IL99485A - Ligands useful in radiographic imaging agents - Google Patents
Ligands useful in radiographic imaging agentsInfo
- Publication number
- IL99485A IL99485A IL9948591A IL9948591A IL99485A IL 99485 A IL99485 A IL 99485A IL 9948591 A IL9948591 A IL 9948591A IL 9948591 A IL9948591 A IL 9948591A IL 99485 A IL99485 A IL 99485A
- Authority
- IL
- Israel
- Prior art keywords
- hydrogen
- group
- suitable protecting
- protecting group
- ligand
- Prior art date
Links
- 239000003446 ligand Substances 0.000 title claims description 28
- 239000012216 imaging agent Substances 0.000 title description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 33
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 18
- 229910052713 technetium Inorganic materials 0.000 description 12
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000003384 imaging method Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- XPQIPUZPSLAZDV-UHFFFAOYSA-N 2-pyridylethylamine Chemical compound NCCC1=CC=CC=N1 XPQIPUZPSLAZDV-UHFFFAOYSA-N 0.000 description 3
- -1 Ca*2 Chemical class 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229940056501 technetium 99m Drugs 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 238000002610 neuroimaging Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229910052702 rhenium Inorganic materials 0.000 description 2
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 2
- 125000001302 tertiary amino group Chemical group 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RMGWCRLOIZZBJX-UHFFFAOYSA-N (2,5-dioxopyrrolidin-3-yl) 2-benzoylsulfanylacetate Chemical compound C1C(=O)NC(=O)C1OC(=O)CSC(=O)C1=CC=CC=C1 RMGWCRLOIZZBJX-UHFFFAOYSA-N 0.000 description 1
- WUAPFZMCVAUBPE-NJFSPNSNSA-N 188Re Chemical compound [188Re] WUAPFZMCVAUBPE-NJFSPNSNSA-N 0.000 description 1
- LWARMDZJCXRHNN-UHFFFAOYSA-N 2-acetamido-n-(2-pyridin-2-ylethyl)-4-sulfanylbutanamide Chemical compound CC(=O)NC(CCS)C(=O)NCCC1=CC=CC=N1 LWARMDZJCXRHNN-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 1
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- NRFJZTXWLKPZAV-UHFFFAOYSA-N N-(2-oxo-3-thiolanyl)acetamide Chemical compound CC(=O)NC1CCSC1=O NRFJZTXWLKPZAV-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000018526 Narcotic-Related disease Diseases 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229960004753 citiolone Drugs 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical class OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- NBEMQPLNBYYUAZ-UHFFFAOYSA-N ethyl acetate;propan-2-one Chemical compound CC(C)=O.CCOC(C)=O NBEMQPLNBYYUAZ-UHFFFAOYSA-N 0.000 description 1
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-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
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- KIWQWJKWBHZMDT-UHFFFAOYSA-N homocysteine thiolactone Chemical compound NC1CCSC1=O KIWQWJKWBHZMDT-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical class O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 201000005040 opiate dependence Diseases 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- WUAPFZMCVAUBPE-IGMARMGPSA-N rhenium-186 Chemical compound [186Re] WUAPFZMCVAUBPE-IGMARMGPSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- RSPCKAHMRANGJZ-UHFFFAOYSA-N thiohydroxylamine Chemical compound SN RSPCKAHMRANGJZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/815—Protease inhibitors from leeches, e.g. hirudin, eglin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/655—Somatostatins
- C07K14/6555—Somatostatins at least 1 amino acid in D-form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- Endocrinology (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Tropical Medicine & Parasitology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
Ligands useful in radiographic imaging agents MALLINCKRODT MEDICAL, INC.
C. 84436 99485/3 - 1 - Background of the Invention The present invention relates to novel ligands for forming radionuclide complexes.
The use of radiographic imaging agents for visualizing skeletal structures, organs, or tissues, is well known in the area of biological and medical research and diagnostic procedures. The procedure whereby such imaging is accomplished, gene-rally involves the preparation of radioactive ac-ents , which, when introduced to the biological subject, are localized in the specific skeletal structures, organs ox tissues to be studied.
The localized radioactive ageaits may then be traced, plotted or scintiphotographec! by radiation detectors, such as, traversing scanners or scintillation cameras.
The distribution and relative intensity of the detected radioactive agents indicates the position of the tissue in which the agent is localized, and also shows the presence of aberrations, pathological conditions or the like.
In general, the radiographic imaging agents comprise radionuclide-labelled compounds; such as complexes of technetium 99m, rhenium 186 or rhenium 188, or other applicable radionuclides; with appropriate carriers, and auxiliary agents, such as delivery vehicles suitable for injection into, or aspiration by, the patient, physiological buffers and salts, and the like. - 2 - 99485/2 Detailed Description of the Invention The following description includes matter which is not claimed, but is retained herein for the sake of completeness .
The present invention relates particularly to novel aminothiol ligands that are suitable for complexing with a radionuclide, and are useful as general imaging agents for diagnostic purposes. In particular the present invention relates to novel ligands having the general formula : —N—R* wherein R1 and may the same or different and are selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalk l , mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl , or carbamoyl; A is selected from the group consisting of wherein n is 1 to 3, wherein R3, R4 and R5 are defined in the same manner as R1 and R2 above, and wherein Y is -CH-(CH2)a-S-J or -H wherein m is 1 to 3, wherein Z is selected from the group consisting of 99485/2 3 wherein Rs and R7 are defined in the same manner as R1 and R2 above, and wherein J is hydrogen or another suitable protecting group such as ethylaminocarbonyl; and B is selected from the group consisting of 0 R 0 R 0 II I - CC¾ ) - , -C-C-(CH2) , or -U I - Y Y wherein p is 1 to 3, wherein 1 is 0 or 1, wherein RB and R9 are defined in the same manner as R1 and R2 above, and wherein Y is as defined above.
In a preferred embodiment, ligands according to the present invention have the general formula (I) above, wherein R1 is hydrogen; R2 is selected from the group consisting of butoxycarbonyl , acetyl, ethyl, or hydrogen; A is -(CH2)B- wherein n * 2; and B is O * -C-C-(CH.),- Y wherein 1 = 0, Rs is hydrogen and Y is 2 -CH-(CH2)a-S-J wherein m = 1, Z is -H, and J is a suitable protecting group .
Also novel are ligands having the general formula: wherein R10 is selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly-hydroxyalkyl , mono- or poly- alkoxyalkyl, acyl, 99485/2 alkoxycarbonyl , or carbamoyl; R11 is a suitable sulfur protecting group selected from the group defined in the same manner as R10 above; D is selected from the group consisting of wherein i is 1 to 3, wherein R1Z, R13 and Ru are defined in the same manner as R10 above, and wherein X is Q I -CH-(CH2) -S-L wherein g is 1 to 3, wherein Q is selected from the group consisting of wherein R15 and Rlfi are defined in the same manner as R10 above, and wherein L is hydrogen or another suitable protecting group such as eth laminocarbonyl; and E is selected from the group consisting of - (CH2)h- , -C-CH2-NH-C-CH2- , , --Cϋ--CCHH-- ,, or -C-CH - CH- k17 R18 R19 wherein h is 1 to 3, wherein R17, R18 and R19 are defined in the same manner as R10 above.
Other ligands have the general formula (II) above , wherein 10 Is- hydrogen; Ru is 0 // D is -(CHj)j- wherein i The novel ligands described above, may be incorporated into radionuclide complexes used as radiographic imaging agents. The complexes of the present invention are prepared by reacting one of the aforementioned ligands with a radionuclide containing solution under radionuclide complex forming reaction conditions. In particular, if a technetium agent is desired, the reaction* is carried out with a pertechnetate solution under technetium 99m complex forming reaction conditions. The solvent may then be removed by any appropriate means, such as evaporation. The complexes are then prepared for administration to the patient by -dissolution or suspension in a pharmaceutically acceptable vehicle.
The ligands of the present invention may be prepared from commercially available starting materials such as 2- (2-aminoethyl)pyridine, 2-aminomethyl pyridine, homocysteinethiolactone, etc. by standard synthetic methods as described in the following Exaaples 1 - 7.
Radionuclide complexes may have the general formula: (III) 99485/2 6 wherein M is an appropriate radionuclide such as technetium or rhenium, and R1 and R2 are as defined above in formula (I). In a preferred embodiment a technetium radionuclide complex having the general formula (III) may be formed from a pertechnetate solution and a ligand having the general formula (I) above, wherein R1 is hydrogen; R2 is butoxycarbonyl , acetyl, ethyl or hydrogen; A is -(CH,) - wherein n = 2; and B is O R8 -C-C-(CH2),- Y wherein 1 = 0, R* is hydrogen and Y is Z -CH-(CH2)m-S-J wherein m = 1, Z is -H, and J -is a suitable protecting grou .
Also, radionuclide complexes may have the general formula: wherein M represents an appropriate radionuclide, such as technetium or rhenium and wherein R10 is as defined above in formula (II). In a preferred embodiment, a technetium radionuclide complex having the general formula (IV) may be formed from a pertechnetate solution and a ligand having the general formula (II) above, wherein R10 is hydrogen; R11 is D is -(CH2),- wherein i = 1; and E is The radionuclide containing solution nay be obtained from radionuclide generators in a known manner. For example, when forming a technetium complex, the pertechnetate solution may be obtained fron a technetium generator in a known manner. The radionuclide complex forming reaction is then carried out under appropriate reaction conditions. For example, the technetium 99m complex forming reaction is carried out under technetium complex forming temperatures, e.g. 20* C to 100 *C for 10 minutes to several hours. A large excess of the appropriate ligands over the radionuclide complex forming amounts is preferably used. For example, when forming a technetium complex, at least a ten fold excess of the ligands over the pertechnetate solution is used. The pertechnetate is used in technetium complex forming amounts, e.g. about 106 to 1012 molar amounts.
It is believed that certain radionuclide complexes of the present invention incorporating the ligands of the present invention have particular functional use as brain imaging agents. In particular, it is believed that these agents will act as opium alkaloid (e.g. morphine) mimics which may be selectively localized in the brain receptors, and may therefore exhibit optimal properties to function as diagnostic agents for the detection of brain disorders such as Alzheimer's disease, Parkinson's disease, narcotic addiction, etc.
A preferred complex for use in a brain imaging agent has the following formula: wherein. R1 is as defined above in formula (I)/ and wherein Z is a primary, secondary or tertiary amino functionality. This complex may be formed by reaction of a pertechnetate solution with a ligand according to the present invention having the general formula (I) above, wherein R1 is, in particular, hydrogen, hydroxyl, or methoxyl; R2 is CH,; A is R4 R5 3 I I -CH -C- I Y wherein R4 and R5 are hydrogen and Y is Z -CH-(CH2)m-S-J wherein m = 1, Z is ^R6 -N \»' wherein R6 is hydrogen or CH- and R7 is hydrogen or CH3/ and J is a suitable protecting group; and B is O R8 II I -C-C-(CH2),- Y wherein 1 = 1, R8 is hydrogen and Y is -H.
A further preferred complex for use in a brain agent has the following formula: wherein R10 is as defined above in formula (II), and wherein Q is a primary, secondary or tertiary amino functionality.
This complex may be formed by reaction of a pertechnetate solution with a ligand having the general formula (II) above, wherein R10 is, in particular, hydrogen, hydroxyl, or methoxyl; Ru is hydrogen or another suitable protecting group; D is R.13 R14 -CH - C- I X wherein R13 and Rl* are hydrogen and X is Q I -CH-(CH2)g-S-L wherein g = 1, Q is ,R -N ^R16 .wherein R,s is hydrogen or CH3 and R16 is hydrogen or CH3, and L is a suitable protecting group; and E is 0 II -C-CH - CH- R18 R19 wherein R18 and R19 are hydrogen.
Also related to imaging agents containing a radionuclide complex as described above, in an amount sufficient for imaging, together with a pharmaceutically acceptable radiological vehicle. The radiological vehicle should be suitable for injection or aspiration, such as human serum albumin; aqueous buffer solutions, e.g tris (hydromethyl) aminomethane (and its salts), phosphate, citrate, bicarbonate, etc; sterile water; physiological saline; and balanced ionic solutions containing chloride and or dicarbonate salts or normal blood plasma cations such as Ca*2, Na*, K+, and Mg+2.
The concentration of the imaging agent in the radiological vehicle should be sufficient to provide satisfactory imaging, for example, when using an aqueous solution, the dosage is about 1.0 to 50 millicuries. The imaging agent should be administered so as to remain in the patient for about 1 to 3 hours, although both longer and shorter time periods are acceptable. Therefore, convenient ampules containing 1 to 10 ml of aqueous solution may be prepared.
Imaging may be carried out in the normal manner, for example by injecting a sufficient amount of the imaging composition to provide adequate imaging and then scanning with a suitable machine, such as a gamma camera.
The complexes may be prepared in accordance with the examples set forth below.
Example 1 Preparation of 5-aza-3-(N-t-butoxycarbonyl ) amino- 1 - mercapto-4-oxo-7- f 2 -pyridvl ) -heptane A mixture of 2- (2-aminoethyl)pyridine (2.44 g, 0.02 mol) and N-t butoxycarbonyl-homocysteinethiolactone (4.22 g, 0.02 mol) in acetonitrile (50 ml) was heated under reflux for 12 hours. Thereafter, the reaction mixture was kept at room temperature for 6 hours by which time colorless crystals had separated. The solid was collected by filtration, washed with cold acetonitrile, and dried. 13C-NMR (CDC13) 6171.2, 159.3, 155.4, 149.2, 136.4, 123.3, 121.5, 79.9, 53.7, 38.8, 36.9, 34.8, 32.6, 28.3.
Example 2 Preparation of 3-acetamido-5-aza- l-mercapto-4-oxo-7- (2-pyridyl) heptane A mixture of N-acetylhomocysteinethiolactone (4.77 g, 0.03 mol) and 2- (2-aminoethyl) pyridine (3.66 g, 0.03 mol) in acetonitrile (50 ml) was heated under reflux for 12 hours. The solvent was removed under reduced pressure and the residue was treated with ethyl acetate (50 ml). The precipitate was collected, dried and recrystallized from acetonitrile to give colorless solid. 13C-NMR (CDClj) & 171.4, 170.6, 159.4, 149.3, 136.6, 123.4, 121.8, 51.7, 38.5, 36.8, 34.9, 32.7, 22.8.
Example 3 Preparation of 3-amino-5-a2a-l-mercapto-4-oxo-7- (2- pyridyl) heptane A solution of the butoxycarbonyl derivative from Example 1, (4 g) and trifluoroacetic acid (20 ml) was kept at room temperature for 1 hour. The reaction mixture was poured onto ether (500 ml). the precipitate was collected, washed with ether and dried. The compound was pure enough for the next step.
Example 4 Preparation of 5-aza-3-ethvlamino-l-gercapto-4-oxo- 7-(2-pyridyl) heptane A solution of diborane in tetrahydrofuran (1 M, Aldrich) (60 ml) was added dropwise to an ice-cold solution of the diamide of Example 2 (4 g) in tetrahydrofuran (20 ml). After the addition, the reaction mixture was heated under reflux for 2 hours. The reaction mixture was then cooled in an ice bath and excess diborane was decomposed by dropwise addition of ice-cold water. The solution was taken to dryness under reduced pressure and the residue was redissolved in methylene chloride (100 ml) washed with water (2 x 100 ml), dried (Na2S04), filtered and the filtrate was taken to dryness under reduced pressure. The residue was chromatographed over silica gel (200 g) using CH2C12/CH-0H (9:1) as eluent to furnish the desired co«pound as colorless gum (1 g) . nC-NMR (CDC13) 6 174.7, 159.0, 148.9, 137.2, 123.7, 121.9, 61.2, 49.8, 42.3, 38.3, 37.4, 36.8, 20.8, 14.7.
Example 5 Preparation of 7- ( S-benzoyl ) mercapto-2.5-diaza-3.6- dioxo-l-f2-pvridyl) heptane A mixture of S- (benzoyl)mercaptoacetoxy succinimide (1.4 g) and l-amino-3-aza-2-oxo-4-(2-pyridyl) butane (0.8 g) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The white precipitate was collected, washed with water, dried, and recrystallized from acetonitrile to give 700 mg of colorless solid. 13C-N R (CDC13) & 191.9, 168.9, 156.5, 149.2, 137.0, 136.1, 134.3, 128.9, 127.7, 122.5, 122.0, 44.3, 43.3, 32.5.
Example 6 Tc labelling of the lioand of Example 1 A mixture of the ligand produced in Example 1 (10 mg) in ethanol (0.9 ml) was treated with 0.01 N NaOH (0.1 ml) and technetium tartarate solution (0.1 ml). The entire mixture was heated at 100 *C for 30 ninutes. After cooling, the neutral complex was purified by reverse phase HPLC.
Example 7 "!Tc labelling of the ligand of Example 5 A mixture of the ligand produced in Example 5 (10 mg) in ethanol (0.1 ml) and 0.0001 N NaOH (0.9 ml) and technetium tartarate solution (0.1 ml) was heated at 100 *C for 45 minutes to yield neutral complex in high yield and purity. No HPLC purification was required.
Example 8 Preparation of 5 -aza-3- (N-t-butoxvcarbony1 ) amino- 1 - S-f (N-ethyl carbamoyl 1 mercapto-4-oxo-7- ( 2-pvridvH - heptane A mixture of 2-aminomethyl pyridine (2.44 g, 0.02 mol) and N-t butoxycarbonyl-homocysteinethiolactone (4.22 g, 0.02 mol) in acetonitrile (50 ml) was heated under reflux for 16 hours. Thereafter, the reaction mixture was cooled to room temperature and was treated with ethyl isocyanate (2 ml). The solution was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was treated with CH.C1. (50 ml) and water (50ml). The organic layer was separated, washed with water, dried (MgS0), filtered, and the filtrate taken to dryness under reduced pressure to give the desired compound as a pale yellow gum.
Purification by silica gel chromatography (ethyl acetate acetone, 4:1) yeilded pure ligand (1.2g) as an off white solid. 13C-NMR (CDC13) 6 171.6, 156.6, 155.6, 149.0, 136.7, 122.3, 121.7, 80.0, 53.7, 44.6, 36.4, 33.9, 28.3, 26.1, 14.9.
The foregoing has been a discussion of the preferred embodiments of the present invention, but is not intended to limit the invention in any way. Rather, many modifications, variations and changes in detail may be made within the scope of the present invention.
Claims (1)
1. A ligand useful in forming radionuclide complexes, said ligand having the general formula: wherein R1 and R may the same or different and are selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl , mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl , or carbamoyl; A is selected from the group consisting of R3 R4 R5 -(CH2)n- , -C 1- , or -C1H -C1- Y Y wherein n is 1 to 3, wherein R3, R4 and R5 are defined in the same manner as R1 and R2 above, and wherein Y is Z J -CH-(CH2)B-S-J , or -H wherein m is 1 to 3, wherein Z is selected from the group consisting of R6 / -H , -NH, , or -N wherein R6 and R7 are defined in the same manner as R1 and R2 above, and wherein J is a suitable protecting group.; and B is selected from the group consisting of O R8 0 R9 0 If I If I 1/ -(CH2)p- , -0-C-(CH2)r , or -C-C -C- Y Y wherein p is 1 to 3( wherein 1 is 0 or 1, wherein R8 and R9 are defined in the same manner as R1 and R2 above, and wherein Y is as defined above. A ligand according to claim 1, wherein R1 is hydrogen; R2 is butoxycarbonyl; A is -(CH2)n- wherein n = 2; and B is 0 R8 II I -C-C-(CH2),- Y wherein 1 = 0, R8 is hydrogen and Y is Z I -CH-(CH2 ) m- S -J wherein m = 1, Z is -H, and J is a suitable protecting group. A ligand according to claim 1, wherein Rl is hydrogen; R2 is acetyl; A is -(CH2)n- wherein n = 2; and B is O R8 II I -C-C-(CH2)r Y wherein 1 = 0, R8 is hydrogen and Y is Z I -CH-(CH2)m-S-J wherein m = 1, Z is -H, and J is a suitable protecting group. A ligand according to claim 1, wherein R1 is hydrogen; R2 is ethyl; A is ~(CH2)n- wherein n = 2; and B is O R8 II I -C-C-(CH2),- Y wherein 1 = 0 R8 is hydrogen and Y is -CH- (CH2)[n-S-J wherein m = 1, Z is -H, and J is a suitable protecting group. A ligand according to claim 1, wherein R is hydrogen; R2 is hydrogen; A is -(CH2)n- wherein n 2; and B is 0 R8 II I -C-C-(CH2),- Y wherein 1 = 0, R8 i s hydrogen and Y is Z I -CH-(CH2)m-S-J wherein m = 1, Z is -H, and J is a suitable protecting group. the Appl i cants RELNHOLlk COHN AND PARTNERS
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| US58431790A | 1990-09-14 | 1990-09-14 |
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| AU (1) | AU8721591A (en) |
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| WO (1) | WO1992005154A1 (en) |
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| US5382654A (en) * | 1992-02-05 | 1995-01-17 | Mallinckrodt Medical, Inc. | Radiolabelled peptide compounds |
| US5656253A (en) * | 1990-09-14 | 1997-08-12 | Mallinckrodt Medical, Inc. | Ligands useful in radiographic imaging |
| US6019958A (en) * | 1991-02-08 | 2000-02-01 | Diatide, Inc. | Technetium-99m labeled peptides for imaging inflammation |
| US5645815A (en) | 1991-02-08 | 1997-07-08 | Diatide, Inc. | Radiolabled compounds for thrombus imaging |
| US5552525A (en) * | 1991-02-08 | 1996-09-03 | Diatech Inc. | Technetium-99m labeled peptides for imaging inflammation |
| WO1992013572A1 (en) * | 1991-02-08 | 1992-08-20 | Diatech, Inc. | TECHNETIUM-99m LABELED POLYPEPTIDES FOR IMAGING |
| WO1993023085A1 (en) * | 1992-05-21 | 1993-11-25 | Diatech, Inc. | TECHNETIUM-99m LABELED PEPTIDES FOR THROMBUS IMAGING |
| US5736122A (en) * | 1991-02-08 | 1998-04-07 | Diatide, Inc. | Technetium-99m labeled peptides for thrombus imaging |
| US5330737A (en) * | 1991-12-06 | 1994-07-19 | Mallinckrodt Medical, Inc. | Nitrogen-sulfur ligands as opiate receptor drug mimics |
| EP1099693A1 (en) * | 1992-02-05 | 2001-05-16 | Mallinckrodt Inc. | Radiolabelled peptide compounds |
| US5371184A (en) * | 1992-02-05 | 1994-12-06 | Mallinckrodt Medical, Inc. | Radiolabelled peptide compounds |
| AU3610593A (en) * | 1992-02-06 | 1993-09-03 | Mallinckrodt Medical, Inc. | Ligands for improving metal chelate formation kinetics |
| US5508020A (en) * | 1992-06-05 | 1996-04-16 | Diatech, Inc. | Technetium-99M labeled peptides for imaging |
| US5968476A (en) * | 1992-05-21 | 1999-10-19 | Diatide, Inc. | Technetium-99m labeled peptides for thrombus imaging |
| US5879657A (en) * | 1993-03-30 | 1999-03-09 | The Dupont Merck Pharmaceutical Company | Radiolabeled platelet GPIIb/IIIa receptor antagonists as imaging agents for the diagnosis of thromboembolic disorders |
| ES2201284T3 (en) * | 1996-03-13 | 2004-03-16 | Bristol-Myers Squibb Pharma Company | NEW TERNARY RADIOPHARMACEUTICAL COMPLEXES. |
| US5986074A (en) * | 1996-05-06 | 1999-11-16 | Emory University | Metal chelates as pharmaceutical imaging agents, processes of making such and uses thereof |
| US5955053A (en) * | 1996-05-06 | 1999-09-21 | Emory University | Metal chelates as pharmaceutical imaging agents, processes of making such and uses thereof |
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| EP0200211A1 (en) * | 1985-05-01 | 1986-11-05 | The Research Foundation Of State University Of New York | Diagnostic radiopharmaceutical compounds |
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| WO1992005154A1 (en) | 1992-04-02 |
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