yield) of the title compound.
IR (neat, cm"): 2970, 2936, 2876, 1750, 1685, 1601, 1552, 1511, 1462,
1441,1404,1386,1362,1308,1231,1196,1154,1106,1056,1034,984,
846, 807, 790, 770.
CHN elemental is: C, 42.43; H, 5.43; N, 14.03.
Fe content: 9.5% [w / w]
Example 14
Trls-(5-ethyl-4,6-dlmethylpyrimidineol 1-oxide)-lron(lll) complex
6.68 mmol (1.44 g] 5-ethyl-4,6-dimethylpyrimidineol 1-oxide
hydrochloride [Yomdguchi et 01., J. Inorg. Biochemistry 2006, 100, 260-
269) and 2.23 mmol [0.485 g) of FeCl3 * 6H20 were dissolved in 7 ml of
water. The solution was adjusted with 1 M NoOH to pH 6.0 and stirred for
0.5 h. The product was filtered off, washed with water and dried at 50 ° C
in o vacuum oven. This gave 0.98 g (75% Fe yield) of the title
compound.
IR (neat, cm"): 2965, 1589, 1512, 1450, 1375, 1228, 1181, 1100, 1057,
1011, 958, 863, 768, 716, 685, 664.
CHN tal analysis: C, 49.67; H, 5.83; N, 14.52.
Fe-content: 9.54% [w / w]
Chloride content: 0.0% [w / w]
Example 15
4-tert-butylpyrimidineoi 1-oxlde)-Iron(ll|) complex
O\Fe/O\N \
O/ \OiN/
AN,O
.5 mmol (7.65 g) 4-tert-butylpyrimidineol 1-oxide hydrochloride were
dissolved in 15 ml water and 11.84 mmol (3.20 g] FeC|3 * 6H20 were
added. The suspension was ed to pH 6.1 with 69.4 ml of 1 M NdOH
and d further for 0.5 h. The product was filtered off, washed with
water and dried at 50 ° C in or vacuum oven. This gave 6.44 g [99% Fe-
yield) of the title compound.
IR (neat, cm"): 2965, 1598, 1535, 1506, 1477, 1419, 1364, 1339, 1273.
1238,1217,1159,1122,1025, 967, 829, 810, 779, 717, 701.
Fe content: 10.15% [w / w]
Chloride content: 0.65% [w / w]
Example 16
Trls-(5,6-dimethylpyrlmldIneol 1-oxlde)-lron(|ll) complex
14.4 mmol (2.93 g) 5,6-dimethylpyrimidin—2-ol hydrochloride were
dissolved in 20 ml water and 4.6 mmol FeCI3 [0.76 9] dissolved in 10 ml
of water were added. The solution was adjusted with 6.26 ml of 1 M
NaOH to pH 5.8 and stirred for 0.5 h. The product was filtered off,
washed with water and dried at 50 ° C in a vacuum oven. This gave 2.22
g (92% Fe-yield) of the title compound.
IR (neat, cm"): 3409, 1613, 1518, 1443, 1403, 1361, 1241, 1221, 1202,
1177, 1094, 1007, 880, 762, 714.
TO CHN tal analysis: C, 40.77; H, 4.95; N, 15.85.
Fe content: 10.68% [w / w]
Chloride content: 1.1% [w / w]
Example 17
Trls—(6-n-propyipyrimidineol 1-oxlde)-Iron(lll) complex
NpTAO
\ /°‘~ \
O/ \O/K/
N/KN/0
15 mmol (2.97 g] 6-n-propylpyrimidineol 1-oxide hydrochloride and 5
mmol (1.334 g) FeC|3 * 6H20 were dissolved in 42 ml water and 18 ml of
ethanol and maintained at 50 °C. 30% sodium hydroxide solution was
added to pH 5.2 and the suspension was cooled to room temperature.
The product was filtered off, washed with water and dried at 50 °C in a
vacuum oven. This gave 2.2 g [85% Fe-yield] of the title nd.
IR (neat, cm"): 3072, 2961, 1594, 1541, 1507, 1460, 1426, 1380, 1337,
1246, 1141, 1108, 1088, 979, 870, 838, 799, 768, 733, 691.
Fe content: 10.74% [w / w]
Chloride content: 0.0% [w / w]
Example 18
4-(ethylomlno)pyrimidineol 1-oxlde)-lron(||l) complex
' A.
eye0/ \OiN/ N/\
A ,o
3 mmol (0.602 g] 4-[ethyldmino]—pyrimidine—2-o| 1-oxide hydrochloride
(Yomoguchi et 01, J. Inorg Biochemistry 2006, 100, 260-269) were
dissolved in 20 ml water, and 1 mmol (0.27 g] FeCl3 * 6H20 dissolved in 2
ml of water were added. The on was adjusted with 1 M NoOH to pH
.7 and stirred for another 15 min. The product was filtered off, washed
with water and dried at 50 °C in o vacuum oven. This gave 0.43 g [85%
Fe-yield] of the title compound.
IR (neat, cm"): 3287, 2975, 1620, 1588, 1531, 1490, 1448, 1381, 1344,
1283, 1254, 1178, 1156, 1096, 1066, 1014, 826, 784, 754, 708
Fe-content: 11.03% [w / w]
Chloride content: 0.47% [w / w]
Pharmacological testing method:
The excellent Fe utilizations that can be accomplished through the Fe
complexes according to the invention were measured by means of the
following mouse model.
Male NMRI (SPF) mice [approximately 3 weeks old) were fed a low-iron
diet (approx. 5 ppm iron) for approximately 3 weeks. The iron complexes
were then stered to them by means of a stomach tube [2 mg
iron/kg body weight/day) for 2 times 5 days, with an interruption of 2 days
(days i - 5 and 8 - l2). Utilization on day 15 was ated from the
hemoglobin increase and the body weight increase in accordance with
the formula
Airon ation * 100 ut.—Fe ut. Control) * 100
Utilization [%) = _ (Fe
FeDos. FeDos.
[(Hb2[3] BW9H4) _ Hb] BW4] _
* * * 0.07 9r 0.0034 (Hb2[3] Control * BW9[14]
_ Hbi
Control Control * BWA l) * 007 * 00034)] * 100/ Fe DOS'
[(Hb2lsl " (Hb2lsl
* BW9l14)_ Hbl * 3W4) * 0-000238 Control * BW9['l4| Control “
Hbt Comm .. BW4 Como.) * 0.000238] * 100 / Fe DOS.
(HD2131 —
* BW9[14)— Hbl * BW4 Hbzlal Control * BW9(14] Control + Hbi Control *
BW4 Como.) . 0.0238 / Fe DOS.
0.07 = Factor for 70 ml blood per kg body weight (BW)
0.0034 = Factor for 0.0034 g Fe/g Hb
Hb1 = Hemoglobin level (g/I) on day l
Hbm, = Hemoglobin level (g/I) on day 8 [or 15]
3O BW4 = body weight [g] on day l
BWWA, = body weight [g] on day 8 (or 15)
Hb1 Como. = e hemoglobin level (g/l) on day l in the control
group,
Hbmmontrol = average hemoglobin level (g/I) on day 8 (or 15) in the
control group,
BW4 Comm. = average body weight (g) on day l in the control group,
BWWMmomm. = average body weight (g) on day 8 (or 15) in the control
group,
Fe Dos. = entire stered iron [mg Fe] over 5 or to days,
Fe ut. =
(Hbm, * BW9r141— Hb1 , 8W4) * 0.07 * 0.0034 (mg Fe)
A Utilization = Fe tot. utilized (examined group) — Fe ut. Control group,
utilized from food, [mg Fe)
Table i - iron utilizations:
Example-No. ation n 15 d
(abs. %)
not determined
comparative example*
* Comparative example:
As a ative example the tris(pyridinoneol-i-oxide)-iron(lll)
i5 complex compound of the formula:
04lFem)O—N\
ONOO//\\ /
was ed according to EP 0138420 and tested to demonstrate the
influence of the heterocyclic base body. EP 0138420 discloses in
example 7 only trislpyridinonoi-i-oxide]-iron(|l|] x compounds
which carry a further substituent on the pyridine ring. Unsubstituted
tris[pyridinoneol-i-oxide)-iron(l|l) complex compounds as used in the
present comparative example are not disclosed therein. As can be seen
from the results in the above-mentioned table the corresponding
pyrimidine compound of example 1 according to the present invention
exhibits significantly improved iron ation compared to the
comparative pyridine nd according to EP Ol 38420.
Claims (13)
1. Use of iron(III) pyrimidineoloxide complex nds or pharmaceutically acceptable salts thereof , which contain at least one ligand of the formula (I): wherein the arrows respectively represent a coordinate bond to one or ent iron atoms, and R1, R2, R3 may be the same or different and are selected from the group consisting of: - hydrogen, - alkyl, which may be tuted with cycloalkyl or with 1 to 3 substituents ed from the group consisting of o hydroxy, o aryl, which may be substituted with one or more substituents selected from halogen, hydroxy, alkyl, as defined above and alkoxy, as defined below, o heteroaryl, which may be substituted with one or more substituents selected from halogen, hydroxy, alkyl, as defined above and alkoxy, as defined above, AH26(9820323_1):JIN o alkoxy (RO-), with R being alkyl as defined above, o alkoxycarbonyl (RO-CO-), with R being alkyl as defined above o acyl, o halogen, o amino ( -NH2) or a 5 or 6 -membered cyclic amino that may contain further hetero atoms selected from N, O, S, and which each may be substituted to form mono- or dialkylamino or monoor diarylamino, with aryl being aryl or heteroaryl, or mixed alkylarylamino groups, each with alkyl, aryl or heteroaryl as defined above, o arbonyl, derived by adding a carbonyl group to amino or a 5 or 6-membered cyclic amino, each as defined above, and o cyano, - n, - , as defined above, - aryl, as defined above, - alkoxycarbonyl, as defined above, - amino, as defined above, and - aminocarbonyl, as defined above, or R1 and R2 or R2 and R3 together with the carbon atoms to which they are bonded, form an optionally substituted ted or unsaturated 5 - or 6- membered ring, which may optionally contain one or more heteroatoms for the manufacture of a medicament for the treatment and prophylaxis of iron deficiency symptoms and iron deficiency anemias and the symptoms associated therewith.
2. The use according to claim 1, wherein the iron(III) complex compounds or pharmaceutically acceptable salts thereof n at least one ligand of the formula (I): AH26(9820323_1):JIN wherein the arrows respectively represent a coordinate bond to one or different iron atoms, and R1, R2, R3 may be the same or different and are selected from the group consisting of: - en, - alkyl, as defined in claim 2, - halogen, - alkoxy, as defined in claim 2, - aryl, as d in claim 2, - alkoxycarbonyl, as defined in claim 2, and - aminocarbonyl, as defined in claim 2 or R1 and R2 or R2 and R3 together with the carbon atoms to which they are bonded, form an optionally substituted saturated or unsaturated 5 - or 6- membered ring, which may optionally contain one or more heteroatoms.
3. The use according to any one of claims 1 or 2, wherein the iron(III) complex compounds or pharmaceutically able salts thereof contain at least one ligand of the formula (I): AH26(9820323_1):JIN wherein the arrows respectively represent a coordinate bond to one or different iron atoms, and R1, R2, R3 may be the same or different and are selected from the group consisting of: - hydrogen - alkyl, as defined in claim 2, and - n or R1 and R2 or R2 and R3 together with the carbon atoms to which they are bonded form a 5- or ered carbocyclic ring.
4. The use according to any one of claims 1 to 3, wherein the iron(III) complex compounds or pharmaceutically acceptable salts thereof cont ain at least one ligand of the formula (I): the arrows tively represent a coordinate bond to one or different iron atoms, R1, R2, R3 may be the same or different and are selected from the group consisting of hydrogen, alkyl which may optionally be substituted by alkoxy, and halogen, or R1 and R2 or R2 and R3 form together a propylene ( -CH2-CH2-CH2-), a butylene (-CH2-CH2-CH2-CH2-), azabutylene or oxabutylene group. AH26(9820323_1):JIN
5. The use according to any one of claims 1 to 4, wherein R1, R2, R3 are identical or ent and are selected from the group ting of hydrogen and alkyl, with the proviso that at least one of the substituents R 1, R2, and R3 is alkyl.
6. The use according to any one of claims 1 to 5, wherein wherein R2 is hydrogen, and R1 and R3 are each the same or different and are selected from alkyl.
7. The use according to any one of claims 1 to 6, wherein the iron(III) complex compounds are of the formula: wherein R1, R2, R3 may be the same or different and are defined as above, and pharmaceutically acceptable salts thereof.
8. The use according to any one of claims 1 to 7, n the symptoms include: fatigue, listlessness, lack of concentration, low cognitive efficiency, difficulties in finding the right words, forgetfulness, unnatural pa llor, irritability, acceleration of heart rate (tachycardia), sore or swollen tongue, ed spleen, desire for strange foods (pica), headaches, lack of appetite, sed susceptibility to infections, depressive moods.
9. The use according to any one of claims 1 to 7 for the ent of iron deficiency anemia in pregnant women, latent iron deficiency anemia in children and adolescents, iron deficiency anemia caused by gastrointestinal AH26(9820323_1):JIN abnormalities, iron deficiency anemia due to blood loss, s uch as gastrointestinal hemorrhage (e.g. due to ulcers, carcinoma, hemorrhoids, inflammatory disorders, taking of acetylsalicylic acid), iron deficiency anemia caused by menstruation, iron deficiency anemia caused by injuries, iron deficiency anemia due to psilosis (sprue), iron deficiency anemia due to reduced dietary iron uptake, in particular in selectively eating children and adolescents, immunodeficiency caused by iron deficiency anemia, brain function impairment caused by iron deficiency anemias, rest less leg syndrome caused by iron deficiency anemias, iron deficiency anemias in the case of cancer, iron ency anemias caused by chemotherapies, iron ency anemias triggered by inflammation (AI), iron deficiency anemias in the case of congestive c insufficiency (CHF; congestive heart failure), iron deficiency anemias in the case of chronic renal insufficiency stage 3 -5 (CKD 3-5; chronic kidney es stage 3-5), iron deficiency anemias red by chronic inflammation (ACD), iron deficiency s in the case of rheumatoid arthritis (RA), iron deficiency anemias in the case of systemic lupus erythematosus (SLE) and iron deficiency anemias in the case of inflammatory bowel diseases (IBD).
10. The use according to any one of the claims 1 to 9, n the medicament is formulated for oral stration.
11. The use according to claim 10, wherein a solid formulation such as pills, tablets, enteric-coated tablets, film tablets, layer tablets, sustained release ations, depot formulations, dragees, suppositories, granulates, apsules, microformulations, nanoformulations, capsules, enteric -coated capsules and powders, or a liquid formulation including a drinkable formulation such as a syrup, elixir, solution, suspension, juice is for administration.
12. The use according to any one of claims 1 to 11, wherein the medicament further comprises at least one physiological compatible carrier or excipient.
13. Use of a composition containing iron(III) complex compounds as defined in any one of claims 1 to 7, in ation with at least one further AH26(9820323_1):JIN medicament which acts on the iron lism for the preparation of medicaments for the treatment of iron deficiency anemia. Vifor (International) AG By the Attorneys for the Applicant SPRUSON & FERGUSON Per: AH26(9820323_1):JIN
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11160151 | 2011-03-29 | ||
EP11160151.4 | 2011-03-29 | ||
PCT/EP2012/055512 WO2012130882A1 (en) | 2011-03-29 | 2012-03-28 | Fe(iii) complexes for the treatment and prophylaxis of iron deficiency symptoms and iron deficiency anaemias |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ616045A NZ616045A (en) | 2015-04-24 |
NZ616045B2 true NZ616045B2 (en) | 2015-07-28 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2793153C (en) | Fe(iii) complex compounds for the treatment and prophylaxis of iron deficiency symptoms and iron deficiency anemias | |
JP2013502399A (en) | Novel quinoline hepcidin antagonist | |
AU2012234292B2 (en) | Fe(III) complexes for the treatment and prophylaxis of iron deficiency symptoms and iron deficiency anaemias | |
US9439910B2 (en) | Fe(III)-pyrazine complex compounds for treatment and prophylaxis of iron-deficiency phenomena and iron-deficiency anaemia | |
ES2548407T3 (en) | Compounds of 2,4-dioxo-1-carbonyl complexes of Fe (III) for use in the treatment and prophylaxis of iron deficiency states and iron deficiency anemias | |
NZ616045B2 (en) | Fe(iii) complexes for the treatment and prophylaxis of iron deficiency symptoms and iron deficiency anaemias | |
AU2014242974A1 (en) | Fe(lll) complexes for treatment and prophylaxis of iron deficiency symptoms and iron deficiency anaemias | |
TW201113274A (en) | Novel ethanediamine hepcidine antagonists |