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WO1992012154A1 - Derive d'immidazotriazine - Google Patents

Derive d'immidazotriazine Download PDF

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Publication number
WO1992012154A1
WO1992012154A1 PCT/JP1991/001768 JP9101768W WO9212154A1 WO 1992012154 A1 WO1992012154 A1 WO 1992012154A1 JP 9101768 W JP9101768 W JP 9101768W WO 9212154 A1 WO9212154 A1 WO 9212154A1
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WO
WIPO (PCT)
Prior art keywords
compound
salt
group
alkyl
formula
Prior art date
Application number
PCT/JP1991/001768
Other languages
English (en)
Inventor
Teruo Oku
Yoshio Kawai
Hiroshi Marusawa
Hirokazu Tanaka
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB909028217A external-priority patent/GB9028217D0/en
Priority claimed from GB919113017A external-priority patent/GB9113017D0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Publication of WO1992012154A1 publication Critical patent/WO1992012154A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to new imidazotriazine
  • Interleukin-1 Interleukin-1
  • IL-1 Interleukin-1
  • This invention relates to new imidazotriazine
  • this invention relates to new imidazotriazine derivatives and pharmaceutically acceptable salts thereof which have pharmacological activities, processes for preparation thereof, a
  • composition comprising the same and a use of the same.
  • one object of this invention is to provide the new and useful imidazotriazine derivatives and pharmaceutically acceptable salts thereof which possess a strong inhibitory activity on the production of
  • Interleukin-1 IL-1
  • TNF tumor necrosis factor
  • Another object of this invention is to provide processes for preparation of the imidazotriazine
  • IL-1 and TNF mediated diseases such as chronic inflammatory diseases, specific autoimmune diseases, sepsis-induced organ injury, and the like in human being and animals.
  • the object imidazotriazine derivatives of the present invention are novel and can be represented by the
  • R 1 is hydrogen, lower alkyl or acyl
  • R 2 is hydrogen, or acyl
  • R 3 is aryl which may have suitable
  • R is heterocyclic group which may have
  • heterocyclic(lower) alkyl heterocyclicthio, or heterocyclicsulfinyl.
  • the object compound (I) of the present invention can be prepared by the following processes.
  • Process (1) (1)
  • R 1 , R 2 , R 3 and R 4 are each as defined above,
  • R 12 and R 13 are each hydrogen, or
  • R 12 and R 13 are linked together to form
  • X 1 is an acid residue, carboxy or protected carboxy
  • X 2 is an acid residue
  • R 5 is protected carboxy
  • R a 1 and R 2 are each acyl
  • R 6 is hydrogen or C 1 -C 5 alkyl
  • R a 3 is aryl having protected carboxy group(s)
  • R b 3 is aryl having carboxy group(s)
  • R b 1 is acyl having protected hydroxy group(s)
  • R c 1 is acyl having hydroxy group(s).
  • R 1 a , R 2 a , R 3 and R 4 are each as defined above,
  • R 10 and R 11 are each heterocyclic group
  • X 3 and X 4 are each an acid residue, and X 5 is halogen.
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include e.g. a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.) an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt,
  • a salt with an inorganic base for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.) an ammonium salt
  • a salt with an organic base for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt,
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic carboxylic or sulfonic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
  • a salt with a basic or acidic amino acid e.g.
  • lower is used to intend a group having 1 to 6 , preferably 1 to 4, carbon atom(s), unless otherwise provided.
  • Suitable "lower alkyl” and “lower alkyl moiety" in the term “heterocyclic(lower) alkyl” may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like, in which more preferable example may be C 1 -C 4 alkyl.
  • Suitable "acyl” may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
  • This acyl group may be derived, for example, from an organic carboxylic, an organic carbonic, an organic sulfuric, an organic sulfonic and an organic carbamic acids.
  • acyl may be illustrated as follows :- Carbamoyl
  • Alliphatic acyl such as lower or higher alkanoyl (e.g.
  • alkylsulfonyl e.g. methylsulfonyl
  • alkoxysulfonyl e.g. methoxysulfonyl, ethoxysulfonyl, etc.; or the like;
  • Aromatic acyl such as
  • aroyl e.g. benzoyl, toluoyl, naphthoyl, etc.
  • ar(lower)alkanoyl e.g. phenyl(lower)alkanoyl (e.g.
  • phenylisobutylyl phenylpentanoyl, phenylhexanoyl, etc.
  • naphthyl(lower)alkanoyl e.g. naphthylacetyl
  • ar( lower)alkenoyl e.g. phenyl( lower)alkenoyl (e.g.
  • naphthyl(lower)alkenoyl e.g. naphthylpropenoyl
  • ar(lower)alkoxycarbonyl e.g. phenyl(lower) alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), etc.]; aryloxycarbonyl (e.g. phenoxycarbonyl, naphthyloxycarbonyl, etc.);
  • aryloxy(lower)alkanoyl e.g. phenoxyacetyl
  • arylcarbamoyl e.g. phenylcarbamoyl, etc.
  • arylthiocarbamoyl e.g. phenylthiocarbamoyl, etc.
  • arylglyoxyloyl e.g. phenylglyoxyloyl, naphthylglyoxyloyl, etc.
  • arylsulfonyl e.g. phenylsulfonyl, naphthylsulfonyl, etc.; or the like;
  • Heterocyclic acyl such as
  • heterocyclic (lower) alkanoyl e.g. thienylacetyl
  • heterocyclic(lower)alkenoyl e.g. heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl,
  • heterocyclicglyoxyloyl e.g. thiazolylglyoxyloyl
  • heterocyclic group and heterocyclic moiety in the terms “heterocycliccarbonyl”,
  • heterocyclic(lower)alkanoyl heterocyclic(lower)alkenoyl and heterocyclicglyoxyloyl means saturated or
  • heterocyclic group may be heterocyclic group such as
  • 4-nitrogen atom(s) for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide,
  • triazolyl e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.
  • tetrazolyl e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.
  • nitrogen atom(s) for example pyrrolidinyl
  • indolinyl indolizinyl, benzimidazolyl, quinolyl, dihydroguinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;
  • oxazolyl isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5- xadiazolyl, etc.) etc.;
  • 6-membered) heteromonocyclic group containing an oxygen atom for example, furyl, etc.
  • acyl moiety as stated above may have one to five, same or different, suitable substituent(s) such as halogen (e.g. fluorine, chlorine, bromine or iodine), lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.);
  • suitable substituent(s) such as halogen (e.g. fluorine, chlorine, bromine or iodine), lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.);
  • lower alkoxy e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, hexyloxy, etc.
  • Suitable "mono(or di or tri)halo(lower)alkyl” means straight or branched lower alkyl having one to three
  • halogen e.g. chlorine, bromine, iodine, fluorine
  • Suitable "protected hydroxy” may include acyloxy and the like.
  • acyl moiety in the term “acyloxy” can be referred to the ones as exemplified above.
  • Suitable "protected carboxy” may include esterified carboxy and the like.
  • ester moiety of an esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.) which may have at least one suitable substituent(s), for
  • lower alkanoyloxy(lower) alkyl ester e.g., lower alkanoyloxy(lower) alkyl ester
  • pivaloyloxymethyl ester pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1(or 2)-acetoxyethyl ester, 1(or 2 or 3)-acetoxypropyl ester l(or 2 or 3 or 4)-acetoxybutyl ester, 1(or 2)-propionyloxyethyl ester, 1(or 2 or 3)-propionyloxypropyl ester, 1(or
  • alkanesulfonyK lower) alkyl ester e.g. 2-mesylethyl ester, etc.
  • mono(or di or tri)-halo(lower)alkyl ester e.g.
  • 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc. lower alkoxycarbonyloxy( lower) alkyl ester (e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester, etc.).
  • lower alkenyl ester e.g. vinyl ester, allyl ester, etc.
  • lower alkynyl ester e.g. ethynyl ester, propynyl ester, etc.
  • ar( lower)alkyl ester which may have at least one suitable substituent(s) such as mono(or di or
  • substituent(s) e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.
  • substituent(s) e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.
  • Suitable "aryl” may include phenyl, naphthyl and the like.
  • Suitable "acid residue” may include halogen [e.g.
  • Suitable "C 1 -C 5 alkyl” may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl and the like.
  • Suitable "substituent" in the term “aryl which may have suitable substituent( s) " may include halogen
  • Suitable "substituent" in the term “heterocyclic group which may have suitable substituent(s)” may include an acid residue, carboxy, lower alkyl, protected carboxy, or the like.
  • heterocyclic(lower)alkyl "heterocyclicthio” and
  • heterocyclicsulfinyl can be referred to the ones as exemplified above.
  • the compound (la) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof and the compound (IV).
  • the reaction is usually carried out in a conventional solvent such as alcohol (e.g., methanol, ethanol, etc.), tetrahydrofuran, N,N-dimethylformamide, dichloromethane, acetic acid, or any other solvent which does not adversely influence the reaction.
  • a conventional solvent such as alcohol (e.g., methanol, ethanol, etc.), tetrahydrofuran, N,N-dimethylformamide, dichloromethane, acetic acid, or any other solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the compound (lb) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to oxidation reaction.
  • Oxidation is carried out in a conventional manner, which is capable of oxidizing N-protected carboxy
  • suitable oxidizing reagent may be sulfur, oxygen, alkali metal alkoxide (e.g., potassium t-butoxide, etc.), or the like.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol. isopropyl alcohol, t-butyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, chloroform, dimethyl acetamide, decalin, tetralin,
  • a conventional solvent such as water, alcohol (e.g., methanol, ethanol. isopropyl alcohol, t-butyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, chloroform, dimethyl acetamide, decalin, tetralin,
  • hydrophilic solvents may be used in a mixture with water.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to deacylation reaction. Suitable method of this reaction may include conventional one such as hydrolysis, reduction and the like.
  • the hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium,
  • alkali metal lower alkoxide e.g.
  • Suitable acid may include an organic acid [e.g.
  • cation trapping agents e.g. anisole, phenol, etc.
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used in chemical reduction are a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid,
  • a metal e.g. tin, zinc, iron, etc.
  • metallic compound e.g. chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e.g. formic acid, acetic acid, propionic acid
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g.
  • platinum plate spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalysts e.g. spongy palladium, palladium black
  • palladium oxide palladium on carbon
  • colloidal palladium palladium on barium sulfate
  • nickel catalysts e.g. reduced nickel, nickel oxide, Raney nickel, etc.
  • cobalt catalysts e.g. reduced cobalt, Raney cobalt, etc.
  • iron catalysts e.g. reduced iron, Raney iron, etc.
  • copper catalysts e.g. reduced copper, Raney copper, Ullman copper, etc.
  • the reduction is usually carried out in a
  • N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof are in liquid, they can also be used as a solvent.
  • reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
  • the present invention includes, within the scope of the invention, the cases that the protected carboxy group in R 3 is transformed into a carboxy group or hydroxymethyl during the reaction and that the protected carboxy group in R 4 is transformed into a carboxy group during the reaction.
  • the compound (If) or a salt thereof can be prepared by subjecting the compound (Ie) or a salt thereof to acylation reaction.
  • Suitable acylating agent to be used in the present acylation reaction may include the compound of the
  • R 1 a is acyl
  • Suitable reactive derivative of the compound (IX) may include an acid halide, an acid anhydride, an activated amide, an activated ester, isocyanate, and the like.
  • the suitable example may be an acid chloride, an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid,
  • dibenzylphosphoric acid dibenzylphosphoric acid, halogenated phosphoric acid, etc.
  • dialkylphosphorous acid dialkylphosphorous acid
  • sulfurous acid dialkylphosphorous acid
  • methanesulfonic acid ethanesulfonic acid, etc.
  • sulfuric acid alkylcarbonic acid
  • aliphatic carboxylic acid e.g. pivalic acid, pentanoic acid, isopentanoic acid
  • phenylazophenyl ester phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a N-hydroxy compound (e.g. N,N-dimethylhydroxylamine,
  • the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction.
  • a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction.
  • a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
  • N,N'-diethylcarbodiimide N,N'-diisopropylcarbodiimide
  • N,N-carbonylbis-(2-methylimidazole) pentamethyleneketene- N-cyclohexylimine, diphenylketene-N-cyclohexylimine;
  • ethoxyacetylene 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride),
  • reaction may also be carried out in the presence of an inorganic or organic base such as an a ⁇ kali metal bicarbonate, tri(lower)alkylamine, pyridine,
  • an inorganic or organic base such as an a ⁇ kali metal bicarbonate, tri(lower)alkylamine, pyridine,
  • N-(lower)alkylmorphorine N,N-di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the present invention includes, within the scope of the invention, the case that hydrogen in R 2 is transformed into a acyl group during the reaction.
  • the compound (Ig) or a salt thereof can be prepared by reacting the compound (Ie) or a salt thereof with the compound (V) and then by subjecting the resultant compound to reduction reaction.
  • Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used in chemical reduction are hydrides (e.g. hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.) or a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. formic acid, acetic acid,
  • hydrides e.g. hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.
  • a metal e.g. tin, zinc, iron, etc.
  • metallic compound e.g. chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e.g. formic acid, acetic acid,
  • propionic acid trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. spongy palladium, palladium black,
  • palladium oxide palladium on carbon
  • colloidal palladium palladium on barium sulfate
  • nickel catalysts e.g. reduced nickel, nickel oxide, Raney nickel, etc.
  • cobalt catalysts e.g. reduced cobalt, Raney cobalt,etc.
  • iron catalysts e.g. reduced iron, Raney iron, etc.
  • copper catalysts e.g. reduced copper, Raney copper, Ullman copper etc.
  • the reaction is usually carried out in a solvent such as water, alcohol (e.g. methanol, ethanol, etc.),
  • reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (Ii) or a salt thereof can be prepared by subjecting the compound (Ih) or a salt thereof to acylation reaction.
  • This reaction can be carried out in a similar manner to that of the aforementioned Process (4), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (4).
  • the compound (Ie) or a salt thereof can be prepared by subjecting the compound (If) or a salt thereof to deacylation reaction. This reaction can be carried out in a similar manner to that of the aforementioned Process (3), and therefore the reagents to be used and the
  • reaction conditions e.g., solvent, reaction temperature, etc.
  • Process (3) e.g., solvent, reaction temperature, etc.
  • the compound (Id) or a salt thereof can be prepared by subjecting the compound (X) or a salt thereof to reduction reaction. This reduction can be carried out in a similar manner to that of the aforementioned Process (5), and therefore the reagents to be used and the
  • reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (Ik) or a salt thereof can be prepared by subjecting the compound (Ij) or a salt thereof to elimination reaction of the carboxy protective group(s).
  • This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.
  • This reaction can be carried out in a similar manner to that of the aforementioned Process (3), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (3).
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (Im) or a salt thereof can be prepared by reacting the compound (Il) or a salt thereof to
  • This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.
  • This reaction can be carried out in a similar manner to that of the aforementioned Process (3) and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (3).
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (VIII) or a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the compound (VII) or a salt thereof.
  • This reaction is usually carried out in a solvent such as alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, methylene
  • a solvent such as alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, methylene
  • Process (B) is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (IIa) or a salt thereof can be prepared by subjecting the compound (VIII) or a salt thereof to reduction. This reduction can be carried out in a similar manner to that of the aforementioned Process (5), and therefore the reagents to be used and the reaction
  • the compound (lib) or a salt thereof can be prepared by subjecting the compound (IIa) or a salt thereof to acylation reaction.
  • This reaction can be carried out in a similar manner to that of the aforementioned Process (4), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (4).
  • the compound (XIII) or a salt thereof can be prepared by reacting the compound (XI) or a salt thereof with the compound (XII) or a salt thereof.
  • This reaction can be carried out in accordance with the method disclosed in the Preparation 4 dejcribed later or a similar manner thereto.
  • the compound (XIVa) or a salt thereof can be prepared by subjecting the compound (XIII) or a salt thereof to reduction reaction. This reduction can be carried out in a similar manner to that of the aforementioned Process (5), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (5).
  • Process (F)
  • the compound (XIVb) or a salt thereof can be prepared by reacting the compound (XV) or a salt thereof with the compound (VI) or a salt thereof.
  • This reaction can be carried out in accordance with the method disclosed in the Preparation 7 described later or a similar manner thereto.
  • the compound (XIV) or a salt thereof can be prepared by reacting the compound (XVI) or a salt thereof with the compound (XVII) or a salt thereof.
  • This reaction can be carried out in accordance with the method disclosed in the Preparation 8 described later or a similar manner thereto.
  • This reaction can be carried out in accordance with the method disclosed in the Preparation 6 and 9-(1) described later or a similar manner thereto.
  • the compound (X) or a salt thereof can be prepared by reacting the compound (XVIII) or a salt thereof with the compound (VII) or a salt thereof.
  • This reaction can be carried out in a similar manner to that of the aforementioned Process (A), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (A).
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (Xb) or a salt thereof can be prepared by subjecting the compound (Xa) or a salt thereof to oxidation reaction.
  • Oxidation is carried out in a conventional manner, which is capable of sulfur atom(s) to oxidized sulfur atom(s), and suitable oxidizing reagent may be oxygen acid such as periodate (e.g. sodium periodate, etc.), peroxy acid such as peroxybenzoic acids (e.g. peroxybenzoic acid, m-chloroperoxybenzoic acid, etc.), and the like.
  • oxygen acid such as periodate (e.g. sodium periodate, etc.), peroxy acid such as peroxybenzoic acids (e.g. peroxybenzoic acid, m-chloroperoxybenzoic acid, etc.), and the like.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N-dimethyl acetamide,
  • a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N-dimethyl acetamide,
  • hydrophilic solvents may be used in a mixture with water.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the new imidazotriazine derivatives (I) and a pharmaceutically acceptable salt thereof can be used for prophylactic and therapeutic treatment of IL-1 and TNF mediated diseases such as chronic inflammatory diseases (e.g. rheumatoid arthritis, osteoarthritis, etc.)
  • osteoporosis rejection by transplantation, asthma, endotoxin shock, specific autoimmune diseases [e.g.
  • ankylosing spondylitis autoimmune hematological disorders (e.g. hemolyticodo anaemia, aplastic anaemia, pure red cell anaemia, idiopathic thrombocytopenia, etc.), systemic lupus erythematosus, polychondritis, scleroderma, Wegener granulamotosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis,
  • Grave's disease sarcoidosis, multiple scleosis, primary billiary cirrhosis, juvenile diabetes (diabetes mellitus type I), Reiter's syndrome, non infection uveitis, autoimmune keratitis (e.g. keratoconjuntivitis sicca, vernal
  • keratoconjunctivitis etc.
  • interstitial lung fibrosis psoriatic arthritis
  • glomerulonephritis ⁇ e.g. nephrotic syndrome (e.g. idiopathic nephrotic syndrome, minimal change nephropathy, etc.), etc. ⁇ , etc.]
  • cancer cachexia AIDS cachexia and the like.
  • Interleukin-1 IL-1
  • Purified human peripheral blood monocyte were stimulated with bacterial lipopolysaccharide (1 ⁇ g/10 4 cells) in the absence or presence of appropriately diluted test compounds for 2 days at 37°C in a humidified 5% CO 2 atmosphere. Culture supernatants were tested for IL-1 ELISA assay.
  • Test compounds were dissolved in absolute DMSO
  • IL-1 levels were quantified by a commercial ELISA kit (Ohtuka assay, Japan) using a sandwitch technique.
  • the sensitivity levels for the detection of IL-1 ⁇ were 20 pg/ml.
  • the inhibitory concentration that caused a 50% inhibition was calculated by regression analysis of the dose-response data.
  • TNF necrosis factor
  • TNF levels were quantified by a commercial ELISA kit (Endogen, Inc. USA) using a sandwitch technique.
  • the sensitivity levels for the detection of TNF were 12 pg/ml.
  • the inhibitory concentration that caused a 50% inhibition was calculated by regression analysis of the dose-response data.
  • a conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
  • a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
  • the pharmaceutical preparation may be compounded in a solid form such as granule, capsule, tablet, dragee or suppository, or in a liquid form such as solution,
  • auxiliary substance such as stabilizing agent. wetting or emulsifying agent, buffer or any other commonly used additives.
  • the effective ingredient may usually be administered with a unit dose of 0.001 mg/kg to 500 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, 1 to 4 times a day.
  • the above dosage may be increased or decreased according to age, weight and conditions of the patient or the
  • R 1 is hydrogen, lower alkyl, lower or higher alkanoyl
  • N,N-di( lower)alkylamino most preferably C 1 -C 10 alkanoyl which may have one to five substituent(s) selected from the group consisting of halogen, lower alkoxy and N,N-di(lower)alkylamino], carbamoyl which may have one or two suitable substituent(s)
  • phenylsulfonyl which may have mono(or di or tri)halo(lower)alkyl
  • arylcarbonyl which may have one to three suitable substituent(s) [more preferably arylcarbonyl which may have one or two substituent(s) selected from the group consisting of carboxy and protected carboxy, most preferably phenylcarbonyl which may have carboxy or protected carboxy], cyclo( lower) alkylcarbonyl
  • ar(lower)alkanoyl which may have one to three
  • ar(lower)alkanoyl which may have one to three
  • ar(lower)alkanoyl which may have one to three
  • ar(lower)alkanoyl which may have one or two
  • phenyl( lower) alkanoyl which may have one or two substituent( s) selected from the group consisting of lower alkoxy and halogeen], or heterocycliccarbonyl
  • heteromonocycliccarbonyl in which heteromonocyclic group contains 1 to 4 nitrogen atom(s),
  • heteromonocyclic group contains 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), or
  • heteromonocycliccarbonyl in which heteromonocyclic group contains 1 to 2 sulfur atom(s), most preferably pyridylcarbonyl morpholinylcarbonyl or thienylcarbonyl],
  • R 3 is aryl which may have one to three substituent(s)
  • halogen selected from the group consisting of halogen, mono(or di or tri)halo(lower) alkyl,
  • tri)haloaryl most preferably mono(or di or
  • heterocyclic group which may have one to three suitable substituent(s) [more preferably unsaturated 5 or 6-membered heteronomoncyclic group. containing 1 to 2 sulfur atom(s) which may have one or two
  • R 4 is heterocyclic group [more preferably unsaturated 5 or
  • dihydropyridyl pyridyl, quinolyl, dihydroquinolyl or imidazolyl
  • pyridyl pyridyl, quinolyl, dihydroquinolyl or imidazolyl
  • heteromonocyclicthio unsaturated 5 or 6-membered heteromonocyclicthio in which heteromonocyclic group contains 1 to 4 nitrogen atom(s) [more preferably pyridylthio], or
  • heteromonocyclic group contains 1 to 4 nitrogen atom(s) [more preferably pyridylsulfinyl].

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Abstract

Dérivés d'immidazotriazine de formule (I), dans laquelle R1 représente hydrogène, alkyle inférieur ou acyle, R2 représente hydrogène ou acyle, R3 représente aryle pouvant avoir un ou des substituant(s) adéquats, etc., et R4 représente un groupe hétérocyclique pouvant avoir un ou des substituant(s) adéquats, alkyle hétérocyclique, sulfinyle hétérocyclique ou thio hétérocyclique. Lesdits dérivés présentent une activité inhibitrice de l'interleukine 1 (IL-1) et du facteur de nécrose tumorale (TNF).
PCT/JP1991/001768 1990-12-31 1991-12-26 Derive d'immidazotriazine WO1992012154A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB909028217A GB9028217D0 (en) 1990-12-31 1990-12-31 Imidazotriazine derivatives
GB9028217.9 1990-12-31
GB919113017A GB9113017D0 (en) 1991-06-17 1991-06-17 Imidazotriazine derivatives
GB9113017.9 1991-06-17

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WO1992012154A1 true WO1992012154A1 (fr) 1992-07-23

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JP (1) JPH06502178A (fr)
WO (1) WO1992012154A1 (fr)

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WO1994019350A1 (fr) * 1993-02-26 1994-09-01 Fujisawa Pharmaceutical Co., Ltd. Pyrazolitriazines a activite inhibant l'interleukine-1 et le facteur de necrose tumorale
US6046208A (en) * 1996-01-11 2000-04-04 Smithkline Beecham Corporation Substituted imidazole compounds
US6096753A (en) * 1996-12-05 2000-08-01 Amgen Inc. Substituted pyrimidinone and pyridone compounds and methods of use
US6110959A (en) * 1996-03-18 2000-08-29 Eisai Co., Ltd. Carboxylic acid derivatives having fused rings
EP0969093A3 (fr) * 1993-09-17 2000-09-13 Smithkline Beecham Protéine fixatrice de médicaments
US6180643B1 (en) 1996-11-19 2001-01-30 Amgen Inc. Aryl and heteroaryl substituted fused pyrrole antiinflammatory agents
US6268370B1 (en) 1992-01-13 2001-07-31 Smithkline Beecham Corporation Compounds
US6410729B1 (en) 1996-12-05 2002-06-25 Amgen Inc. Substituted pyrimidine compounds and methods of use
US6455528B1 (en) 1997-10-14 2002-09-24 Mitsubishi Pharma Corporation Piperazine compounds and medicinal use thereof
US6548503B1 (en) 1998-11-04 2003-04-15 Smithkline Beecham Corporation Pyridin-4-yl or pyrimidin-4-yl substituted pyrazines
US6730683B2 (en) 1997-12-19 2004-05-04 Smithkline Beecham Corporation Compounds of heteroaryl substituted imidazole, their pharmaceutical compositions and uses
US6759410B1 (en) 1999-11-23 2004-07-06 Smithline Beecham Corporation 3,4-dihydro-(1H)-quinazolin-2-ones and their use as CSBP/p38 kinase inhibitors
US6858617B2 (en) 1998-05-26 2005-02-22 Smithkline Beecham Corporation Substituted imidazole compounds
US6982270B1 (en) 1999-11-23 2006-01-03 Smithkline Beecham Corporation 3,4-dihydro-(1H)quinazolin-2-one compounds as CSBP/p38 kinase inhibitors
US7053098B1 (en) 1999-11-23 2006-05-30 Smithkline Beecham Corporation 3,4-Dihydro-(1H) quinazolin-2-one compounds as CSBP/P38 kinase inhibitors
US7053099B1 (en) 1999-11-23 2006-05-30 Smithkline Beecham Corporation 3,4-dihydro-(1H)quinazolin-2-one compounds as CSBP/p38 kinase inhibitors
EP1707205A2 (fr) 2002-07-09 2006-10-04 Boehringer Ingelheim Pharma GmbH & Co. KG Compositions pharmaceutiques contenant un antichlinergique et un inhibiteur du p38 pour le traitement de maladies respiratoires
US7235551B2 (en) 2000-03-02 2007-06-26 Smithkline Beecham Corporation 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases
US7423042B2 (en) 2005-03-25 2008-09-09 Glaxo Group Limited Compounds
WO2008142031A1 (fr) 2007-05-18 2008-11-27 Institut Curie La p38alpha cible thérapeutique dans le cancer de la vessie
US7479558B2 (en) 2005-03-25 2009-01-20 Glaxo Group Limited Process for preparing pyrido[2,3-d]pyrimidin-7-one and 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives
EP2116245A2 (fr) 2004-08-07 2009-11-11 Boehringer Ingelheim International GmbH combinaisons d'inhibiteurs de la kinase EGFR pour le traitement de désordres respiratoires et de l'appareil digestif
US7629350B2 (en) 2002-04-19 2009-12-08 Smithkline Beecham Corporation Compounds
US7674789B2 (en) 2005-03-25 2010-03-09 Glaxo Group Limited Compounds
US7678801B2 (en) 2005-03-25 2010-03-16 Glaxo Group Limited Compounds
US7759486B2 (en) 2000-10-23 2010-07-20 Glaxosmithkline Llc 2,4,5-Trisubstituted pyrimidine compounds
EP2384751A1 (fr) 2004-12-24 2011-11-09 Boehringer Ingelheim International Gmbh Médicaments pour le traitement ou la prévention des maladies fibrogènes
WO2015086503A1 (fr) * 2013-12-09 2015-06-18 Ucb Biopharma Sprl Dérivés d'imidazotriazine à titre de modulateurs de l'activité du tnf

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WO2001015525A1 (fr) * 1999-08-31 2001-03-08 Fujisawa Pharmaceutical Co., Ltd. Conservateurs pour organes
AU2001295992A1 (en) * 2000-10-24 2002-05-06 Sankyo Company Limited Imidazopyridine derivatives
WO2011051858A1 (fr) * 2009-10-28 2011-05-05 Pfizer Inc. Dérivés d'imidazole en tant qu'inhibiteurs de caséine kinase

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WO1991000092A1 (fr) * 1989-06-13 1991-01-10 Smithkline Beecham Corporation Inhibition de la production d'interleukine-1 et du facteur de necrose de tumeurs par l'utilisation de monocytes et/ou de macrophages

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US6268370B1 (en) 1992-01-13 2001-07-31 Smithkline Beecham Corporation Compounds
AU681625B2 (en) * 1993-02-26 1997-09-04 Fujisawa Pharmaceutical Co., Ltd. Pyrazolitriazines with interleukin-1 and tumour necrosis factor inhibitory activity
CN1041929C (zh) * 1993-02-26 1999-02-03 藤泽药品工业株式会社 新的杂环衍生物及其制备方法和用途,和含该衍生物的药物组合物
WO1994019350A1 (fr) * 1993-02-26 1994-09-01 Fujisawa Pharmaceutical Co., Ltd. Pyrazolitriazines a activite inhibant l'interleukine-1 et le facteur de necrose tumorale
EP0969093A3 (fr) * 1993-09-17 2000-09-13 Smithkline Beecham Protéine fixatrice de médicaments
US6046208A (en) * 1996-01-11 2000-04-04 Smithkline Beecham Corporation Substituted imidazole compounds
US6110959A (en) * 1996-03-18 2000-08-29 Eisai Co., Ltd. Carboxylic acid derivatives having fused rings
US6358995B1 (en) 1996-03-18 2002-03-19 Eisai Co., Ltd. Carboxylic acid derivatives having fused rings
US6121309A (en) * 1996-03-18 2000-09-19 Eisai Co., Ltd. Fused-ring carboxylic acid derivatives
US6440973B1 (en) 1996-11-19 2002-08-27 Amgen Inc. Aryl and heteroaryl substituted fused pyrrole antiinflammatory agents
US6180643B1 (en) 1996-11-19 2001-01-30 Amgen Inc. Aryl and heteroaryl substituted fused pyrrole antiinflammatory agents
US6605634B2 (en) 1996-11-19 2003-08-12 Amgen, Inc. Aryl and heteroaryl substituted fused pyrrole anti-inflammatory agents
US6410729B1 (en) 1996-12-05 2002-06-25 Amgen Inc. Substituted pyrimidine compounds and methods of use
US6420385B1 (en) 1996-12-05 2002-07-16 Amgen Inc. Substituted pyrimidinone and pyridone compounds and methods of use
US6096753A (en) * 1996-12-05 2000-08-01 Amgen Inc. Substituted pyrimidinone and pyridone compounds and methods of use
US6610698B2 (en) 1996-12-05 2003-08-26 Amgen, Inc. Substituted pyrimidine compounds and methods of use
US6649604B2 (en) 1996-12-05 2003-11-18 Amgen Inc. Substituted pyridone compounds and methods of use
US6455528B1 (en) 1997-10-14 2002-09-24 Mitsubishi Pharma Corporation Piperazine compounds and medicinal use thereof
US6730683B2 (en) 1997-12-19 2004-05-04 Smithkline Beecham Corporation Compounds of heteroaryl substituted imidazole, their pharmaceutical compositions and uses
US6858617B2 (en) 1998-05-26 2005-02-22 Smithkline Beecham Corporation Substituted imidazole compounds
US6861417B2 (en) 1998-11-04 2005-03-01 Smithkline Beecham Corporation Pyridin-4-YL or pyrimidin-4-YL substituted pyrazines
US6548503B1 (en) 1998-11-04 2003-04-15 Smithkline Beecham Corporation Pyridin-4-yl or pyrimidin-4-yl substituted pyrazines
US6982270B1 (en) 1999-11-23 2006-01-03 Smithkline Beecham Corporation 3,4-dihydro-(1H)quinazolin-2-one compounds as CSBP/p38 kinase inhibitors
US7053098B1 (en) 1999-11-23 2006-05-30 Smithkline Beecham Corporation 3,4-Dihydro-(1H) quinazolin-2-one compounds as CSBP/P38 kinase inhibitors
US7053099B1 (en) 1999-11-23 2006-05-30 Smithkline Beecham Corporation 3,4-dihydro-(1H)quinazolin-2-one compounds as CSBP/p38 kinase inhibitors
US6759410B1 (en) 1999-11-23 2004-07-06 Smithline Beecham Corporation 3,4-dihydro-(1H)-quinazolin-2-ones and their use as CSBP/p38 kinase inhibitors
US7235551B2 (en) 2000-03-02 2007-06-26 Smithkline Beecham Corporation 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases
US7700768B2 (en) 2000-03-02 2010-04-20 Glaxosmithkline Llc Compounds
US7629462B2 (en) 2000-03-02 2009-12-08 Smithkline Beecham Corporation Tetrasubstituted pyrimidine compounds as chemical intermediates
US7759486B2 (en) 2000-10-23 2010-07-20 Glaxosmithkline Llc 2,4,5-Trisubstituted pyrimidine compounds
US7629350B2 (en) 2002-04-19 2009-12-08 Smithkline Beecham Corporation Compounds
EP1707205A2 (fr) 2002-07-09 2006-10-04 Boehringer Ingelheim Pharma GmbH & Co. KG Compositions pharmaceutiques contenant un antichlinergique et un inhibiteur du p38 pour le traitement de maladies respiratoires
EP2116245A2 (fr) 2004-08-07 2009-11-11 Boehringer Ingelheim International GmbH combinaisons d'inhibiteurs de la kinase EGFR pour le traitement de désordres respiratoires et de l'appareil digestif
EP2384751A1 (fr) 2004-12-24 2011-11-09 Boehringer Ingelheim International Gmbh Médicaments pour le traitement ou la prévention des maladies fibrogènes
EP2878297A1 (fr) 2004-12-24 2015-06-03 Boehringer Ingelheim International GmbH Médicaments pour le traitement ou la prévention des maladies fibrogènes
US7479558B2 (en) 2005-03-25 2009-01-20 Glaxo Group Limited Process for preparing pyrido[2,3-d]pyrimidin-7-one and 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives
US7674789B2 (en) 2005-03-25 2010-03-09 Glaxo Group Limited Compounds
US7678801B2 (en) 2005-03-25 2010-03-16 Glaxo Group Limited Compounds
US7423042B2 (en) 2005-03-25 2008-09-09 Glaxo Group Limited Compounds
WO2008142031A1 (fr) 2007-05-18 2008-11-27 Institut Curie La p38alpha cible thérapeutique dans le cancer de la vessie
WO2015086503A1 (fr) * 2013-12-09 2015-06-18 Ucb Biopharma Sprl Dérivés d'imidazotriazine à titre de modulateurs de l'activité du tnf
CN105814060A (zh) * 2013-12-09 2016-07-27 Ucb生物制药私人有限公司 用作tnf活性调节剂的咪唑并三嗪衍生物
US9714251B2 (en) 2013-12-09 2017-07-25 Ucb Biopharma Sprl Imidazotriazine derivatives as modulators of TNF activity
CN105814060B (zh) * 2013-12-09 2018-02-13 Ucb生物制药私人有限公司 用作tnf活性调节剂的咪唑并三嗪衍生物

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