WO1999033835A1 - Derives d'acide quinoleine-carboxylique a cycle condense - Google Patents

Derives d'acide quinoleine-carboxylique a cycle condense Download PDF

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Publication number
WO1999033835A1
WO1999033835A1 PCT/JP1998/005866 JP9805866W WO9933835A1 WO 1999033835 A1 WO1999033835 A1 WO 1999033835A1 JP 9805866 W JP9805866 W JP 9805866W WO 9933835 A1 WO9933835 A1 WO 9933835A1
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group
methyl
acceptable salt
ester
methoxy
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PCT/JP1998/005866
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English (en)
Japanese (ja)
Inventor
Tomoaki Komai
Toshinori Ohmine
Hidehiko Furukawa
Masako Ishimura
Toshinori Agatuma
Yoshiaki Kuroki
Tetsushi Katsube
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Sankyo Company, Limited
Ube Industries Ltd.
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Priority to AU16884/99A priority Critical patent/AU1688499A/en
Publication of WO1999033835A1 publication Critical patent/WO1999033835A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/06—Peri-condensed systems

Definitions

  • the present invention relates to a novel quinoline carboxylic acid derivative, which inhibits the growth of viruses, particularly human immunodeficiency virus (hereinafter referred to as HIV) and human cytomegalovirus (hereinafter referred to as HCMV).
  • HIV human immunodeficiency virus
  • HCMV human cytomegalovirus
  • the present invention relates to a novel fused quinoline carboxylic acid derivative, or a pharmaceutically acceptable salt or ester thereof.
  • HIV infects the CD 4-positive lymphocytes (helper / b Ndeyusa I) was primarily gradually reduce the number of cells in vivo and eventually severe acquired immunodeficiency syndrome (hereinafter AIDS ).
  • AIDS severe acquired immunodeficiency syndrome
  • HCMV is a virus that infects humans indigenously and is known to hide in various organs and frequently reactivate to cause fl opportunistic infections.
  • HCMV is weakly pathogenic and has only subclinical infections, but is immunocompromised, for example, after organ transplantation on immunosuppressive therapy, receiving radiation and chemotherapy.
  • CMV is the primary factor in opportunistic infections and is known to cause severe symptoms.
  • Ganciclovir and fosca-net are commercially available for the treatment of HCMV infection.
  • all of these drugs have strong side effects and the emergence of resistant viruses after long-term use. It has been reported that a fused quinoline carboxylic acid compound having the following formula has an antibacterial activity, but there is no report on an antiviral activity (Japanese Patent Laid-Open No. 59-14989, J. Heterocyclic Chem. 28, 1061 (1991)).
  • the present inventors have studied the anti-HIV activity of various quinoline carboxylic acid derivatives.As a result, they are different from the above-mentioned compounds in the chemical structure and the aryl group which may be substituted at the 10-position of the above formula. Is a condensed quinoline carboxylic acid derivative which is a pyrazinyl or homopiragel group substituted with a heteroaromatic ring, etc.
  • R 1 is a substituent R. And an aryl group having 6 to 10 carbon atoms which may be substituted with, or a substituent R. 5 or 6 membered heteroaromatic group containing 1 or 2 heteroatoms selected from N, O and S which may be substituted with benzene or lysine And the substituent R. Is a halogen atom, a hydroxy group, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 6 carbon atoms, and 1 carbon atom.
  • R 2 and R 3 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
  • X represents O or S;
  • m represents an integer of 2 or 3 .
  • the present invention also relates to a pharmacologically acceptable salt of the compound of the formula (I) and an ester of the compound of the formula (I).
  • the present invention provides a pharmaceutical composition, particularly a composition for treating or preventing AIDS disease, comprising a compound of the above formula (II) or a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.
  • a composition for the treatment or prevention of a submegalovirus infection is used.
  • the present invention relates to a medicament, in particular, the above compound or a medicament thereof for producing a composition for treating or preventing AIDS disease or a composition for treating or preventing cytomegalovirus infection.
  • the use of the above acceptable salts or esters thereof are examples of the above acceptable salts or esters thereof.
  • the present invention provides a method for treating AIDS disease or cytomegalovirus infection, which comprises administering to a warm-blooded animal a pharmacologically effective amount of the compound of the formula (I) or a pharmacologically acceptable salt or ester thereof. It relates to a method of treatment or prevention.
  • a pharmacologically effective amount of the compound of the formula (I) or a pharmacologically acceptable salt or ester thereof It relates to a method of treatment or prevention.
  • the “aryl group” for R 1 in the general formula (1) include a phenyl, 1-naphthyl and 2-naphthyl group, and a phenyl group is preferable.
  • a 5-membered or 6-membered heteroaromatic group j containing 1 or 2 heteroatoms selected from N, O and S which may be condensed with a benzene or pyridine ring for R 1 , for example, Chenyl, furyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazul, pyridazinyl, benzoxazolyl, benzothiazolyl, benzimidazolinole, benzoisoxazolinole, benzoisothiazolyl, benzoxazolo [5,4- Pyridyl, thiazolo [5, 4-b] pyridyl, imidazo [5, 4-b] pyridyl, oxazolo [4, 51-b] pyridyl, thiazolo [4, 5-b] pyridyl, thiazolo [ 5,4—c]
  • R 1 SR Conversion of R 1 SR.
  • halogen atom in the above include, for example, a fluorine, chlorine, bromine, and iodine atom, and a fluorine or chlorine atom is preferable.
  • Substituent R examples of the "alkyl group having 1 to 6 carbon atoms” include, for example, methylol, ethyl, propyl, isopropyl, butynole, s-butyl, isobutylinole, t-butyl, pentyl and hexyl groups.
  • alkyl group having 1 to 4 carbon atoms is preferably an alkyl group having 1 to 4 carbon atoms, more preferably a methyl or ethyl group, and particularly preferably a methyl group.
  • Substituent R examples of the “alkyl group having 1 to 6 carbon atoms substituted with a halogen atom” in the above include, for example, monofluoromethyl, difluoromethyl, trifluoromethinole; 2-fluorenetinole; 2-phenylene propyl, 3— Fluorop mouth pill; 2—Fluorobtinole, 3—Fluorobtinole, 4—Funoleolobutinole;
  • alkoxy group having 1 to 6 carbon atoms examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy and hexyloxy groups. It is preferably an alkoxy group having 1 to 4 carbon atoms, more preferably a methoxy or ethoxy group, particularly preferably a methoxy group.
  • alkylthio group having 1 to 6 carbon atoms examples include a methylthio, ethinorethio, propylthio, isopropylthio, butinorethio, isobutylthio, s-butylthio, t-butylthio, pentylthio, and hexylthio group. It is preferably an alkylthio group having 1 to 4 carbon atoms, more preferably a methylthio or ethylthio group, and particularly preferably a methylthio group. Substituent R.
  • the “optionally substituted aryl group” has the same meaning as described above, and is preferably a phenyl group.
  • the "halogen atom”, the “alkyl group having 1 to 6 carbon atoms” and the “alkoxy group having 1 to 6 carbon atoms” of the substituents of the "optionally substituted aryl group” Is equivalent to Si substituent R.
  • the substituent of the "optionally substituted aryl group” is preferably a fluorine, chlorine, methyl, methoxy, nitro, hydroxy or cyano group. Substituent R.
  • Examples of the optionally substituted aryl group J include, for example, pheninole, 2 — fenole, fenole, 3 — fenole, 4 — fenole, 2 — Black mouth feninole, 3 — black mouth feninole, 4 single mouth pheninole; 2 — bromopheninole, 3 — bromophenyl, 4 — bromopheninole; 2 — methinolephenyl, 3 — methylphenyl, 4 — methinolepheninole; 2—Echinoref ⁇ ninore,
  • a phenyl group which may have a substituent, or a heteroatom selected from N, O and S which may have a substituent and may be condensed with a benzene or pyridine ring, Or a 5- or 6-membered heteroaromatic group containing two, and the substituent is a halogen atom, a hydroxy group, an alkyl having 1 to 4 carbon atoms, or a substituted carbon atom substituted by a fluorine atom.
  • a phenyl group which may be substituted by fluorine, chlorine, hydroxy, methyl, methoxy, methylthio or trifluoromethyl; fluorine, tfi ⁇ , hydroxy, methynole, phenyl, 4-fluorophenyl, 4 2-thiazolyl group optionally substituted with monophenyl, 4-methylphenyl, 4-methoxyphenyl or 4- 12-trophenyl; fluorine, chlorine, hydroxy, methyl or methoxy.
  • 2-benzothiazolyl group fluorine, chlorine, hydroxy, methyl, meth 2-benzoxazolyl group optionally substituted by xy or methylthio; thiazolo [5,4-b] pyridine-1-2-optionally substituted by fluorine, chlorine, hydroxy, methyl, methoxy or methylthio Group
  • feninole 4-funolenophenyl, 2-methoxyphenine, 4-methoxyphene, 3—cloth feninole, 2-thiazolinole, 4-methinole, 1,2-thiazolyl , 3,4—Dimethyl-2-thiazolyl, 2-pyridyl, 2-pyrimidinyl, 5-funoleolol 2-pyridimigenole, 5—hydroxy-2—pyrimidyl, 5-methoxy-2-pyrimidinyl, 2-benzothiazolinole, 6-Methoxy 2-benzothiazolyl, 2-benzoxazolyl or thiazo [5,4-b] pyridine-12-yl group.
  • alkyl groups having 1 to 6 carbon atoms include, for example, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, isobutyl, t-butyl, pentyl and hexyl groups. And preferably a methyl, ethyl, propyl or isopropyl group, more preferably a methyl, ethyl or propyl group, particularly preferably a methyl or ethyl group, most preferably Preferably, it is a methyl group.
  • R 2 and R 3 are preferably a hydrogen atom, a methyl, an ethyl or a propyl group, more preferably a hydrogen atom, a methyl or an ethyl group, particularly preferably a hydrogen atom or a methyl group. Most preferably, it is a hydrogen atom.
  • X is preferably an oxygen atom.
  • m is preferably 2.
  • the “ester” of the compound represented by the general formula (I) indicates an ester as a prodrug formed by a carboxyl group and / or a hydroxy group present in the compound, and the pharmacological property of the compound The ester is not particularly limited as long as it does not inhibit the action and does not show significant toxicity.
  • Examples of the ester residue as a prodrug formed by the carboxyl group include an alkyl group having 1 to 4 carbon atoms such as a methyl, ethyl, ⁇ , propyl, isopropyl, butyl, and isobutyl group.
  • an alkyl group having 1 to 4 carbon atoms 1 (alkanoyloxy having 2 to 5 carbon atoms), an alkyl group having 1 to 2 carbon atoms, 1 — (alkoxycarbonyl having 1 to 4 carbon atoms) Oxy) —alkyl group having 1 to 2 carbon atoms, mono or di (alkyl group having 1 to 2 carbon atoms), substitution ability rubamoylmethyl group, N, N-di (alkyl having 1 to 2 carbon atoms), substituted amino group C 2 -C 3 alkyl group, tri (C 1 -C 2 alkyl) ammonium-C 1 -C 2 alkyl group, one or two selected from N, O and S A 5- or 6-membered heterosaturated monocyclic group-substituted alkyl group having 2 to 3 carbon atoms, including a hetero atom, or (5-methynole (or 5-phenyl) -12-oxo-1 1 , 3-dio
  • acyl residue of the ester as a prodrug formed by the hydroxy group examples include alkanoyl groups having 2 to 5 carbon atoms such as acetyl, propanoyl, butanol, isobutanoyl, and vivaloil groups. Preferably, it is an acetyl or bivaloyl group.
  • the “pharmacologically acceptable salt” of the compound represented by the above general formula (I) and its ester is also encompassed in the present description,
  • salts include acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodic acid, sulfate and phosphate; methanesulfonate, ethanesulfonate Acid addition of organic acids such as salts, benzenesulfonates, p-toluenesulfonates, oxalates, maleates, fumaric acid ⁇ , acetates, tartrates and citrates; or sodium salts, potassium And metal salts of carboxylic acids such as calcium salts, calcium salts, magnesium salts, manganese salts, iron salts and aluminum salts.
  • mineral acids such as hydrochloride, hydrobromide, hydroiodic acid, sulfate and phosphate
  • methanesulfonate such as salts, benzenesulfonates, p-toluenesulfonates, oxalates, maleates, fumaric acid ⁇ , acetates, tart
  • the active ingredient of the present invention may exist as a hydrate or a solvate.
  • the compound represented by the above general formula (I) may have two or four optical isomers based on the configuration of the carbon atom to which the substituents R 2 and R 3 are bonded.
  • the present invention also encompasses individual optical isomers and mixtures of these optical isomers in any proportion.
  • the contraction represented by the general formula (1) of the above (1)! Among the quinolinecarboxylic acid derivatives, preferred are the following derivatives (2) to (10).
  • R 1 a phenyl group which may have a substituent ⁇ or a ⁇ -substituent, which may be condensed with a benzene or pyridine ring N
  • alkyl groups alkyl groups having 1 to 4 carbon atoms, substituted by fluorine atoms, 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, alkylthio S having 1 to 4 carbon atoms, or fluorine
  • R 1 may have a substituent, phenyl, 2-phenyl, 2-furinole, 2-oxazolyl, 2-thiazolyl, 2-imidazolinole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidininole, 5-pyrimidinyl, 2-pyrazul, 3-pyridazinyl, 2-benzoxazolyl, 2-benzothiazolyl , 2-Benzomidazolinole, monobenzoisoxazolyl, 3-benzoisothiazolinole, oxazo [5, 4-b] Pyridine-12-yl, thiazolo [5, 4-b] Pyridine-12-inole, imidazo [5, 4-b] Pyridine-12-yl, oxazolo [4, 5-b] Pyridin-2-yl, thiazolo [4, 5-b] pyridine-1-yl, thiazolo [5, 4-
  • R 1 may be substituted by fluorine, chlorine, hydroxy, methyl, methoxy, methylthio or trifluoromethyl; a phenyl group; fluorine, chlorine, hydroxy, methyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methynolephen, 4-methoxyphenyl or 4-nitrophenyl 2-thiazolyl group which may be substituted; fluor, chlorine, phenyl 2-pyridyl group optionally substituted with hydroxy, methyl or methoxyl; 2-pyrimidinyl group optionally substituted with fluorine, salt, hydroxy, methyl or methoxy; fluorine, chlorine 2-benzothioazolyl group which may be substituted with, hydroxy, methyl, methoxy or methylthio; fluorine, chlorine, hydroxy 2-benzoxazolyl group which may be substituted by cis, methyl, methoxy or methylthio; or thiazolo which
  • R 1 force; phenyl, 4-fluorophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3—cloth, 2-phenyl Azolyl, 4-methyl-2-thiazolyl, 3,4-dimethyl-2-thiazolinole, 2-pyridyl, 2-pyrimidinyl, 5-fluoro-2-pyrimidinole, 5-hydroxy-1-pyrimidinyl, 5 .—Methoxy-1-pyrimidinyl, 2-benzothiazolyl, 6-methoxy-2-benzothiazolinole, 2-benzobenzoxazolyl or thiazolo [5,4-b] pyridine-Fused ring that is a pyridine-2-yl group Phosphorus carboxylic acid derivatives or pharmacologically acceptable salts thereof and esters thereof,
  • R 2 and R 3 are the same or different and each is a hydrogen, methyl, ethyl or propyl group, or a pharmaceutically acceptable derivative thereof. Salts and esters thereof,
  • 1 2 and 1 3 are condensed keno Li Nkarubon acid derivative or a pharmacologically acceptable salt and ester le is hydrogen atom,
  • R 1 force; optionally substituted phenyl, 2-phenyl, 2-furinole, 2-oxazolyl, 2-thiazolinole, 2-imidazolyl , 2 —pyridyl, 3 —pyridyl, 4-pyridyl, 2 —pyrimigenole, 4 —pyrimidinyl, 5 —pyrimidinyl, 2 —pyrazul, 3 —pyridazinole, 2-benzoxoxazolyl, 2-benzothiazolyl , 2-Benzomidazolinole, 3 Benzosozoxazolyl, 3-Benzoisothiazolinole, Oxazolo [5,4-b] pyridine-12-yl, thiazolo [5,4-b] Pyridine-12-inole, Imidazo [5,4-b] Pyridine-1-2-yl, oxazolo [4,5-b] pyridin-2-yl, thi
  • [5,4-c] pyridine-12-yl or thiazolo [4,5-c] pyridine-12-yl group wherein the substituent is fluorine, chlorine, hydroxy, methyl, ethyl, Trifluorome ⁇ ⁇ , methoxy, ethoxy, methinorecho, echinorecho, fueinore, 4 — fenoleo fuenore, 4 one-clope fuenore, 4 — methinolefénore, 4-metroxie , 4-nitrophenyl, 4-hydroxyphenyl or 4-cyanophenyl, R 2 and R 3 are the same or different and are a hydrogen atom, methyl, butyl or propyl group, and X is ⁇ (Oxygen atom), wherein m is 2 and a fused quinoline carboxylic acid derivative or a pharmaceutically acceptable salt and an ester thereof;
  • R 1 is a phenyl group which may be substituted with fluorine, chlorine, hydroxy, methyl, methoxy, methylthio or trifluoromethyl-; fluorine, chlorine, hydroxy, methyl, Phenyl, 4-fluorophenyl, 4-cyclophenyl, 4-methynolephenyl, 4-methoxyphenyl or 4-dithiophenyl optionally substituted 2-thiazolyl group; fluorine, 2-pyridyl which may be substituted with hydrogen, hydroxy, methyl or methoxy; substituted with fluorine, salt, hydroxy, methyl or methoxy 2-pyrimidinyl group which may be substituted; 2-benzothiazolyl group which may be substituted by fluorine, chlorine, hydroxy, methyl, methoxy or methylthio; fluorinated, chlorine, hydroxy, methyl, methoxy or methylthio A 2-benzoxazolyl group which may be substituted with a thiazol
  • R 1 force S, feninole, 4 — phenyolofeninole, 2- methoxypheninole, 4 — methoxyfeninole, 3 — clofeninole, 2 — thiazolinole , 4 —Methyl-2 —thiazolyl, 3,4 —Dimethyl-2-thiazolinole, 2 —pyridyl, 2 —pyrimidinyl, 5 —fluoro-2-pyrimidyl, 5-hydroxy-2 —pyrimidinyl, 5-methoxy 2 — Pyrimidinyl, 2-benzothiazolinole, 6-methoxy-2-benzothiazolyl, 2-benzoxazolyl or thiazolo [5,4-b] pyridin-12-yl group, wherein R 2 and R 3 are the same or -A condensed quinoline carboxylic acid derivative having a hydrogen atom or a methyl group,
  • the compound represented by the general formula (1) which is the active ingredient of the present invention, can be produced by the following methods ⁇ , ⁇ or C.
  • R ′, RR 3 , X and m have the same meanings as described above, L represents a fluorine atom or an acetyl group, and Ha 1 represents a halogen atom (preferably a fluorine or chlorine atom. ).
  • a quinoline carboxylic acid compound (II) is subjected to force-blowing of a cyclic diamine (II) in the presence or absence of a deoxidizing agent, in the presence or absence of a solvent, to give the desired compound (1).
  • a solvent used in this reaction include sulfoxides such as dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, and hexamethylphosphoric acid triamide.
  • Nonprotonic polar solvents such as amides (especially dimethyl sulfoxide or N, N-dimethylformamide) are suitable, but other ketones such as acetone and methylethylketone; Use ethers such as getyl ether, tetrahydrofuran and dioxane; esters such as ethyl acetate; alcohols such as methanol, ethanol, propanol, isopropanol and butanol; and nitriles such as acetate tritol. You can also.
  • amides especially dimethyl sulfoxide or N, N-dimethylformamide
  • ketones such as acetone and methylethylketone
  • Use ethers such as getyl ether, tetrahydrofuran and dioxane
  • esters such as ethyl acetate
  • alcohols such as methanol, ethanol, propanol, isopropanol and butanol
  • Examples of the deoxidizing agent include 1,8-diazabicyclo [5.4-0] -17-indene, 1,5-diazabicyclo [4.3.0] —5-nonene, triethylamine, N Tertiary amines such as N, N-diisopropylethylamine, tributylamine, pyridine, picolin, lutidine and collidine; sodium methoxide, sodium methoxide and potassium t— Metal alkoxides such as butoxide; inorganic bases such as sodium carbonate and carbonated lime can be used, and tertiary amines (particularly triethylamine) are preferred.
  • the amount of the deoxidizing agent used is preferably equimolar to 5 times the molar amount of the compound (II).
  • the tertiary amines described in flii it can be used in a large excess as a solvent.
  • Excessive diamines (110 also acts as a deoxidizing agent, so the reaction proceeds smoothly without adding any other deoxidizing agent.
  • the reaction is carried out at 0 "C to 200 ° C. C (preferably 80 ° C. to 150 ° C.), and is usually carried out for 0.5 to 24 hours (preferably 2 to 12 hours).
  • the cyclic diamines (III) are added to the boron carboxylate compound (IV) of a carboxyquinoline in the presence or absence of a deoxidizing agent and a solvent in the same manner as in the method A.
  • Or absence a method in which compound (V) is obtained by force-pulling down and then reacted in a hydroalcoholic alcohol in the presence of a base to dechelate to produce the desired compound (I).
  • the same deoxidizing agent and solvent as described in the method A are used, and the reaction temperature is 0 ° C to 150 ° C (preferably 0 ° C to 80 ° C). ) In the range of 0.5 o'clock to 24 o'clock (preferably) hours to 10 o'clock.
  • the base used for the de-chelation in the above-mentioned Method B include sodium hydroxide and alkali metal hydroxides such as sodium hydroxide, sodium carbonate and the like.
  • Alkali metal carbonates such as potassium carbonate; 1,8-diazabicyclo [5.4.0] — 7-ndecene, 1,5-diazabicyclo [4.3.0] — 5—nonene, triethylamine, N Tertiary amines such as N, N-diisopropylethylamine and 4-dimethylaminopyridine; or metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. And tertiary amines (particularly, triethylamine or 1,8-diazabicyclo [5.4.0] —7-indene).
  • the use efficiency of the salt is preferably equimolar to 10-fold molar amount to compound (V), but a large excess of 1: can also be used.
  • a water-containing alcohol used as a solvent for example, can be used methanol containing from 5 to 9 0 wt ° / 0 of water, ethanol, propanol, isopropanoyl no Honoré ⁇ Binomatawa butanol Preferably, it is methanol or ethanol containing 5 to 30% by weight of water.
  • the reaction is carried out at a temperature ranging from 0 ° C to 150 ° C (preferably 50 ° C to 120 ° C), from 0. hour fill to 24 hours (preferably 1 to 10 hours). Q) This is done over time.
  • the compound (VIII) is used in place of the starting compound (IV) in the method B, and the reaction is carried out in the same manner as in the method B to obtain a compound (VIII). Then, the compound is removed in the presence of a base.
  • This is a method for producing the target compound (I) by a hydrogen halide reaction.
  • Examples of the base used in the dehydrohalogenation reaction in Method C include the same bases as those used in the above-described dechelation.
  • tertiary amines particularly, 8-diazabicyclo [5.4.0] — 7-indene or triethylamine.
  • the amount of the base to be used is 1 to 30 moles (preferably 1 to 20 moles) relative to compound (VIII).
  • Examples of the solvent include non-profit compounds such as sulphoxides such as dimethylsulfoxide, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphate triamide.
  • Polar solvents phenols such as methanol, ethanol, butanol and butanol; etc .; acetonitrile Nitrils such as toluene; water and their mixed solvents can be used, and preferred are alcohols (particularly methanol and ethanol) or hydrous alcohols (particularly hydrous methanol and hydrous ethanol).
  • the reaction is 0. C. to 150.degree. C. (preferably 50.degree. C. to 120.degree. C.) for 0.5 to 24 hours (preferably 1 to 10 hours). .
  • the compound (1 ′) in which the substituent R 1 of the general formula (I) is a heteroaromatic ring group can also be produced by the following Method D.
  • R 2 , R ⁇ X and m have the same meaning as described above, R 1 ′ is a heteroaromatic group, and Ha 1 represents a halogen atom.
  • the reaction in Method D is performed in the same manner as described in Method A. That is, by coupling the quinoline carboxylic acid compound (IX) with an equimolar to 5-fold molar amount of the compound (X) in the presence of a deoxidizing agent, in the presence or absence of a solvent, the compound ( 1 ') is manufactured.
  • Examples of the solvent used in the method D include sulfoxides such as dimethyl sulfoxide, amides such as N, N-dimethylformamide, N, N-dimethylinoleacetamide, and hexamethylphosphoric acid triamide.
  • sulfoxides such as dimethyl sulfoxide
  • amides such as N, N-dimethylformamide, N, N-dimethylinoleacetamide, and hexamethylphosphoric acid triamide.
  • Such non-protonic polar solvents are suitable, but other ketones such as acetone, methylethylketone, etc .; getyl ether, tetrahydrofuran, dioxane, etc. Ethers; esters such as ethyl acetate; methanol, ethanol, propanol, and isoprono.
  • alcohols such as ethanol and butanol
  • butyryls such as acetonitrile
  • the deoxidizing agent include 1,8-diazabicyclo [5.4.0] -7-indene, 1,5-diazabicyclo [4.3.0] -15-nonene, triethylamine, tributyla Tertiary amines such as amine, pyridine, picoline, lutidine and collidine; or inorganic bases such as sodium carbonate and carbonated carbonate can be used. In particular, potassium carbonate.
  • the amount of the deoxidizing agent to be used is preferably equimolar to 10-fold molar with respect to the compound (X), but when the tertiary amines are used, they should be used in large excess as a solvent. Can also.
  • This reaction is carried out at a temperature of 0 ° C. to 200 ° C. (preferably 80 ° C. to 150 ° C.), usually for 1 hour to 24 hours (preferably 2 to 10 hours).
  • Q) It is done over.
  • a substituent R is used.
  • a hydroxy group is protected with a protected S (preferably a benzyl group) such as a benzyl group, a methyl group, a t-butyl group, a methoxymethyl group, a methoxymethyloxy group or a t-butyldimethylsilyl group.
  • a protected S preferably a benzyl group
  • the compound (I) in which the corresponding hydroxy group is protected is obtained by any one of the above methods A to D using the obtained compound, and the protecting group is then removed to obtain the substituent R.
  • a compound having a hydroxy group- can be easily produced.
  • the introduction and removal of the protecting group for the hydroxy group can be appropriately selected from known methods (see TWGreene and Pi) and H. Wuts Protective Groups in Organic Synthesis 2nd Ed. John Wiley and Sons.).
  • the removal of the benzyl group can be carried out by a method using a thioazirnotritrifluoroacetic acid, a thiol compound (especially ethyl mercaptan), a boron trifluoride etherate complex, or trimethylsilyl iodide (preferably thiol thiol).
  • the method can be easily carried out by dissolving Z-trifluoroacetic acid).
  • the target compound of this reaction can be obtained by treating the reaction mixture according to a conventional method, and, if necessary, using a usual purification method such as a recrystallization method or column chromatography. And can be purified.
  • the compound (1) thus obtained can be converted into a desired pharmacologically acceptable salt or ester derivative according to a conventional method, if necessary.
  • Compound (II) used as a starting material in the above-mentioned Method A is disclosed, for example, in JP-A-59-14889 or J. Heterocyc 1 icchem., 28, 1061 (1992). 1) or a method similar thereto
  • the starting compound (IV) in the method B can be obtained from the compound (II) or its ester by a known method, for example, a method using borofluoric acid, a boron fluoride ether complex or triacetoxyboric acid. It is easily manufactured.
  • the compound (III) used in the above method (1) can be easily prepared, for example, by the method described in JP-A-6-116241 or JP-A-8-187375 or a method analogous thereto. It is manufactured in.
  • the starting compound (VO can be produced, for example, by the method described in Japanese Patent Application Laid-Open No. Sho 62-155,282 or a method similar thereto. In the method D, it is used as a starting material.
  • the compound (IX) is produced by reacting the compound (II) or (IV) as a starting material with a cyclic diamine (III) wherein R 1 is a hydrogen atom in the same manner as in the method A or the method B.
  • the compound represented by the above general formula (I) produced as described above may have an optically active substance, in which case, the compound is optically resolved at an appropriate stage.
  • the corresponding optical isomer of the target compound (I) can be obtained.
  • Each optical isomer is processed according to the optical resolution method of As described above, the carboxyl group of the compound represented by the general formula (I) may form an ester acceptable on the drug 1 as described above.
  • Conventional methods for example, in the former case, a dehydration condensation method using an acid catalyst, a method via an acid halide, and a dehydration condensation method using a carbodiimide
  • Basic conditions G exchange reaction below below.
  • the compounds of the general formula (I) of the present invention, their pharmaceutically acceptable esters and their pharmaceutically acceptable salts have excellent antiviral activity (in particular, anti-HIV and anti-HCMV activity). It is useful as a therapeutic agent for infectious diseases caused by viruses. Dosage forms for that purpose include, for example, oral administration by tablets, capsules, granules, powders, syrups, etc., or parenteral administration by intravenous injections, intramuscular injections, suppositories, etc. No. These drugs are manufactured by a known method using additives such as a shaping agent, a binder, a disintegrant, a lubricant, a stabilizer, and a flavoring agent, if necessary.
  • additives such as a shaping agent, a binder, a disintegrant, a lubricant, a stabilizer, and a flavoring agent, if necessary.
  • the dosage varies depending on age, body weight, symptoms, dosage form and number of administrations.
  • the lower limit is 1 mg (preferably 10 mg) per 13 doses.
  • 100 mg (preferably 500 mg) is administered once or in several divided doses.
  • the compound of the general formula (I) did not show toxicity even when orally administered to a rat a dose several times the above-mentioned administration fi (converted to body weight).
  • the title compound was obtained as a yellow powder in the same manner as in Example 1 except that 1- (2-pyrimidyl) pidazine was used instead of 1- (2-benzodiazolyl) pidazine.
  • the title compound was obtained as a white powder in the same manner as in Example 21 except that a link mouth was used instead of ethanol.
  • the title compound was obtained as a pale yellowish white powder in the same manner as in Example 23.
  • the powder of the above formulation is mixed, wet-granulated using corn starch paste, dried, and then tableted with a tableting machine to give a tablet of 200 mg per tablet. These tablets can be sugar-coated if necessary.
  • the anti-HIV activity of the compound of the present invention is measured according to the method of R. Pauwe 1 and the like (J. Viro 1 ogica 1 Mehods 20, 309-32 1 (1 988)). went. That is, MT-4 cells are centrifuged, and the cell suspension in which the obtained cell sediment is suspended is infected with HIV by inoculation, followed by addition of 10% fetal calf serum RPM I-164 0 medium (hereinafter referred to as serum medium) was added, washed, and centrifuged. The thus II IV infected cells ⁇ Pi HIV uninfected cells obtained were suspended in serum medium so that each becomes 4 X 1 0 5 or Zm 1.
  • the cytotoxicity-suppressing activity of non-compound-free HIV-infected cells was set at 100%, and that of compound-free H1V-infected cells was set at 0%.
  • the concentration (EC 5 ) of the compound showing% cytotoxicity-inhibiting activity was determined. Further, as the cytotoxic activity of the compounds, the growth of HIV uninfected cells sought 5 0% inhibition concentration (CC 50), Jiji 5. / £ ⁇ 5.
  • the value was taken as the selection coefficient (SI) of the anti-141 V activity, and Table 7 shows the test results.
  • Example 1 0.15 2.6 17.3
  • Example 2 0 0 0 8 0 .1 6 2 0
  • Example 4 0 1 7 2. 5 1 4.7
  • Example 5 0 1 5 2. 7 1 8
  • Example 7 0 4 4 2 1 0 5 -Example 8 0 2 1 .2 6
  • Example 9 0 2 5. 4 2 7
  • Example 1 3 0 6 7 2 8.3
  • Example 1 4 0 1 .8 1 1.8
  • Example 1 5 0 5. 7.6
  • Comparative compounds> 25.0 The compounds of the present invention exhibited excellent anti-HIV activity and low cytotoxicity.
  • the compounds of Zang Examples 2, 9, 10 and 13 exhibited excellent anti-HIV activity with a selectivity factor (SI) of 20 or more.
  • the anti-HCMV activity of the compounds of the invention can be determined according to the method reported by Tims et al. (J. Antimi crobial and Chemotherapy Vol. 8, pp. 62-75, 1989), according to the general method.
  • the plaque reduction method was used. That is, human embryonic fibroblasts (MR C - 5) HCMV strain (AD 1 6 9) in monolayer culture 1 00 plaque forming units (pf U) Bruno 1 0 5 cells equivalent to infected, the test compounds The cells were cultured at 37 ° C for 8 minutes in the presence of the microorganism. 0.5 ° / for culture after infection.
  • the cell phase was overlaid with Eagle's MEM medium (supplemented with 2% fetal calf serum) containing agar, fixed 10 days after infection, and stained with methylene blue. A drug concentration-dependent curve of the plaque formation reduction rate compared to the drug-untreated control was plotted. 0% P11 concentration: (IC 50 ) was determined.
  • the cytotoxicity of the compound was measured using MT-4 cells according to the method of R. Pauwe 1 et al. (J. Virological Methods 20, 309-321, 1988). went. That is, 10% fetal calf serum added R PM I-164 0 medium
  • MT-4 cells were suspended in a serum medium (hereinafter referred to as serum medium) at a concentration of 4 x 10 5 Zm1, and the compound, which had been serially diluted in serum medium, was placed in a 96-well plate for tissue culture. 4. Add 100 ⁇ l to the wells. 3/7 in the presence of carbon dioxide. 5 Ptiij cells were cultured. After completion of the culture, the number of viable cells was measured using MMT (3- (45-dimethylthiazol-1-yl) -125-diphenyltetrazolamide bromide). The percentage of the number of viable cells to which the compound was added when the concentration was 0% was determined, and the concentration of the compound at which 50 % of the cells survived (CC 50 ) was determined.
  • serum medium serum medium
  • MMT 3- (45-dimethylthiazol-1-yl) -125-diphenyltetrazolamide bromide
  • Human 14-week-old fetal lung-derived cell line MR C-5 was purchased from Dainippon Pharmaceutical and supplied with 10% immobilized fetal serum (FBS) and 5% Penicillin-Streptomycin Solution (Sigma) II After incubation in Minimum Essential Medium, Hank's salts (MEM-H), apply 10% immobilized fetal blood (FBS) and 0.2% Penicill in-Streptomycin Solution (Sigma). [I 7] The medium was exchanged for Minimum Essential Medium, Earle's salts (MEM-E), and the cells were cultured. The medium was changed every 3 to 4 days.
  • HCMV AD169 strain Human Cytomegalovirus (HCMV) AD169 strain was purchased from ATCC. Winores cultivated as follows. First, 4 ml of a virus solution diluted to 0.1 virion per cell was added to MRC-5 cells, which form a nearly monolayer in a medium-angle flask, and 37. Cells were infected by incubation for 90 minutes at C. Then remove the virus solution and add 8 ml of MEM-E containing 2% FBS. The cells were cultured for 7 to 10 days in a carbon dioxide gas incubator C. After confirming that viral damage (CPE) has appeared in most cells, After peeling the cells from the flask with a Rusker, the lid was closed and the cells were sonicated for 2 minutes to disrupt the cells and release virus particles.
  • CPE viral damage
  • the virus titer of the stock solution (plaque foming unite, PFU) was calculated from the following equation.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne des dérivés d'acide quinoléine-carboxylique à cycle condensé, ces dérivés présentant une activité qui inhibe la propagation de virus. Ces dérivés sont des composés représentés par la formule générale (I), ou des sels ou des esters pharmaceutiquement acceptables de ceux-ci, ou les deux: R1 étant un aryle éventuellement substitué, un cycle hétéroaromatique éventuellement substitué, ou similaire; R2 et R3 représentant chacun hydrogène ou alkyle inférieur, X représentant O ou S; et m étant égal à 2 ou 3.
PCT/JP1998/005866 1997-12-24 1998-12-24 Derives d'acide quinoleine-carboxylique a cycle condense WO1999033835A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU16884/99A AU1688499A (en) 1997-12-24 1998-12-24 Fused-ring quinolinecarboxylic acid derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP35394797 1997-12-24
JP9/353947 1997-12-24
JP10/94257 1998-04-07
JP9425798 1998-04-07

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS591489A (ja) * 1982-06-29 1984-01-06 Dai Ichi Seiyaku Co Ltd ピリドベンゾオキサジン誘導体
JPS60202822A (ja) * 1984-03-28 1985-10-14 Dai Ichi Seiyaku Co Ltd 抗ウイルス薬
JPH0649074A (ja) * 1992-04-02 1994-02-22 Bayer Ag 新規な９−フルオロ−７−オキソ−７Ｈ−ピリド［１，２，３−ｄｅ］［１，４］ベンズオキサジン−６−カルボン酸およびエステル
JPH09323932A (ja) * 1996-01-31 1997-12-16 Sankyo Co Ltd エイズ治療剤又は予防剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS591489A (ja) * 1982-06-29 1984-01-06 Dai Ichi Seiyaku Co Ltd ピリドベンゾオキサジン誘導体
JPS60202822A (ja) * 1984-03-28 1985-10-14 Dai Ichi Seiyaku Co Ltd 抗ウイルス薬
JPH0649074A (ja) * 1992-04-02 1994-02-22 Bayer Ag 新規な９−フルオロ−７−オキソ−７Ｈ−ピリド［１，２，３−ｄｅ］［１，４］ベンズオキサジン−６−カルボン酸およびエステル
JPH09323932A (ja) * 1996-01-31 1997-12-16 Sankyo Co Ltd エイズ治療剤又は予防剤

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