CA2339090A1 - Methimazole derivatives and tautomeric cyclic thiones to treat autoimmune diseases - Google Patents

Methimazole derivatives and tautomeric cyclic thiones to treat autoimmune diseases Download PDF

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Publication number
CA2339090A1
CA2339090A1 CA002339090A CA2339090A CA2339090A1 CA 2339090 A1 CA2339090 A1 CA 2339090A1 CA 002339090 A CA002339090 A CA 002339090A CA 2339090 A CA2339090 A CA 2339090A CA 2339090 A1 CA2339090 A1 CA 2339090A1
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pharmaceutical composition
composition according
alkyl
patient
group
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CA2339090C (en
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Leonard D. Kohn
Robert W. Curley
John M. Rice
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Sentron Medical Inc
US Government
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Individual
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6897—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids involving reporter genes operably linked to promoters

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Endocrinology (AREA)
  • Dermatology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides methods for treating autoimmune diseases in mammals and for preventing or treating transplantation rejection in a transplant recipient. These methods utilize specifically-defined methimazole derivatives and tautomeric cyclic thione compounds, as well as pharmaceutical compositions containing those compounds.
These compounds and compositions have been found to be at least as effective as methimazole in terms of pharmaceutical activity, while having less of an adverse effect on thyroid function. They are also more soluble in conventional pharmaceutical vehicles than methimazole. An assay for screening the activity of compounds useful against autoimmune diseases (ability to suppress expression of MHC Class I and II molecules) is also taught.

Claims (58)

1. A pharmaceutical composition comprising a safe and effective amount of a compound selected from wherein Y is selected from the group consisting of H, C1-C4 alkyl, C1-C4 substituted alkyl, -NO2, and the phenyl moiety and wherein no more than one Y group in said active compound may be the phenyl moiety; R1 is selected from the group consisting of H, -OH, C1-C4 alkyl, and C1-C4 substituted alkyl; R2 is selected from the group consisting of H, C1-C4 alkyl and C1-C4 substituted alkyl; R3 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 substituted alkyl, and -CH2Ph; R4 is selected from the group consisting of H, C1-C4 alkyl, and C1-C4 substituted alkyl; X is selected from S and O; and Z is selected from -SR3, -OR3 and C1-C4 alkyl; and wherein at least two of the R2 and R3 groups in said compound are C1-C4 alkyl when Y is not a phenyl moiety, and at least one Y
is -NO2 when Z is alkyl; and a pharmaceutically-acceptable carrier.

compound are C1-C4 alkyl when Y is not a phenyl moiety, and at least one Y
is -NO2 when Z is alkyl; and a pharmaceutically-acceptable carrier.
2. A pharmaceutical composition according to Claim 1 wherein Z is selected from -SR3 and OR3.
3. A pharmaceutical composition according to Claim 2 wherein Z is -SR3 and X
is S.
4. A pharmaceutical composition according to Claim 3 wherein Y is H.
5. A pharmaceutical composition according to Claim 4 wherein R3 is C1-C4 alkyl.
6. A pharmaceutical composition according to Claim 5 wherein R3 is methyl.
7. A pharmaceutical composition according to Claim 6 wherein at least one of the R2 groups is methyl.
8. A pharmaceutical composition according to Claim 4 wherein both R2 groups are methyl.
9. A pharmaceutical composition according to Claim 6 wherein the active compound has the formula
10. A pharmaceutical composition according to Claim 1 wherein the active compound has the formula
11. A pharmaceutical composition according to Claim 4 wherein the active compound has the formula
12. A pharmaceutical composition according to Claim 1 wherein the active compound has the formula
13. A pharmaceutical composition according to Claim 1 wherein the active compound has the formula
14. A pharmaceutical composition according to Claim 3 wherein one of the Y
groups is the phenyl moiety.
15. A pharmaceutical composition according to Claim 14 wherein R1 and R4 are H.
16. A pharmaceutical composition according to Claim 15 wherein R3 is methyl and at least one of the R2 groups is methyl.
17. A pharmaceutical composition according to Claim 16 wherein R3 is H.
18. A pharmaceutical composition according to Claim 17 wherein both R2 groups are methyl.
19. A pharmaceutical composition according to Claim 15 wherein the active compound is selected from the group consisting of
20. A pharmaceutical composition according to Claim 1 in unit dosage form.
21. A pharmaceutical composition according to Claim 1 which comprises from about 0.01 % to about 25% of the active. compound and from about 75% to about 99.99% of the pharmaceutically-acceptable carrier.
22. A pharmaceutical compound comprising; a safe and effective amount of a compound selected from wherein R5 and R6 are selected from the following moiety pairs CH3, CH3;
Ph, H and H, Ph; R7 is selected from H and CH3; and R8 is selected from O, S, NH and NCH3; and a pharmaceutically-acceptable carrier.
23. A method of treating autoimmune diseases in a patient in need of such treatment by administering to that patient a safe and effective amount of the pharmaceutical composition according to Claim 1.
24. A method of treatment according to Claim 23 wherein the pharmaceutical composition is administered intraperitoneally, intravenously, intramuscularly, orally, or topically.
25. A method of treatment according to Claim 24 wherein the pharmaceutical composition is administered orally.
26. A method of treatment according to Claim 25 wherein the pharmaceutical composition is in unit dosage form.
27. A method of treatment according to Claim 24 wherein pharmaceutical composition is administered in an amount such that the active compound is dosed at from about 0.05 to about 50 milligrams per day.
28. A method of treating autoimmune diseases in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to Claim 9.
29. A method of treating autoimmune diseases in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to Claim 10.
30. A method of treating autoimmune diseases in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to Claim 11.
31. A method of treating autoimmune diseases in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to Claim 12.
32. A method of treating autoimmune diseases in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to Claim 13.
33. A method of treating autoimmune diseases in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to Claim 19.
34. A method of treating SLE in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to Claim 1.
35. A method of treating diabetes in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to Claim 1.
36. A method of assessing the ability of a drug to suppress based MHC class I
activity, said method comprising:
(a) introducing a reporter gene construct made up of one or more reporter genes operably linked to an MHC Class I regulatory nucleic acid sequence into a population of mammalian cells;
(b) treating said cells with said MHC Class I suppressing drug; and (c) measuring the activity of said one or more reporter genes attached to said MHC Class I regulatory sequence.
37. A method of assessing the ability of a drug to suppress the effect of ~-interferon on the expression of MHC Class I and MHC Class II molecules, said method comprising:
(a) introducing a reporter gene construct made up of one or more reporter genes operably linked to an MHC Class I or MHC Class II
regulatory nucleic acid sequence into a population of mammalian cells;
(b) treating said cells with ~-interferon and with said MHC Class I or MHC Class II suppressing drug; and (c) measuring activity of said one or more reporter genes attached to said MHC Class I or MHC Class II regulatory sequence.
38. The method of Claim 37 wherein said reporter gene construct is introduced into said mammalian cells by means selected from the group consisting of electroporation, transduction, transfection and lipofection.
39. The method of Claim 38 wherein said mammalian cells are selected from the group consisting of thyrocytes, hepatocytes, neural tissue, muscle, fibroblasts, adipocytes and HELA cells.
40. The method of Claim 39 wherein said reporter gene is selected from the group consisting of chloramphenicol acetyltransferase (CAT) gene, the .beta.-galactosidase gene, the luciferase gene and human growth hormone (hGH).
41. The method of Claim 40 wherein the reporter gene construct is transfected into said mammalian cells.
42. The method of Claim 41 wherein the mammalian cells are FRTL-5 thyroid cells.
43. The method of Claim 42 wherein the reporter gene is selected from p(-203)MHC-class I-LUC and p(-137)MHC-class II-LUC.
44. A mammalian cell into which has been introduced a reporter gene construct made up of one or more reporter genes operably linked to an MHC Class I
or MHC Class II regulatory nucleric acid sequence.
45. A mammalian cell of Claim 44 whereon said reporter gene is selected from the group consisting of chloramphenicol acetytransferase (CAT) gene, .beta.-galactosidase gene, luciferase gene, and human growth hormone (hGH).
46. A mammalian cell of Claim 45 selected form the group consisting of thyrocytes, hepatocytes, neural tissue, muscle, fibroblasts, adipocytes, and HELA cells.
47. A mammalian cell of Claim 46 wherein said reporter gene construct is introduced by means selected from the group consisting of electroporation, transduction, transfection and lipofection.
48. A mammalian cell according to Claim 47 which is a FRTL-5 thyroid cell into which has been transfected the reporter gene construct.
49. A mammalian cell according to Claim 48 wherein the reporter gene is selected from p(-203)MHC-class I-LUC and p(-137)MHC-class II-LUC.
50. The compound having the formula wherein R2 is selected from the group consisting of H, C1-C4 alkyl and C1-C4 substituted alkyl.
51: The compound of Claim 50 wherein R2 is selected from the group consisting of C1-C4 alkyl and C1-C4 substituted alkyl.
52. The compound of Claim 51 wherein R2 is methyl.
53. A pharmaceutical composition comprising a safe and effective amount of a compound selected from wherein Y is selected form the group consisting of H, C1-C4 alkyl, C1-C4 substituted alkyl, -NO2, and the phenyl moiety and wherein no more than one Y group is said active compound may be the phenyl moiety; R1 is selected from the group consisting H, -OH, halogens, C1-C4 alkyl, C1-C4 substituted alkyl, C1-C4 ester and C1-C4 substituted ester;
R2 is selected from the group consisting of H, C1-C4 alkyl and C1-C4 substituted alkyl; R3 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 substituted alkyl, and -CH2Ph; R4 is selected from the group consisting of H, C1-C4 alkyl and C1-C4 substituted alkyl; X is selected from S and O; Z
is selected from -SR3, -OR3, -S(O)R3, -SR3, and C1-C4 alkyl; and wherein at least two of the R2 and R3 groups in said compound are C1-C4 alkyl when Y
is not a phenyl moiety, and at least one Y is -NO2; when Z is alkyl:
and a pharmaceutically-acceptable carrier.
54. A pharmaceutical composition according to Claim 53 wherein the active compound is selected from the group consisting of wherein R9 is selected from the group consisting of -OH, -M and -OOCCH2M; wherein M is selected from F, Cl, Br and I.
55. A pharmaceutical composition according to claim 53 wherein the active compound is selected from the group consisting of wherein R10 is selected from the group consisting of H, -NO2, Ph, 4-HOPh and 4-MPh, wherein M is selected from. F, Cl, Br and I.
56. A method of treating autoimmune diseases in a patient in need of such treatment by administering to that patient a safe and effective amount of the pharmaceutical composition accord to claim 53.
57. A method of treating autoimmune disease in a patient in need of such treatment by administering to that patient a safe and effective amount of the pharmaceutical composition according to claim 54.
58. A method of treating autoimmune diseases in a patient in need of such treatment by administering to that patient a safe and effective amount of the pharmaceutical composition according to claim 55.
CA002339090A 1998-08-31 1999-08-27 Methimazole derivatives and tautomeric cyclic thiones to treat autoimmune diseases Expired - Fee Related CA2339090C (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US14431198A 1998-08-31 1998-08-31
US09/144,311 1998-08-31
US09/382,960 US6365616B1 (en) 1998-08-31 1999-08-25 Methimazole derivatives and tautomeric cyclic thiones to treat autoimmune diseases
US09/382,960 1999-08-25
PCT/US1999/019862 WO2000012175A2 (en) 1998-08-31 1999-08-27 Methimazole derivatives and tautomeric cyclic thiones to treat autoimmune diseases

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CA2339090A1 true CA2339090A1 (en) 2000-03-09
CA2339090C CA2339090C (en) 2009-11-17

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EP (1) EP1112072A2 (en)
AU (1) AU775606B2 (en)
CA (1) CA2339090C (en)
WO (1) WO2000012175A2 (en)

Families Citing this family (12)

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AUPP438598A0 (en) 1998-06-29 1998-07-23 Garvan Institute Of Medical Research NPY-Y7 receptor gene
AU2004201249B2 (en) * 1998-09-11 2007-06-07 Sentron Medical, Inc. Immune activation by double-stranded polynucleotides
CA2559712A1 (en) * 2004-03-16 2005-10-13 Interthyr Corporation Methimazole derivatives and tautomeric cyclic thiones to inhibit cell adhesion
US20060211752A1 (en) 2004-03-16 2006-09-21 Kohn Leonard D Use of phenylmethimazoles, methimazole derivatives, and tautomeric cyclic thiones for the treatment of autoimmune/inflammatory diseases associated with toll-like receptor overexpression
US9339403B2 (en) 2004-11-12 2016-05-17 Icon Medical Corp. Medical adhesive for medical devices
US7455688B2 (en) 2004-11-12 2008-11-25 Con Interventional Systems, Inc. Ostial stent
US9107899B2 (en) 2005-03-03 2015-08-18 Icon Medical Corporation Metal alloys for medical devices
US8398916B2 (en) 2010-03-04 2013-03-19 Icon Medical Corp. Method for forming a tubular medical device
WO2015066490A1 (en) 2013-10-31 2015-05-07 Ohio University Prevention and treatment of non-alcoholic fatty liver disease
US11266767B2 (en) 2014-06-24 2022-03-08 Mirus Llc Metal alloys for medical devices
US10392381B2 (en) 2014-07-18 2019-08-27 Ohio University Prevention and treatment of non-alcoholic fatty liver disease
US11766506B2 (en) 2016-03-04 2023-09-26 Mirus Llc Stent device for spinal fusion

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FR1509975A (en) * 1965-10-21 1968-01-19 Geigy Ag J R Imidazole derivatives and their preparation
US3641049A (en) * 1968-10-29 1972-02-08 Jan Olof Sandstrom Imidazoline-2-thiones
US3728455A (en) * 1971-06-24 1973-04-17 American Cyanamid Co Novel compositions of matter
US4346095A (en) * 1978-02-10 1982-08-24 Mercer James B Therapeutic treatment for viral hepatitis infection
US4537775A (en) * 1979-08-06 1985-08-27 Mercer James B Therapeutic treatment for viral infections
US4952594A (en) * 1973-06-18 1990-08-28 Mercer James B Reagents and method for therapeutic treatment of multiple sclerosis
US4491588A (en) * 1982-03-31 1985-01-01 University Of Tennessee Research Corporation Treatment of psoriasis and seborrheic dermatitis with imidazole antibiotics
US4675337A (en) * 1986-02-28 1987-06-23 Merck & Co., Inc. Non-mutagenic 1,2-disubstituted 4-nitro-imidazoles useful as antiprotozoal agents
EP0702554A1 (en) * 1993-06-07 1996-03-27 THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by the Secretary, Department of Health and Human Services Use of an mhc class i suppressor drug for the treatment of autoimmune diseases and transplantation rejection
FR2722098B1 (en) * 1994-07-06 1996-08-23 Cird Galderma NEW MEDICINES BASED ON METRO-NIDAZOLE OR A SYNERGETIC MIXTURE OF METRONIDAZOLE AND CLINDAMYCIN
WO1997019932A1 (en) * 1995-11-28 1997-06-05 American Home Products Corporation 2-thioxo-imidazolidin-4-one derivatives and their use for increasing hdl cholesterol concentration
US6197806B1 (en) * 1995-12-20 2001-03-06 Nippon Zoki Pharmaceutical Co., Ltd. Eliminating agent for activated oxygen and free radicals

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AU775606B2 (en) 2004-08-05
CA2339090C (en) 2009-11-17
WO2000012175A2 (en) 2000-03-09
AU5794199A (en) 2000-03-21
WO2000012175A3 (en) 2000-06-29
EP1112072A2 (en) 2001-07-04

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