WO2003082265A2 - Pharmaceutical composition for treating or preventing virus infectious diseases - Google Patents

Pharmaceutical composition for treating or preventing virus infectious diseases Download PDF

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WO2003082265A2
WO2003082265A2 PCT/JP2003/003929 JP0303929W WO03082265A2 WO 2003082265 A2 WO2003082265 A2 WO 2003082265A2 JP 0303929 W JP0303929 W JP 0303929W WO 03082265 A2 WO03082265 A2 WO 03082265A2
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group
alkyl
aryl
pharmaceutically acceptable
substituted
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PCT/JP2003/003929
Inventor
Takayuki Inoue
Katsuyuki Maki
Kazuaki Hatakenaka
Yukiko Yamagisi
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Fujisawa Pharmaceutical Co
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Priority claimed from AUPS1481A external-priority patent/AUPS148102A0/en
Priority claimed from AU2002953603A external-priority patent/AU2002953603A0/en
Application filed by Fujisawa Pharmaceutical Co filed Critical Fujisawa Pharmaceutical Co
Publication of WO2003082265A2 publication Critical patent/WO2003082265A2/en

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    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A61K31/055—Phenols the aromatic ring being substituted by halogen
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine

Definitions

  • This invention relates to pharmaceutical compositions for treating or preventing virus infectious diseases, particularly to those for treating or preventing virus infectious diseases caused by viruses belonging to Flaviviridae family.
  • Flaviviridae family consists of hepacivirus genus, pestivirus genus, flaviviruses and other several viruses that are currently unassigned to specific genera. Viruses belonging to this family cause significant diseases in human beings and animals. For example, hepatitis C virus (HCV) included in hepacivirus genus is a major cause of human hepatitis globally. It is known that most HCV infections become persistent and about 60 % of the cases develop chronic liver disease. Chronic HCV infection can lead to development of cirrhosis, hepatocellular carcinoma and liver failure. The treatment currently available for HCV infection is to administrate interferon (IFN), " ribavirin, or a combination of these two medicines. However, according to clinical studies, it is said that the effectiveness of the above treatment for HCV is variable and its cure rate is low.
  • IFN interferon
  • Pestivirus infections of domesticated livestock cause significant economic losses worldwide. Pestiviruses cause a range of clinical manifestations including abortion, teratogenesis, respiratory problem, chronic wasting disease, immune system dysfunction and predisposition to secondary viral and bacterial infections.
  • Flaviviruses are major pathogens of human beings and are also prevalent throughout the world. There are at least 38 flaviviruses associated with human diseases, including the dengue fever viruses, yellow fever virus and Japanese encephalititis virus. Flaviviruses cause a range of acute febrile illnesses and encephalitic and hemorrhagic diseases.
  • HCV contains a positive strand RNA genome comprising approximately 9400 nucleotides coding for a polyprotein of 3009-3030 amino acids whose organization is similar to that of flaviviruses and pestiviruses.
  • RdRp virus-encoded RNA-dependent RNA polymerase
  • NS5B protein in the case of the hepaciviruses and pestiviruses
  • NS5 protein in the case of the flaviviruses.
  • RdRp is a key component of the virus replicase complex, enabling the virus to replicate its RNA genome and produce progeny viruses.
  • RdRp Some compounds having inhibitory activity of RdRp have been known, for example, barbituric acid derivatives in WO00/ 13708, benzothiophene derivatives in WO00/ 18231, pyrrolidine derivatives in WO00/ 10573, diketoacid derivatives in WO00/06529, fused ring derivatives in WOO 1/47883 and nucleoside derivatives in WO01/32153.
  • An object of this invention is to provide a pharmaceutical composition containing a fused benzene derivative selected from the compounds represented by the formulae (la) to (Ie), its prodrug or a pharmaceutically acceptable salt thereof, which has a RdRp inhibiting activity, as an active ingredient in admixture of a pharmaceutically acceptable carrier.
  • Another object of this invention is to provide a method of treating or preventing virus infectious diseases by administering the fused benzene derivative, its prodrug or a pharmaceutically acceptable salt thereof in an effective amount to inhibit RdRp.
  • a further object of the invention is to provide a use of the fused benzene derivative, its prodrug or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition.
  • the fused benzene derivatives included in the pharmaceutical composition of this invention are represented by the following formulae (la), (lb), (lc), (Id) and (Ie): Formula (la) :
  • R la is hydrogen atom, or nitro or a lower alkoxy group
  • R 2a is hydrogen atom, or nitro, amino, an acylamino or lower alkanesulfonyl group, or
  • Ria and R 2a together with the adjacent carbon atoms to which they are attached form an aryl group
  • R 5a and R 6a are, the same or different, hydrogen atom or hydroxy group, or
  • R 5a and R 6a form oxo group
  • R 8a and R 9a are, the same or different, hydrogen atom or hydroxy group, or
  • R8a and R 9a form oxo group
  • X a is N-R 7a or O wherein R 7a is hydrogen atom, or hydroxy, a lower alkyl, aryl, ar (lower) alkyl or ar (lower) alkoxy group, among which the ar (lower) alkoxy group may be substituted with one or more substituent(s),
  • R 3a and R 4a together with the carbon atoms to which they are attached may form a cycloalkane ring or wherein Y a is CH or N, and R 10a is hydroxy, an aryl, arylamino or lower alkoxy group, among which the aryl and arylamino groups may be substituted with one or more substituent(s), or
  • R 3a together with R 5a or R 6a with the carbon atoms to which they are attached may form a bond or a cycloalkane ring
  • R lb is hydrogen or halogen atom, or nitro, a lower alkyl, halo (lower) alkyl, lower alkoxy or halo (lower) alkoxy group,
  • R 2b and R 3b are, the same or different, hydrogen atom, or a lower alkyl, aryl, ar(lower)alkyl, heterocyclic or acyl group, among which the lower alkyl and ar (lower) alkyl groups may be substituted with one or more substituent(s), or R 2b and R 3b together with the carbon atoms to which they are attached form a cycloalkane ring which may be substituted with halo(lower)alkyl-substituted aryl,
  • R 4b and R 5b are, the same or different, hydrogen or halogen atom, or an aryl or ar (lower) alkyl group, among which the ar (lower) alkyl group may be substituted with one or more halogen atom(s), or R 4b and R 5b form oxo group or an ethylene group which may be substituted with one or two substituent(s),
  • R lc is hydrogen or a halogen atom, or nitro, a lower alkyl, lower alkoxy or lower alkylthio group, and
  • R 2c is hydrogen or halogen atom or a lower alkoxy group
  • R 3c is hydrogen or a halogen atom, or nitro, a lower alkyl or halo (lower) alkoxy group
  • R ld is hydrogen atom, or nitro, amino or an acylamino group
  • R 2d is an optionally substituted aryl or ar (lower) alkyl group
  • Xd is CH or N
  • R le is hydrogen atom or a lower alkoxy group
  • R 2e is hydrogen atom
  • R 3e and R 4e are hydrogen atoms or form oxo group
  • R 5e , R 6e , R 7e and R 8e are, the same or different, hydrogen atom, or hydroxy, a lower alkyl, lower alkoxy, aryl, acyloxy or carbocyclic group, among which the lower alkyl, aryl and carbocyclic groups may be substituted with one or more substituent(s), and further R 6e and R 7e together with the carbon atoms to which they are attached may form an optionally substituted unsaturated heterocyclic ring.
  • one or more means 1 to 6, preferably 1 to 3, and more preferably 1 or 2.
  • Suitable examples of the lower alkanesulfonyl group for R 2a are methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl and pentanesulfonyl.
  • Suitable examples of the lower alkoxy group for R la , R 10a , R lb , R lc , R 2c , R le , R 5e , R 6e , R 7e and R 8e the lower alkoxy moieties in the halo (lower) alkyl group for R lb , R 2b and R 3b and ar(lower)alkoxy group for R 7a are methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy.
  • Suitable examples of the halogen atom for R lb , R 4 , R5 b , Ri , R2c and R 3c and halogen moieties in the halo (lower) alkyl group for R lb , R 2b and R 3 and halo (lower) alkoxy group for R lb and R 3c are fluorine, chlorine, bromine and iodine.
  • Rlto R2b ; R3b ? R4b ; R5b ; R1 C> R2c ; R2d ; R 2 ⁇ j R5e ; R6e ; R7e and R 8e and the aryl moieties in the arylamino group for R 10a , ar(lower)alkyl group for R 3a , R 4a , R 7a , R 3b , R 4b , R 5 and R d and ar (lower) alkoxy group for R 7a are aromatic hydrocarbon residues containing 6 to 12 carbon atoms, such as phenyl, tolyl, xylyl and naphthyl.
  • Suitable examples of the heterocyclic group for R 2 and R 3b are saturated or unsaturated, monocyclic or condensed heterocyclic groups containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms.
  • heterocyclic group Preferable examples of the heterocyclic group are described in the following.
  • unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl;
  • unsaturated condensed heterocyclic group containing 1 to 3 nitrogen atoms for example, benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, quinolyl, isoquinolyl, indolyl or indolinyl;
  • unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms for example, benzofuryl or benzodioxolyl;
  • unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl, benzisothiazolyl or phenothiazinyl.
  • unsaturated heterocyclic ring for R 6e and R 7e are unsaturated, mono- or condensed-heterocyclic rings containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms such as
  • unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic ring containing 1 to 4 nitrogen atoms for example, pyrrole, dihydropyrrole, pyrroline, imidazole, pyrazole, pyridine, tetrahydropyridine, pyrimidine, tetrahydropyrimidine, pyrazine, pyridazine, triazole or tetrazole;
  • unsaturated condensed heterocyclic ring containing 1 to 3 nitrogen atoms for example, benzopyrrole, benzimidazole, benzopyrazole, benzotriazole, quinoline, isoquinoline or indole;
  • unsaturated condensed heterocyclic ring containing 1 to 2 oxygen atoms for example, benzofuran, dihydrobenzofuran or benzodioxole;
  • acyl group for R 2b and R 3b and acyl moieties in the acylamino group for R 2a and R ld and acyloxy group for R 5e , R 6e , R 7e and R 8e are aliphatic acyl, aromatic acyl and heterocyclic acyl, which are derived from carboxylic acid, and lower alkylcarbamoyl and arylcarbamoyl groups, which are derived from carbamic acid.
  • aliphatic acyl group are examples of aliphatic acyl group.
  • lower alkanoyl e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl or hexanoyl
  • cyclo (lower) alkylcarbonyl e.g. cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl or cyclohexylcarbonyl
  • lower alkenoyl e.g. acryloyl, methacryloyl, crotonoyl or 3-methylbutanoyl
  • the examples of the aromatic acyl group are aroyls (e.g. benzoyl and naphthoyl) which may be substituted with nitro, amino, thenoylamino, or the like.
  • the examples of the heterocyclic acyl group are the heterocyclic carbonyl groups such as furoyl, thenoyl, nicotinoyl and the like.
  • the examples of the lower alkylcarbamoyl group are methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl and the like.
  • arylcarbamoyl group examples are phenylcarbamoyl and naphthylcarbamoyl.
  • Suitable examples of the cycloalkane ring for R 3a , R 4a , R 5a , R 6a , R 2b and R 3b are cyclic hydrocarbon having 3 to 7 carbon atom, such as cyclobutane, cyclopentane, cyclohexane and cycloheptane.
  • Suitable examples of the carbocyclic group for R 5e , R 6e , R 6e and R 8e are cyclic hydrocarbon residues having 3 to 7 carbon atoms, such as cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl and indenyl.
  • Suitable examples of the halo (lower) alkyl group for R lb , R 2b and R 3b and the halo (lower) alkyl moiety in the halo (lower) alkoxy group for R lb and R 3c are C ⁇ - , preferably C1-2 alkyl groups containing 1 to 5, preferably 1 to 3 halogen atoms, preferably fluorine, chlorine and/ or bromine atom(s), more preferably fluorine and/ or chlorine atom(s).
  • Preferable examples thereof are chloromethyl, bromomethyl, 1-fluoroethyl, 2-fluoroethyl, trifluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, 2,2-difiuoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl.
  • Suitable examples of the ar (lower) alkyl group for R 3a , R 4a , R 7a , R b , R 3b , R 4 , R 5b and R 2d and the ar (lower) alkyl moiety in the ar (lower) alkoxy group for R 7a are benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, benzhydryl, trityl and naphthylmethyl.
  • Suitable examples of the halo(lower)alkyl-substituted aryl group for R 2b and R 3b are (chloromethyl) phenyl, (trifluoromethyl)phenyl and (2,2,2-trichloroethyl)naphthyl.
  • R 2d , R 5e , R 6e , R 7e and R 8e are substituted with one or more substituent(s), said substituent may be hydroxy; amino; carboxy; cyano; nitro; carbamoyl; oxo; halogen (e.g., fluorine, bromine or chlorine); lower alkyl (e.g., methyl, ethyl, isopropyl or tert-butyl) optionally substituted with lower alkoxy (e.g., methoxy); aryl (e.g., phenyl or naphthyl ) optionally substituted with one or more of halogen (e.g., fluorine, bromine or chlorine); heterocyclyl (e.g., pyridyl, morpholinyl, pyrrolidinyl, piperazinyl or pyrimidyl); halo (lower) alkyl (e.g., trifluoromethyl); ar (lower)
  • Suitable pharmaceutically acceptable salts of the fused benzene derivative i.e., (la) to (Ie) are conventional and non-toxic salts, for example an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartarate, oxalate, methanesulfonate, benzenesulfonate or toluenesulfonate), an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate or phosphate), a salt with an amino acid (e.g. aspartate or glutamate), and the like.
  • organic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartarate, oxalate, methanesulfonate, benzenesulfonate or toluenesulfonate
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide
  • the fused benzene derivative may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomer s .
  • the fused benzene derivative may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
  • the fused benzene derivative and its salt can be in a form of a solvate, which is also included within the scope of the present invention.
  • the solvate preferably include a hydrate and an ethanolate. Also included in the scope of the invention are radiolabelled derivatives of fused benzene derivatives which are suitable for biological studies.
  • the "prodrug” may be a derivative of the fused benzene derivative having a chemically or metabolically degradable group, which becomes pharmaceutically active substance after biotransformation .
  • fused benzene derivatives, their prodrugs or salts thereof are commercially available.
  • Novel fused benzene derivative, its prodrug or a salt thereof can be prepared by the following processes.
  • the other fused benzene derivatives can be prepared by the known processes or analogous processes thereto or by analogous processes to the following Examples.
  • Suitable leaving group for X may be halogen (e.g., fluoro, chloro, bromo or iodo), arenesulfonyloxy (e.g., benzenesulfonyloxy or tosyloxy), alkanesulfonyloxy (e.g., mesyloxy or ethanesulfonyloxy), or the like, among which the preferable one is halogen.
  • halogen e.g., fluoro, chloro, bromo or iodo
  • arenesulfonyloxy e.g., benzenesulfonyloxy or tosyloxy
  • alkanesulfonyloxy e.g., mesyloxy or ethanesulfonyloxy
  • the processes 1 to 5 can be carried out according to the processes described in the Examples below.
  • RdRp RNA-dependent RNA polymerase
  • the cDNA coding region was ligated to glutathione S-transferase (GST) expression vector (pGEX4T-2) at BamH I and Sal I sites. Bacteria was transfected with the recombinant vector according to the heat shock method. Expression of the truncated HCV RdRp were accelerated by 0.4 mM isopropyl- ⁇ -D-thiogalactopyranoside (IPTG) and monitored by SDS-PAGE analysis. The sonicated bacterial suspension in buffer A (PBS including ImM DTT and 1% Triton X-100) was processed to purify the truncated RdRp as follows.
  • the lysate was adjusted to 0.33 M NaCl and applied to DEAE sephacel column.
  • the fraction passed through the DEAE column was incubated batchwise with DEAE Glutathione Sepharose 4B beads equilibrated with buffer A for 1 hour at 4°C.
  • the beads was washed and the truncated RdRp was eluted in buffer B (50mM Tris-HCl (pH 8.0), 10 mM glutathione, 10 mM DTT and 0.1 % Triton X- 100) including 500 mM NaCl.
  • the eluted supernatant was dialyzed against buffer B containing 150 mM NaCl and loaded onto Heparin Sepharose CL-6B column equilibrated with LG buffer (20 mM Tri-HCl (pH 7.5), ImM EDTA, 5mM DTT, 20% glycerol and 0.5% Triton X-100) containing 0.15 M NaCl.
  • LG buffer (20 mM Tri-HCl (pH 7.5), ImM EDTA, 5mM DTT, 20% glycerol and 0.5% Triton X-100) containing 0.15 M NaCl.
  • the bound proteins were evaluated using 0.15 to 1M NaCl gradient and fractionated in 2 ml.
  • the fractions containing truncated RdRp which was confirmed by SDS-PAGE were loaded onto poly (U) Sepharose 4B equilibrated with LG buffer including 0.15 M NaCl.
  • the bound proteins were also eluted using 0.15 to 1M NaCl gradient and fractionated in 2 ml.
  • the fractions containing truncated RdRp were corrected and stored as a glycerol solution at -80°C . Truncated RdRp in the final pool was confirmed by western blotting.
  • This assay method was modified procedure of the methods described in the publications: Behrens SE, Tomei L and De Francesco R, EMBO J., 1996, Jan 2, 15 (1), 12-22; Lohmann V, Korner F, Herian U and Bartenschlager R, J. Virol, 1997, Nov, 71 (11), 8416-28; and Yamashita T, Kaneko S, Shirota Y, Qin W, Nomura T, Kobayashi K and Murakami S, J. Bol. Chem., 1998, Jun 19, 273 (25), 15479-86.
  • RdRp reaction was carried out in a 20 ⁇ 1 of RdRp buffer (20 mM Tris-HCl (pH 7.5), ImM EDTA, 5mM MgCl 2 , 25 mM KCl and ImM DTT), 0.01 % BSA, 0.05 mg/ml Actionmycin D, 1.5 U RNasin, 0.075 mCi/ml [H3]-GTP, 4 pmmol biotinylatted oligo(G) 12, 500 ng ⁇ oly(C), the truncated RdRp final fraction. After 2 hours of incubation at 22°C, productive radioactivity was separated from non-reactive one according to the following two methods.
  • SPA method streptavidin conjugated SPA bead and uM GTP was added to the reaction mixture. The radioactivity captured with the beads was measured in the scintillation counter.
  • exclusion column chromatography uM GTP was added to the reaction mixture and loaded onto Sephadex G-50, a quick spin column. After centrifugation of the column, the radioactivity in the elution was measured in the scintillation counter. The radioactivity corresponding to increasing doses of each compound was plotted and IC50 values were determined.
  • the fused benzene derivatives included in the pharmaceutical compositions of the present invention have a potent RdRp inhibitory activity as shown in the above. Therefore, it is suggested that the fused benzene derivatives may have protective benefit in the treatment of HCV infection disease.
  • composition comprising a fused benzene derivative, its prodrug or a pharmaceutically acceptable salt thereof as an active ingredient
  • a pharmaceutically acceptable carrier such as an organic or inorganic carrier or excipient suitable for external (topical), enteral, intravenous, intramuscular, parenteral or intramucous applications in a pharmaceutical preparation for example, in solid, semisolid or liquid form.
  • composition comprising a fused benzene derivative, its prodrug or a pharmaceutically acceptable salt thereof can be formulated, for example, with the conventional non-toxic, pharmaceutically acceptable carriers for ointment, cream, plaster, tablets, pellets, capsules, suppositories, solution (saline, for example), emulsion, suspension (olive oil, for example), aerosols, pills, powders, syrups, injections, troches, cataplasms, aromatic waters, lotions, buccal tablets, sublingual tablets, nasal drops or any other form suitable for use.
  • the carriers which can be used are water, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paster, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other conventional carriers suitable for use in manufacturing each preparation.
  • auxiliary, stabilizing, thickening or coloring agent and perfume may be optionally used.
  • the fused benzene derivative, its prodrug or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical composition in an effective amount to treat or prevent the diseases.
  • the present invention provides a pharmaceutical composition containing a fused benzene derivative, its prodrug or a pharmaceutically acceptable salt thereof in admixture of a pharmaceutically acceptable carrier for treating or preventing virus infections and associated disease caused by viruses within the Flaviviridae family : chronic liver disease, cirrhosis, hepatocellular carcinoma and liver failure; abortion, teratogenesis, respiratory problem, chronic wasting disease, immune system dysfunction and predisposition to secondary viral and bacterial infections; dengue fever viruses, yellow fever virus and Japanese encephalititis virus.
  • Mammals which may be treated by the pharmaceutical composition of the present invention include livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and humans, preferably humans.
  • an average single dose of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, and 1000 mg of the fused benzene derivative may be effective for treating the above-mentioned diseases.
  • amounts between 0.01 mg/body and about 1,000 mg/body may be administered per day.
  • Example 5 l,3(2H,4H)-Isoquinolinedione (200 mg), potassium carbonate (189 mg) and N,N-dimethylformamide (4 ml) were mixed and cooled to
  • Triethylamine 0.079 ml
  • benzoyl chloride (0.127 ml) were added to a mixture of 6-amino-l,3(2H,4H)-isoquinolinedione (80 mg) in
  • Example 11 Sodium borohydride (141 mg) was added to a solution of l,3(2H,4H)-isoquinolinedione (300 mg) in methanol (20 ml) and dichloromethane (45 ml) under nitrogen atmosphere at room temperature. The reaction mixture was stirred for 15 hours at room temperature, and concentrated in vacuo. Chloroform and water were added to the residue. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel with a mixture of chloroform/ methanol (10: 1) as eluent. The obtained product was triturated with diethyl ether to give 3-hydroxy-3,4-dihydro-l(2H)-isoquinolinone (30.3 mg) as a pale yellow solid. mp. 110- 112°C
  • Example 12 l,3(2H,4H)-Isoquinolinedione (200 mg) and potassium carbonate (352 mg) were suspended in N,N-dimethylformamide (4 ml), and cooled to 0°C under nitrogen atmosphere. Then iodomethane
  • Example 13 A solution of hydroxylamine hydrochloride (1.26 g) in ethanol (2 ml) and water (2 ml) was added dropwise to a solution of l,3-dihydro-2H-inden-2-one (2 g) in pyridine (6 ml). The mixture was stirred for 3 hours at room temperature. Water was added to the mixture, and resulting precipitate was collected by filtration to give l,3-dihydro-2H-inden-2-one oxime (1.93 g) as an off-white solid, mp. 154-155.5°C
  • Phosphorus pentachloride (2.23 g) was added to a solution of 1 ,3-dihydro-2H-inden-2-one oxime (1.5 g) in chloroform (45 ml) under nitrogen atmosphere at -30°C. The mixture was stirred for 10 minutes at -30°C and for 3 hours at room temperature, and then poured into ice-water. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel with a mixture of chloroform/methanol (20: 1) as eluent.
  • Example 19 tert-Butyl (triphenylphosphoranylidene)-acetate (437 mg) was added portionwise to a solution of l-(4-bromo-2-fluorobenzyl)-5-nitro-lH-indole-2,3-dione (400 mg) in tetrahydrofuran (8 ml) under nitrogen atmosphere at room temperature. The reaction mixture was stirred for 2 hours at 60°C, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with a mixture of n-hexane /ethyl acetate (3: 1) as eluent.
  • Trifluoroacetic acid 1 ml was added to a solution of tert-butyl (2E)-[l-(4-bromo-2-fluorobenzyl)-5-nitro-2-oxo-l,2-dihydro-3H-indol-3- ylidene]ethanoate (100 mg) in dichloromethane (0.5 ml) at 0°C. The mixture was stirred for 30 minutes at room temperature, and concentrated in vacuo.
  • Tin(II) chloride dihydrate (11 g) was added to a suspension of 5-nitro-2-(4-nitrophenyl)-lH-benzimidazole (2.3 g) in concentrated hydrochloric acid (25 ml). The mixture was heated to reflux for 4 hours and cooled to room temperature. Ethanol was added to the solution. The resulting precipitate was collected by filtration in vacuo.
  • Example 27 The following compounds (1) and (2) were obtained in a manner similar to Example 26.
  • Acetyl chloride (0.166 ml) was added dropwise to a solution of 2-(4-aminophenyl)-lH-benzimidazol-5-amine (209 mg) and N,N-diisopropylethylamine (0.406 ml) in tetrahydrofuran (4.5 ml) under nitrogen atmosphere at -78°C. The mixture was stirred for 22 hours at room temperature, and diluted in ethyl acetate. The separated organic solution was washed with water, an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo.
  • Example 30 The following compounds in (1) to (3) were obtained in a manner similar to Example 29.
  • Example 32 S.M.I (1 g) in ethanol (15 ml) was added to a solution of ammonium chloride (156 mg) in water (1.5 ml). Then iron (697 mg) was added to the solution at room temperature, and the mixture was refluxed for 3 hours. After cooled to room temperature, the mixture was filtered through a celite pad. The filtrate was concentrated in vacuo. The resulting solid was washed with water and acetonitrile to give 4-(3H-imidazo[4,5-b]pyridin-2-yl)phenylamine (207.5 mg) as a darkish yellow solid. mp. >300°C
  • Ethyl 4,4,4-trifluoro-3-oxobutanoate (0.821ml) was added to a solution of 2,2-dihydroxy- lH-indene- l,3(2H)-dione (1 g) in warm water (20 ml). The mixture was stirred for 2 hours at 90°C, and cooled to room temperature. The resulting precipitate was collected by filtration, and crystallized from diethyl ether/n-hexane.
  • the mixture was diluted in chloroform, and washed with a aqueous saturated sodium hydrogen carbonate solution, water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo.
  • the resulting residue was purified by flash column chromatography over silica gel with a mixture of chloroform /ethyl acetate (20: 1) as eluent.
  • Example 40 4N Solution of hydrochloric acid in ethyl acetate (6 ml) was added to a solution of tert-butyl (3aS,8bR)-3a,8b-dihydroxy- 2-methyl-4-oxo-4,8b-dihydro-3aH-indeno[ 1 ,2-b]furan-3-carboxylate (617 rag) in ethyl acetate (2 ml).
  • Example 42 A suspension of l,3(2H,4H)-isoquinolinedione (500mg) in ethyl acetate (15ml) was added to a mixture of ruthenium (IV) oxide hydrate (31mg) and 10% sodium periodate (30mg) at room temperature. The reaction mixture was vigorously stirred at room temperature for 15 minutes. After the layers were separated, the aqueous layer was extracted with AcOEt (3 times). The combined organic solution was treated with 2-propanol (2ml) for 2.5 hours to decompose ruthenium (VIII) oxide and then the black precipitates (ruthenium (IV) oxide) were filtered off.

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Description

DESCRIPTION
PHARMACEUTICAL COMPOSITION FOR TREATING OR PREVENTING VIRUS INFECTIOUS DISEASES
TECHNICAL FIELD
This invention relates to pharmaceutical compositions for treating or preventing virus infectious diseases, particularly to those for treating or preventing virus infectious diseases caused by viruses belonging to Flaviviridae family.
BACKGROUND ART
Flaviviridae family consists of hepacivirus genus, pestivirus genus, flaviviruses and other several viruses that are currently unassigned to specific genera. Viruses belonging to this family cause significant diseases in human beings and animals. For example, hepatitis C virus (HCV) included in hepacivirus genus is a major cause of human hepatitis globally. It is known that most HCV infections become persistent and about 60 % of the cases develop chronic liver disease. Chronic HCV infection can lead to development of cirrhosis, hepatocellular carcinoma and liver failure. The treatment currently available for HCV infection is to administrate interferon (IFN)," ribavirin, or a combination of these two medicines. However, according to clinical studies, it is said that the effectiveness of the above treatment for HCV is variable and its cure rate is low.
Pestivirus infections of domesticated livestock cause significant economic losses worldwide. Pestiviruses cause a range of clinical manifestations including abortion, teratogenesis, respiratory problem, chronic wasting disease, immune system dysfunction and predisposition to secondary viral and bacterial infections.
Flaviviruses are major pathogens of human beings and are also prevalent throughout the world. There are at least 38 flaviviruses associated with human diseases, including the dengue fever viruses, yellow fever virus and Japanese encephalititis virus. Flaviviruses cause a range of acute febrile illnesses and encephalitic and hemorrhagic diseases.
It is known that HCV contains a positive strand RNA genome comprising approximately 9400 nucleotides coding for a polyprotein of 3009-3030 amino acids whose organization is similar to that of flaviviruses and pestiviruses.
In considering approaches to the prevention and treatment of virus infectious diseases, it is often desirable to identify virus-specific functions that may be exploited in such approaches. In particular, it is known that virus-encoded RNA-dependent RNA polymerase (RdRp), which is a protein, plays a central role in the life cycle of many RNA viruses. RdRp is termed NS5B protein in the case of the hepaciviruses and pestiviruses, and NS5 protein in the case of the flaviviruses. RdRp is a key component of the virus replicase complex, enabling the virus to replicate its RNA genome and produce progeny viruses. Some compounds having inhibitory activity of RdRp have been known, for example, barbituric acid derivatives in WO00/ 13708, benzothiophene derivatives in WO00/ 18231, pyrrolidine derivatives in WO00/ 10573, diketoacid derivatives in WO00/06529, fused ring derivatives in WOO 1/47883 and nucleoside derivatives in WO01/32153.
DISCLOSURE OF INVENTION
An object of this invention is to provide a pharmaceutical composition containing a fused benzene derivative selected from the compounds represented by the formulae (la) to (Ie), its prodrug or a pharmaceutically acceptable salt thereof, which has a RdRp inhibiting activity, as an active ingredient in admixture of a pharmaceutically acceptable carrier.
Another object of this invention is to provide a method of treating or preventing virus infectious diseases by administering the fused benzene derivative, its prodrug or a pharmaceutically acceptable salt thereof in an effective amount to inhibit RdRp.
A further object of the invention is to provide a use of the fused benzene derivative, its prodrug or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition. The fused benzene derivatives included in the pharmaceutical composition of this invention are represented by the following formulae (la), (lb), (lc), (Id) and (Ie): Formula (la) :
Figure imgf000004_0001
wherein
Rla is hydrogen atom, or nitro or a lower alkoxy group, and
R2a is hydrogen atom, or nitro, amino, an acylamino or lower alkanesulfonyl group, or
Ria and R2a together with the adjacent carbon atoms to which they are attached form an aryl group,
R3a and R4a g^ the same or different, hydrogen atom, or a lower alkyl, ar(lower)alkyl, aryl group or the group of the formula
-CH=N-O-ar(lower)alkyl, among which the ar (lower) alkyl and the group of the formula -CH=N-O-ar(lower)alkyl may be substituted with one or more substituent(s) , or R3a and R4a form oxo group,
R5a and R6a are, the same or different, hydrogen atom or hydroxy group, or
R5a and R6a form oxo group,
R8a and R9a are, the same or different, hydrogen atom or hydroxy group, or
R8a and R9a form oxo group,
Xa is N-R7a or O wherein R7a is hydrogen atom, or hydroxy, a lower alkyl, aryl, ar (lower) alkyl or ar (lower) alkoxy group, among which the ar (lower) alkoxy group may be substituted with one or more substituent(s),
further R3a and R4a together with the carbon atoms to which they are attached may form a cycloalkane ring or
Figure imgf000005_0001
wherein Ya is CH or N, and R10a is hydroxy, an aryl, arylamino or lower alkoxy group, among which the aryl and arylamino groups may be substituted with one or more substituent(s), or
R3a together with R5a or R6a with the carbon atoms to which they are attached may form a bond or a cycloalkane ring,
Formula (lb):
Figure imgf000005_0002
wherein
Rlb is hydrogen or halogen atom, or nitro, a lower alkyl, halo (lower) alkyl, lower alkoxy or halo (lower) alkoxy group,
R2b and R3b are, the same or different, hydrogen atom, or a lower alkyl, aryl, ar(lower)alkyl, heterocyclic or acyl group, among which the lower alkyl and ar (lower) alkyl groups may be substituted with one or more substituent(s), or R2b and R3b together with the carbon atoms to which they are attached form a cycloalkane ring which may be substituted with halo(lower)alkyl-substituted aryl,
R4b and R5b are, the same or different, hydrogen or halogen atom, or an aryl or ar (lower) alkyl group, among which the ar (lower) alkyl group may be substituted with one or more halogen atom(s), or R4b and R5b form oxo group or an ethylene group which may be substituted with one or two substituent(s),
Formula (lc):
Figure imgf000006_0001
wherein
Rlc is hydrogen or a halogen atom, or nitro, a lower alkyl, lower alkoxy or lower alkylthio group, and
R2c is hydrogen or halogen atom or a lower alkoxy group, or
Rlc and R c together with the adjacent carbon atoms to which they are attached form an aryl group,
R3c is hydrogen or a halogen atom, or nitro, a lower alkyl or halo (lower) alkoxy group, and
X<= is CH or N,
Formula (Id):
Figure imgf000006_0002
wherein
Rld is hydrogen atom, or nitro, amino or an acylamino group, R2d is an optionally substituted aryl or ar (lower) alkyl group, and Xd is CH or N,
and Formula (Ie):
Figure imgf000006_0003
wherein
Rle is hydrogen atom or a lower alkoxy group,
R2e is hydrogen atom, or
Rle and R2e together with the adjacent carbon atoms to which they are attached form an aryl group,
R3e and R4e are hydrogen atoms or form oxo group,
Figure imgf000007_0001
,OH R7e and Ye is CH2, C=O, NH, =C^ or =Q^ 8e
OH Roe
wherein R5e, R6e, R7e and R8e are, the same or different, hydrogen atom, or hydroxy, a lower alkyl, lower alkoxy, aryl, acyloxy or carbocyclic group, among which the lower alkyl, aryl and carbocyclic groups may be substituted with one or more substituent(s), and further R6e and R7e together with the carbon atoms to which they are attached may form an optionally substituted unsaturated heterocyclic ring.
Suitable examples and illustrations of the various definitions in the formulae (la) to (Ie) are explained in detail as follows. The term "lower" means a group having 1 to 6 carbon atom(s), unless otherwise provided.
The term "one or more" means 1 to 6, preferably 1 to 3, and more preferably 1 or 2.
Suitable examples of the lower alkyl group for R3a, R4a, R7a, Rlb, R2b, R3b, Rlc, R3c, R5e, R6e, R7e and R8e and the lower alkyl moieties in the ar (lower) alkyl group for R3a, R4a, R7a, R2 , R3b, R4b, R5b and R2d, halo (lower) alkoxy group for Rlb and R3c and lower alkylthio group for Rlc and are straight or branched ones having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-ethylbutyl, isobutyl, tert-butyl, pentyl and n-hexyl. Suitable examples of the lower alkanesulfonyl group for R2a are methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl and pentanesulfonyl.
Suitable examples of the lower alkoxy group for Rla, R10a, Rlb, Rlc, R2c, Rle, R5e, R6e, R7e and R8e the lower alkoxy moieties in the halo (lower) alkyl group for Rlb, R2b and R3b and ar(lower)alkoxy group for R7a are methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy.
Suitable examples of the halogen atom for Rlb, R4 , R5b, Ri , R2c and R3c and halogen moieties in the halo (lower) alkyl group for Rlb, R2b and R3 and halo (lower) alkoxy group for Rlb and R3c are fluorine, chlorine, bromine and iodine.
Suitable examples of the aryl group for Rla, R2a, R3a, R4a, R7 ,
Rlto R2b; R3b? R4b; R5b; R1C> R2c; R2d; R2βj R5e; R6e; R7e and R8e and the aryl moieties in the arylamino group for R10a, ar(lower)alkyl group for R3a, R4a, R7a, R3b, R4b, R5 and R d and ar (lower) alkoxy group for R7a are aromatic hydrocarbon residues containing 6 to 12 carbon atoms, such as phenyl, tolyl, xylyl and naphthyl.
Suitable examples of the heterocyclic group for R2 and R3b are saturated or unsaturated, monocyclic or condensed heterocyclic groups containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms.
Preferable examples of the heterocyclic group are described in the following.
(1) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl;
(2) saturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperidino or piperazinyl;
(3) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl or oxadiazolyl; (4) saturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, morpholinyl;
(5) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl or thiadiazolyl;
(6) saturated 3 to 7-membered preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiomorpholinyl or thiazolidinyl;
(7) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms, for example, furyl or pyranyl;
(8) saturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms, for example, 1,4-dioxanyl; (9) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms, for example, thienyl;
(10) saturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms, for example, tetrahydro thienyl;
(11) unsaturated condensed heterocyclic group containing 1 to 3 nitrogen atoms, for example, benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, quinolyl, isoquinolyl, indolyl or indolinyl; (12) unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms, for example, benzofuryl or benzodioxolyl;
(13) unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms, for example, benzo[b]thienyl;
(14) unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl or phenoxazinyl; and
(15) unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl, benzisothiazolyl or phenothiazinyl. Suitable examples of the unsaturated heterocyclic ring for R6e and R7e are unsaturated, mono- or condensed-heterocyclic rings containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms such as
(1) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic ring containing 1 to 4 nitrogen atoms, for example, pyrrole, dihydropyrrole, pyrroline, imidazole, pyrazole, pyridine, tetrahydropyridine, pyrimidine, tetrahydropyrimidine, pyrazine, pyridazine, triazole or tetrazole;
(2) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic ring containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazole or isoxazole;
(3) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic ring containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, isothiazole or thiadiazole; (4) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic ring containing 1 to 2 oxygen atoms, for example, furan, dihydrofuran or pyran;
(5) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic ring containing 1 to 2 sulfur atoms, for example, thiophene;
(6) unsaturated condensed heterocyclic ring containing 1 to 3 nitrogen atoms, for example, benzopyrrole, benzimidazole, benzopyrazole, benzotriazole, quinoline, isoquinoline or indole;
(7) unsaturated condensed heterocyclic ring containing 1 to 2 oxygen atoms, for example, benzofuran, dihydrobenzofuran or benzodioxole;
(8) unsaturated condensed heterocyclic ring containing 1 to 2 sulfur atoms, for example, benzo[b]thiophene;
(9) unsaturated condensed heterocyclic ring containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazole, benzoxadiazole or phenoxazine; and
(10) unsaturated condensed heterocyclic ring containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, benzothiazole, benzisothiazole or phenothiazine. Suitable examples of the acyl group for R2b and R3b and acyl moieties in the acylamino group for R2a and Rld and acyloxy group for R5e, R6e, R7e and R8e are aliphatic acyl, aromatic acyl and heterocyclic acyl, which are derived from carboxylic acid, and lower alkylcarbamoyl and arylcarbamoyl groups, which are derived from carbamic acid. The examples of aliphatic acyl group are
(1) lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl or hexanoyl) ;
(2) cyclo (lower) alkylcarbonyl (e.g. cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl or cyclohexylcarbonyl); and (3) lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl or 3-methylbutanoyl) .
The examples of the aromatic acyl group are aroyls (e.g. benzoyl and naphthoyl) which may be substituted with nitro, amino, thenoylamino, or the like. The examples of the heterocyclic acyl group are the heterocyclic carbonyl groups such as furoyl, thenoyl, nicotinoyl and the like.
The examples of the lower alkylcarbamoyl group are methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl and the like.
The examples of the arylcarbamoyl group are phenylcarbamoyl and naphthylcarbamoyl.
Suitable examples of the cycloalkane ring for R3a, R4a, R5a, R6a, R2b and R3b are cyclic hydrocarbon having 3 to 7 carbon atom, such as cyclobutane, cyclopentane, cyclohexane and cycloheptane.
Suitable examples of the carbocyclic group for R5e, R6e, R6e and R8e are cyclic hydrocarbon residues having 3 to 7 carbon atoms, such as cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl and indenyl.
Suitable examples of the halo (lower) alkyl group for Rlb, R2b and R3b and the halo (lower) alkyl moiety in the halo (lower) alkoxy group for Rlb and R3c are Cι- , preferably C1-2 alkyl groups containing 1 to 5, preferably 1 to 3 halogen atoms, preferably fluorine, chlorine and/ or bromine atom(s), more preferably fluorine and/ or chlorine atom(s). Preferable examples thereof are chloromethyl, bromomethyl, 1-fluoroethyl, 2-fluoroethyl, trifluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, 2,2-difiuoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl. Suitable examples of the ar (lower) alkyl group for R3a, R4a, R7a, R b, R3b, R4 , R5b and R2d and the ar (lower) alkyl moiety in the ar (lower) alkoxy group for R7a are benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, benzhydryl, trityl and naphthylmethyl.
Suitable examples of the halo(lower)alkyl-substituted aryl group for R2b and R3b are (chloromethyl) phenyl, (trifluoromethyl)phenyl and (2,2,2-trichloroethyl)naphthyl.
When the above groups for R3a, R4a, R7a, Ri°a, R2b, R3b, R4b, R ,
R2d, R5e, R6e, R7e and R8e are substituted with one or more substituent(s), said substituent may be hydroxy; amino; carboxy; cyano; nitro; carbamoyl; oxo; halogen (e.g., fluorine, bromine or chlorine); lower alkyl (e.g., methyl, ethyl, isopropyl or tert-butyl) optionally substituted with lower alkoxy (e.g., methoxy); aryl (e.g., phenyl or naphthyl ) optionally substituted with one or more of halogen (e.g., fluorine, bromine or chlorine); heterocyclyl (e.g., pyridyl, morpholinyl, pyrrolidinyl, piperazinyl or pyrimidyl); halo (lower) alkyl (e.g., trifluoromethyl); ar (lower) alkyl (e.g., benzyl); lower alkoxy (e.g., methoxy, ethoxy, butoxy or n-propoxy); aryloxy (e.g., phenoxy); lower alkanoyloxy (acetyloxy); lower alkanoyl (e.g., acetyl or formyl); aroyl (e.g., benzoyl); halo (lower) alkanoyl (e.g., triflluoroacetyl); heterocyclylcarbonyl (e.g., furoyl or morpholinylcarbonyl); lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl or isopropoxycarbonyl) ; ar (lower) alkoxycarbonyl (e.g., benzyloxycarbonyl) ; arylcarbamoyl (e.g., phenylcarbamoyl);ar(lower)alkylcarbamoyl (e.g., benzylcarbamoyl); (lower) alkanoylamino (e.g., acetylamino); aroylamino (e.g., benzoylamino) optionally substituted with heterocyclylcarbonylamino (e.g., thenoylamino); heterocyclylcarbonylamino (e.g., thenoylamino); (lower) alkylthio (e.g., methylthio); or the like.
Suitable pharmaceutically acceptable salts of the fused benzene derivative, i.e., (la) to (Ie) are conventional and non-toxic salts, for example an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartarate, oxalate, methanesulfonate, benzenesulfonate or toluenesulfonate), an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate or phosphate), a salt with an amino acid (e.g. aspartate or glutamate), and the like.
The fused benzene derivative may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomer s .
The fused benzene derivative may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
The fused benzene derivative and its salt can be in a form of a solvate, which is also included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate. Also included in the scope of the invention are radiolabelled derivatives of fused benzene derivatives which are suitable for biological studies.
The "prodrug" may be a derivative of the fused benzene derivative having a chemically or metabolically degradable group, which becomes pharmaceutically active substance after biotransformation .
Some fused benzene derivatives, their prodrugs or salts thereof are commercially available. Novel fused benzene derivative, its prodrug or a salt thereof can be prepared by the following processes. The other fused benzene derivatives can be prepared by the known processes or analogous processes thereto or by analogous processes to the following Examples.
Process 1 for compound (la)
Figure imgf000013_0001
(Ha) (Ia-1) Process 2 for compound (lb)
Figure imgf000014_0001
(lib) (lb)
Process 3 for compound (lc)
Figure imgf000014_0002
Process 4 for compound (Id)
Figure imgf000014_0003
did) (Id)
Process 5 for compound (Ie)
Figure imgf000014_0004
(He) (Ie-1)
wherein Ria, R a, R3a, R a, R a, Rib, R2b, R3b, R4b? R5b; RIC) R2C; R3CJ χc> Ridj R2d, Xd, Rie and R2e are each as defined above, and X is a leaving group.
Suitable leaving group for X may be halogen (e.g., fluoro, chloro, bromo or iodo), arenesulfonyloxy (e.g., benzenesulfonyloxy or tosyloxy), alkanesulfonyloxy (e.g., mesyloxy or ethanesulfonyloxy), or the like, among which the preferable one is halogen.
The processes 1 to 5 can be carried out according to the processes described in the Examples below.
In order to illustrate the usefulness of the pharmaceutical composition according to the present invention, the pharmacological test of the fused benzene derivative is explained in the following.
The evaluation as inhibitors against HCV RNA-dependent RNA polymerase (RdRp) was carried out by using C terminal truncated recombinant HCV NS5B and oligo (G) 12/poly C as primer/ template. The in vitro RdRp activity was measured by determining the incorporation of [H3] GMP into the template /primer by either of Scintillation Proximity Assay (SPA) or exclusion column chromatography.
1. Expression and purification of truncated HCV RdRp for evaluation test HCV NS5B protein which lacked highly hydrophobic C-terminal
21 amino acids was expressed in bacteria (E.coli BL-21) because the full length HCV NS5B protein was frequently precipitated for poor solubility during purification steps. Furthermore, truncated RdRp was expressed as N-terminally GST fused and C-terminally His tagged protein in order to facilitate its purification. The cDNA coding region of C terminal truncated and C-terminally His tagged HCV NS5B protein of HCV BK strain (genotype lb) were introduced BamH I site and translation initiation codon (ATG) at the 5' end and Sal I site at the down stream of stop codon. The cDNA coding region was ligated to glutathione S-transferase (GST) expression vector (pGEX4T-2) at BamH I and Sal I sites. Bacteria was transfected with the recombinant vector according to the heat shock method. Expression of the truncated HCV RdRp were accelerated by 0.4 mM isopropyl- β -D-thiogalactopyranoside (IPTG) and monitored by SDS-PAGE analysis. The sonicated bacterial suspension in buffer A (PBS including ImM DTT and 1% Triton X-100) was processed to purify the truncated RdRp as follows. The lysate was adjusted to 0.33 M NaCl and applied to DEAE sephacel column. The fraction passed through the DEAE column was incubated batchwise with DEAE Glutathione Sepharose 4B beads equilibrated with buffer A for 1 hour at 4°C. The beads was washed and the truncated RdRp was eluted in buffer B (50mM Tris-HCl (pH 8.0), 10 mM glutathione, 10 mM DTT and 0.1 % Triton X- 100) including 500 mM NaCl. The eluted supernatant was dialyzed against buffer B containing 150 mM NaCl and loaded onto Heparin Sepharose CL-6B column equilibrated with LG buffer (20 mM Tri-HCl (pH 7.5), ImM EDTA, 5mM DTT, 20% glycerol and 0.5% Triton X-100) containing 0.15 M NaCl. The bound proteins were evaluated using 0.15 to 1M NaCl gradient and fractionated in 2 ml. The fractions containing truncated RdRp which was confirmed by SDS-PAGE were loaded onto poly (U) Sepharose 4B equilibrated with LG buffer including 0.15 M NaCl. The bound proteins were also eluted using 0.15 to 1M NaCl gradient and fractionated in 2 ml. The fractions containing truncated RdRp were corrected and stored as a glycerol solution at -80°C . Truncated RdRp in the final pool was confirmed by western blotting.
2. In vitro truncated RdRp assay
This assay method was modified procedure of the methods described in the publications: Behrens SE, Tomei L and De Francesco R, EMBO J., 1996, Jan 2, 15 (1), 12-22; Lohmann V, Korner F, Herian U and Bartenschlager R, J. Virol, 1997, Nov, 71 (11), 8416-28; and Yamashita T, Kaneko S, Shirota Y, Qin W, Nomura T, Kobayashi K and Murakami S, J. Bol. Chem., 1998, Jun 19, 273 (25), 15479-86.
RdRp reaction was carried out in a 20 μ 1 of RdRp buffer (20 mM Tris-HCl (pH 7.5), ImM EDTA, 5mM MgCl2, 25 mM KCl and ImM DTT), 0.01 % BSA, 0.05 mg/ml Actionmycin D, 1.5 U RNasin, 0.075 mCi/ml [H3]-GTP, 4 pmmol biotinylatted oligo(G) 12, 500 ng ρoly(C), the truncated RdRp final fraction. After 2 hours of incubation at 22°C, productive radioactivity was separated from non-reactive one according to the following two methods. For SPA method, streptavidin conjugated SPA bead and uM GTP was added to the reaction mixture. The radioactivity captured with the beads was measured in the scintillation counter. For exclusion column chromatography, uM GTP was added to the reaction mixture and loaded onto Sephadex G-50, a quick spin column. After centrifugation of the column, the radioactivity in the elution was measured in the scintillation counter. The radioactivity corresponding to increasing doses of each compound was plotted and IC50 values were determined.
3. Result
Table 1 in vitro RdRp activity (IC50) of the test compound.
Figure imgf000017_0001
The fused benzene derivatives included in the pharmaceutical compositions of the present invention have a potent RdRp inhibitory activity as shown in the above. Therefore, it is suggested that the fused benzene derivatives may have protective benefit in the treatment of HCV infection disease.
The composition comprising a fused benzene derivative, its prodrug or a pharmaceutically acceptable salt thereof as an active ingredient can be in admixture of a pharmaceutically acceptable carrier such as an organic or inorganic carrier or excipient suitable for external (topical), enteral, intravenous, intramuscular, parenteral or intramucous applications in a pharmaceutical preparation for example, in solid, semisolid or liquid form. The composition comprising a fused benzene derivative, its prodrug or a pharmaceutically acceptable salt thereof can be formulated, for example, with the conventional non-toxic, pharmaceutically acceptable carriers for ointment, cream, plaster, tablets, pellets, capsules, suppositories, solution (saline, for example), emulsion, suspension (olive oil, for example), aerosols, pills, powders, syrups, injections, troches, cataplasms, aromatic waters, lotions, buccal tablets, sublingual tablets, nasal drops or any other form suitable for use. The carriers which can be used are water, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paster, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other conventional carriers suitable for use in manufacturing each preparation. In addition to the above, auxiliary, stabilizing, thickening or coloring agent and perfume may be optionally used. The fused benzene derivative, its prodrug or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical composition in an effective amount to treat or prevent the diseases.
The present invention provides a pharmaceutical composition containing a fused benzene derivative, its prodrug or a pharmaceutically acceptable salt thereof in admixture of a pharmaceutically acceptable carrier for treating or preventing virus infections and associated disease caused by viruses within the Flaviviridae family : chronic liver disease, cirrhosis, hepatocellular carcinoma and liver failure; abortion, teratogenesis, respiratory problem, chronic wasting disease, immune system dysfunction and predisposition to secondary viral and bacterial infections; dengue fever viruses, yellow fever virus and Japanese encephalititis virus.
Mammals which may be treated by the pharmaceutical composition of the present invention include livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and humans, preferably humans.
While the dosage of therapeutically effective amount of the fused benzene derivative varies depending upon the age and condition of each patient, an average single dose of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, and 1000 mg of the fused benzene derivative may be effective for treating the above-mentioned diseases. In general, amounts between 0.01 mg/body and about 1,000 mg/body may be administered per day.
BEST MODE FOR CARRYING OUT THE INVENTION
The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail, but are not to be construed to limit the scope of the present invention.
Preparation 1
A solution of 2-bromo-5-nitrobenzoic acid (6.3g) in dimethyl malonate (58.5 ml) was perfused with nitrogen gas for 15 minutes. Sodium methoxide (3.32 g) was added to the solution in one portion, and the resulting mixture was stirred at room temperature for 15 minutes. Then cuprous bromide (367 mg) was added to the solution in one portion. The mixture was heated for 5 hours at 85°C and cooled to room temperature. Water (100 ml) was added to the mixture. The aqueous layer was extracted with diethyl ether (100 ml * 3), and then acidified with 2N-hydrochloric acid. The acidic aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting solid was washed with diethyl ether/n-hexane, and then isopropyl ether to give 2-[2-methoxy-l-(methoxycarbonyl)-2-oxoethyl]-5-nitrobenzoic acid (4.3 g) as an off-white solid, mp. 169-170°C
NMR(DMSO-d6, δ ): 3.70(6H, s), 5.87(1H, s), 7.66(1H, d, J=8.5Hz), 8.44(1H, dd, J=8.5, 2.5Hz), 8.66(1H, d, J=2.5Hz). Mass : 296(M-1)+
Preparation 2 lN-Sodium hydroxide (20.2 ml) was added to a solution of 2-[2-methoxy-l-(methoxycarbonyl)-2-oxoethyl]-5-nitrobenzoic acid (2 g) in methanol (20 ml) . The reaction mixture was stirred for 7 hours at 70°Cand cooled to room temperature. Methanol was removed from the mixture in vacuo. The resultant aqueous mixture was acidified with 6N-hydrochloric acid at 0°C. The aqueous solution was extracted with ethyl acetate (twice). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting solid was washed with dichloromethane to give 2-(carboxymethyl)-5-nitrobenzoic acid (1.27 g) as a pale yellow solid, mp. 182-184°C NMR(DMSO-d6, δ ): 4.11(2H, s), 7.67(1H, d, J=8.5Hz), 8.375(1H, dd, J=8.5, 2.5Hz), 8.62(1H, d, J=2.5Hz). Mass : 224(M-1)+
Preparation 3
A mixture of 2-(carboxymethyl)-5-nitrobenzoic acid (100 mg), 1 ,2-dichloroethane (2 ml) and acetic anhydride (0.126 ml) was refluxed under nitrogen atmosphere for 5 hours and cooled to room temperature. The reaction mixture was concentrated in vacuo. The resulting solid was washed with diethyl ether to give 7-nitro- lH-2-benzopyran-l,3(4H)-dione (61.2 mg) as a pale brown solid. mp. 151-153°C
NMRfDMSO-de, *-? ): 4.42(2H, s), 7.74(1H, d, J=8.5Hz), 8.54(1H, d, J=8.5Hz), 8.68(1H, s). Mass : 206(M- 1)+
Preparation 4
A mixture of ethyl 3-oxobutanoate (37.9 ml), ethanol (100 ml), sodium ethoxide (16.9 g), cuprous bromide (7.12 g) and 2-chloro-4-nitrobenzoic acid (20 g) was heated to 90°C under nitrogen atmosphere for 5 hours and cooled to room temperature. The mixture was filtered through a celite pad. The filtrate was concentrated in vacuo. The residue was dissolved in 2N-hydrochloric acid, and the acidic solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel with a mixture of chloroform/ methanol (10: 1) as eluent. The obtained oilly product was solidified with isopropyl ether/ n-hexane to give 2-(2-ethoxy-2-oxoethyl)-4-nitrobenzoic acid (5.03 g) as an off-white solid. mp. 140.5- 141°C
NMR(DMSO-d6, δ ): 1.17(3H, t, J=7.0Hz), 4.07(2H, q, J=7.0Hz), 4.16(2H, s), 8.12(1H, d, J=8.5Hz), 8.23(1H, dd, J=8.5, 2.0Hz), 8.30(1H, d,
J=2.0Hz). Mass : 252(M-1)+
Preparation 5
2-(2-Ethoxy-2-oxoethyl)-4-(methylsulfonyl)benzoic acid was obtained in a manner similar to Preparation 4. mp. 147-148°C
NMR(DMSO-d6, <5 ): 1.18(3H, t, J=7.0Hz), 3.27(3H, s), 4.07(2H, q, J=7.0Hz), 4.12(2H, s), 7.95(1H, d, J=8.5Hz), 7.97(1H, s), 8.12(1H, d, J=8.5Hz), 13.48(1H, brs). Mass : 285(M-1)+ Preparation 6 lN-Sodium hydroxide (3.95 ml) was added to a solution of 2-(2-ethoxy-2-oxoethyl)-4-nitrobenzoic acid (400 mg) in 1,4-dioxane (8 ml). The mixture was stirred at room temperature for 2 hours, and acidified with lN-hydrochloric acid. The organic solvent was evaporated in vacuo, and the resulting precipitate was collected by filtration. The solid was washed with diethyl ether to give 2-(carboxymethyl)-4-nitrobenzoic acid (284.9 mg) as a colorless solid. mp. 192.5- 193°C
NMR(DMSO-d5, <5 ): 4.10(2H, s), 8.09(1H, d, J=8.5Hz), 8.22(1H, dd, J=8.5, 2.0Hz), 8.28(1H, d, J=2.0Hz). Mass : 224(M-1)+
Preparation 7
2-(Carboxymethyl)-4-(methylsulfonyl)benzoic acid was obtained in a manner similar to Preparation 6. mp. 220-221°C
NMR(DMSO-d6, ό ): 3.27(3H, s), 4.06(2H, s), 7.93(1H, d, J=8.5Hz), 7.94(1H, s), 8.09(1H, d, J=8.5Hz).
Mass : 257(M-1)+
Preparation 8
A mixture of 2-(carboxymethyl)-4-nitrobenzoic acid (2 g), toluene (30 ml) and acetic anhydride (1.68 ml) was refluxed under nitrogen atmosphere for 5 hours and cooled to room temperature. The reaction mixture was concentrated in vacuo. The resulting solid was washed with diethyl ether to give
6-nitro-lH-2-benzopyran-l,3(4H)-dione (1.56 g) as a pale yellow solid. mp. 140-143°C
NMR(DMSO-d6, 5 ): 4.40(2H, s), 8.28(2H, s), 8.35(1H, s).
Mass : 206(M-1)+
Preparation 9 The following compounds (1) and (2) were obtained in a manner similar to Preparation 8.
(1) 6-(Methylsulfonyl)-lH-2-benzopyran- l,3(4H)-dione mp. 249-250°C NMRfDMSO-dβ. ff ): 3.32(3H, s), 4.38(2H, s), 8.03(1H, d, J=8.0Hz), 8.05(1H, s), 8.28(1H, d, J=8.0Hz). Mass : 239(M- 1)+
(2) lH-Naphtho[2,3-c]pyran- 1 ,3(4H)-dione mp. 165-166.5°C
Preparation 10
A mixture of naphtho[2,3-c]furan-l,3-dione (10 g) in tetrahydrofuran (50 ml) and N,N-dimethylformamide (50 ml) was added dropwise to a suspension of sodium borohydride (1.91 g) in tetrahydrofuran (25 ml) under nitrogen atmosphere over 10 minutes at
0°C. The reaction mixture was stirred for 45 minutes at room temperature, and acidified with 6N-hydrochloric acid at 0°C. The mixture was concentrated in vacuo to a volume of ca. 80ml. The resulting precipitate was collected, and washed with water and diethyl ether to give naphtho[2,3-c]furan-l(3H)-one (4.77 g) as a colorless solid. mp. 195-197°C
NMR(DMSO-d6) <5 ): 5.84(2H, s), 7.65(1H, t, J=8.0Hz), 7.73(1H, t, J=8.0Hz), 8.10(1H, d, J=8.0Hz), 8.16(1H, s), 8.22(1H, d, J=8.0Hz),
8.60(1H, s).
Mass : 185(M+1)+
Preparation 11 A mixture of naphtho[2,3-c]furan-l(3H)-one (8 g) and finely ground potassium cyanide (9.33 g) was heated for 5 hours at 200°C and cooled to room temperature. Water (80 ml) was added to the mixture, and resulting insoluble material was filtered off. The filtrate was acidified with 6N hydrochloric acid and extracted with ethyl acetate (twice). The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was washed with diethyl ether, and then added to a solution of potassium hydroxide (9.26 g) in water (40 ml). The mixture was refluxed for 2 hours, and cooled to room temperature. The mixture was acidified with 6N hydrochloric acid. The resulting solid collected by filtration was washed with water and ethanol to give 3-(carboxymethyl)-2-naphthoic acid (3.32 g) as a pale brown solid, mp. 202-203°C NMR(DMSO-d6, δ ): 4.08(2H, s), 7.57(1H, t, J=8.0Hz), 7.64(1H, t, J=8.0Hz), 7.83(1H, s), 7.91(1H, d, J=8.0Hz), 8.07(1H, d, J=8.0Hz), 8.55(1H, s). Mass : 229(M-1)+
Preparation 12
2-(2-Amino-2-oxoethyl)-4-(methylsulfonyl)benzoic acid was obtained in a manner similar to Example 1. mp. 209-212°C
NMR(DMSO-d6, S ): 3.24(3H, s), 3.87(2H, s), 6.90(1H, brs), 7.79(1H, brs), 7.82(1H, d, J=2.0Hz), 7.84(1H, dd, J=8.0, 2.0Hz), 7.94(1H, d, J=8.0Hz).
Example 1
28% Aqueous solution of ammonium hydroxide (8 ml) was added dropwise to a solution of lH-isochromene- l,3(4H)-dione (10 g) in N,N-dimethylformamide (20 ml) at 0°C. The reaction mixture was stirred for 15 minutes at 0°C, and concentrated in vacuo. The resulting solid was suspended in xylene (100 ml), and the suspension was stirred for 5.5 hours at 150°C and cooled to room temperature. The resulting precipitate was collected by filtration, washed with xylene, water and ethanol. The residue was purified by flash column chromatography over silica gel with a mixture of chloroform /methanol (10: 1) as eluent. The obtained solid was triturated with acetonitrile to give l,3(2H,4H)-isoquinolinedione (4.01 g) as a pale yellow solid, mp. 241.5-242.5°C NMR(DMSO-d6,<5): 4.04(2H, s), 7.39(1H, d, J=8.0Hz), 7.46(1H, t, J=8.0Hz), 7.65(1H, dt, J=1.5, 8.0Hz), 8.01(1H, dd, J=8.0, 1.5Hz), 11.31(1H, s).
Example 2
The following compounds (1) to (3) were obtained in a manner similar to Example 1.
(1) 7-Nitro- l,3(2H,4H)-isoquinolinedione mp.202-203°C NMR(DMSO-d6,<5): 4.19(2Hχl/2, s), 5.84(lHχl/2, s), 7.56(lHχl/2, d, J=8.5Hz), 7.68(lHχl/2, d, J=8.5Hz), 8.21(lHχl/2, dd, J=8.5, 2.0Hz), 8.46(lHχl/2, dd, J=8.5, 2.0Hz), 8.67(lHχl/2, d, J=2.0Hz), 8.74(lHχl/2, d, J=2.0Hz), 11.65(lHχl/2, s), 11.98(lHχl/2, s). Mass : 205(M-1)+
(2) 6-Nitro- l,3(2H,4H)-isoquinolinedione mp.261-262°C
NMR(DMSO-d6,5): 4.17(2H, s), 8.24(2H, s), 8.30(1H, s), 11.61(1H, s).
Mass :205(M-1)+
(3) Benzo[g]isoquinoline- 1 ,3(2H,4H)-dione mp.247-249°C
NMR(DMSO-d6,(5): 4.20(2H, s), 7.58(1H, t, J=8.0Hz), 7.67(1H, t, J=8.0Hz), 7.90(1H, s), 7.97(1H, d, J=8.0Hz), 8.16(1H, d, J=8.0Hz), 8.72(1H, s), 11.41(1H, s).
Example 3
A mixture of lH-isochromene-l,3(4H)-dione (500 mg), 2-chlorobenzylamine (0.409 ml) and toluene (4 ml) was refluxed under nitrogen atmosphere for 8 hours and cooled to room temperature. The mixture was diluted with chloroform. The solution was washed with lN-hydrochloric acid, water, an aqueous saturated sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel with a mixture of chloroform/methanol
(30: 1) as eluent. The obtained solid was triturated with ethanol to give
2-(2-chlorobenzyl)-l,3(2H,4H)-isoquinolinedione (243.6 mg) as an off-white solid. mp. 136.5- 137°C
NMR(DMSO-d6, <5 ): 4.30(2H, s), 5.09(2H, s), 7.11(1H, d, J=7.0Hz),
7.19-7.33(2H, m), 7.42-7.55(3H, m), 7.71(1H, t, J=7.0Hz), 8.06(1H, d,
J=7.5Hz).
Mass : 284(M-1)+
Example 4
The following compounds (1) to (3) were obtained in a manner similar to Example 3.
(1) 2-Phenyl-l,3(2H,4H)-isoquinolinedione mp. 194-195°C
Figure imgf000026_0001
): 4.28(2H, s), 7.26(2H, d, J=8.0Hz), 7.38-7.55(5H, m),
7.72(1H, t, J=8.0Hz), 8.06(1H, d, J=8.0Hz).
Mass : 236(M-1)+
(2) 2-(2-Phenylethyl)-l,3(2H,4H)-isoquinolinedione mp. 130-131.5°C
NMR(DMSO-d6, 5 ): 2.81(2H, t, J=8.0Hz), 4.05(2H, t, J=8.0Hz), 4.15(2H, s), 7.18-7.34(5H, m), 7.40(1H, d, J=7.5Hz), 7.48(1H, t, J=7.5Hz),
7.67(1H, t, J=7.5Hz), 8.05(1H, d, J=7.5Hz).
(3) 2-(Benzyloxy)-l,3(2H,4H)-isoquinolinedione mp. 146-146.5°C
NMR(DMSO-d6, ό ): 4.30(2H, s), 5.04(2H, s), 7.36-7.46(4H, m), 7.51(1H, t, J=8.0Hz), 7.55-7.61(2H, m), 7.70(1H, t, J=8.0Hz), 8.07(1H, d, J=8.0Hz).
Mass : 268(M+1)+
Example 5 l,3(2H,4H)-Isoquinolinedione (200 mg), potassium carbonate (189 mg) and N,N-dimethylformamide (4 ml) were mixed and cooled to
0°C under nitrogen atmosphere.
4-Bromo-l-(bromomethyl)-2-fluorobenzene (332 mg) was added to the mixture at 0°C. The suspension was stirred at room temperature for 2 hours. Water was added to the mixture at 0°C, and the resulting precipitate was filtered in vacuo. The obtained solid was purified by flash column chromatography over silica gel with a mixture of chloroform /methanol (10: 1) as eluent. The obtained solid was triturated with ethanol to give 4,4-bis(4-bromo-2-fluorobenzyl)- l,3(2H,4H)-isoquinolinedione (131.7 mg) as a colorless solid. mp. 203-204°C
NMR(DMSO-d6, δ ): 3.56(2H, d, J=14.5Hz), 3.61(2H, d, J=14.5Hz),
6.68(2H, t, J=8.0Hz), 7.16(2H, dd, J=8.0, 2.0Hz), 7.30(2H, dd, J=10.0, 2.0Hz), 7.42(1H, t, J=8.0Hz), 7.73(1H, t, J=8.0Hz), 7.78(1H, d, J=8.0Hz),
7.97(1H, d, J=8.0Hz), 11.50(1H, s).
Example 6
4,4-Bis(2-nitrobenzyl)- 1 ,3(2H,4H)-isoquinolinedione was obtained in a manner similar to Example 5. mp. 246-247°C
NMR(DMSO-d6, δ* ): 3.88(2H, d, J= 14.0Hz), 4.01(2H, d, J= 14.0Hz), 6.82(2H, dd, J=9.5, 2.0Hz), 7.30-7.44(4H, m), 7.48(1H, t, J=7.5Hz), 7.65-7.74(3H, m), 7.76-7.86(2H, m), 11.44(1H, s).
Example 7
A mixture of 6-nitro-l,3(2H,4H)-isoquinolinedione (3 g) and 10% palladium carbon (291 mg) in methanol (30 ml) and tetrahydrofurane (60 ml) was stirred under 3 atm hydrogen gas for 2 hours at ambient temperature. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with a mixture of chlorofor /methanol (10: 1) as eluent. The obtained solid was triturated with ethanol to give 6-amino-l,3(2H,4H)-isoquinolinedione (72.0 mg) as an orange solid. mp. 231-233°C
NMRpMSO-de, ^ ): 3.83(2H, s), 6.1 1(2H, s), 6.36(1H, d, J=2.0Hz),
6.55(1H, dd, J=8.5, 2.0Hz), 7.66(1H, d, J=8.5Hz), 10.77(1H, brs).
Example 8
Triethylamine (0.079 ml) and benzoyl chloride (0.127 ml) were added to a mixture of 6-amino-l,3(2H,4H)-isoquinolinedione (80 mg) in
1,2-dichloroethane (2 ml) under nitrogen atmosphere. The reaction mixture was refluxed for 5 hours and cooled to room temperature.
The resulting precipitate was collected by filtration and washed with ethanol to give
N-(l,3-dioxo-l,2,3,4-tetrahydro-6-isoquinolinyl)benzamide (37.6 mg) as a pale darkish yellow solid. mp. 288-290°C
NMR(DMSO-d6, δ ): 4.05(2H, s), 7.51-7.68(3H, m), 7.82(1H, dd, J=8.5,
2.0Hz), 7.91(1H, d, J=2.0Hz), 7.93-8.00(2H, m), 8.00(1H, d, J=8.5Hz),
10.60(1H, s), 11.21(1H, s).
Example 9
A solution of 2-(2-amino-2-oxoethyl)-4-(methylsulfonyl)benzoic acid (345 mg) in l-methyl-2-pyrrolidinone (4 ml) was stirred for 3 hours at 150°C and cooled to room temperature. Water was added to the mixture and the precipitate was collected by filtration. The solid was purified by flash column chromatography over silica gel with a mixture of chloroform/methanol (10: 1) as eluent. The obtained product was triturated with acetonitrile to give
6-(methylsulfonyl)- l,3(2H,4H)-isoquinolinedione (35.8 mg) as an off-white solid . mp. 293-294°C
NMR(DMSO-d6, 5 ): 3.29(3H, s), 4.15(2H, s), 7.98(1H, d, J=8.0Hz),
7.99(1H, s), 8.24(1H, d, J=8.0Hz), 1 1.56(1H, brs).
Mass : 238(M-1)+ Example 10
Sodium borohydride (93.9 mg) was added to a solution of l,3(2H,4H)-isoquinolinedione (200 mg) in methanol (15 ml) and dichloromethane (35 ml) under nitrogen atmosphere at room temperature. The reaction mixture was stirred for 18 hours at room temperature, and concentrated in vacuo. Chloroform and lN-hydrochloric acid were added to the residue. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel with a mixture of chloroform/ methanol (20: 1) as eluent. The obtained product was triturated with diethyl ether to give l(2H)-isoquinolinone (66.1 mg) as an off-white solid, mp. 210.5-211.5°C NMRpMSO-de, ^ ): 6.55(1H, d, J=7.0Hz), 7.17(1H, t, J=7.0Hz), 7.48(1H, t, J=8.0Hz), 7.66(1H, t, J=8.0Hz), 7.66-7.75(lH, m), 8.18(1H, d, J=8.0Hz), 11.25(1H, brs). Mass : 146(M+ 1)+
Example 11 Sodium borohydride (141 mg) was added to a solution of l,3(2H,4H)-isoquinolinedione (300 mg) in methanol (20 ml) and dichloromethane (45 ml) under nitrogen atmosphere at room temperature. The reaction mixture was stirred for 15 hours at room temperature, and concentrated in vacuo. Chloroform and water were added to the residue. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel with a mixture of chloroform/ methanol (10: 1) as eluent. The obtained product was triturated with diethyl ether to give 3-hydroxy-3,4-dihydro-l(2H)-isoquinolinone (30.3 mg) as a pale yellow solid. mp. 110- 112°C
NMR(DMSO-d6, δ ): 2.89(1H, dd, J=16.0, 2.5Hz), 3.16(1H, dd, J=16.0, 4.0Hz), 5.02-5.08(lH, m), 5.80(1H, d, J=4.5Hz), 7.30(1H, d, J=7.5Hz), 7.34(1H, t, J=7.5Hz), 7.48(1H, dt, J= 1.5, 7.5Hz), 7.86(1H, dd, J=7.5, 1.5Hz), 8.45(1H, d, J=3.5Hz). Mass : 164(M+1)+
Example 12 l,3(2H,4H)-Isoquinolinedione (200 mg) and potassium carbonate (352 mg) were suspended in N,N-dimethylformamide (4 ml), and cooled to 0°C under nitrogen atmosphere. Then iodomethane
(0.155 ml) was added to the suspension at 0°C, and the suspension was stirred at room temperature for 3.5 hours. IN-Hydrochloric acid was added to the mixture at 0°C, and the mixture was extracted with ethyl . acetate (twice) . The combined organic layers were washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo.
The residue was purified by flash column chromatography over silica gel with a mixture of chloroform/methanol (20: 1) as eluent. The obtained product was triturated with a mixture of diethyl ether/ isopropyl ether to give
4,4-dimethyl- l,3(2H,4H)-isoquinolinedione (76.8 mg) as an off-white solid. mp. 115.5-117°C
NMR(DMSO-d6, δ ): 1.53(6H, s), 7.45-7.51(lH, m), 7.68-7.76(2H, m),
8.04(1H, d, J=7.5Hz), 11.34(1H, brs).
Example 13 A solution of hydroxylamine hydrochloride (1.26 g) in ethanol (2 ml) and water (2 ml) was added dropwise to a solution of l,3-dihydro-2H-inden-2-one (2 g) in pyridine (6 ml). The mixture was stirred for 3 hours at room temperature. Water was added to the mixture, and resulting precipitate was collected by filtration to give l,3-dihydro-2H-inden-2-one oxime (1.93 g) as an off-white solid, mp. 154-155.5°C
NMRpMSO-de, ^ ): 3.69(4H, d, J=5.5Hz), 7.17-7.25(2H, m), 7.25-7.35(2H, m), 10.66(1H, s). Example 14
Phosphorus pentachloride (2.23 g) was added to a solution of 1 ,3-dihydro-2H-inden-2-one oxime (1.5 g) in chloroform (45 ml) under nitrogen atmosphere at -30°C. The mixture was stirred for 10 minutes at -30°C and for 3 hours at room temperature, and then poured into ice-water. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel with a mixture of chloroform/methanol (20: 1) as eluent. The obtained product was triturated with a mixture of diethyl ether/ ethanol to give l,4-dihydro-3(2H)-isoquinolinone (735.6 mg) as an off-white solid. mp. 154-155°C
NMR(DMSO-d6, <5 ): 3.43(2H, s), 4.33(2H, s), 7.15-7.29(4H, m), 8.00(1H, brs). Mass : 148(M+1)+
Example 15
A mixture of 2-(benzyloxy)- l,3(2H,4H)-isoquinolinedione (165 mg) and 10 % palladium carbon (12.3 mg) in methanol (5 ml) was stirred under 3 atm hydrogen gas at ambient temperature for 1.5 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The resulting solid was washed with ethanol to give 2-hydroxy-l,3(2H,4H)-isoquinolinedione (40.2 mg) as a pale gray solid. mp. 189-190°C
NMR(DMSO-d6, <5 ): 4.27(2H, s), 7.39(1H, d, J=8.0Hz), 7.48(1H, t, J=8.0Hz), 7.66(1H, t, J=8.0Hz), 8.03(1H, d, J=8.0Hz), 11.40(1H, s). Mass : 176(M-1)+
Example 16
A solution of 5-nitro-lH-indole-2,3-dione (300 mg) in N,N-dimethylformamide (3 ml) was cooled to 0°C under nitrogen atmosphere. Sodium hydride (60 % dispersion in mineral oil, 74.9 mg) was added portionwise to the solution at 0°C, and the mixture was stirred for 15 minutes at room temperature. Then (bromomethyl)benzene (0.204 ml) was added to the solution at room temperature, and the mixture was stirred for 4 hours at ambient temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with an aqueous saturated ammonium chloride solution, water (twice) and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel with a mixture of n-hexane/ ethyl acetate (3: 1— »■ 1: 1) as eluent. The obtained yellow amorphous was crystallized from diethyl ether to give l-benzyl-5-nitro-lH-indole-2,3-dione (308.3 mg) as an orange solid . mp. 175-176.5°C NMR(DMSO-d6, S ): 5.00(2H, s), 7.14(1H, d, J=8.5Hz), 7.25-7.39(3H, m), 7.47(2H, d, J=7.0Hz), 8.27(1H, d, J=2.5Hz), 8.45(1H, dd, J=8.5, 2.5Hz).
Example 17
The following compounds (1) to (13) were obtained in a manner similar to Example 16. (1) 5-Nitro- l-(4-nitrobenzyl)-lH-indole-2,3-dione mp. 220.5-222°C
NMR(DMSO-d6, <5 ): 5.17(2H, s), 7.13(1H, d, J=8.5Hz), 7.77(2H, d,
J=9.0Hz), 8.22(2H, d, J=9.0Hz), 8.30(1H, d, J=2.5Hz), 8.45(1H, dd,
J=8.5, 2.5Hz). Mass : 326(M-1)+
(2) 5-Nitro- l-(3-nitrobenzyl)- lH-indole-2,3-dione mp. 154-155.5°C
NMR(DMSO-d6, <5 ): 5.17(2H, s), 7.19(1H, d, J=8.5Hz), 7.66(1H, t, J=8.5Hz), 7.96(1H, d, J=8.5Hz), 8.16(1H, d, J=8.5Hz), 8.29(1H, d, J=2.5Hz), 8.41(1H, s), 8.45(1H, dd, J=8.5, 2.5Hz).
(3) 5-Nitro- l-(3-pyridinylmethyl)- lH-indole-2,3-dione NMR(DMSO-d6, δ* ): 5.05(2H, s), 7.24(1H, d, J=9.0Hz), 7.38(1H, dd, J=8.0, 5.0Hz), 7.88(1H, d, J=8.0Hz), 8.28(1H, d, J=2.0Hz), 8.47(1H, dd, J=9.0, 2.0HZ), 8.51(1H, dd, J=5.0, 2.0Hz), 8.72(1H, d, J=2.0Hz).
(4) l-(4-Bromobenzyl)-5-nitro- lH-indole-2,3-dione mp. 182- 183°C
NMR(DMSO-d6, δ ): 4.98(2H, s), 7.13(1H, d, J=9.0Hz), 7.44(2H, d, J=8.5Hz), 7.55(2H, d, J=8.5Hz), 8.27(1H, d, J=2.5Hz), 8.45(1H, dd, J=9.0, 2.5Hz).
(5) l-(2-Fluorobenzyl)-5-nitro-lH-indole-2,3-dione mp. 164-165°C
NMR(DMSO-d6, <5 ): 5.04(2H, s), 7.16(1H, t, J=7.5Hz), 7.22(1H, d, J=9.0Hz), 7.21-7.31(1H, m), 7.33-7.43(lH, m), 7.52(1H, dt, J=1.5, 7.5Hz), 8.28(1H, d, J=2.5Hz), 8.49(1H, dd, J=9.0, 2.5Hz).
(6) l-(4-Bromo-2-fluorobenzyl)-5-nitro- lH-indole-2,3-dione mp. 184-185°C
NMR(DMSO-d6, <5 ): 5.00(2H, s), 7.23(1H, d, J=8.5Hz), 7.39(1H, dd, J=8.0, 2.0Hz), 7.51(1H, t, J=8.0Hz), 7.62(1H, dd, J=9.5, 2.0Hz), 8.28(1H, d, J=2.5Hz), 8.48(1H, dd, J=8.5, 2.5Hz).
(7) 5-Nitro- 1 - (2 -nitrobenzyl) - 1 H-indole-2 ,3-dione mp. 199-200°C
NMR(DMSO-d6, δ ): 5.36(2H, s), 7.22(1H, d, J=8.5Hz), 7.54-7.71(2H, m), 7.75(1H, d, J=8.0Hz), 8.23(1H, dd, J=8.0, 1.5Hz), 8.32(1H, d, J=2.5Hz), 8.44(1H, dd, J=8.5, 2.5Hz). Mass : 326(M- 1)+
(8) l-(2-Methylbenzyl)-5-nitro-lH-indole-2,3-dione mp. 182.5- 183°C
NMR(DMSO-d6, <5 ): 2.39(3H, s), 4.95(2H, s), 7.06(1H, d, J=8.5Hz), 7.10(1H, t, J=7.5Hz), 7.19(1H, t, J=7.5Hz), 7.24(1H, d, J=7.5Hz), 7.30(1H, d, J=7.5Hz), 8.30(1H, d, J=2.5Hz), 8.45(1H, dd, J=8.5, 2.5Hz). (9) 5-Nitro- l-(4-pyridinylmethyl)- lH-indole-2,3-dione mp. 184.5- 185.5°C
NMR(DMSO-d6, δ ): 5.06(2H, s), 7.11(1H, d, J=8.5Hz), 7.49(2H, d, J=5.5Hz), 8.30(1H, d, J=2.0Hz), 8.45(1H, dd, J=8.5, 2.0Hz), 8.53(2H, d, J=5.5Hz). Mass : 284(M+ 1)+
(10) 5-Nitro- l-(2-pyridinylmethyl)- lH-indole-2,3-dione mp. 174-175°C
NMR(DMSO-d6, δ ): 5.10(2H, s), 7.22(1H, d, J=8.5Hz), 7.32(1H, dd, J=7.5, 4.5Hz), 7.54(1H, d, J=7.5Hz), 7.70(1H, dt, J=2.0, 7.5Hz), 8.29(1H, d, J=2.5Hz), 8.48(1H, dd, J=8.5, 2.5Hz), 8.52(1H, dd, J=4.5. 2.0Hz). Mass : 284(M+1)+
(11) l-(4-Nitrobenzyl)-5-(trifluoromethyl)- lH-indole-2,3-dione mp. 265-266°C
NMR(DMSO-d6, δ ): 5.49(2H, s), 7.05(1H, d, J=8.5Hz), 7.75(2H, d, J=8.5Hz), 8.01(1H, d, J=2.0Hz), 8.22(1H, dd, J=8.5, 2.0Hz), 8.27(2H, d, J=8.5Hz).
(12) l-(4-Bromo-2-fluorobenzyl)-5-(trifluoromethoxy)- lH-indole-2,3- dione mp. 137.5- 138°C
NMR(DMSO-d6, δ ): 4.93(2H, s), 7.09(1H, d, J=9.5Hz), 7.38(1H, dd, J=8.0, 2.0Hz), 7.49(1H, t, J=8.0Hz), 7.57-7.68(3H, m).
(13) 1 - (4-Nitrobenzyl) - 5- (trifluoromethoxy) - 1 H-indole-2 ,3-dione mp. 150-150.5°C
NMR(DMSO-d6, δ ): 5.09(2H, s), 7.01(1H, d, J=8.5Hz), 7.61(1H, d, J=8.5Hz), 7.65(1H, s), 7.75(2H, d, J=9.0Hz), 8.21(2H, d, J=9.0Hz). Mass : 365(M-1)+ Example 18
A solution of lH-indole-2,3-dione (300 mg) in N,N-dimethylformamide (3 ml) was cooled to 0°C under nitrogen atmosphere. Sodium hydride (60 % dispersion in mineral oil, 81.6 mg) was added portion wise to the solution at 0°C, and the mixture was stirred at room temperature for 40 minutes. Then benzoyl chloride (0.237 ml) was added to the solution at room temperature, and the mixture was stirred at ambient temperature for 30 minutes. Ice-water was added to the mixture, and the precipitate was collected by filtration. The solid was washed with water and ethanol to give 1 -benzoyl- lH-indole-2,3-dione (394.6 mg) as a yellow solid, mp. 203-205°C NMR(DMSO-d6, δ ): 7.39(1H, t, J=7.5Hz), 7.52(2H, t, J=7.5Hz), 7.67(1H, t, J=7.5Hz), 7.79(1H, d, J=7.5Hz), 7.80(1H, t, J=7.5Hz), 7.89(2H, d, J=7.5Hz), 7.94(1H, d, J=7.5Hz).
Example 19 tert-Butyl (triphenylphosphoranylidene)-acetate (437 mg) was added portionwise to a solution of l-(4-bromo-2-fluorobenzyl)-5-nitro-lH-indole-2,3-dione (400 mg) in tetrahydrofuran (8 ml) under nitrogen atmosphere at room temperature. The reaction mixture was stirred for 2 hours at 60°C, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with a mixture of n-hexane /ethyl acetate (3: 1) as eluent. The obtained product was triturated with ethanol to give tert-butyl (2E)-[l-(4-bromo-2-fluorobenzyl)-5-nitro-2-oxo-l,2-dihydro-3H-indol-3- ylidene]ethanoate (294.1 mg) as a yellow solid, mp. 150-151.5°C NMR(DMSO-d6, <5 ): 1.58(9H, s), 5.07(2H, s), 6.83(1H, s), 7.22(1H, d,
J=9.0Hz), 7.30(1H, t, J=8.0Hz), 7.38(1H, dd, J=8.0, 2.0Hz),7.60(lH, dd, J=10.0, 2.0Hz), 8.36(1H, dd, J=9.0, 2.5Hz), 9.22(1H, d, J=2.5Hz).
Example 20 tert-Butyl (2E)-(5-nitro-2-oxo- 1 ,2-dihydro-3H-indol-3- ylidenejethanoate was obtained in a similar manner to Example 19. mp. 161-162°C
NMRpMSO-de. S ): 1.57(9H, s), 6.68(1H, s), 7.07(1H, d, J=8.5Hz), 8.30(1H, dd, J=8.5, 2.5Hz), 9.18(1H, d, J=2.5Hz), 11.50(1H, brs). Mass : 289(M- 1)+
Example 21
Trifluoroacetic acid ( 1 ml) was added to a solution of tert-butyl (2E)-[l-(4-bromo-2-fluorobenzyl)-5-nitro-2-oxo-l,2-dihydro-3H-indol-3- ylidene]ethanoate (100 mg) in dichloromethane (0.5 ml) at 0°C. The mixture was stirred for 30 minutes at room temperature, and concentrated in vacuo. The resulting solid was washed with ethanol to give (2E)-[l-(4-bromo-2-fluorobenzyl)-5-nitro-2-oxo-l,2-dihydro-3H -indol-3-ylidene]ethanoic acid (62.9 mg) as a yellow solid, mp. 214-214.5°C
NMR(DMSO-d6, δ ): 5.07(2H, s), 6.91(1H, s), 7.22(1H, d, J=9.0Hz), 7.30(1H, t, J=8.0Hz), 7.38(1H, dd, J=8.0, 2.0Hz), 7.60(1H, dd, J=10.0, 2.0Hz), 8.35(1H, dd, J=9.0, 2.5Hz), 9.28(1H, d, J=2.5Hz), 13.84(1H, brs).
Mass : 419(M-1)+
Example 22
(2E)-(5-Nitro-2-oxo- 1 ,2-dihydro-3H-indol-3-ylidene)ethanoic acid was obtained in a manner similar to Example 21.
NMR(DMSO-d6, <5 ): 6.77(1H, s), 7.07(1H, d, J=9.0Hz), 8.30(1H, dd, J=9.0, 2.5Hz), 9.24(1H, d, J=2.5Hz), 11.49(1H, s), 13.70(1H, brs). Mass : 233(M-1)+
Example 23
2H-Pyrido[2,3-d][l,3]oxazine-2,4(lH)-dione (800 mg), 5-nitro-lH-indole-2,3-dione (937 mg), 1 ,3-diisopropylcarbodiimide (0.763 ml), 1-methylpiperidine (1.93 mg) and pyridine (3.5 ml) were mixed under nitrogen atmosphere. The mixture was heated for 1.5 hours at 100°Cwith stirring and then cooled to room temperature.
Methanol (20 ml) was added to the mixture. The resulting precipitate was collected by filtration and washed with methanol to give
9-nitropyrido[2',3':4,5]pyrimido[l,2-a]indole-5, l l-dione (515 mg) as a brown solid. mp. >300°C
NMR(DMSO-d6, <5 ): 7.71(1H, brs), 8.54-8.79(2H, m), 8.77(2H, d,
J=8.0Hz), 9.12(1H, dd, J=4.5, 2.0Hz).
Mass : 295(M+1)+
Example 24
A solution of 4-nitro-l,2-benzenediamine (3 g) and
4-nitrobenzoic acid (3.6 g) in phosphorus oxychloride (100 ml) was heated to reflux for 2 hours. The mixture was cooled to room temperature, poured on to ice, and stirred for 30 minutes. The resulting solid was collected by filtration, and washed with an aqueous saturated sodium hydrogen carbonate solution, water and methanol to give 5-nitro-2-(4-nitrophenyl)-lH-benzimidazole (2.41 g) as a pale green solid. mp. >300°C
NMR(DMSO-d6, (5 ): 7.84(1H, d, J=8.5Hz), 8.18(1H, dd, J=8.5, 1.5Hz),
8.46(4H, s), 8.56(1H, d, J=8.5Hz).
Mass : 283(M-1)+
Example 25
The following compounds in (1) and (2) were obtained in a manner similar to Example 24.
(1) 5-Nitro-2-(3-nitrophenyl)- lH-benzimidazole mp. >300°C NMR(DMSO-d6, <5 ): 7.84(1H, d, J=8.5Hz), 7.91(1H, t, J=8.5Hz), 8.17(1H, dd, J=8.5, 2.5Hz), 8.41(1H, dd, J=8.5, 2.5Hz), 8.54(1H, d, J=2.5Hz),
8.66(1H, d, J=8.5Hz), 9.05(1H, d, J=2.5Hz), 13.96(1H, brs).
Mass : 283(M-1)+ (2) 5-Nitro-2-(4-nitrobenzyl)- lH-benzimidazole mp. 235-236.5°C
NMR(DMSO-d6, <5 ): 4.45(2H, s), 7.64(2H, d, J=9.0Hz), 7.68(1H, d, J=8.5Hz), 8.09(1H, dd, J=8.5, 2.5Hz), 8.22(2H, d, J=9.0Hz), 8.43(1H, d, J=2.5Hz), 13.10(1H, s). Mass : 299(M+1)+
Example 26
Tin(II) chloride dihydrate (11 g) was added to a suspension of 5-nitro-2-(4-nitrophenyl)-lH-benzimidazole (2.3 g) in concentrated hydrochloric acid (25 ml). The mixture was heated to reflux for 4 hours and cooled to room temperature. Ethanol was added to the solution. The resulting precipitate was collected by filtration in vacuo.
The solid was dissolved in water again, and the solution was made basic by the addition of 28 % aqueous solution of ammonium hydroxide. The precipitate was collected by filtration to give
2-(4-aminophenyl)-lH-benzimidazol-5-amine (1.33 g) as a darkish green solid . mp. >300°C NMR(DMSO-d6, δ ): 6.47(1H, dd, J=8.5, 2.5Hz), 6.63(2H, d, J=8.5Hz),
6.64(1H, d, J=2.5Hz), 7.17(1H, d, J=8.5Hz), 7.73(2H, d, J=8.5Hz).
Mass : 225(M+1)+
Example 27 The following compounds (1) and (2) were obtained in a manner similar to Example 26.
(1) 2-(3-Aminophenyl)- lH-benzimidazol-5-amine NMR(DMSO-d6, <5 ): 4.92(2H, s), 5.21(2H, s), 6.49(1H, dd, J=8.5, 2.0Hz), 6.59(1H, d, J=7.5Hz), 6.61(1H, d, J=2.0Hz), 7.07-7.20(2H, m), 7.25(1H, d, J=8.5Hz), 7.31(1H, s), 12.06(1H, s). Mass : 225(M+1)+
(2) 2-(4-Aminobenzyl)- lH-benzimidazol-5-amine NMR(DMSO-d6, δ ): 4.91(2H, s), 6.40(1H, dd, J=8.5, 2.0Hz), 6.48(2H, d, J=8.5Hz), 6.52(1H, d, J=2.0Hz), 6.92(2H, d, J=8.5Hz), 7.13(1H, d, J=8.5Hz), 11.50(1H, s). Mass : 239(M+1)+
Example 28
Acetyl chloride (0.166 ml) was added dropwise to a solution of 2-(4-aminophenyl)-lH-benzimidazol-5-amine (209 mg) and N,N-diisopropylethylamine (0.406 ml) in tetrahydrofuran (4.5 ml) under nitrogen atmosphere at -78°C. The mixture was stirred for 22 hours at room temperature, and diluted in ethyl acetate. The separated organic solution was washed with water, an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The resulting solid was recrystallized from N,N-dimethylformamide/water to give N-{4-[5-(acetylamino)-lH- benzimidazol-2-yl]phenyI}acetamide (40.5 mg) as a pale brown solid, mp. >300°C
NMR(DMSO-d6, $ ): 2.07(3H, s), 2.09(3H, s), 7.23(1H, dd, J=8.5, 1.0Hz), 7.49(1H, d, J=8.5Hz), 7.74(2H, d, J=8.5Hz), 8.05(2H, d, J=8.5Hz), 8.07(1H, d, J=1.0Hz), 9.98(1H, s), 10.19(1H, s), 12.90(1H, brs). Mass : 309(M+1)+
Example 29
2-Thiophenecarbonyl chloride (0.267 ml) was added dropwise to a solution of 2-(4-aminophenyl)-lH-benzimidazol-5-amine (224 mg) in pyridine (2 ml) under nitrogen atmosphere. The mixture was stirred for 6 hours at 60°C, and diluted in chloroform. The separated organic solution was washed with lN-hydrochloric acid, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The resulting solid was recrystallized from N,N-dimethylformamide/water to give N-(4-{5-[(2-thienylcarbonyl)amino]-lH-benzimidazol-2-yl}phenyl)-2-thio phenecarboxamide (301.8 mg) as a pale darkish green solid, mp. >300°C
NMR(DMSO-d6, 5 ): 7.21-7.30(2H, m), 7.78(2H, s), 7.87-7.96(2H, m), 8.08(2H, d, J=8.5Hz), 8.11-8.17(2H, m), 8.24(2H, d, J=8.5Hz), 8.37(1H, s), 10.58(1H, s), 10.71(1H, s). Mass : 445(M+ l)+
Example 30 The following compounds in (1) to (3) were obtained in a manner similar to Example 29.
(1) N-[4-(3H-Imidazo[4,5-b]pyridin-2-yl)phenyl]-2-thiophene -carboxamide mp. >300°C NMR(DMSO-d6, δ ): 7.17-7.33(2H, m), 7.83-8.13(3H, m), 7.93(2H, d, J=7.5Hz), 8.23(2H, d, J=7.5Hz), 8.27-8.42( lH, m). Mass : 321(M+ 1)+
(2) N-(3-{5-[(2-Thienylcarbonyl)amino]- lH-benzimidazol-2-yl}- phenyl)-2-thiophenecarboxamide mp. 175- 185°C
NMR(DMSO-d6, <5 ): 7.21-7.29(2H, m), 7.42-7.67(3H, m), 7.80-7.94(4H, m), 8.03-8.17(3H, m), 8.60(1H, s), 10.24(lHχ l/3, s), 10.30( lHχ2/3, s), 10.45( 1H, s), 12.90(lHχ2/3, s), 12.94(lHχ l/3, s). Mass : 445(M+ 1)+
(3) N-[4-({5-[(2-Thienylcarbonyl)amino]- lH-benzimidazol-2-yl}- methyl)phenyl]-2-thiophenecarboxamide mp. 163- 168°C NMR(DMSO-d6, <5 ): 4.14(2H, s), 7.18-7.25(2H, m), 7.31(2H, d, J=8.5Hz), 7.32-7.55(2H, m), 7.66(2H, d, J=8.5Hz), 7.81-7.89(2H, m), 7.92-8.07(3H, m), 10.20(1H, brs), 10.22(1H, s), 12.24(1H, brs). Mass : 459(M+ 1)+
Example 31
A mixture of 2,3-pyridinediamine (1 g), 4-nitrobenzoic acid (1.68 g) and polyphosphoric acid (10 ml) was heated for 2 hours at 175°C. After cooled to 0°C, the mixture was adjusted to neutral with solid sodium carbonate. The resulting precipitate was collected by filtration, and washed with water. The solid was recrystallized from N,N-dimethylformamide to give
2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine (2.20 g) as a yellow solid, mp. >300°C NMR(DMSO-d6, <5 ): 7.31(1H, dd, J=8.0, 5.0Hz), 8.11(1H, dd, J=8.0, 1.0Hz), 8.42(1H, dd, J=5.0, 1.0Hz), 8.43(2H, d, J=9.0Hz), 8.49(2H, d, J=9.0Hz).
Example 32 S.M.I (1 g) in ethanol (15 ml) was added to a solution of ammonium chloride (156 mg) in water (1.5 ml). Then iron (697 mg) was added to the solution at room temperature, and the mixture was refluxed for 3 hours. After cooled to room temperature, the mixture was filtered through a celite pad. The filtrate was concentrated in vacuo. The resulting solid was washed with water and acetonitrile to give 4-(3H-imidazo[4,5-b]pyridin-2-yl)phenylamine (207.5 mg) as a darkish yellow solid. mp. >300°C
NMR(DMSO-d6, δ- ): 6.67(2H, d, J=7.5Hz), 7.15(1H, brs), 7.85(1H, brs), 7.90(2H, d, J=7.5Hz), 8.22(1H, brs).
Mass : 211(M+1)+
Example 33
A solution of 2,2-dihydroxy-lH-indene-l,3(2H)-dione (2 g) in warm water (40 ml) and a solution of methyl (2E)-3-amino-2-butenoate (1.29 g) in warm water (26 ml) were both filtered into a same flask. After 13 hours, the resulting solid was collected by filtration to give methyl (3aS,8bS)-3a,8b-dihydroxy-2-methyl-4-oxo-l,3a,4,8b- tetrahydroindeno[l,2-b]pyrrole-3-carboxylate (3.1 g) as an off-white solid. mp. 203-203.5°C
NMR(DMSO-d6) 5 ): 2.05(3H, s), 3.51(3H, s), 5.43(1H, s), 6.38(1H, s), 7.51-7.56(1H, m), 7.66(1H, d, J=8.0Hz), 7.74-7.82(2H, m), 8.83(1H, s). Mass : 276(M+1)+ Example 34
The following compounds (1) to (9) were obtained in a manner similar to Example 33. (1) Ethyl (3aS,8bR)-3a,8b-dihydroxy-2-methyl-4-oxo-4,8b-dihydro-
3aH-indeno[ 1 ,2-b]furan-3-carboxylate mp. 101- 104.5°C
NMRpMSO-dβ. δ ): 0.95(3Hχ l /32, t, J=7.0Hz), 1.21(3Hχ31 /32, t, J=7.0Hz), 2.13(3Hχ31/32, s), 2.42(3Hχ l/32, s), 4.00-4.14(2H, m), 6.13( 1H, brs), 7.61-7.89(4H, m), 8.03(lHχ l/32, s), 8.05(lHχ31 /32, s). Mass : 289(M- 1)+
(2) (3aS,8bR)-3-Acetyl-3a,8b-dihydroxy-2-methyl-3a,8b- dihydro-4H-indeno[ 1 ,2-b]furan-4-one mp. 173- 175°C
NMR(DMSO-d6, ά ): 2.12(3H, s), 2.39(3H, s), 6.52(1H, brs), 7.63-8.02(4H, m), 8.23(1H, brs). Mass : 261(M+ 1)+
(3) (3aS,8bS)-3a,8b-Dihydroxy-2-methyl-4-oxo- l,3a,4,8b- tetrahydroindeno[ 1 ,2-b]pyrrole-3-carbonitrile mp. 206-207°C
NMR(DMSO-d6, <5 ): 1.87(3H, s), 6.10(1H, s), 6.71(1H, s), 7.59(1H, t,
J=7.5Hz), 7.74(1H, d, J=7.5Hz), 7.79(1H, d, J=7.5Hz), 7.86(1H, t, J=7.5Hz), 8.83( 1H, s).
Mass : 243(M+ 1)+
(4) (3aS,8bR)-3a,8b-Dihydroxy-2-methyl-4-oxo-N-phenyl-
4,8b-dihydro-3aH-indeno[ 1 ,2-b]furan-3-carboxamide mp. 215-215.5°C
NMR(DMSO-d6, £ ): 2.34(3H, s), 6.59(1H, s), 6.67-6.73(lH, m), 7.24-7.31(2H, m), 7.38-7.48(4H, m), 7.52-7.61(2H, m), 7.74-7.77(lH, m), 12.84(1H, s). Mass : 338(M+ 1)+ (5) Ethyl (3aS,8bR)-3a,8b-dihydroxy-4-oxo-2-phenyl-4,8b-dihydro-
3aH-indeno[ 1 ,2-b]furan-3-carboxylate mp. 1 14- 1 15°C NMR(DMSO-d6, S ): 1.05(3Hχ l/2, t, J=7.0Hz), 1.09(3Hχ l/2, t, J=7.0Hz), 3.96-4.11(2H, m), 5.25(lHχ l /2, s), 6.39( lHχ l/2, brs), 7.08(lHχ l/2, s), 7.36-8.09(9H, m), 8.23(lH l/2, s). Mass : 353(M+ 1)+
(6) Benzyl (3aS,8bR)-3a,8b-dihydroxy-2-methyl-4-oxo-4,8b- dihydro-3aH-indeno[ 1 ,2-b]furan-3-carboxylate mp. 143- 144°C
NMR(DMSO-d6, (5 ): 2.14(3H, s), 5.15(2H, s), 6.24(1H, s), 7.29-7.40(3H, m), 7.46(2H, d, J=7.5Hz), 7.62-7.88(4H, m), 8.11(1H, s). Mass : 353(M+1)+
(7) Methyl (3aS,8bR)-3a,8b-dihydroxy-2-methyl-4-oxo-4,8b- dihydro-3aH-indeno[ 1 ,2-b]furan-3-carboxylate mp. 65-66°C NMR(DMSO-d6, δ ): 2.14(3H, s), 3.61(3H, s), 6.20(1H, brs), 7.61-7.89(4H, m), 8.07(1H, brs). Mass : 277(M+ 1)+
(8) Isopropyl (3aS,8bR)-3a,8b-dihydroxy-2-methyl-4-oxo-4,8b- dihydro-3aH-indeno[ 1 ,2-b]furan-3-carboxylate mp. 138-139°C
NMR(DMSO-d6, ά ): 1.21(6H, d, J=6.5Hz), 2.12(3H, s), 4.89(1H, m),
6.04(1H, brs), 7.60-7.87(4H, m), 8.02( 1H, brs).
Mass : 305(M+1)+
(9) Ethyl 2-(2-hydroxy- 1 ,3-dioxo-2,3-dihydro- lH-inden-2-yl)-
4,4-dimethyl-3-oxopentanoate mp. 94-95°C NMR(DMSO-d6, ό- ): 0.98(3H, brs), 2.38-2.70(9H, m), 3.20-3.50(1H, ), 4.15(1H, brs), 5.07(2H, q, J=6.0Hz), 7.33-7.78(4H, m). Mass : 333(M+ 1)+
Example 35
A solution of 2,2-dihydroxy- lH-indene- l,3(2H)-dione (2 g) in warm water (40 ml) and a solution of tert-butyl 3-oxobutanoate (1.78 g) in warm water (30 ml) were both filtered into a same flask. After 15.5 hours, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel with a mixture of chloroform/methanol (20: 1) as eluent. The obtained product was triturated with n-hexane to give tert-butyl (3aS,8bR)-3a,8b-dihydroxy-2-methyl-4-oxo- 4,8b-dihydro-3aH-indeno[l,2-b]furan-3-carboxylate (1.73 g) as a colorless solid, mp. 117- 120°C
NMR(DMSO-d6, δ* ): 1.07(9Hχ l /8, s), 1.43(9Hχ7/8, s), 2.09(3Hχ7/8, s), 2.43(3H l/8, s), 5.94(1H, brs), 7.62-8.06(5H, m). Mass : 319(M+ 1)+
Example 36
The following compounds in (1) to (4) were obtained in a manner similar to Example 35. ( 1) Ethyl (3aS,8bR)-2-ethyl-3a,8b-dihydroxy-4-oxo-4,8b-dihydro-
3aH-indeno[ 1 ,2-b]furan-3-carboxylate mp. 109.5-112°C
NMR(DMSO-d6, 5 ): 0.94(3H, t, J=7.5Hz), 1.20(3H, t, J=7.5Hz),
2.46-2.64(2H, m), 4.00-4.14(2H, m), 6.13( 1H, brs), 7.60-7.89(4H, m), 8.05(1H, brs).
Mass : 305(M+ 1)+
(2) Ethyl (3aS,8bR)-3a,8b-dihydroxy-2-isopropyl-4-oxo-4,8b- dihydro-3aH-indeno[ 1 ,2-b]furan-3-carboxylate mp. 98-99°C
NMR(DMSO-d6, δ ): 0.75(3H, d, J=7.0Hz), 1. 14(3H, d, J=7.0Hz), 1.20(3H, t, J=7.0Hz), 3.49(1H, m), 3.99-4.13(2H, m), 6.12(1H, brs), 7.60-7.88(4H, m), 8.05(1H, brs). Mass : 319(M+ 1)+
(3) Methyl (3aS,8bR)-3a,8b-dihydroxy-2-(2-methoxyethyl)-4-oxo- 4,8b-dihydro-3aH-indeno[ 1 ,2-b]furan-3-carboxylate mp. 120- 122°C NMR(DMSO-d6, c5 ): 2.77-2.93(2H, m), 3.04(3H, s), 3.31-3.45(2H, m), 3.61(3H, s), 6.24(1H, brs), 7.61-7.89(4H, m), 8.11(1H, brs). Mass : 321(M+ 1)+
(4) l, l, l-Trifluoro-3-(l, l,2-trihydroxy-3-oxo-2,3-dihydro- lH-inden-2-yl)-2,4-pentanedione mp. 136- 136.5°C
NMR(DMSO-d6, c5 ): 2.38(3Hχ2/3, s), 2.43(3H l/3, s), 3.58(lHχ l/3, s), 3.72(lHχ2/3, s), 6.79(lHχ l /3, s), 6.84(lHχ2/3, s), 7.04(lHχ2/3, s), 7.57-7.88[4H+(lH l /3), m], 7.89(lHχ l/3, s), 7.96( lHχ2/3, s). Mass : 331(M- 1)+
Example 37
Ethyl 4,4,4-trifluoro-3-oxobutanoate (0.821ml) was added to a solution of 2,2-dihydroxy- lH-indene- l,3(2H)-dione (1 g) in warm water (20 ml). The mixture was stirred for 2 hours at 90°C, and cooled to room temperature. The resulting precipitate was collected by filtration, and crystallized from diethyl ether/n-hexane. The solid was recrystallized from ethyl acetate /n-hexane to give ethyl 4,4,4-trifluoro-3-oxo-2-( 1 , 1 ,2-trihydroxy-3-oxo-2,3-dihydro- lH-inden-2 -yl)butanoate (898.1 mg) as a colorless solid, mp. 133- 134.5°C
NMRpMSO-de, ^ ): 1.15(3Hχ5/7, t, J=7.0Hz), 1.24(3Hχ2/7, t, J=7.0Hz), 3.41(lHχ2/7, s), 3.55( lHχ5/7, s), 4.06(2Hχ5/7, q, J=7.0Hz), 4.19(2Hχ2/7, q, J=7.0Hz), 6.66(lHχ5/7, s), 6.70(lHχ2/7, s), 7.26(lHχ5/7, s), 7.33(lHχ2/7, s), 7.57-7.88(4H+(lHχ5/7), m), 7.91(lHχ2/7, s). Mass : 361(M-1)+
Example 38
2.0 M Solution of (trimethylsilyl)diazomethane in n-hexane (0.517 ml) was added to a solution of ethyl
(3aS,8bR)-3a,8b-dihydroxy-2-methyl-4-oxo-4,8b-dihydro-3aH-indeno[l, 2-b]furan-3-carboxylate (100 mg) in diethyl ether (1 ml) and methanol (0.5 ml) under nitrogen atmosphere at 0°C. The mixture was stirred for 16 hours at room temperature, and concentrated in vacuo. The resulting residue was purified by preparative silica gel column chromatography with a mixture of n-hexane/ ethyl acetate (4 : 1) as eluent to give ethyl (3aR,8bR)-3a-hydroxy-8b-methoxy-2-methyl-4- oxo-4,8b-dihydro-3aH-indeno[l,2-b]furan-3-carboxylate (33.1 mg) as a yellow oil.
NMR(DMSO-d6, δ* ): 1.23(3H, t, J=7.0Hz), 2.20(3H, s), 3.58(3H, s), 4.03-4.17(2H, m), 6.29(1H, s), 7.70(1H, t, J=7.0Hz), 7.78(1H, d, J=7.0Hz), 7.86(1H, t, J=7.0Hz), 7.87(1H, d, J=7.0Hz). Mass : 305(M+1)+
Example 39
Ethyl (3aS,8bR)-3a,8b-dihydroxy-2-methyl-4-oxo-4,8b- dihydro-3aH-indeno[l,2-b]furan-3-carboxylate (210 mg), dichloromethane (10 ml), 4-(dimethylamino)pyridine (20 mg), pyridine (0.059 ml) and acetic anhydride (0.14 ml) were mixed under nitrogen atmosphere at 0°C. The mixture was stirred for 6 hours at room temperature. The mixture was diluted in chloroform, and washed with a aqueous saturated sodium hydrogen carbonate solution, water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by flash column chromatography over silica gel with a mixture of chloroform /ethyl acetate (20: 1) as eluent. The obtained product was triturated with n-hexane to give ethyl (3aR,8bS)-3a,8b-bis(acetyloxy)-2-methyl-4-oxo-4,8b-dihydro-3aH-inden o[l,2-b]furan-3-carboxylate (204.3 mg) as a colorless solid, mp. 150-151°C
NMR(DMSO-d6, δ ): 1.25(3H, t, J=7.0Hz), 2.08(3H, s), 2.15(3H, s), 2.21(3H, s), 4.15(2H, q, J=7.0Hz), 7.77(1H, t, J=7.5Hz), 7.83(1H, d, J=7.5Hz), 7.94(1H, t, J=7.5Hz), 8.00(1H, d, J=7.5Hz). Mass : 375(M+1)+
Example 40 4N Solution of hydrochloric acid in ethyl acetate (6 ml) was added to a solution of tert-butyl (3aS,8bR)-3a,8b-dihydroxy- 2-methyl-4-oxo-4,8b-dihydro-3aH-indeno[ 1 ,2-b]furan-3-carboxylate (617 rag) in ethyl acetate (2 ml). The mixture was stirred for 5.5 hours at room temperature, and the resulting precipitate was collected to give (3aS,8bR)-3a,8b-dihydroxy-2-methyl-4-oxo-4,8b-dihydro-3aH-indeno[ 1 , 2-b]furan-3-carboxylic acid (418.9 mg) as a colorless solid, mp. 150.5- 151°C
NMRPMSO^ S ): 2.11(3H, s), 6.12(1H, brs), 7.59-7.73(2H, m), 7.77-7.87(2H, m), 8.02(1H, s), 11.87(1H, brs). Mass : 261 (M-l)+
Example 41
(4bS,9bR)-4b-(Acetyloxy)- 10-oxo-4b, 10-dihydro-9bH-benzo[b]in deno[2,l-d]furan-9b-yl acetate and 2-[2-(acetyloxy)-l,3-dioxo- 2,3-dihydro-lH-inden-2-yl]phenyl acetate were obtained in a manner similar to Example 40.
(4bS,9bR)-4b-(Acetyloxy)-10-oxo-4b,10-dihydro-9bH-benzo[b]indeno[2, l-d]furan-9b-yl acetate colorless solid mp. 228-229.5°C
NMR(CDC13, £ ): 2.15(3H, S), 2.17(3H, S), 6.87(1H, d, J=7.5Hz), 7.06(1H, t, J=7.5Hz), 7.36(1H, t, J=7.5Hz), 7.60(1H, t, J=7.5Hz), 7.61(1H, d, J=7.5Hz), 7.80(1H, t, J=7.5Hz), 7.84(1H, d, J=7.5Hz), 8.16(1H, d, J=7.5Hz).
2-[2-(acetyloxy)- 1 ,3-dioxo-2,3-dihydro- lH-inden-2-yl]phenyl acetate colorless solid mp. 139-140°C NMRpMSO-de, ^ ): 1.87(3H, s), 2.22(3H, s), 7.08(1H, dd, J=7.5, l.OHz), 7.40(1H, dt, J=1.0, 7.5Hz), 7.47(1H, dt, J=1.0, 7.5Hz), 7.77(1H, dd, J=7.5, l.OHz), 8.04-8.14(4H, m).
Example 42 A suspension of l,3(2H,4H)-isoquinolinedione (500mg) in ethyl acetate (15ml) was added to a mixture of ruthenium (IV) oxide hydrate (31mg) and 10% sodium periodate (30mg) at room temperature. The reaction mixture was vigorously stirred at room temperature for 15 minutes. After the layers were separated, the aqueous layer was extracted with AcOEt (3 times). The combined organic solution was treated with 2-propanol (2ml) for 2.5 hours to decompose ruthenium (VIII) oxide and then the black precipitates (ruthenium (IV) oxide) were filtered off. The filtrate was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel with a chloroform / methanol (10: 1) as eluent. The residual solid was recrystallized from ethyl acetate to give l,3,4(2H)-isoquinolinetrione (162.7mg) as a pale yellow solid, mp. 230-231°C NMR(DMSO-d6, δ ): 7.88(1H, dt, J=2.0, 7.5Hz), 7.93(1H, dt, J=2.0, 7.5Hz), 8.05(1H, dd, J=7.5, 2.0Hz), 8.13(1H, dd, J=7.5, 2.0Hz), 11.97(1H, s).

Claims

1. A pharmaceutical composition comprising a compound of the formula (la):
Figure imgf000049_0001
wherein
Rla is hydrogen atom, or nitro, or a lower alkoxy group, and
R2a is hydrogen atom, or nitro, amino, an acylamino or lower alkanesulfonyl group, or
Ria and R2a together with the adjacent carbon atoms to which they are attached form an aryl group,
R3a and R4a are, the same or different, hydrogen atom, or a lower alkyl, ar (lower) alkyl or aryl group or the group of the formula
-CH=N-O-ar(lower)alkyl, among which the ar (lower) alkyl and the group of the formula -CH=N-O-ar(lower)alkyl may be substituted with one or more substituent(s), or R3a and R4a form oxo group,
R5a and R6a are, the same or different, hydrogen atom or hydroxy group, or
R5a and R6a form oxo group,
R8a and R a are, the same or different, hydrogen atom or hydroxy group, or
R8a and R9a form oxo group,
Xa is N-R7a or O wherein R7a is hydrogen atom or hydroxy, a lower alkyl, aryl, ar (lower) alkyl or ar (lower) alkoxy group, among which the ar (lower) alkoxy group may be substituted with one or more substituent(s),
further R3a and R4a together with the carbon atoms to which they are attached may form a cycloalkane ring or
Figure imgf000050_0001
wherein Ya is CH or N, and R °a is hydroxy, an aryl, arylamino or lower alkoxy group, among which the aryl and arylamino groups may be substituted with one or more substituent(s), or
R3a together with R5a or R6a with the carbon atoms to which they are attached may form a bond or a cycloalkane ring,
its prodrug or a pharmaceutically acceptable salt thereof in admixture of a pharmaceutically acceptable carrier.
2. A pharmaceutical composition comprising a compound of the formula (lb):
Figure imgf000050_0002
wherein Rib is hydrogen or a halogen atom, or nitro, a lower alkyl, halo(lower)alkyl, lower alkoxy or halo (lower) alkoxy group,
R b and R3b are, the same or different, hydrogen atom, or a lower alkyl, aryl, ar (lower) alkyl, heterocyclic or acyl group, among which the lower alkyl and ar (lower) alkyl groups may be substituted with one or more substituent(s), or
R2b and R3b together with the carbon atoms to which they are attached form a cycloalkane ring which may be substituted with halo(lower)alkyl-substituted aryl, R4b and R5b are, the same or different, hydrogen or halogen atom, or an aryl or ar (lower) alkyl group, among which the ar (lower) alkyl group may be substituted with one or more halogen atom(s), or R4b and R5b form oxo group or an ethylene group which may be substituted with one or two substituent(s),
its prodrug or a pharmaceutically acceptable salt thereof in admixture of a pharmaceutically acceptable carrier.
3. A pharmaceutical composition comprising a compound of the formula (lc):
Figure imgf000051_0001
wherein
Ric is hydrogen or halogen atom, or nitro, a lower alkyl, lower alkoxy or lower alkylthio group, and R2c is hydrogen or halogen atom or a lower alkoxy group, or
Rlc and R2c together with the adjacent carbon atoms to which they are attached form an aryl group,
R3c is hydrogen or halogen atom, or nitro, a lower alkyl or halo (lower) alkoxy group, and
X= is CH or N,
its prodrug or a pharmaceutically acceptable salt thereof in admixture of a pharmaceutically acceptable carrier.
4. A pharmaceutical composition comprising a compound of the formula (Id):
Figure imgf000051_0002
wherein
Rld is hydrogen atom, or nitro, amino or an acylamino group, R2d is an optionally substituted aryl or ar (lower) alkyl group, and Xd is CH or N, its prodrug or a pharmaceutically acceptable salt thereof in admixture of a pharmaceutically acceptable carrier.
5. A pharmaceutical composition comprising a compound of the formula (Ie):
Figure imgf000052_0001
wherein
Rle is hydrogen atom or a lower alkoxy group,
R2e is hydrogen atom, or
Rle and R2e together with the adjacent carbon atoms to which they are attached form an aryl group,
R3e and R4e are hydrogen atoms or form oxo group,
Figure imgf000052_0002
OH R7e and Y« is CH2, C=O, NH, =C Λ1 ,or =C 8e
OH°r =C'R*
wherein R5e, R6e, R7e and R8e are, the same or different, hydrogen atom or hydroxy, a lower alkyl, lower alkoxy, aryl, acyloxy or carbocyclic group, among which the lower alkyl, aryl and carbocyclic groups may be substituted with one or more substituent(s), and further R6e and R7e together with the carbon atoms to which they are attached may form an optionally substituted unsaturated heterocyclic ring,
its prodrug or a pharmaceutically acceptable salt thereof in admixture of a pharmaceutically acceptable carrier.
6. The pharmaceutical composition of any one of Claims 1 to 5 for treating or preventing virus infectious diseases .
7. The pharmaceutical composition of Claim 6 wherein the virus infectious diseases are the ones caused by viruses within the Flaviviridae family selected from a group consisting of chronic liver disease, cirrhosis, hepatocellular carcinoma and liver failure; abortion, teratogenesis, respiratory problem, chronic wasting disease, immune system dysfunction and predisposition to secondary viral and bacterial infections; and dengue fever viruses, yellow fever virus and Japanese encephalititis virus.
8. A method of treating or preventing virus infectious diseases by administering a composition of any one of Claims 1 to 5, which contains an effective amount of a compound (la) to (Ie) , to human beings or an animal who needs to be treated or prevented.
9. A use of a compound (la) to (Ie) for preparing a composition of any one of in Claims 1 to 5.
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