WO2002094796A2 - Derives de la benzo[g]quinoxaline composes efficaces contre les maladies infectieuses - Google Patents

Derives de la benzo[g]quinoxaline composes efficaces contre les maladies infectieuses Download PDF

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WO2002094796A2
WO2002094796A2 PCT/EP2002/005573 EP0205573W WO02094796A2 WO 2002094796 A2 WO2002094796 A2 WO 2002094796A2 EP 0205573 W EP0205573 W EP 0205573W WO 02094796 A2 WO02094796 A2 WO 02094796A2
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benzo
quinoxaline
quinoxalin
amine
phenyl
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PCT/EP2002/005573
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WO2002094796A3 (fr
Inventor
János PATÓ
György Kéri
László ÖRFI
Frigyes Wáczek
Zoltán Horváth
Péter BÁNHEGYI
István Szabadkai
Jenö MAROSFALVI
Bálint HEGYMEGI-BARAKONYI
Zsolt SZÉKELYHIDI
Zoltán Greff
Axel Choidas
Gerald Bacher
Henrik Daub
Sabine Obert
Alexander Kurtenbach
Peter Habenberger
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Axxima Pharmaceuticals Ag
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Priority to AU2002312927A priority Critical patent/AU2002312927A1/en
Publication of WO2002094796A2 publication Critical patent/WO2002094796A2/fr
Priority to US10/715,591 priority patent/US20040171603A1/en
Publication of WO2002094796A3 publication Critical patent/WO2002094796A3/fr
Priority to US12/462,236 priority patent/US20090298842A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • 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
    • C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/50—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to ring nitrogen atoms
    • C07D241/52—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems

Definitions

  • the present invention relates to benzo[g]quinoxaline derivatives, processes for manufacturing said benzo[g]quinoxaline derivatives, the use of the benzo[g]quinoxaline derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of infectious diseases and opportunistic infections, diabetes, cancer, inflammation, as well as compositions containing at least one benzo[g]quinoxaline derivative and/or pharmaceutically acceptable salt thereof. Furthermore, the present invention is directed to methods for preventing and/or treating of infectious diseases, diabetes, cancer, and inflammation as well as other TNF ⁇ mediated diseases using the inventive benzo[g]quinoxaline derivatives.
  • Mycobacteria are the causative agents of tuberculosis, leprosy and mycobacteria-induced meningitis. They are divided in different groups by their ability to generate symptomatic diseases. For example members of the 'Avium'- complex of mycobacteria (i.e. M. tuberculosis, M. avium, M. bovis, M. af canum and M. microti) induce the severe and in many cases fatal disease tuberculosis. Tuberculosis usually affects the lungs, although in up to one-third of cases other organs are involved. If untreated, the disease may be fatal within five years in more than half of the cases.
  • Leprosy Haansen's disease
  • M. leprae M. leprae
  • Therapy for leprosy still remains difficult, especially in developing countries, because of the long duration and high cost of therapy required, the frequency of adverse reactions to drugs, the acquisition of drug resistance, the difficulty of determining a disease end point or cure, and given that M. leprae still cannot be grown in vitro, the difficulty of conducting susceptible testing. Although less pathogenic than M.
  • tuberculosis the nontuberculous mycobacteria can cause pulmonary, skin, bone and joint, lymph node and soft tissue infections as well as disseminated disease in immunocompromised hosts, including patients with AIDS and other immunodeficiencies.
  • AIDS patients develop disseminated disease with Mycobacterium avium-intracellulare (MAI). Infections due to M. haemophilum occur most commonly as disseminated disease in immunocompromised patients with and without AIDS.
  • tuberculosis is an important opportunistic disease among HIV-infected persons worldwide. In some developing countries of Africa, Southeast Asia and Latin America, an estimated amount of 8.5 million persons were coinfected as of the middle of 1996.
  • HIV of AIDS patients directly attacks the critical immune mechanisms involved in protection against tuberculosis so that tuberculosis can appear at any stage of HIV infection.
  • Mycobacteremia and meningitis also occur particularly during advanced HIV diseases.
  • M. xenopi most often causes nosocomial infections. These infections most commonly occur in the environment of the hospital's hot-water systems.
  • M. genavense is a newly recognized organism that grows only in liquid media. This organism almost exclusively infects AIDS patients, causing disseminated disease.
  • HBV Hepatitis B Virus
  • Hepatitis is an inflammation of the liver that is most often caused by infection with one of five viruses, hepatitis A, B, C, D or E. In cases, particularly in those related to hepatitis B and C, "chronic hepatitis" may result. Chronic hepatitis occurs when the body is unable to completely clear the virus even though the symptoms may not persist. Continued presence of the virus over a number of years can lead to cirrhosis (scarring of the liver) or hepatocellular carcinoma (liver cancer). HBV is transmitted through sexual contact, vertical transmission (mother to child at birth) or by coming into contact with contaminated blood. It is estimated that over 2 billion people worldwide have been infected with hepatitis B virus.
  • Chronic carriers of HBV have been defined as those who are HBV surface antigen positive for more than 6 months. Approximately 5-10% of those adults who are infected with the virus will become carriers, an estimated 5-10% of those people infected each year will progress to chronic liver disease, cirrhosis and possibly liver cancer. About 5,000 people die in the United States each year related to Hepatitis B, 1 ,000 die of HBV-related liver cancer.
  • the incubation period of HBV usually lasts from 2 to 4 months, although it may be very short (10 days) or extremely long (9 months).
  • HBs- and HBe-antigen are detectable in the patient's serum.
  • the onset of acute hepatitis is characterized by the occurrence of anti-HBc antibodies which at first exclusively belong to the IgM class. From this time on anti-HBc antibodies will be detectable in the patient's serum for the rest of his life, no matter whether there is an acute hepatitis B, a form of persisting virus infection or some naturally acquired immunity to HBV.
  • the most significant event indicating a chronic course of hepatitis B is the absence of the HBsAg/anti-HBs serocon version. If this phenomenon has not occurred within 6 months after the onset of the disease, persistence of the HBV infection and the related clinical pictures (asymptomatic HBsAg carrier, chronic liver disease, cirrhosis, or hepatoma) have to be reckoned with.
  • One aspect of the present invention is related to compounds of the general formula (I):
  • R 1 and R 2 are independently of each other — ⁇ CH 2 )p— NH— (CH 2 )r,— 9 , — (CH 2 )s — S — (CH 2 ) m — R , — (CH 2 ) m — O — (CH 2 ) P — R , — (CH 2 )r — R ,
  • R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently of each other — H, — F, — Cl
  • R 9 , R 10 , and R 11 are independently of each other — CN, — NR 16 R 17 ,
  • R 12 , R 13 , R 14 , and R 15 are independently of each other — R 3 , — R 4 , — R 5 ,
  • R 16 and R 17 are independently of each other — H, — CH 3l — C 2 H 5 , — CsH 7 , — CH(CH 3 ) 2 , — C4H9, — C5H11, — C 6 Hi 3 , — cyclo-C 6 Hn, — cyclo-C 5 H 9 , — cyclo-C 4 H 7 , — cyclo-C 3 H 5 , — (CH 2 )r-CH(CH 3 )2, — CH(CH 3 )C 2 H 5 ,
  • n, p, q, s are independently of each other integer from 0 - 6, r is an integer from 1 - 6, and the corresponding N-oxides in position 1 and/or 4 of these compounds; and the corresponding reduced forms of these compounds wherein the double bond in position 1 and/or 3 is hydrogenated; and pharmaceutically acceptable salts of these compounds.
  • kits for treating mycobacteria-induced infections or diseases and mycobacteria-induced opportunistic infections relate to benzo[g]quinoxaline derivatives of the general formula (I) as new pharmaceutically active agents, especially for the prophylaxis and/or treatment of mycobacteria-induced infections or diseases and mycobacteria-induced opportunistic infections, and methods for treating mycobacteria-induced infections or diseases in mammals, including humans.
  • mycobacterial-induced infections or diseases comprise tuberculosis, leprosy and mycobacteria-induced meningitis.
  • inventive benzo[g]quinoxaline compounds of the general formula (I) and/or pharmaceutically acceptable salts thereof are administered in a dosage corresponding to an effective concentration in the range of 0.01 - 50 ⁇ M, preferably in the range of 0.01 - 10 ⁇ M, more preferably in the range of 0.01 - 1 ⁇ M, and most preferably in the range of 0.01 - 0.1 ⁇ M.
  • a further aspect of the present invention relates to the use of the benzo[g]quinoxaline compounds of the general formula (I) and/or pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical formulation for prophylaxis and/or treatment of mycobacteria-induced infections, including mycobacteria-induced opportunistic infections.
  • R 1 and R 2 are independently of each other — (CH 2 )p— NH— (CH 2 )n— R 9 ,
  • R ⁇ , R", R°, R D , R', and R 8 are independently of each other — H, — F, — Cl, — Br, —I, — SO3H, — S0 3 NH 2 ;
  • R , R ⁇ io , and R ,11 are independently of each other )N, — R 16 R 17 ,
  • R 12 , R 13 , R 14 , and R'° are independently of each other — R ⁇ , —FC, — R°, — R 6 , — R 16 , — R 17 , — (CH 2 ) s -C00R 16 , —OR 16 , - ⁇ SR 16 , — NR 16 R 17 , — OOCR 16 , —NH-CO-R 16 , —CO-NH-R 16 , —CO-R 17 ;
  • R 16 and R 17 are independently of each other — H, — CH 3 , — C 2 H 5 , — C 3 H 7 , — CH(CH 3 ) 2 , — C4H9, — C 5 Hn, — C 6 H 13 , —cyclo-C ⁇ Hn, — cyclo-C 5 H 9 , — cyclo-C 4 H 7 , — CVCI0-C3H5, — (CH2)r-CH(CH 3 )2, — CH(CH 3 )C 2 H 5 ,
  • m is an integer from 0 - 6
  • n is an integer from 0 - 6
  • p is an integer from 0 - 6
  • q is an integer from 0 - 6
  • r is an integer from 1 - 6
  • s is an integer from 0 - 6, and their corresponding N-oxides in position 1 and/or 4; and the corresponding reduced forms of these compounds wherein the double bond in position 1 and/or 3 is hydrogenated; and pharmaceutically acceptable salts thereof.
  • R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently of each other — H, — F, — Cl, — Br, — I, — SO 3 H;
  • R 9 , R 10 , and R 11 are independently of each other — CN, — NR 6 6 0 R1
  • R" R'°, R and R 15 are independently of each other — R 3 , — R 4 , — R 5 ,
  • m is an integer from 0 - 6
  • n is an integer from 0 - 6
  • p is an integer from 0 - 6
  • q is an integer from 0 - 6
  • r is an integer from 1 - 6
  • s is an integer from 0 - 6, and their corresponding N-oxides in position 1 and/or 4; and the corresponding reduced forms of these compounds wherein the double bond in position 1 and/or 3 is hydrogenated; and pharmaceutically acceptable salts thereof.
  • Another group of inventive compounds comprises the following residues wherein R 1 and R are independently of each other — NH— (CH 2 ) ⁇ — R >
  • R 3 , R 9 , R 10 , R 11 , R 16 , R 17 have the meaning as defined above, m is an integer from 0 - 4, n is an integer from 0 - 4, p is an integer from 0 - 4, s is an integer from 0 - 4.
  • R 9 , R 10 , and R 11 are independently of each other — CN, — NR 16 R 17 ,
  • R 3 , R 4 , R 12 , R 13 , R ,14 , R ,15 , R ,16 , R ⁇ 17 have the meaning as defined above.
  • R ,12 R >13 , R ,14 , and R ,1'5° are independently of each other — R°, — T, — R°
  • R , R 4 , R 5 , R°, R , R 1 ' have the meaning as defined above.
  • a polar solvent preferably DMF, N,N-dimethylacetamide, acetic acid, methanol, ethanol, propanol, isopropanol, THF, dioxane, acetone or mixtures of these solvents and is treated with a 1 ,2-diketone of the general formula (III)
  • reaction is carried out at elevated reaction temperatures, preferably at the boiling point of the solvent or solvent mixture for a time period ranging from 30 minutes to 24h, depending on the reactants, solvents, and reaction temperature.
  • reaction temperatures preferably at the boiling point of the solvent or solvent mixture for a time period ranging from 30 minutes to 24h, depending on the reactants, solvents, and reaction temperature.
  • reaction temperatures preferably 50 - 160°C, more preferably 60 - 120°C, still more preferably 70 - 100°C, and most preferably 75 - 85°C.
  • Reaction times are preferably between 0.5 - 10h, more preferably between 1 - 5h, and most preferably between 2 and 4 hours.
  • the product precipitates during the reaction and can be isolated by filtration.
  • the product is washed with ether and dried in vacuum. Further purification can be obtained by recrystallization or column chromatography or any other method known to a person skilled in the art.
  • R 2 - R 8 have the meanings as defined above and wherein Hal represents a halogen selected from — F, — Cl, — Br, — I, preferably — Cl or — Br.
  • the integer u can be selected from 0 - 6, preferably 0 or 1.
  • This compound is dissolved in a preferably anhydrous aprotic medium such as dioxane or THF when an activated methylene compound is used as nucleophile or in a polar protic or aprotic solvent such as DMF, N,N-dimethylacetamide, methanol, ethanol, propanol, THF, dioxane, acetone or mixtures thereof in the case a amine, thiol, or alcohol is used as nucleophile.
  • a preferably anhydrous aprotic medium such as dioxane or THF when an activated methylene compound is used as nucleophile or in a polar protic or aprotic solvent such as DMF, N,N-dimethylacetamide, methanol, ethanol, propanol, THF, dioxane, acetone or mixtures thereof in the case a amine, thiol, or alcohol is used as nucleophile.
  • the nucleophile has the general formula (V)
  • the reactant (V) may optionally be dissolved in a suitable polar solvent.
  • a suitable polar solvent such as NaH, BuLi, MeLi, tert.-BuLi, K-t-BuO, K2CO3, triethylamine, pyridine, sodium acetate, sodium benzoate and preferably NaH is necessary.
  • Said nucleophiles which require the addition of a base are activated methylene compounds, alcohols, and thiols.
  • a tertiary amine such as triethylamine or pyridine may optionally added to the reaction mixture before the addition of the nucleophile.
  • Thiols as nucleophile require only weak bases such as acetates or benzoates, while alcohols are preferably reacted with the compound of general formula (IV) by means of carbonates or alkoxides. Strong bases such as NaH, BuLi, MeLi, or tert.-BuLi are used for methylene compounds.
  • reaction is carried out preferably under elevated temperatures and more preferably at the boiling point of the solvent or solvent mixture refluxing the reaction mixture for a time period ranging from 30 minutes to 24h depending on the reactants, solvents and reaction temperature.
  • reaction temperatures 20 - 100°C, more preferably 25 - 70°C, and most preferably 30 -
  • reaction times are preferably between 0.5 - 24h, more preferably between 1 - 10h, and most preferably between 2 and 4 hours. An increase of the reaction temperature will decrease the reaction time. Thus, reactions carried out at about
  • the product precipitates during the reaction and can be isolated by filtration.
  • the product is washed with ether and dried in vacuum. Further purification can be obtained by recrystallization or column chromatography or any other method known to a person skilled in the art.
  • a third alternative process for manufacturing the inventive benzo[g]-quinoxaline compounds uses the following dihalo compound of the general formula (VI)
  • Hal represents a halogen selected from — F, — Cl, — Br, — I, and u and v are independently of each other an integer from 0 - 6. Said dihalo compound is reacted either with at least two mol equivalents of a nucleophile of the general formula
  • thiols react faster than thiols and these reactions can be carried out at room temperature or slightly elevated temperatures up to 60°C while thiols normally need to be refluxed, preferably at temperatures between 70 and 100°C.
  • the present invention relates to a method for down-regulating or inhibiting growth and/or inducing death of Mycobacterium tuberculosis in an individual comprising the step of administering a pharmaceutically effective amount of an inventive benzo[g]quinoxaline compound.
  • a further aspect is directed to a method for preventing and/or treating Mycobacterium tuberculosis induced infections and diseases, including Mycobacterium tuberculosis induced opportunistic infections in an individual or in cells comprising the step of administering a pharmaceutically effective amount of a benzo[g]quinoxaline derivative.
  • mycobacterial protein kinases are possible targets for the pharmaceutically active benzo[g]quinoxaline derivatives of the present invention.
  • the present invention provides benzo[g]quinoxaline derivatives as effective compounds against mycobacterial infections and diseases, including mycobacterial-induced opportunistic infections, and a method for prophylaxis and/or treatment of infectious diseases caused by mycobacteria.
  • inventive compounds are able to at least partially inhibit serine-threonine protein kinases of Mycobacterium tuberculosis, for instance Pkn A, Pkn B, Pkn D, Pkn E, Pkn F, Pkn G, Pkn H, Pkn I, Pkn J, Pkn K and Pkn L.
  • the benzo[g]quinoxaline derivatives of the general formula (I) are effective compounds for prophylaxis and/or treatment of mycobacteria-induced infections and diseases, including mycobacteria-induced opportunistic infections.
  • mycobacteria-induced infections and diseases are tuberculosis, leprosy or mycobacteria-induced meningitis.
  • Mycobacteria which induce or cause these infections and diseases, including opportunistic infections are members of the group comprising the tuberculous mycobacteria M. tuberculosis, M. bovis, and M. africanum, the mycobacterium M. leprae and the nontuberculous mycobacteria M.
  • mycobacteriologists have distinguished the Mycobacterium tuberculosis complex, consisting of M. tuberculosis, M. bovis, and M. africanum, from all other mycobacteria. Except for Mycobacteria leprae, the other mycobacteria are referred to as atypical mycobacteria or nontuberculous mycobacteria (NTM).
  • inventive benzo[g]quinoxaline compounds of the present invention are effective agents for the prophylaxis and/or treatment of mycobacteria-induced infections.
  • the following table illustrates the activity of selected benzo[g]quinoxaline derivatives against mycobacteria.
  • Table 1 Growth inhibition of M. bovis BCG, E. coli XI-1 blue and M. tuberculosis Erdmann by benzo[g]quinoxaline derivatives.
  • the present invention provides also a method for preventing and/or treating mycobacteria-induced infections and diseases, including opportunistic infections, in a mammal, including a human, which comprises administering to the mammal an amount of at least one benzo[g]quinoxaline compound of the general formula (I) and/or a pharmaceutically acceptable salt thereof effective to prevent and/or treat mycobacteria-induced infections.
  • these methods are used for the treatment of mycobacteria-induced infections like tuberculosis, leprosy or mycobacteria-induced meningitis.
  • the compound of the general formula (I) and/or pharmaceutically acceptable salts thereof can also be used for the prophylaxis and/or treatment of diabetes mellitus Type I and Type II, cancer, cancer cachexia, necrosis, gastric ulcers, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), influenza, multiple sclerosis, neuropathic diseases, neuropathic pain and polyneuropathy, neurological disorders, multiple sclerosis, Huntington's chorea, gastrointestinal ulcerative, inflammatory diseases and inflammations, peripheral and/or central nerve diseases, degradation of the peripheral and/or central nerve system, skin diseases, atopic eczema, psoriasis, urticaria and allergic reactions, rheumatoid arthritis, osteoarthritis, ulcerative colitis, Crohn's disease, ishemic diseases and ishemic heart disease, liver diseases and dysfunction of
  • the present invention discloses the use of the benzo[g]quinoxaline derivatives as well as their application in various methods for preventing and/or treating infectious diseases, including opportunistic infections in a mammal, including a human.
  • Said methods comprise the administration of at least one benzo[g]quinoxaline derivative or a salt thereof in an amount, effective to prevent and/or treat said infectious disease.
  • said benzo[g]quinoxalines or salts thereof can be used for the manufacture of a pharmaceutical formulation for prophylaxis and/or treatment of the above mentioned diseases, especially infectious diseases and opportunistic diseases caused by viruses.
  • viruses are retroviruses (lentiviruses and oncoretroviruses), adenoviruses, hepadnaviruses, herpesviruses, influenza viruses and paramyxoviruses.
  • Viruses which integrate in the genome of a cell are retroviruses, adenoviruses, herpesviruses and influenza viruses and sometimes hepadnaviruses while paramyxoviruses do not integrate in the genome of a cell are.
  • inventive benzo[g]quinoxaline compounds for the treatment of drug resistant virus strain.
  • the retroviruses may be selected from the group comprising lentiviruses and oncoretroviruses.
  • lentiviruses are FIV, SIV, BIV, HIV-1 , HIV-2, visna virus, caprine arthritis-encephalitis virus (CAEV), and equine infectious anemia virus (EIAV) as summarized in Table 2.
  • the retrovirus represents the lentivirus HIV-1 or HIV-2.
  • HTLV-I, HTLV-II and BLV belong to the oncoretroviruses.
  • the excellent antiviral activity of the inventive benzo[g]quinoxaline compounds can preferably be used to treat retroviruses wherein the retrovirus is a T-cell tropic HIV strain or wherein the retrovirus is a macrophage-tropic HIV strain.
  • the benzo[g]quinoxaline derivatives had successfully applied against a HIV-1 or HIV-2 strain which is resistant against protease inhibitors and/or reverse transcriptase inhibitors. Table 2: Lentiviruses
  • the present invention discloses a method for preventing and/or treating infections of retroviruses, especially HIV, in a mammal, including a human, which comprises administering to the mammal an amount of at least one benzo[g]quinoxaline compound and/or pharmaceutically acceptable salts thereof, effective to prevent and/or treat said retroviral infection, especially HIV.
  • Table 3 shows selected benzo[g]quinoxaline derivatives which have been tested as HIV inhibitors and their inhibition value.
  • the inventive benzo[g]quinoxaline compounds are potent HIV inhibitors.
  • the benzo[g]quinoxaline compounds are able to inhibit HI virus replication up to a value of 63% after 6 days at a concentration of 1 ⁇ M.
  • Table 3 Inhibitory effect of benzo[g]quinoxaline compounds on HIV replication.
  • Table 3 proves that the inventive benzo[g]quinoxaline compounds are higly potent HIV replication inhibitors and, therefore, can be used as pharmaceutically active agents in order to prevent and/or treat HIV infection.
  • Paramyxoviruses comprise respiratory syncytial virus, parainfluenza viruses, mumps virus, and measles virus. More preferably, the paramyxovirus is respiratory syncytial virus.
  • the herpesvirus family comprises the human herpesviruses 1 to 8 and different herpes viruses for various animal species as shown below in Table 4:
  • herpes simplex virus 2 virus 1 virus 1
  • herpes B virus varicella virus human herpesvirus 3 pseudorabiesvirus (Varicella Zoster virus) bovine herpesvirus 1 equine-abortion virus ⁇ -herpesvirus cytomegalovirus human herpesvirus 5 (HCMV) muromegalovirus murine herpesvirus 1 roseolovirus human herpesvirus 6, aotine herpesvirus 1 , 3 human herpesvirus 7 ⁇ -herpesvirus lymphocrytovirus human herpesvirus 4 cercopithecine herpes ⁇
  • Epstein-Barr virus virus 2 pongine herpesvirus 1 rhadinovirus human herpesvirus 8 ateline herpesvirus 2 saimirine herpesvirus 1
  • the herpesvirus is selected from Herpes simplex virus I, Herpes simplex virus II, Varicella Zoster virus, Epstein-Barr virus, HCMV, or HHV8.
  • the hepadnavirus are selected from HBV, Ground-Squirrel-Hepatitis virus (GSHV), or Woodchuck hepatitis virus (WHV).
  • GSHV Ground-Squirrel-Hepatitis virus
  • WV Woodchuck hepatitis virus
  • Table 5 shows a selected benzo[g]quinoxaline compound that is able to decrease the activity of the herpes viral target UL-97 for 75%.
  • UL-97 is a validated target for herpes viral infections and it is known that a inhibition of UL-97 leads to an inhibition of the proliferation of human cytomegalo virus.
  • the compounds of the present invention are useful as inhibitors for the herpes viral protein kinase UL- 97.
  • a method for preventing and/or treating CMV in a mammal comprising administering to the mammal an amount of at least one benzo[g]quinoxaline derivative and/or a pharmaceutically acceptable salt thereof which is effective to inhibit the herpes viral kinase UL-97.
  • Table 6 shows the inhibitory effect of selected benzo[g]quinoxaline derivatives on the HCMV target RICK.
  • Another aspect of the present invention is directed to the use of the benzo[g]quinoxaline compounds for prophylaxis and/or treatment of influenza and to a method for preventing and/or treating influenza.
  • various benzo[g]quinoxaline derivatives are capable of inhibiting almost completely the replication of influenza viruses.
  • the inventive compounds are also potent inhibitors for the human protein kinases SRPK1 and SRPK2. Said kinases play an important role in HBV infection.
  • a method for preventing and/or treating HBV in a mammal, including a human comprises administering to the mammal an amount of at least one benzo[g]quinoxaline derivative and/or a pharmaceutically acceptable salt thereof, which is effective to inhibit the human protein kinase SRPK1 and/or SRPK2. From the results observed with compounds 13, 5, 369, 43 and 44, the class of benzo[g]quinoxalines is indicated to provide potent inhibitors of hepatitis B viral replication (cf. Table 8).
  • inventive benzo[g]quinoxaline compounds and their salts are potent inhibitors for a variety of kinases and phosphatases, especially of protein kinases and phosphatases and most preferably of human protein kinases and phosphatases.
  • Table 8 Inhibition of HBV replication by selected benzo[g]quinoxaline derivatives:
  • a further aspect of the present invention relates to the use of a benzo[g]quinoxaline compound and/or a salt thereof for prophylaxis and/or treatment of TNF- ⁇ mediated diseases.
  • a method for prophylaxis and/or treatment of TNF- ⁇ mediated diseases is disclosed. Said method comprises the administration of at least one benzo[g]quinoxaline derivative to a mammal, including a human, in need thereof, effective to treat and/or prevent said TNF- ⁇ mediated diseases.
  • TNF- ⁇ mediated diseases are summarized in WO 99/32110.
  • Clinical studies have linked TNF- ⁇ production and/or signaling to a wide number of diseases including, for instance, rheumatoid arthritis, inflammatory and immunomodulatory diseases, such as acute rheumatic fever, bone resorption, postmenopausal osteoporosis, sepsis, gram negative sepsis, septic shock, endotoxic shock, toxic shock syndrome, systemic inflammatory response syndrome, inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, Jarisch-Herxheimer reactions, asthma, adult respiratory distress syndrome, acute pulmonary fobrotic diseases, pulmonary sarcoidosis, allergic respiratory diseases, silicosis, coal woke ⁇ s pneumoconiosis, alveolar injury, hepatic failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria, non-insulin-depending diabetes mellitus, congestive heart failure, damage following heart disease, at
  • a method had been established for regulating and/or inhibiting of nuclear export of TNF- ⁇ mRNA in TNF- ⁇ mediated diseases comprising administering a subject in need thereof a pharmaceutically effective amount of at least one benzo[g]quinoxaline compound and/or a pharmaceutically active salt thereof, effective to treat and/or regulate said nuclear export of TNF- ⁇ mRNA in TNF- ⁇ mediated diseases.
  • Results are shown in Table 9.
  • the selected benzo[g]quinoxaline compounds are highly potent inhibitors for TNF- ⁇ signaling and TNF- ⁇ mediated diseases.
  • the benzo[g]quinoxaline derivatives exhibit pharmaceutical activity for prophylaxis and/or treatment of a malignant diseases.
  • Said malignant diseases comprise cancer, epithelial cell-derived tumor, a monocytosis, a basal and squamous cell carcinoma, a hyperproliferating skin disease and psoriasis.
  • the cancer is preferably selected from the group comprising bladder, breast, central nervous system, colon, gastric, lung, melanoma, head and neck, ovarian, cervix, glioblastoma, prostate, testis, leucemia, liver, and renal cancer.
  • Targets for cancer treatment are, for instance, the protein kinases InsR, Abl, Akt, Adk1 , PDGFR, and/or Src.
  • inventive benzo[g]quinoxaline derivatives can be used as inhibitors for the human protein kinases InsR, Abl, Akt, Adk1 , PDGFR, and/or Src and a method for preventing and/or treating cancer in a mammal, including a human, is disclosed wherein said method comprises administering to the mammal an amount of at least one benzo[g]quinoxaline compound and/or pharmaceutically acceptable salts thereof effective to inhibit at least partially one of the human protein kinases Abl (2.7.1.112), Akt (2.7.1.-), Adk1 , PDGFR (2.7.1.112), and/or Src (2.7.1.112).
  • Table 10 reveals that the inventive benzo[g]quinoxaline compounds are potent inhibitors for the prophylaxis and/or treatment of cancer.
  • the cancer targets Akt, Abl, PDGFR and Src are inhibited with IC 5 o values between 0,3 and 16 ⁇ M.
  • Another aspect is directed to a method for preventing and/or treating malignant diseases in a mammal, including a human, which comprises administering to the mammal an amount of at least one compound of general formula (I) and/or pharmaceutically acceptable salts thereof effective to prevent and/or treat said malignant disease.
  • the malignant disease is selected from the group of diseases mentioned above.
  • Table 11 proves that the benzo[g]quinoxaline compounds are potent pharmaceutical agents for preventing and/or treating cancer.
  • Table 11 Cytotoxicity of selected benzo[g]quinoxaline derivatives measured in A549 and Jurkat cells.
  • the compounds of the present invention are also useful for the inhibition of cellular proliferation of cancer cells.
  • a method for inhibiting cellular hyperproliferation of cancer cells was established. Said method comprises the administration of a pharmaceutically effective amount of at least one compound of the general formula (I) and/or pharmaceutically active salts thereof to a subject in need, effective to inhibit said cellular hyperproliferation of cancer cells.
  • Biological test reveal that the benzo[g]quinoxaline derivatives are also good pharmaceutically active agents for preventing and/or treating diabetes mellitus type I and/or diabetes mellitus type II in a mammal, including a human.
  • a method was worked out, wherein a pharmaceutically active amount of at least one benzo[g]quinoxaline derivative was administered to a mammal, including a human, effective to activate the human protein kinase InsR.
  • the insulin receptor InsR is a validated target for the treatment of diabetes mellitus type I and/or diabetes mellitus type II.
  • Table 12 shows that the benzo[g]quinoxaline compounds of the present invention are able to activate the insulin receptor InsR and therefore can be used to treat diabetes mellitus type I and/or type II.
  • the inventive benzo[g]quinoxaline compounds inhibit the human cellular protein kinase Akt which is also a known target for diabetes
  • the benzo[g]quinoxaline derivatives also act as pharmaceutically active agents for the treatment of diabetes mellitus type I and/or diabetes mellitus type II by inhibiting said kinase Akt.
  • Table 13 Inhibition of human cellular protein kinase Akt know as a target for diabetes by selected benzo[g]quinoxaline derivatives:
  • Another aspect of the present invention relates to the use of the benzo[g]quinoxaline compound and/or a salt thereof for prophylaxis and/or treatment of HCV.
  • Tables 14 and 15 prove the activity of selected benzo[g]quinoxaline compounds against hepatitis C viruses.
  • Table 14 Effect of benzo[g]quinoxaline compounds on viability of Huh-5-2 replicon cells by the Alamar Blue toxicity assay.
  • Table 15 Effect of benzo[g]quinoxaline compounds on autonomous replication of HCV replicons in the Huh-5-2 cell line by luciferase reporter assay.
  • Toxicity was low for both compounds up to a concentration of 20 ⁇ M.
  • Replication of subgenomic HCV replicon RNA as measured in the luciferase reporter assay was reduced for compound 13 with an IC50 of 5 ⁇ M and for compound 97 with an IC50 of 9 ⁇ M.
  • Another aspect of the present invention is related to two novel targets for the treatment of HBV.
  • Said two human protein kinases are known as SRPK1 and SRPK2 and have been validated as targets for the treatment of HBV and diseases associated with HBV infection.
  • Ligands are messengers that bind to specific receptors on the surface of target cells.
  • the receptors trigger the activation of a cascade of downstream signaling molecules, thereby transmitting the message from the exterior of the cell to its nucleus.
  • the message reaches the nucleus, it initiates the modulation of specific genes, resulting in the production of RNA and finally proteins that carry out a specific biological function.
  • Disturbed activity of signal transduction molecules may lead to the malfunctioning of cells and disease processes. Specifically, interaction of HBV with host cells is necessary for the virus to replicate.
  • the present invention is also based upon the surprising fact that the human cellular protein kinases SR (serine/arginine-rich) protein-specific kinase 1 (SRPK1 ; Genbank accession number U09564) and SR protein-specific kinase 2 (SRPK2; Genbank accession number U88666/NM_003138) associate specifically with the HBV capsid protein and phosphorylate it.
  • SRPK1 human cellular protein kinases
  • SRPK2 Genbank accession number U88666/NM_003138
  • SRPK1 and SRPK2 constitute qualified targets for the indication Hepatitis B and allow the establishment of methods for the identification of compounds useful for prophylaxis and/or treatment of HBV infections and diseases induced by said infections, and allow directly the prophylaxis and treatment of HBV infections and associated diseases.
  • the antiviral therapeutic research approach described herein focuses on discovering the cellular signal transduction pathways involved in viral transfections. Identification of the signal transduction molecules that are key to viral infection provides for, among other things, novel targets for antiviral therapeutics, a novel class of antiviral therapeutics, and new screening methods (e.g., assays) and materials to find and develop new antiviral agents.
  • Target identification is basically the identification of a particular biological component, namely a protein and its association with particular disease states or regulatory systems.
  • a protein identified in a search for a pharmaceutically active chemical compound (drug) that can affect a disease or its symptoms is called a target.
  • Said target is involved in the regulation or control of biological systems and its function can be interfered with by a drug.
  • Hepatitis B virus virions consist of viral capsids that contain the partially double- stranded DNA genome and are surrounded by envelopes made up of a host-cell derived lipid bilayer and the viral envelope proteins.
  • the HBV capsid is composed of a single type of protein, the HBV core protein.
  • the N-terminal 144 amino acids of core protein maintain the ability to self-assemble when expressed in heterologous systems, the 34 amino acid long C-terminus is arginine-rich and shows nonspecific binding to nucleic acids (reviewed in Nassal M. Hepatitis B virus morphogenesis, Curr. Top. Microbiol. Immunol. 1996, 214, 297-337).
  • HBV core protein is a phospho protein (Machida A et al, J. Virol. 1991 , 65(11), 6024- 30; Lanford R.E., Notvall L, Virology 1990, 176(1), 222-33; Roossinck MJ, Siddiqui A. J Virol. 1987 Apr;61(4):955-61), and 3 phosphorylation sites have been identified in the arginine-rich C-terminus (S155, S162, S170 in subtype ayw; Liao W., Ou J.H. J. Virol. 1995, 69(2), 1025-9).
  • SRPK1 Genbank accession number U09564
  • SRPK2 Genbank accession number U88666/NM__003138
  • two GST-HBV core protein associated protein kinases could be detected which were capable of phosphorylating the HBV core protein in vitro.
  • One of the distinct protein spots on the 2D gel was isolated and identified as SRPK1 by MALDI-TOF-MS analysis. This result was further confirmed by sequencing of selected tryptic peptides using a Q-TOF instrument for MS/MS analysis.
  • the second associating protein kinase was identified as the related SRPK2 by immunoblot analysis.
  • both SRPK1 and SRPK2 phosphorylate HBV core protein on the same serine residues which have previously been identified as in-vivo phosphorylation sites.
  • moderate overexpression of either kinase correlates well with increased total cellular kinase activity towards HBV core protein in-vitro. Therefore SRPK1 and SRPK2 constitute qualified targets for the indication Hepatitis B and will allow testing for kinase-specific inhibitors in vitro.
  • one aspect of the present invention is directed to a screening method for the identification of compounds useful for prophylaxis and/or treatment of HBV infections and/or diseases. Specifically, this method involves contacting a test compound with the human cellular protein kinase SRPK1 and/or SRPK2 and detecting the activity of said human cellular protein kinase SRPK1 and/or SRPK2.
  • detection includes any method known in the art useful to indicate the presence, absence, or amount of a detection target.
  • Such methods may include, but are not limited to, any molecular or cellular techniques, used singularly or in combination, including, but not limited to: hybridization and/or binding techniques, including blotting techniques and immunoassays; labeling techniques (chemiluminescent, colorimetric, fluorescent, radioisotopic); spectroscopic techniques; separations technology, including precipitations, electrophoresis, chromatography, centrifugation, ultrafiltration, cell sorting; and enzymatic manipulations (e.g., digestion).
  • hybridization and/or binding techniques including blotting techniques and immunoassays; labeling techniques (chemiluminescent, colorimetric, fluorescent, radioisotopic); spectroscopic techniques; separations technology, including precipitations, electrophoresis, chromatography, centrifugation, ultrafiltration, cell sorting; and enzymatic manipulations (e.g., digestion).
  • HBV induced or HBV associated diseases refers to the group of diseases comprising chronic hepatitis, liver cirrhosis and hepatocellular carcinoma.
  • Also described in the present invention are monoclonal or polyclonal antibodies which bind to the human cellular protein kinase SRPK1 and/or SRPK2.
  • a further aspect of the present invention relates to a method for preventing and/or treating HBV infections and/or associated diseases in an individual comprising the step of administering a pharmaceutically effective amount of an agent which inhibits at least partially the activity of the human cellular protein kinase SRPK1 and/or SRPK2, or which inhibits at least partially the production of the human cellular protein kinase SRPK1 and/or SRPK2.
  • an agent which inhibits at least partially the activity of the human cellular protein kinase SRPK1 and/or SRPK2, or which inhibits at least partially the production of the human cellular protein kinase SRPK1 and/or SRPK2.
  • inventive benzo[g]quinoxaline compounds according to formula (I).
  • the term "individual” preferably refers to mammals, especially humans.
  • the methods disclosed herein can also be used for the treatment of hepatitis B virus strains resistant to current medications, in particular to nucleoside analog drugs like lamivudine.
  • Lamivudine-resistant strains of HBV emerge upon prolonged treatment and are the primary cause of treatment failure (Fontaine H. et al., Letter, Ann. Intern. Med. 1999, 131, 716-717; Ling R. et al., Selection of mutations in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine, Hepatology 1996 24, 711-713).
  • inhibitors refers to any compound capable of downregulating, decreasing, suppressing or otherwise regulating the amount and/or activity of an enzyme, preferably a kinase or phosphatase, and most preferably a human protein kinase, such as SRPK1 and/or SRPK2.
  • said inhibitors including suicide inhibitors, may be proteins, oligo- and polypeptides, nucleic acids, genes, small chemical molecules, such as benzo[g]quinoxaline derivatives, or other chemical moieties.
  • SRPK2 was overexpressed in eucaryotic cells, immunoprecipitated and incubated with test compounds before in-vitro kinase assays were performed.
  • Selected benzo[g]quinoxaline compounds as shown in Tables 16 and 17 have been identified as potent HBV replication inhibitors.
  • Table 16 shows the inhibition of SRPK1 and Table 17 the inhibition of SRPK2.
  • Another aspect of the present invention is directed to a method for regulating the production and/or replication of HBV in an individual comprising the step of administering an individual a pharmaceutically effective amount of an agent wherein said agent inhibits at least partially the activity of the human cellular protein kinase SRPK1 and/or SRPK2, or wherein said agent at least partially inhibits the production and/or replication of the human cellular protein kinase SRPK1 and/or SRPK2.
  • the term "agent” refers to any chemical compound, such as a benzo[g]quinoxaline compound, capable of down- or upregulating, de- or increasing, suppressing, activating, stimulating or otherwise regulating the amount and/or activity of the human cellular protein kinase SRPK1 and/or SRPK2.
  • said agents may be proteins, oligo- and polypeptides, nucleic acids, small chemical molecules, or other chemical moieties.
  • a similar aspect relates to a method for regulating the production and/or replication of HBV in cells comprising the step of administering the cells a pharmaceutically effective amount of an agent wherein said agent inhibits at least partially the activity of the human cellular protein kinase SRPK1 and/or SRPK2, or wherein said agent at least partially inhibits the production of the human cellular protein kinase SRPK1 and/or SRPK2.
  • Monoclonal or polyclonal antibodies which bind to the human cellular protein kinase SRPK1 and/or SRPK2 may be used as effective agents within the above- mentioned methods.
  • regulating expression and/or activity generally refers to any process that functions to control or modulate the quantity or activity (functionality) of a cellular component. Static regulation maintains expression and/or activity at some given level. Upregulation refers to a relative increase in expression and/or activity. Accordingly downregulation refers to a relative decrease in expression and/or activity. Downregulation is synonymous with inhibition of a given cellular component's activity.
  • a further aspect is related to a method for regulating the expression of the human cellular protein kinase SRPK1 and/or SRPK2 in an individual comprising the step of administering the individual a pharmaceutically effective amount of an agent wherein said agent inhibits at least partially the transcription of DNA or the translation of RNA encoding SRPK1 or SRPK2.
  • a still further aspect of the present invention relates to a method for regulating the expression of the human cellular protein kinase SRPK1 and/or SRPK2 in cells comprising the step of administering the cells a pharmaceutically effective amount of an agent wherein said agent inhibits at least partially the transcription of DNA or the translation of RNA encoding SRPK1 or SRPK2.
  • a "pharmaceutical effective amount" of an inhibitor is an amount effective to achieve the desired physiological result, either in cells treated in vitro or in a subject treated in vivo.
  • a pharmaceutically effective amount is an amount sufficient to inhibit, for some period of time, one or more of the clinically defined pathological processes associated with the viral infection.
  • the effective amount may vary depending on the specific inhibitor selected, and is also dependent on a variety of factors and conditions related to the subject to be treated and the severity of the infection. For example, if the inhibitor is to be administered in vivo, factors such as the age, weight and health of the patient as well as dose response curves and toxicity data obtained in pre-clinical animal work would be among those considered.
  • the inhibitor is to be contacted with the cells in vitro, one would also design a variety of pre-clinical in vitro studies to assess such parameters as uptake, half-life, dose, toxicity, etc.
  • the determination of a pharmaceutically effective amount for a given agent is well within the ability of those skilled in the art.
  • a therapeutically effective amount or dosage of a compound such as the inventive benzo[g]quinoxaline derivatives, staurosporine, 3-(1H-indol-3-yl- methylene)-2-oxo-2,3-dihydro-1 H-indole-5-carboxylic, roscovitine, 2,3-bis-(1 H- indol-3-yl)-maleimide, or rottlerin, refers to that amount of the compound that results in an at least partial inhibition of virus production in the patient, which may be measured in several ways, e.g., reduction in HBV DNA, HBe-Ag and HBs-Ag levels in the patient's serum, and/or improvement in alanine amino transferase levels and liver histology and consequently results in a desired clinical benefit such as reduced viral load, suppression of progression of liver disease, and induction of immunological clearance or seroconversion.
  • a compound such as the inventive benzo[g]quinoxaline derivatives, stau
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical, pharmacological, and toxicological procedures in cell cultures or experimental animals for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effect is the therapeutic index and can be expressed as the ratio between LD50 and ED50.
  • the dosage of the compound lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage of the compound corresponds to an effective concentration in the range of 0.05 - 30 ⁇ M, more preferably in the range of 0.1 - 10 ⁇ M.
  • the actual amount of the composition administered will be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • oligonucleotides or oligonucleotide derivatives The transcription of DNA and the translation of RNA can be inhibited by oligonucleotides or oligonucleotide derivatives.
  • the present invention discloses oligonucleotides and derivatives of oligonucleotides which may be used in the above-mentioned methods.
  • the oligonucleotide and/or its derivatives bind to the DNA and/or RNA encoding the human cellular protein kinase SRPK1 or SRPK2 and suppress the transcription of DNA or translation of RNA.
  • Some methods of the present invention identify compounds useful for prophylaxis and/or treatment of HBV infections and/or diseases induced by HBV infections by screening a test compound, or a library of test compounds, for its ability to inhibit the above-mentioned human cellular protein kinases SRPK1 and/or SRPK2.
  • assay protocols and detection techniques are well known in the art and easily adapted for this purpose by a skilled practitioner. Such methods include, but are not limited to, high throughput assays (e.g., kinase assays), and in vitro and in vivo cellular and tissue assays.
  • the present invention incorporates by reference in their entirety techniques well known in the field of molecular biology. These techniques include, but are not limited to, techniques described in the following publications: Ausubel, F.M. et al. eds., "Short Protocols In Molecular Biology” 4 th Ed. 1999, John Wiley & Sons, NY (ISBN 0-471 -32938-X); Old, R.W. & S.B. Primrose “Principles of Gene Manipulation: An Introduction To Genetic Engineering” 3 rd Ed. 1985, Blackwell Scientific Publications, Boston. Studies in Microbiology: V.2, 409 pp. (ISBN 0-632-01318-4); Mayer, R.J. & J.H. Walker eds. "Immunochemical Methods In Cell and Molecular Biology” 1987, Academic Press, London. 325 pp. (ISBN 0-12480-855-7);
  • compositions comprising at least one compound of the general formula (I) as an active ingredient together with one or more pharmaceutically acceptable carriers), excipient(s) or diluents.
  • the benzo[g]quinoxaline compounds of the present invention are basic and form pharmaceutically acceptable salts with organic and inorganic acids.
  • suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p- aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid,
  • salts may be formed with inorganic as well as organic bases such as, for example, NaOH, KOH, NH OH, tetraalkylammonium hydroxide, and the like.
  • the compounds of the general formula (I) can also be administered in form of their pharmaceutically active salts optionally using substantially nontoxic pharmaceutically acceptable carriers, excipients or diluents.
  • the medications of the present invention are prepared in a conventional solid or liquid carrier or diluents and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way.
  • the preferred preparations are in administratable form which is suitable for oral application. These administratable forms, for example, include pills, tablets, film tablets, coated tablets, capsules, powders and deposits.
  • the subject of the present invention also includes pharmaceutical preparations for parenteral, including dermal, intradermal, intragastrical, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, rectal, subcutaneous, sublingual, topical or transdermal application, which in addition to typical vehicles and diluents contain a benzo[g]quinoxaline compound of the general formula (I) and/or a pharmaceutically acceptable salt thereof as active ingredient.
  • compositions of the present invention containing benzo[g]quinoxaline derivatives of the general formula (I) as active ingredients, will typically be administered in admixture with suitable carrier materials selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • suitable carrier materials selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component may be combined with any oral nontoxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture.
  • Powders and tablets may be comprised of from about 5 to about 95 percent inventive composition.
  • Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrants include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects, i.e. antihistaminic activity and the like.
  • Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injections or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.
  • a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidifies.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • inventive benzo[g]quinoxaline compounds of the present invention may also be deliverable transdermally.
  • the transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • capsule refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients.
  • Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins.
  • the capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
  • Tablet means compressed or molded solid dosage form containing the active ingredients with suitable diluents.
  • the tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction well known to a person skilled in the art.
  • Oral gels refers to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.
  • Powders for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.
  • Suitable diluents are substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol, starches derived from wheat, corn rice and potato, and celluloses such as microcrystalline cellulose.
  • the amount of diluents in the composition can range from about 5 to about 95% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight.
  • disintegrants refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments.
  • Suitable disintegrants include starches, "cold water soluble" modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures.
  • the amount of disintegrant in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 5 to about 10% by weight.
  • Binders characterize substances that bind or "glue” powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate.
  • the amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.
  • Lubricant refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear.
  • Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L- leucine.
  • Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press.
  • the amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.
  • Glidents are materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform.
  • Suitable glidents include silicon dioxide and talc.
  • the amount of glident in the composition can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.
  • Coloring agents are excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide.
  • the amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1 %.
  • compositions useful for the prophylaxis and/or treatment of an individual afflicted with HBV comprising at least one agent, such as the inventive benzo[g]quinoxaline compounds, capable of inhibiting at least partially the activity of the human cellular protein kinase SRPK1 and/or SRPK2.
  • compositions comprising a further active ingredient selected from the group comprising pharmaceutically active compounds and/or their pharmaceutically acceptable salts, such as lamivudine ((-)- ⁇ -L-2',3'-dideoxy-3'-thiacytidine marketed as e.g., Zeffix ® , Heptovir ® , 3TC ® , Epivir-HBV, Combivir ® , Trizivir ® by GlaxoSmithKline), alpha interferon (e.g., Intron A ® by Schering-Plough), FTC (e.g., Coviracil ® by Triangle Pharmaceuticals), DAPD (DXG, by Triangle), L- FMAU (e.g., Clevudine ® by Triangle), Adefovir dipivoxil (by Gilead Sciences), tenofovir, epavudine, epcitabine, lobucavir, Penciclovir (Gla), lamivudine ((
  • a further aspect of the present invention describes a combination therapy, wherein an SRPK1 inhibitor and/or SRPK2 inhibitor, such as staurosporine, 3- (1 H-indol-3-yl-methylene)-2-oxo-2,3-dihydro-1 H-indole-5-carboxylic, roscovitine, 2,3-bis-(1H-indol-3-yl)-maleimide, or rottlerin is administered in combination with further therapeutic compounds.
  • an SRPK1 inhibitor and/or SRPK2 inhibitor such as staurosporine, 3- (1 H-indol-3-yl-methylene)-2-oxo-2,3-dihydro-1 H-indole-5-carboxylic, roscovitine, 2,3-bis-(1H-indol-3-yl)-maleimide, or rottlerin is administered in combination with further therapeutic compounds.
  • said further therapeutic compounds are chosen from the group of hepatitis B virus drugs or vaccines comprising lamivudine ((-)- ⁇ -L-2',3'-dideoxy-3'-thiacytidine marketed as e.g., Zeffix ® , Heptovir ® , 3TC ® , Epivir-HBV, Combivir ® , Trizivir ® by GlaxoSmithKline), alpha interferon (e.g., Intron A ® by Schering-Plough), FTC (e.g., Coviracil ® by Triangle Pharmaceuticals), DAPD (DXG, by Triangle), L-FMAU (e.g., Clevudine ® by Triangle), Adefovir dipivoxil (by Gilead Sciences), tenofovir, epavudine, epcitabine, lobucavir, Penciclovir (GlaxoSmithKline), Entecavir/BMS-200475
  • Fig. 1 shows that all three GST-HBV core fusion proteins were phosphorylated in an in-vitro kinase assay.
  • Fig. 2 shows a 45 kDa kinase detected in the total cell lysate that phosphorylates
  • Fig. 3 shown an in-gel kinase assay with GST-HBV-C1 as substrate, in order to identify the protein spots representing the specifically associated kinases.
  • Fig. 4 shows that the transfection of either FLAG-SRPK1 or SRPK2-VSV expression plasmids into cells leads to increased levels of specifically GST-HBV-C1 -associating SRPK1 or SRPK2.
  • Fig. 5 shows that mutation of all three serines to alanines strongly reduced HBV core protein phosphorylation in cells.
  • Fig. 6 shows that both SRPK1 and SRPK2 exhibit the same substrate specificity in-vitro as the cellular kinases in-vivo.
  • Fig. 7 shows that the overexpression of either SRPK1 or SRPK2 correlates with increased GST-HBV-C1 phosphorylation by total cellular proteins in-vitro.
  • Fig. 8 shows the effects of various concentrations of the benzo[g]quinoxaline compound No. 13 on autonomous replication of subgenomic HCV replicons in the Huh-5-2 replicon cell line.
  • Fig. 9 shows the effects of various concentrations of the benzo[g]quinoxaline compound No. 97 on autonomous replication of subgenomic HCV replicons in the Huh-5-2 replicon cell line.
  • LC-MS analyses were performed by Waters chromatograph/ ZMD mass spectrometer equipped with Waters 996 DAD UV detector Waters 2700 autosampler and Waters 600 controller. Supelco Discovery RP-AmideC16 column was used in gradient mode at 3ml/min flow rate.
  • Extractor 3 V Rf Lens: 0.2 V Scan: 120 to 1000 m/z in 1 sec Inter-scan delay: 0.1 s
  • 2,3-Diaminonaphthalene (or its derivative) was dissolved in the mixture of 1 ml DMF and 3 ml ethanol with gentle warming. After dissolving of the amine it was cooled to room temperature and the solution of oxo compound (glyoxales or 1 ,2 diketones) in 1 ml ethanol was added with stirring. The reaction mixture was refluxed for 1 hour then allowed to cool to room temperature while the product crystallized. Crystals were collected by filtration, washed with ether and dried in vacuum.
  • ester function was removed as follows. 20 mg solid NaOH was dissolved in 4 ml water and added to the solution of 0.1 mmol ester in 4 ml tetrahydrofurane.
  • the mixture was stirred for 4 hours at reflux temperature then cooled to room temperature. Its pH was adjusted to pH 3 with 1 N HCI and extracted three times with 80 ml ethyl acetate. The organic layer dried on CaCI 2 , and evaporated to dryness.
  • R1 , R2 CN, COOR, CONHR
  • R1 aryl
  • the mixture was boiled until all the methyl chloride formed in the reaction steamed off.
  • the mixture was evaporated to dryness, the resulting tar compound was dissolved in ethanol and decolorized by charcoal.
  • the product was further purified by dissolving it in 2 M hydrochloric acid and after filtration precipitated with sodium carbonate solution, filtrated and dried in vacuum.
  • R1 aryl
  • Example 15 (Compound 104) 1 -(2-Nitrophenyl)-2-(3-thiophen-2-yl-benzorq1quinoxaline-2- yl)-ethanol
  • R 3 H, 2-thienyl
  • R1 aryl
  • R2 H, 2-thienyl

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Abstract

L'invention porte sur des dérivés de la benzo[g]quinoxaline, de formule générale (I); sur leurs procédés de fabrication; sur leurs utilisations comme agents pharmaceutiques actifs spécialement pour la prophylaxie et/ou le traitement de maladies infectieuses et d'infections opportunistes, du diabète, du cancer et des inflammations. Elle porte également sur des compositions contenant au moins un dérivé de la benzo[g]quinoxaline et/ou l'un de ses sels pharmacocompatibles, et en outre sur des procédés de prévention et/ou traitement de maladies infectieuses, du diabète du cancer, et des inflammations, recourant aux dérivés de la benzo[g]quinoxaline de l'invention.
PCT/EP2002/005573 2001-05-18 2002-05-21 Derives de la benzo[g]quinoxaline composes efficaces contre les maladies infectieuses WO2002094796A2 (fr)

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US10/715,591 US20040171603A1 (en) 2001-05-18 2003-11-18 Novel therapeutic targets for the treatment of mycobacterial infections and compounds useful therefor
US12/462,236 US20090298842A1 (en) 2001-05-18 2009-08-01 Novel therapeutic targets for the treatment of mycobacterial infections and compounds useful therefor

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003084947A1 (fr) * 2002-04-09 2003-10-16 Axxima Pharmaceuticals Ag Derives de 4,5,6,7-tetrahydrobenzo[b]thiophene et methodes d'intervention medicale contre les infections mycobacteriennes
WO2004043937A1 (fr) * 2002-11-13 2004-05-27 Semiconductor Energy Laboratory Co., Ltd. Derive de quinoxaline, dispositif semi-conducteur organique et element electroluminescent
EP1494676A1 (fr) * 2002-04-08 2005-01-12 Merck & Co., Inc. Derives de quinolaxine fusionnee comme inhibiteurs de l'activite d'akt
WO2005056802A2 (fr) * 2003-12-12 2005-06-23 Cancer Research Technology Ltd Materiels et methodes de commande du cycle cellulaire
WO2005063293A1 (fr) * 2003-12-26 2005-07-14 Masatoshi Hagiwara Methode destinee a reguler la phosphorylation de la proteine sr, et agents antiviraux comprenant le regulateur de l'activite de la proteine sr comme principe actif
WO2005065666A1 (fr) * 2003-12-22 2005-07-21 Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Utilisation d'un inhibiteur de la pkc-delta destinee a l'inhibition du melanome metastatique
WO2005097088A2 (fr) * 2004-04-05 2005-10-20 Myogen, Inc. Inhibition de l'export nucleaire en tant que traitement de l'hypertrophie cardiaque et de l'insuffisance cardiaque
JP2006298965A (ja) * 2005-04-15 2006-11-02 Showa Denko Kk ジフェニルキノキサリン骨格を有する化合物を含む導電性組成物
WO2007128086A2 (fr) * 2006-05-05 2007-11-15 Katholieke Universiteit Leuven Nouvel inhibiteur de la réplication virale
WO2009119167A1 (fr) * 2008-03-25 2009-10-01 株式会社キノファーマ Dérivé d'aniline ayant une activité anti-virus à arn
JP2011506480A (ja) * 2007-12-12 2011-03-03 ライジェル ファーマシューティカルズ， インコーポレイテッド 代謝障害のためのカルボキサミド、スルホンアミド、およびアミン化合物
US8198426B2 (en) 2001-01-23 2012-06-12 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Hepatitis c virus replicons and replicon enhanced cells
WO2014105662A1 (fr) * 2012-12-24 2014-07-03 Merck Sharp & Dohme Corp. Inhibiteurs de la glycosidase et leurs utilisations
WO2014165090A1 (fr) * 2013-03-13 2014-10-09 The Broad Institute, Inc. Composés pour le traitement de la tuberculose
WO2017010950A1 (fr) * 2015-07-15 2017-01-19 Agency For Science, Technology And Research Modulation de la réplication du virus de l'hépatite b
CN107556217A (zh) * 2017-09-15 2018-01-09 湖北鑫慧化工有限公司 一种氨基k酸的生产工艺
CN115894870A (zh) * 2022-10-28 2023-04-04 华南理工大学 一种用于光热治疗的苯并双喹喔啉类受体的聚合物、聚合物纳米粒子及其制备和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3145205A (en) * 1962-12-10 1964-08-18 American Home Prod 6-benzoquinoxaline-carboxamides
EP0149802A2 (fr) * 1983-12-21 1985-07-31 Hoechst Aktiengesellschaft 2,3-Bis(arylethényl)-quinoxalines, procédé pour leur préparation et leur usage comme composés photoconducteurs
WO1999025327A2 (fr) * 1997-11-14 1999-05-27 Warner-Lambert Company Intervention de petites molecules dans la replication du vih-1

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0374372A (ja) * 1989-08-16 1991-03-28 Terumo Corp ピラジン誘導体およびこれを含有する血小板凝集抑制剤または抗炎症剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3145205A (en) * 1962-12-10 1964-08-18 American Home Prod 6-benzoquinoxaline-carboxamides
EP0149802A2 (fr) * 1983-12-21 1985-07-31 Hoechst Aktiengesellschaft 2,3-Bis(arylethényl)-quinoxalines, procédé pour leur préparation et leur usage comme composés photoconducteurs
WO1999025327A2 (fr) * 1997-11-14 1999-05-27 Warner-Lambert Company Intervention de petites molecules dans la replication du vih-1

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 115, no. 28, 1991 Columbus, Ohio, US; abstract no. 183362e, page 935; column 2; XP002230870 & JP 03 074372 A (TERUMO CORP.) 28 March 1991 *
CHEMICAL ABSTRACTS, vol. 130, no. 22, 1999 Columbus, Ohio, US; abstract no. 296316w, RODRIGO,G. ET AL.: "KINETICS STUDIES ON THE SYNTHESIS OF A SERIE OF 3-SUBSTITUTED QUINOXALINONES.COMPARISON WITH 3-SUBSTITUTED BENZOQUINOXALINONE" page 649; column 1; XP002230871 & INF. TECNOL., vol. 10, no. 1, 1999, pages 29-35, BUENOS-AYRES *
CHEMICAL ABSTRACTS, vol. 131, no. 24, 1999 Columbus, Ohio, US; abstract no. 317396k, EL ASHRY,ABDEL-RAHMAN: "SYNTHESIS AND ANTI-HEPATITIS B VIRUS ACTIVITY OF SOME 2,3-DIHYDROPROPYL UNNATURAL HETARYLS." page 33; column 1; XP002230872 & ARCH. PHARM., vol. 332, no. 9, 1999, pages 327-30, WEINHEIM *

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US8198426B2 (en) 2001-01-23 2012-06-12 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Hepatitis c virus replicons and replicon enhanced cells
EP1494676A1 (fr) * 2002-04-08 2005-01-12 Merck & Co., Inc. Derives de quinolaxine fusionnee comme inhibiteurs de l'activite d'akt
US7273869B2 (en) 2002-04-08 2007-09-25 Merck & Co., Inc. Inhibitors of Akt activity
EP1494676A4 (fr) * 2002-04-08 2006-05-10 Merck & Co Inc Derives de quinolaxine fusionnee comme inhibiteurs de l'activite d'akt
WO2003084947A1 (fr) * 2002-04-09 2003-10-16 Axxima Pharmaceuticals Ag Derives de 4,5,6,7-tetrahydrobenzo[b]thiophene et methodes d'intervention medicale contre les infections mycobacteriennes
WO2004043937A1 (fr) * 2002-11-13 2004-05-27 Semiconductor Energy Laboratory Co., Ltd. Derive de quinoxaline, dispositif semi-conducteur organique et element electroluminescent
US7355340B2 (en) 2002-11-13 2008-04-08 Semiconductor Energy Laboratory Co., Ltd. Quinoxaline derivatives, organic semiconductor device and electroluminescent device
WO2005056802A3 (fr) * 2003-12-12 2007-04-19 Cancer Rec Tech Ltd Materiels et methodes de commande du cycle cellulaire
WO2005056802A2 (fr) * 2003-12-12 2005-06-23 Cancer Research Technology Ltd Materiels et methodes de commande du cycle cellulaire
WO2005065666A1 (fr) * 2003-12-22 2005-07-21 Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Utilisation d'un inhibiteur de la pkc-delta destinee a l'inhibition du melanome metastatique
WO2005063293A1 (fr) * 2003-12-26 2005-07-14 Masatoshi Hagiwara Methode destinee a reguler la phosphorylation de la proteine sr, et agents antiviraux comprenant le regulateur de l'activite de la proteine sr comme principe actif
US8816089B2 (en) 2003-12-26 2014-08-26 Masatoshi Hagiwara Methods for controlling SR protein phosphorylation, and antiviral agents whose active ingredients comprise agents that control SR protein activity
US8338362B2 (en) 2003-12-26 2012-12-25 Masatoshi Hagiwara Methods for controlling SR protein phosphorylation, and antiviral agents whose active ingredients comprise agents that control SR protein activity
US7569536B2 (en) 2003-12-26 2009-08-04 Masatoshi Hagiwara Method for controlling SR protein phosphorylation, and antiviral agents whose active ingredients comprise agents that control SR protein activity
AU2004308825B2 (en) * 2003-12-26 2011-03-10 Masatoshi Hagiwara Method of regulating phosphorylation of SR protein and antiviral agents comprising SR protein activity regulator as the active ingredient
WO2005097088A3 (fr) * 2004-04-05 2006-01-12 Myogen Inc Inhibition de l'export nucleaire en tant que traitement de l'hypertrophie cardiaque et de l'insuffisance cardiaque
WO2005097088A2 (fr) * 2004-04-05 2005-10-20 Myogen, Inc. Inhibition de l'export nucleaire en tant que traitement de l'hypertrophie cardiaque et de l'insuffisance cardiaque
JP2006298965A (ja) * 2005-04-15 2006-11-02 Showa Denko Kk ジフェニルキノキサリン骨格を有する化合物を含む導電性組成物
WO2007128086A3 (fr) * 2006-05-05 2008-01-24 Univ Leuven Kath Nouvel inhibiteur de la réplication virale
WO2007128086A2 (fr) * 2006-05-05 2007-11-15 Katholieke Universiteit Leuven Nouvel inhibiteur de la réplication virale
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WO2014105662A1 (fr) * 2012-12-24 2014-07-03 Merck Sharp & Dohme Corp. Inhibiteurs de la glycosidase et leurs utilisations
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US10301294B2 (en) 2013-03-13 2019-05-28 The Broad Institute Inc. Compounds for the treatment of tuberculosis
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