WO1997041830A1 - Reparation and prevention of fibrotic lesions - Google Patents
Reparation and prevention of fibrotic lesions Download PDFInfo
- Publication number
- WO1997041830A1 WO1997041830A1 PCT/US1997/007468 US9707468W WO9741830A1 WO 1997041830 A1 WO1997041830 A1 WO 1997041830A1 US 9707468 W US9707468 W US 9707468W WO 9741830 A1 WO9741830 A1 WO 9741830A1
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- WO
- WIPO (PCT)
- Prior art keywords
- pyridone
- methyl
- phenyl
- group
- fibrotic
- Prior art date
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- 0 *C1C(*)=C(*)N(*)C(*)C1O Chemical compound *C1C(*)=C(*)N(*)C(*)C1O 0.000 description 1
Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- 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
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
Definitions
- the present invention relates to medical compositions and methods for the reparation of fibrotic lesional tissues and the prevention of fibrotic lesions, which compositions comprise one or more N-substituted 2(1H) pyridones and/or one or more N-substituted 3(1H) pyridones as active anti-fibrotic ingredient(s) .
- anti-fibro refers to the reparations and/or prevention of pathological polymerization of collagen in lung fibrosis, arteriosclerosis, prostatic hypertrophy, keloid, myocarditis, collagen disease, scar, wrinkle, etc., and reparation as well normalization of the existing pathological fibrotic tissues.
- N-substituted 2(1-H) pyridone compounds and N- substituted 3(1H) pyridone compounds also have anti- fibrotic activity.
- no effective pharmacological agent or composition has been available for the prevention or removal of pathologic fibrotic lesions of the lungs, prostate glands, musculoskeletal diseases, myocardial degeneration, myocardial infarction, arteriosclerosis, and other lesional fibroses.
- glucocorticoids hormones relating to carbohydrate metabolism
- hydrocortisone or prednisolone administered in very large doses have repeatedly been shown to be ineffective against fibrotic disease.
- These glucocorticoids do not arrest or remove such life- threatening fibrotic lesions.
- the glucocorticoids may be effective, however, as anti-inflammatory agents under such condition that they may temporarily ameliorate the secondary acute inflammation flare-ups which intermittently occur in tissues or organs damaged by fibrotic disease.
- excessive and prolonged administration of glucocorticoids in pulmonary fibrotic disease may cause destruction of tissues, due to fibrosis or an exacerbation and acceleration of the fibrotic destruction.
- compositions that comprise one or more N- substituted 2-(lH) pyridone(s) and/or N-substituted 3- (1H) pyridone(s) as active anti-fibrotic ingredient(s) .
- the present invention overcomes the limitations of the prior art by providing, in a preferred embodiment, drugs having pharmacological properties which are useful in the medicinal therapy of fibrotic disease for the reparation and prevention of fibrotic lesional tissues, such drugs including as active ingredient(s) one or more N-substituted 2-(lH) pyridone(s) and/or N-substituted 3- (IH) pyridone(s).
- drugs including as active ingredient(s) one or more N-substituted 2-(lH) pyridone(s) and/or N-substituted 3- (IH) pyridone(s).
- the compositions of this invention are novel as an anti-fibrotic drug, namely, as an agent for treating and preventing fibrosis.
- the active ingredient exerts an anti-fibrotic activity quite dissimilar to and independent of fibrinolytic activity.
- the "anti-fibrotic” activity described herein differs from “fibrinolytic” or “anti-fibrin” activity.
- the “fibrinolytic” or “anti-fibrin” activity refers to the biological ability of a pharmaceutical substance to (1) prevent fibrin formation (prevent formation of a blood clot) or (2) lyse or dissolve a previously formed blood clot.
- anti-fibrotic activity refers to the ability of an active substance to (1) prevent an excessive pathologic accumulation of collagenous scar or connective tissue in various body structures and organs (usually triggered by some injury, allergy, infection, or by some inherited genetic aberration), or (2) cause the non-surgical removal or biological dissolution of an existing excessive and pathologic accumulation of fibrotic collagenous tissue (for example, as in the dissolution of life-threatening fibrotic lesions of the lung found in patients with asbestosis).
- connective tissue proteins Three major classifications of connective tissue proteins are recognized with the largest portions consisting of collagen types (70 to 80%) and elastin types (15 to 20%). A miscellaneous group constitutes the third and smallest class.
- the elastin constitutes the principal protein of yellow connective tissue found in elastic structures such as the walls of larger blood vessels and walls of lung alveoli.
- pulmonary interstitial fibrotic hyperplasia small and firm nodules are palpable throughout the lung tissue, and upon gross examination are recognized from their opaque, airless structure to be foci of abnormal accumulations of fibrotic connective tissue. Such foci vary in size and color according to their age. Their aggressive and continued enlargement and coalescence ultimately leads to collagenous solidification of large segments of the lungs. These enlarging foci also impinge upon the lung capillaries thereby to reduce pulmonary blood flow, and at the same time, impede lymphatic drainage from the lungs. As a consequence, exudate accumulates within the alveoli, and secondary thickening of the alveolar wall ensues.
- the fibrosis of the lung impairs the physiological and biochemical functions of the lung that are independent of the pulmonary gas exchange (oxygen and carbon dioxide) role of the lungs cited above.
- particulate matter for example, tissue cell debris, blood cell aggregates, inert foreign matter, small thrombi
- Heparin is a useful substance that normally prevents the formation of life-threatening blood clots in the major blood vessels (for example, cerebral and coronary blood vessels).
- Pharmacological anti-fibrotic activity as exemplified by the arrest and removal of lung scarring (interstitial hyperplasia and fibrotic foci), or pathologic fibrotic lesions in other organs and tissues described herein, is clearly distinct from and independent of any pharmacological anti-inflammatory activity.
- compositions of this invention are effective for treatment of disease caused by the pathologic and excessive fibrotic accumulations such as pulmonary fibrosis, benign prostate hypertrophy, coronary infarcts, cerebral infarcts, myocardiac fibrosis, musculoskeletal fibrosis, post-surgical adhesions, liver cirrhosis, real fibrotic disease, fibrotic vascular disease (atherosclerosis, varix, or varicose veins), scleroderma, Alzheimer's disease, diabetic retinopathy, glaucoma, etc.
- pathologic and excessive fibrotic accumulations such as pulmonary fibrosis, benign prostate hypertrophy, coronary infarcts, cerebral infarcts, myocardiac fibrosis, musculoskeletal fibrosis, post-surgical adhesions, liver cirrhosis, real fibrotic disease, fibrotic vascular disease (atherosclerosis, varix, or varicose veins), sclero
- the pulmonary fibrosis may have been chemically induced, for example, by the anti-cancer drugs bleomycin or cyclophosphamide or by the weed killer paraquat.
- the compositions of this invention not only arrest the formation of new fibrotic tissue but causes removal of previously formed fibrotic collagen- containing tissue. These pharmacological properties were heretofore unknown.
- the present invention arrests formation of or causes removal of a pathogenic accumulation of water- insoluble collagenous connective tissue (for example, excessive scar or lesional fibrotic tissue, etc.).
- a pathogenic accumulation of water- insoluble collagenous connective tissue for example, excessive scar or lesional fibrotic tissue, etc.
- the invention eliminates or prevents: (1) the mechanical compression or occlusion (stenosis) of blood vessels (for example, pulmonary arteries, veins, and capillaries), pulmonary bronchioles, and alveoli; (2) the inhibition of the primary respiratory function of the alveoli of the lungs, namely, the exchange of oxygen and carbon dioxide gases; and (3) the increased pulmonary blood vessel resistance (cor pulmonale) which readily causes fatal congestive heart failure because of the excessive workload on cardiac muscle that is engendered by the cor pulmonale.
- stenosis blood vessels
- pulmonary arteries, veins, and capillaries pulmonary bronchioles
- alveoli for example, the mechanical compression or
- Rat Male: 1,295(25) 430 ⁇ 29(42) 12,500(10)
- EXAMPLE 1 The results of a histopathological examination of the lungs of rats for fibrosis (interstitial hyperplasia) after receiving 300mg/kg body weight of pirfenidone in the diet for three months are summarized in Table 2. The individual microscopic readings of the lung are also shown in Table 2, where a score schedule of 0, 1, 2, and 3 reflects the degree of fibrosis.
- the data in Table 2 reveal a statistically significant reduction in the amount of fibrosis in rats receiving pirfenidone as compared to placebo control rats (Group 1).
- the mean score for the controls (Group 1) was 1.63 ⁇ 0.23, and for Group IV (pirfenidone, 300mg/kg body weight daily was 0.95 ⁇ 0.23.
- This anti-fibrotic activity was not simply a a palliative (relieving) effect.
- pirfenidone makes possible a pulmonary resolution process whereby a life- threatening solidified fibrotic lung disease can be restored to a relatively normal tissue where the alveoli are no longer collapsed or occluded. That is, the microscopic examination reveals that the tissues are regenerated and become normal, spongy lungs.
- fibrotic or scar tissue e.g., lung fibrosis, etc.
- GROUP IV PIRFENIDONE, 300 mg/kg (p.o.)
- GROUP I-A (cyclophosphamide only, 200 mg/kg, i.p.)
- GROUP II cyclophosphamide, 200 mg/kg, i.p., plus pirfenidone, 500 mg/kg/day, p.o.
- GROUP III saline control; no cyclophosphamide; no pirfenidone
- GROUP IV pirfenidone, 500 mg/kg/day, p.o.; saline; no cyclophosphamide
- Pulmonary fibrosis diagnosed as caused by asbestos was treated with pirfenidone and closely and objectively followed in two subjects. Clinical impressions were dramatic and highly favorable.
- Pulmonary fibrosis diagnosed as idiopathic in nature was treated with pirfenidone and closely and objectively followed in one subject for over two years. Clinical impressions were highly favorable.
- Examples of medical preparations include: (1) capsules, (2) tablets, (3) powders, (4) granules, (5) syrups, (6) injection (intravenous, intramuscular, or drip administration), (7) cream, (8) ointment, (9) inhalation, (10) eye drop, (11) suppositories, (12) pills, etc.
- the average oral dosage for anti-fibrotic activity in humans is 3600 milligrams per day, with a range of from about 2400 milligrams to about 4800 milligrams per day. Administration may be in divided dosage - for example, 1200 milligrams three times per day.
- Rl alkyl group (CH3, C2H5, etc.); A is phenyl, thienyl, etc., or other aryl group.
- R3 alkyl group (CH3, C2H5, etc.); A is phenyl, thienyl, etc., or other aryl group.
- R3 is the site of substitution of the alkyl group with Rl remaining as a hydrogen;
- R2 and R4 are, in every circumstance, hydrogens.
- N-substituted 3-(lH) pyridones useful in the present invention, can be prepared using methods similar to those set forth in the above- referenced US Patent No. 3,839,346.
- the general structural formual for the 3 pyridones is:
- R2 or R3 alkyl group or hydrogen, as above;
- A is phenyl, thienyl, etc., or other aryl.
- Rl and R4 are hydrogen.
- Examples of the 2 and 3 pyridones include: 5-Methyl-l-(3-nitrophenyl-2)-( IH) pyridone 5-Methyl-l-(4 ' -methoxyphenyl)-2-(IH) pyridone 5-Methyl-l-p-tolyl-2-( IH) pyridone 5-Methyl-l-(3 ' -trifluoromethylphenyl)-2-( IH) pyridone l-(4 'Chlorophenyl)-5-Methyl-2)-(lH) pyridone 5-Methyl-l-(2 ' -naphthyl)-2-( IH) pyridone 5-Methyl-l-(1 ' naphthyl)-2-( IH) pyridone 3-Methyl-l-phenyl-2-( IH) pyridone 3-Ethyl-l
- compositions of the present invention have been found to be effective, or can be expected to be effective, in a 35 range of from about one-quarter to about twice the dosages given above for pirfenidone.
- the compositions of the present invention may be administered in forms consisting of capsules, tablets, powders, granules, syrups, injectable fluids, pills, creams, ointments, inhalable fluids, eye drops, and suppositories.
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Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU27519/97A AU725637B2 (en) | 1996-05-09 | 1997-05-03 | Reparation and prevention of fibrotic lesions |
CA002253919A CA2253919A1 (en) | 1996-05-09 | 1997-05-03 | Reparation and prevention of fibrotic lesions |
EP97921495A EP0902680A4 (en) | 1996-05-09 | 1997-05-03 | Reparation and prevention of fibrotic lesions |
IL12689197A IL126891A0 (en) | 1996-05-09 | 1997-05-03 | Reparation and prevention of fibrotic lesions |
JP09540064A JP2000510467A (en) | 1996-05-09 | 1997-05-03 | Repair and prevention of fibrotic lesions |
NO985197A NO985197D0 (en) | 1996-05-09 | 1998-11-06 | Repair and prevention of fibrotic lesions |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/647,006 US5716632A (en) | 1989-11-22 | 1996-05-09 | Compositions and methods for reparation and prevention of fibrotic lesions |
US08/647,006 | 1996-05-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997041830A1 true WO1997041830A1 (en) | 1997-11-13 |
Family
ID=24595333
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/007468 WO1997041830A1 (en) | 1996-05-09 | 1997-05-03 | Reparation and prevention of fibrotic lesions |
Country Status (11)
Country | Link |
---|---|
US (1) | US5716632A (en) |
EP (1) | EP0902680A4 (en) |
JP (1) | JP2000510467A (en) |
KR (1) | KR20000010676A (en) |
AU (1) | AU725637B2 (en) |
CA (1) | CA2253919A1 (en) |
IL (1) | IL126891A0 (en) |
NO (1) | NO985197D0 (en) |
TR (1) | TR199802273T2 (en) |
WO (1) | WO1997041830A1 (en) |
ZA (1) | ZA974041B (en) |
Cited By (12)
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WO2002060446A1 (en) * | 2001-01-29 | 2002-08-08 | Shionogi & Co., Ltd. | Medicinal preparation containing 5-methyl-1-phenyl-2-(1h)-pyridone as active ingredient |
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US8969347B2 (en) | 2008-06-03 | 2015-03-03 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
US9029385B2 (en) | 2007-10-26 | 2015-05-12 | Ganesh Raghu | Compositions and methods for treating fibroproliferative disorders |
US9359379B2 (en) | 2012-10-02 | 2016-06-07 | Intermune, Inc. | Anti-fibrotic pyridinones |
US10188637B2 (en) | 2016-03-29 | 2019-01-29 | Hoffmann-La Roche Inc. | Granulate formulation of 5-methyl-1-phenyl-2-(1H)-pyridone and method of making the same |
US10233195B2 (en) | 2014-04-02 | 2019-03-19 | Intermune, Inc. | Anti-fibrotic pyridinones |
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JPH02215719A (en) * | 1989-02-15 | 1990-08-28 | Yamauchi Akitomo | Agent for repairing fibrosing lesion tissue and preventing fibrosing lesion |
US5310562A (en) * | 1989-11-22 | 1994-05-10 | Margolin Solomon B | Composition and method for reparation and prevention of fibrotic lesions |
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US5789426A (en) * | 1995-01-20 | 1998-08-04 | Cornell Research Foundation, Inc. | Method for the treatment of fibroproliferative disorders by application of inhibitors of protein hydroxylation |
ATE265851T1 (en) * | 1995-03-03 | 2004-05-15 | Solomon B Margolin | TREATMENT OF DISEASES CAUSED BY CYTOKINE GROWTH FACTOR |
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1997
- 1997-05-03 AU AU27519/97A patent/AU725637B2/en not_active Ceased
- 1997-05-03 EP EP97921495A patent/EP0902680A4/en not_active Withdrawn
- 1997-05-03 KR KR1019980708678A patent/KR20000010676A/en not_active Application Discontinuation
- 1997-05-03 TR TR1998/02273T patent/TR199802273T2/en unknown
- 1997-05-03 WO PCT/US1997/007468 patent/WO1997041830A1/en not_active Application Discontinuation
- 1997-05-03 IL IL12689197A patent/IL126891A0/en unknown
- 1997-05-03 CA CA002253919A patent/CA2253919A1/en not_active Abandoned
- 1997-05-03 JP JP09540064A patent/JP2000510467A/en active Pending
- 1997-05-09 ZA ZA974041A patent/ZA974041B/en unknown
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1998
- 1998-11-06 NO NO985197A patent/NO985197D0/en not_active Application Discontinuation
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US6492395B1 (en) | 1998-09-18 | 2002-12-10 | Mepha Ag | Topical formulation of alkyl-, phenyl-pyridone |
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Also Published As
Publication number | Publication date |
---|---|
NO985197L (en) | 1998-11-06 |
IL126891A0 (en) | 1999-09-22 |
AU2751997A (en) | 1997-11-26 |
EP0902680A4 (en) | 2000-04-19 |
CA2253919A1 (en) | 1997-11-13 |
JP2000510467A (en) | 2000-08-15 |
US5716632A (en) | 1998-02-10 |
EP0902680A1 (en) | 1999-03-24 |
TR199802273T2 (en) | 2000-11-21 |
NO985197D0 (en) | 1998-11-06 |
KR20000010676A (en) | 2000-02-25 |
AU725637B2 (en) | 2000-10-19 |
ZA974041B (en) | 1998-11-09 |
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