AU4074789A - Coumarins to inhibit reverse transcriptase in humans - Google Patents
Coumarins to inhibit reverse transcriptase in humansInfo
- Publication number
- AU4074789A AU4074789A AU40747/89A AU4074789A AU4074789A AU 4074789 A AU4074789 A AU 4074789A AU 40747/89 A AU40747/89 A AU 40747/89A AU 4074789 A AU4074789 A AU 4074789A AU 4074789 A AU4074789 A AU 4074789A
- Authority
- AU
- Australia
- Prior art keywords
- coumarin
- compound
- bromo
- carbamoyl
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
Description
COUMARINS TO INHIBIT REVERSE TRANSCRIPTASE IN HUMANS Field of the Invention
This invention is a novel treatment of patients infected with a human immunodeficiency virus. Background of the Invention
The compounds used to practice, the method claimed in this invention are known; however, none of the compounds are known to be useful to treat humans infected with human immunodeficiency virus or strains thereof. An estimated one to one and one-half million people in the United States are infected with a human retrovirus, the human immunodeficiency virus type I, HIV-1, which is the etiological agent of acquired immunodeficiency syndrome, "$2-Billion Program Urged for AIDS", Norman, C, Science, Vol. 234, pages 661-662 (1986). Of those infected, an estimated two hundred and fifty thousands people will develop AIDS in the next five years, "The Epidemiology of AIDS: Current Status and Future Prospects", Curran, J.W., et al., Science, Vol. 229, No. 4720, pages 1352-1357 (1985). On March 20, 1987, the FDA approved the use of the compound, zidovudine (AZT), to treat AIDS patients with a recent initial episode of Pneumocystis carinii pneumonia, AIDS patients with conditions other than Pneumocystis carinii pneumonia or patients infected with the virus with an absolute CD4 lymphocyte count of less than 200/mm3 in the peripheral blood. AZT is a known inhibitor of viral reverse transcriptase, an enzyme necessary for human immunodeficiency virus replication.
It is known in the art that certain antibiotics and polyanionic dyes inhibit retrovirus reverse transcriptase. None of the compounds claimed in this invention were known to specifically inhibit human immunodeficiency virus reverse transcriptase. Summary of the Invention
This invention is a method for treating a human infected with one or more than one strain of a human immunodeficiency virus which comprises administering an effective amount of a compound selected from the group consisting of 6-bromo-3-[(m-chlorophenyl)carbamoyl]-coumarin, 6-bromo-3-[(α,α,α-trifluoro-m-toluyl)carbamoyl]-coumarin, 6-bromo-3-[(2,5-dichlorophenyl)carbamoyl]-coumarin, [[bis(4-hydroxy-2-oxo-2H-1-benzopyran-3-yl)-methyl]cyclopentadienyl]cyclopentadienyliron, 3-cinnamoyl-4-hydroxy-coumarin, hexachlorocoumarin, 7-acetoxy
coumarin or [1-(2-oxo-2H-1-benzopyran-3-yl)ethylidene]-hydrazinecarboxylic acid phenylmethyl ester or pharmaceutically acceptable salts thereof, to the infected human. Detailed Description of the Invention In this document, the term human immunodeficiency virus means human immunodeficiency virus type I, human immunodeficiency virus type II, or strains, apparent to one skilled in the art, which belong to the same viral family and which create similar physiological effects in humans as human immunodeficiency virus types I or II. The structural formulas, if known, of each of the compounds used to practice the method claimed in this invention are given in the structure charts. The following compounds; 6-bromo-3-[(m-chlorophenyl)carbamoyl]-coumarin, 6-bromo-3-[(α,α,α-trifluoro-m-toluyl)-carbamoyl]-coumarin, and 6-bromo-3-[(2,5-dichlorophenyl)carbamoyl]-coumarin, were obtained commercially. The preparation of the compound, 3-cinnamoyl-4-hydroxy-coumarin, is described in "Zur Chemie des 4-Hydroxy-cumarins", Monatshefte fur chemi, Vol. 87, pages 439446 (1956). The preparation of the compound, 7-acetoxycoumarin, is described in Chem. Ber., Vol. 12, pages 993-999 (1879). The compound, hexachlorocoumarin, is prepared when chlorine is bubbled into an ethanolic solution of coumarin in the presence of light. When there is no longer any detectable presence of the starting material in solution, the solvent is removed and the mixture of polychlorinated products is separated by chromatography. The compound, [[bis- (4-hydroxy-2-oxo-2H-1-benzopyran-3-yl)-methyl]cyclopentadienyl]cyclopentadienyl-iron, is prepared by condensing 2.0 equivalents of commercially available 4-hydroxycoumarin with 1.5 equivalents of commercially available ferrocenecarboxaldehyde in ethanol following the general procedures described by Sullivan, et al., JACS, Vol. 65, July-December, pages 2288-2291 (1943) "Studies on 4-Hydroxycoumarins. II. The Condensation of Aldehydes with Hydroxycoumarins". The compound, [1-(2-oxo-2H-1-benzopyran-3-yl)ethylidene]-hydrazinecarboxylic acid phenylmethyl ester, is prepared by condensing commercially available 3-acetylcoumarin with commercially available benzyl carbazate in the presence of glacial acetic acid in absolute methanol. The reagents are refluxed, diluted with water, cooled and filtered to provide the crystalline compound.
These compounds or pharmaceutically acceptable salts thereof can
be used and administered in practicing the method claimed in this invention. Pharmaceutically acceptable salts refers to those salts of the compounds claimed in this invention which would be readily apparent to a manufacturing pharmaceutical chemist to be equivalent to the parent compound in properties such as formulation, stability, patient acceptance and bioavailability.
Those skilled in the art would know how to formulate the compounds used to practice the method claimed in this invention into appropriate pharmaceutical dosage forms. Examples of the dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions.
When the compounds used to practice the method claimed in this invention are administered orally, an effective amount is from about 1 to 100 mg per kg per day. A typical unit dose for a 70 kg human would be from about 200 mg to 1000 mg taken one to four times per day. Either solid or fluid dosage forms can be prepared for oral administration. Solid compositions are prepared by mixing the compounds used to practice the method claimed in this invention with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methyl cellulose, or functionally similar pharmaceutical diluents and carriers. Capsules are prepared by mixing the compounds used to practice the method claimed in this invention with an inert pharmaceutical diluent and placing the mixture into an appropriately sized hard gelatin capsule. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compounds used to practice the method claimed in this invention with an acceptable inert oil such as vegetable oil or light liquid petrolatum. Syrups are prepared by dissolving the compounds used to practice the method claimed in this invention in an aqueous vehicle and adding sugar, aromatic flavoring agents and preservatives . Elixirs are prepared using a hydroalcoholic vehicle such as ethanol, suitable sweeteners such as sugar or saccharin and an aromatic flavoring agent. Suspensions are prepared with an aqueous vehicle and a suspending agent such as acacia, tragacanth, or methyl cellulose.
When the compounds used to practice the method claimed in this invention are administered parenterally, it can be given by injection or by intravenous infusion. An effective amount is from about 1 to
100 mg per kg per day. Parenteral solutions are prepared by dissolving the compounds used to practice the method claimed in this invention in water and filter sterilizing the solution before placing in a suitable sealable vial or ampule. Parenteral suspensions are prepared in substantially the same way except a sterile suspension vehicle is used and the compounds used to practice the method claimed in this invention are sterilized with ethylene oxide or suitable gas before it is suspended in the vehicle.
The exact route of administration, dose, or frequency of administration would be readily determined by those skilled in the art and Is dependant on the age, weight, general physical condition, or other clinical symptoms specific to the patient to be treated.
Patients to be treated would be those individuals: 1) infected with one or more than one strain of a human immunodeficiency virus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) having either a symptomatic AIDS defining infection such as i) disseminated histoplasmosis, ii) isoporiasis, iii) bronchial and pulmonary candidiasis including pneumocystis pneumonia iv) non-Hodgkin's lymphoma or v) Kaposi's sarcoma and being less than sixty years old; or having an absolute CD4 lymphocyte count of less than 200/mm3 in the peripheral blood. Treatment would consist of maintaining an inhibitory level of the compounds disclosed herein in the patient at all times and would continue until the occurrence of a second symptomatic AIDS defining infection indicates alternate therapy is needed.
Without further elaboration, those skilled in the art can practice the present invention to its fullest extent. The following detailed examples further describe how to use the compounds claimed in this invention to treat humans infected with one or more than one strain of a human immunodeficiency virus. These examples are merely illustrative and are not limitations of the preceding disclosure. Those skilled in the art will promptly recognize appropriate variations from the examples. In each example, any compound claimed in this invention could replace the compound used in the particular example.
Example 1 Hard Gelatin Capsules
One thousand two-piece hard gelatin capsules for oral use, each capsule containing 50 mg of hexachlorocoumarin, are prepared from the
following:
Hexachlorocoumarin 50 gm
Lactose 100 gm
Cornstarch 20 gm Talc 20 gm
Magnesium Stearate 2 gm
The hexachlorocoumarin is added to the other ingredients, mixed and encapsulated in the usual manner. Example 2 Tablets One thousand tablets, each containing 50 mg of hexachlorocoumarin, are prepared from the following:
Hexachlorocoumarin 50 gm
Lactose 75 gm
Cornstarch 50 gm Magnesium Stearate 4 gm
Light liquid petrolatum 5 gm
The hexachlorocoumarin is added to the other ingredients, mixed and slugged. The slugs are broken down by forcing through a number sixteen screen. The resulting granules are then compressed into tablets.
Example 3 Parenteral solution
A sterile aqueous solution for parenteral intravenous injection containing 150 mg of hexachlorocoumarin in one liter of solution is prepared from the following: Hexachlorocoumarin 150 mg
Water for injection, qs 1000 mg
The hexachlorocoumarin is sterilized, added to the sterile water, filled into sterile containers and sealed.
The utility of this invention is demonstrated by the ability of the compounds used to practice the method claimed in this invention to inhibit viral reverse transcriptase, an enzyme essential for human immunodeficiency virus replication. This enzyme has characteristics which differentiate it from other known cellular polymerases and it is a unique enzyme which is not found in uninfected cells. Viral reverse transcriptase is found in extracts from bacterial clones prepared according to the procedure described by Goff, S. P., et al., Journal of Virology, Vol. 59, No. 3, pages 743-745 (1986) "Expression of Reverse Transcriptase Activity of Human T-lymphotropic Virus Type
III (HTLV-III/LAV) in Escherichia coli". Inhibition of this enzyme is determined in a cell free assay which measures the level of radioactive precursors incorporated into DNA. Extracts prepared according to the procedure of Kleid, D. G., et al., Science, Vol. 214, No. 4525, pages 1125-1129 (1981) "Cloned Virla Protein Vaccine for Footand-Mouth Disease: Responses in Cattle and Swine" are incubated in a mixture of inhibitor, 20 mM dithiothreitol, 60 mM sodium chloride, 0.05% NP-40, 10 mM magnesium chloride, 50 mM Tris pH 8.3, 10 μM [35S]-labeled deoxynuleoside-5'-triphosphate, 10 /ig/ml RNA template (poly rC or poly rA) and 5 μg/ml DNA primer (oligo dG or oligo dT) for 30 minutes at 37ºC. Incorporation of radio-labeled precursor is determined by spotting aliquots of the reaction mixture on DE81 paper, washing the papers to remove unincorporated precursor, drying and determining counts. Table 1 contains the results of the assay for the compounds used to practice the method claimed in this invention.
TABLE 1
COMPOUND (0. 1 mM ) %INHIBITION
6-bromo-3-[(m-chlorophenyl)- 28carbamoyl]-coumarin
6-bromo-3-[(α,α,α-trifluoro31 m-toluyl)carbamoyl]-coumarin
6-bromo-3-[(2,5-dichlorophenyl)- 42carbamoyl]-coumarin
[[bis(4-hydroxy-2-oxo-2H-1-benzo60 pyran-3-yl)-methyl]cyclopentadienyl]-cyclopentadienyl-iron
3-cinnamoyl-4-hydroxy-coumarin 35
hexachlorocoumarin 34
[1-(2-oxo-2H-1-benzopyran-3-yl)- 31ethylidene]-hydrazinecarboxylic acid phenylmethyl ester
7-acetoxycoumarin 23
PCT WORLD INTELLECTUAL PROPERTY ORGANIZATION International Bureau
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(51) International Patent Classification 4 (11) International Publication Number: WO 89/ 079 A61K 31/37 A3 (43) International Publication Date: 8 September 1989 (08.09.
(21) International Application Number: PCT/US89/00450 (72) Inventors; and
(75) Inventors/Applicants (for US only) : REUSSER, F
(22) International Filing Date: 8 February 1989 (08.02.89) [US/US]; 6548 Trotwood Street, Portage, MI 49 (US). TARPLEY, William, G. [US/US]; 5207 Map
(31) Priority Application Numbers: 162,553 idge, Kalamazoo, MI 49008 (US). DOLAK, Le 190,038 [US/US]; 3261 East B Avenue, Plainwell, MI 49 (US). ALTHAUS, Irene, W. [US/US]; 10220 Shu
(32) Priority Dates: 1 March 1988 (01.03.88) Street, Portage, MI 49002 (US). 4 May 1988 (04.05.88)
(74) Agent: REYNOLDS, John, T. ; Patent Law Dep
(33) Priority Country: US ment, The Upjohn Company, Kalamazoo, MI 49 (US).
(60) Parent Application or Grant
(63) Related by Continuation (81) Designated States: AT (European patent), AU, BE ( US 190,038 (CIP) ropean patent), CH (European patent), DE (Eu Filed on 4 May 1988 (04.05.88) pean patent), DK, FI, FR (European patent), (European patent), IT (European patent), JP, KR,
(71) Applicant (for all designated States except US): THE (European patent), NL (European patent), NO, UPJOHN COMPANY [US/US]; 301 Henrietta Street, (European patent), US. Kalamazoo, MI 49001 (US).
Published
With international search report
Before the expiration of the time limit for amending t claims and to be republished in the event of the receipt amendments.
(88) Date of publication of the international search report:
19 October 1989 (19.10.8
(54) Title: COUMARINS TO INHIBIT REVERSE TRANSCRIPTASE IN HUMANS
(57) Abstract
The following compounds: 6-bromo-3-[(m-chlorophenyl)carbamoyl]-coumarin, 6-bromo-3-[(α,α,α-trifluoro-m-tol yl)carbamoyl]coumarin, 6-bromo-3-[(2,5-dichlorophenyl)carbamoyl]coumarin, [[bis(4-hydroxy-2-oxo-2H- 1 -benzopyranyl)-methyl]cyclopentadienyl]cyclopentadienyl-iron, 3-cinnamoyl-4-hydroxy-coumarin, hexachlorocoumarin, 7-acetox coumarin or [l-(2-oxo-2H-l-benzopyran-3-yl)ethylidene]-hydrazinecarboxylic acid phenylmethyl ester or pharmaceutic ly acceptable salts thereof can be used to treat humans infected with one or more than one strain of a human immunode ciency virus.
FOR THE PURPOSES OFINFORMAπON ONLY
Codes used to identify States party to the PCT on the front ages of pamphlets publishing international applications under the PCT.
AT Austria FR France ML Mali
AU Australia GA Gabon MR Mauritania
BB Barbados GB United Kingdom MW Malawi
BE Belgium HU Hungary NL Netherlands
BG Bulgaria IT Italy NO Norway
BJ Benin JP Japan RO Romania
BR Brazil KP Democratic People's Republic SD Sudan
CF Central African Republic of Korea SE Sweden
CG Congo KR Republic of Korea SN Senegal
CH Switzerland LI Liechtenstein su Soviet Union
CM Cameroon LK Sri Lanka TD Chad
DE Germany, Federal Republic of LU Luxembourg TG Togo
DK Denmark MC Monaco US United States of America
Claims (10)
1. Use of a compound selected from the group consisting of 6-bromo-3-[(m-chlorophenyl)carbamoyl]-coumarin, 6-bromo-3-[(α,α,α-trifluoro-m-toluyl)carbamoyl]-coumarin, 6-bromo-3-[(2,5-dichlorophenyl)carbamoyl]-coumarin, [[bis(4-hydroxy-2-oxo-2H-1-benzopyran-3-yl)-methyl]-cyclopentadienyl]cyclopentadienyl-iron, 3-cinnamoyl-4-hydroxy-coumarin, hexachlorocoumarin, 7-acetoxycoumarin or [1-(2-oxo-2H-1-benzopyran-3-yl)ethylidene]-hydrazinecarboxylic acid phenylmethyl ester or a pharmaceutically acceptable salt thereof, to prepare a medicament to treat a human infected with one or more strains of a human immunodeficiency virus.
2. A method according to claim 1 where the effective amount of the compound is from about 1 to 100 mg per kg per day.
3. A method according to claim 1 where the compound is 6-bromo-3-[(m-chlorophenyl)carbamoyl]-coumarin.
4. A method according to claim 1 where the compound is 6 -bromo-3-[(α,α,α-trifluoro-m-toluyl)carbamoyl]-coumarin.
5. A method according to claim 1 where the compound is 6-bromo-3-[(2,5-dichlorophenyl)carbamoyl]-coumarin.
6. A method according to claim 1 where the compound is [[bis(4-hydroxy-2-oxo-2H-1-benzopyran-3-yl)-methyl]cyclopentadienyl]cyclopentadienyl-iron.
7. A method according to claim 1 where the compound is 3-cinnamoyl-4-hydroxy-coumarin.
8. A method according to claim 1 where the compound is hexachlorocoumarin.
9. A method according to claim 1 where the compound is 7-acetoxycoumarin.
10. A method according to claim 1 where the compound is [1-(2-oxo- 2H-1-benzopyran-3-yl)ethylidene]-hydrazinecarboxylic acid phenylmethyl ester.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16255388A | 1988-03-01 | 1988-03-01 | |
| US19003888A | 1988-05-04 | 1988-05-04 | |
| US162553 | 1998-09-29 | ||
| US190038 | 1998-11-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU4074789A true AU4074789A (en) | 1989-09-22 |
Family
ID=26858857
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU40747/89A Abandoned AU4074789A (en) | 1988-03-01 | 1989-02-08 | Coumarins to inhibit reverse transcriptase in humans |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0403535A1 (en) |
| JP (1) | JPH03503635A (en) |
| AU (1) | AU4074789A (en) |
| DK (1) | DK195690D0 (en) |
| WO (1) | WO1989007939A2 (en) |
Families Citing this family (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991004663A1 (en) * | 1989-09-26 | 1991-04-18 | The Regents Of The University Of California | 6-amino-1,2-benzopyrones useful for treatment of viral diseases |
| IL99731A0 (en) * | 1990-10-18 | 1992-08-18 | Merck & Co Inc | Hydroxylated pyridine derivatives,their preparation and pharmaceutical compositions containing them |
| US5484951A (en) * | 1990-10-19 | 1996-01-16 | Octamer, Incorporated | 5-iodo-6-amino-6-nitroso-1,2-benzopyrones useful as cytostatic and antiviral agents |
| WO1992018123A2 (en) * | 1991-04-10 | 1992-10-29 | Octamer, Inc. | A method for inhibition of retroviral replication |
| US5482975A (en) * | 1991-10-22 | 1996-01-09 | Octamer, Inc. | Adenosine diphosphoribose polymerase binding nitroso aromatic compounds useful as retroviral inactivating agents, anti-retroviral agents and anti-tumor agents |
| US5652260A (en) * | 1991-10-22 | 1997-07-29 | Octamer, Inc. | Adenosine diphosphoribose polymerase binding nitroso aromatic compound useful as retroviral inactivating agents, anti-retroviral agents and anti-tumor agents |
| US5516941A (en) * | 1991-10-22 | 1996-05-14 | Octamer, Inc. | Specific inactivators of "retroviral" (asymmetric) zinc fingers |
| US5877185A (en) * | 1991-10-22 | 1999-03-02 | Octamer, Inc. | Synergistic compositions useful as anti-tumor agents |
| DE4136900C1 (en) * | 1991-11-09 | 1993-07-29 | Schaper & Bruemmer Gmbh & Co Kg, 3320 Salzgitter, De | |
| US5262564A (en) * | 1992-10-30 | 1993-11-16 | Octamer, Inc. | Sulfinic acid adducts of organo nitroso compounds useful as retroviral inactivating agents anti-retroviral agents and anti-tumor agents |
| ZA938019B (en) * | 1992-11-13 | 1995-04-28 | Upjohn Co | Pyran-2-ones and 5,6-dihydropyran-2-ones useful for treating HIV and other retroviruses |
| IL108459A0 (en) * | 1993-02-05 | 1994-04-12 | Opjohn Company | 4-Hydroxy-benzopyran-2-ones and 4-hydroxy-cycloalkyl [B] pyran-2-ones useful for treating infections due to hiv and other retroviruses |
| US5783599A (en) * | 1993-02-24 | 1998-07-21 | Octamer Inc | Methods of treating cancer and viral infections with 5-iodo-6-amino-and 5-iodo-6-nitroso-1 2-benzopyrones |
| US5637589A (en) * | 1993-10-29 | 1997-06-10 | University Of North Carolina At Chapel Hill | Suksdorfin, analogs, compositions thereof, and methods for making and using thereof |
| US5808062A (en) * | 1993-11-19 | 1998-09-15 | Warner-Lambert Company | Pyrone derivatives as protease inhibitors and antiviral agents |
| CZ291856B6 (en) * | 1993-11-19 | 2003-06-18 | Parke, Davis & Company | 5,6-Dihydropyrone derivatives functioning as protease inhibitors, antiviral agents, and pharmaceutical compositions in which these derivatives are comprised |
| US5510375A (en) * | 1993-11-19 | 1996-04-23 | Warner-Lambert Company | Coumarin derivatives as protease inhibitors and antiviral agents |
| US5504104A (en) * | 1993-11-19 | 1996-04-02 | Warner-Lambert Company | Tricyclic pyrone derivatives as protease inhibitors and antiviral agents |
| US5789440A (en) * | 1993-11-19 | 1998-08-04 | Warner-Lambert Company | 5,6-dihydropyrone derivatives as protease inhibitors and antiviral agents |
| US6319929B1 (en) | 1994-04-29 | 2001-11-20 | The University Of North Carolina At Chapel Hill | Suksdorfin analogs, compositions thereof, and methods for making and using thereof |
| IL129871A (en) * | 1994-05-06 | 2003-11-23 | Pharmacia & Upjohn Inc | Process for preparing 4-phenyl-substituted octanoyl-oxazolidin-2-one intermediates that are useful for preparing pyran-2-ones useful for treating retroviral infections |
| US5455110A (en) * | 1994-06-29 | 1995-10-03 | Kimberly-Clark Corporation | Nonwoven laminated fabrics |
| EP0841063A1 (en) * | 1996-03-27 | 1998-05-13 | Toray Industries, Inc. | Ketone derivatives and medicinal use thereof |
| CN1506359A (en) * | 2002-12-05 | 2004-06-23 | �й�ҽѧ��ѧԺҩ���о��� | Coumarin amide derivative and its prepn, medicinal composition and use |
| US8524729B2 (en) | 2003-09-17 | 2013-09-03 | Sumitomo Chemical Company, Limited | Cinnamoyl derivatives and use thereof |
| WO2006037468A1 (en) * | 2004-09-30 | 2006-04-13 | Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa | Hiv reverse transcriptase inhibitors |
| WO2007124617A1 (en) * | 2006-04-28 | 2007-11-08 | Institute Of Mataria Medica, Chinese Academy Of Medical Sciences | Coumarin derivatives, their preparation methods and their pharmaceutic compositions and uses |
| ES2381234T3 (en) | 2007-11-15 | 2012-05-24 | Gilead Sciences, Inc. | Human immunodeficiency virus replication inhibitors |
| EA019259B1 (en) | 2007-11-16 | 2014-02-28 | Джилид Сайенсиз, Инк. | Inhibitors of human immunodeficiency virus replication |
| CN113402491A (en) * | 2021-06-15 | 2021-09-17 | 山东大学苏州研究院 | Coumarin amide compound and preparation method and application thereof |
-
1989
- 1989-02-08 AU AU40747/89A patent/AU4074789A/en not_active Abandoned
- 1989-02-08 WO PCT/US1989/000450 patent/WO1989007939A2/en not_active Application Discontinuation
- 1989-02-08 EP EP89903438A patent/EP0403535A1/en not_active Withdrawn
- 1989-02-08 JP JP1503059A patent/JPH03503635A/en active Pending
-
1990
- 1990-08-16 DK DK195690A patent/DK195690D0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1989007939A2 (en) | 1989-09-08 |
| WO1989007939A3 (en) | 1989-10-19 |
| DK195690A (en) | 1990-08-16 |
| DK195690D0 (en) | 1990-08-16 |
| EP0403535A1 (en) | 1990-12-27 |
| JPH03503635A (en) | 1991-08-15 |
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