WO1998025926A1 - Imidazopyridine derivatives and their production - Google Patents

Imidazopyridine derivatives and their production Download PDF

Info

Publication number
WO1998025926A1
WO1998025926A1 PCT/JP1997/004532 JP9704532W WO9825926A1 WO 1998025926 A1 WO1998025926 A1 WO 1998025926A1 JP 9704532 W JP9704532 W JP 9704532W WO 9825926 A1 WO9825926 A1 WO 9825926A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
optionally substituted
ring
salt
hydrogen atom
Prior art date
Application number
PCT/JP1997/004532
Other languages
French (fr)
Inventor
Tomomi Ikemoto
Original Assignee
Takeda Chemical Industries, 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
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to AU54099/98A priority Critical patent/AU5409998A/en
Publication of WO1998025926A1 publication Critical patent/WO1998025926A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to imidazopyridine derivatives, which are useful as an intermediate for producing fused imidazopyridine derivatives which are useful for prophylaxis and/or treatment of hyperlipemia, and to a method for producing imidazopyridine derivatives or fused imidazopyridine derivatives .
  • the present inventor found a method for easily and efficiently producing the derivatives by reacting imidazopyridine derivatives with hexamethylenetetramine, to produce 3- formylimidazopyridine derivatives and/or fused imidazopyridine derivatives.
  • the present inventor conducted a further study based on these findings and has completed the present invention.
  • the present invention is directed to:
  • ring Q is an optionally substituted pyridine ring
  • R is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon residue or an acyl group, or a salt thereof , which comprises reacting a compound of the formula:
  • ring Q" is an optionally substituted pyridine ring
  • R is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally ⁇ substituted hydrocarbon residue or an acyl group
  • R is an optionally protected carboxyl group, or a salt thereof, which comprises reacting a compound of the formula:
  • ring Q' is an optionally substituted pyridine ring
  • R is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon residue or an acyl group
  • X is a leaving group, or a salt thereof
  • ring Q" is an optionally substituted pyridine ring
  • R is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon residue or an acyl group
  • R is an optionally protected carboxyl group, or a salt thereof, which comprises reacting a compound of the formula:
  • ring Q' is an optionally substituted pyridine ring
  • R has the same meaning as defined above
  • X is a leaving group, or a salt thereof, with a compound of the formula:
  • Ci- alkylsulfonyl e.g. methylsulfonyl, ethylsulfonyl, etc.
  • phenylsulfonyl e.g. amino, amino, C ⁇ _ 3 acylamino (e.g. acetylamino , propionylamino, etc.), (xxi) mono- or di-C ⁇ __, alkylamino (e.g.
  • C ⁇ _ 4 alkyl e.g. methyl, ethyl, propyl , isopropyl, etc.
  • C ⁇ __, haloalkyl e.g. trifluoromethyl, trichloromethyl, 2,2 ,2-trifluoroethyl , etc.
  • a leaving group e.g. trifluoromethyl, trichloromethyl, 2,2 ,2-trifluoroethyl , etc.
  • halogen e.g. chlorine, bromine, iodine, fluorine, etc.
  • sulfonyloxy groups e.g. ethanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy
  • Rings Q, Q' and Q" may have 1 to 3 such substituents in substitutable positions.
  • the "halogen” in this specification means fluorine, chlorine, bromine, iodine, etc.
  • the substituent group on the "optionally substituted hydroxy group" in this specification includes (i) C ⁇ _ 6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), (ii) phenyl , (iii) C 7 . 10 aralkyl (e.g. benzyl, etc.), (iv) for yl, (v) C,_ 6 alkyl-carbonyl (e.g. methylcarbonyl , ethylcarbonyl, etc.), (vi) phenyloxycarbonyl, (vii) C 7 . 10 aralkyloxy- carbonyl (e.g.
  • the substituent group which may be substituted on these groups includes halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), C ⁇ alkyl (e.g. methyl, ethyl, propyl, isopropyl, etc.), phenyl , C 7 . 10 aralkyl (e.g. benzyl etc.), nitro, etc. and the number of substituents may range from 1 to 4.
  • hydrocarbon group in the term “optionally substituted hydrocarbon group” in this specification means alkyl, alkenyl, aralkyl, aryl, etc.
  • the "alkyl” includes "straight-chain or branched C ⁇ _ 15 alkyl” such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl , octyl, nonyl , decyl, undecyl, tridecyl , tetradecyl, pentadecyl , etc., preferably C ⁇ _ 6 alkyl, and "C 3 _ 8 cycloalkyl” such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
  • the substituent groups which may be substituted on said "straight-chain or branched C ⁇ _ 15 alkyl and C 3 _ 8 cycloalkyl" include (i) nitro, (ii) hydroxy, (iii) cyano, (iv) carba oyl, (v) mono- or di-Ci., alkyl- carbamoyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, etc.), (vi) carboxy, (vii) C,_ 4 alkoxy-carbonyl (e.g.
  • alkyl may have 1 to 5 (preferably 1 to 3 ) substituents in the substitutable positions on the alkyl.
  • alkyl are straight- chain or branched C ⁇ g alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • the substituent group which may be substituted on the "C x _ 6 alkyl” includes said halogen, x _ ⁇ alkoxy, hydroxy, C,__, alkoxy-carbonyl, carboxy, carbamoyl, mono- or di-C 1- ⁇ alkyl-carba oyl , pyridylthio, etc.
  • the number of substituents may range from 1 to 3.
  • the "alkenyl” includes "C 2 - ⁇ 8 alkenyl” such as vinyl, allyl, isopropenyl, 3-butenyl, 3-octenyl, 9- octadecenyl, etc.
  • the substituent groups which may be substituted on the "alkenyl” are of the same groups as the substituent groups of said "alkyl".
  • the number of substituent groups may range from 1 to 3.
  • Preferred examples of the "alkenyl” are C 2 _ 6 alkenyl groups such as vinyl, allyl, 2-butenyl, 3-butenyl, etc.
  • the substituent groups which may be substituted on said "C 2 - 6 alkenyl” are of the same groups as the substituent groups of said "C,_ 6 alkyl".
  • the number of substituent groups may range from 1 to 3.
  • the "aralkyl” includes C 7 _ 16 aralkyl, typically, phenyl-C ⁇ _ 6 alkyl such as benzyl, phenethyl, 3- phenylpropyl, 4-phenylbutyl , etc. and naphthyl-C,_ 6 alkyl such as ( 1-naphthyl )methyl , 2-( 1-naphthyl) ethyl , etc .
  • the substituent groups which may be substituted on said "aralkyl” include (i) halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), (ii) C ⁇ __, alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, etc.), (iii) C 2- . 6 alkenyl (e.g. vinyl, allyl, 2-butenyl, 3-butenyl, etc.), (iv) C,_ 3 alkanoyl (e.g. formyl, acetyl, etc.), (v) C L ⁇ alkoxy (e.g.
  • halogen e.g. fluorine, chlorine, bromine, iodine, etc.
  • C ⁇ __ alkyl
  • alkyl e.g. methyl, ethyl, propyl, isopropyl, butyl, etc.
  • the "aralkyl” may have 1 to 4 (preferably 1 to 3 ) substituent groups such as those mentioned above in substitutable positions on the aralkyl.
  • the "aryl” includes aromatic monocyclic, dicyclic or tricyclic C 6 _,_, aryl such as phenyl, 1-naphthyl, 2- naphthyl, phenanthryl, anthryl, etc. Preferred is phenyl .
  • the substituent groups which may be substituted on said "aryl” include (i) halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), (ii) C,__, alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, etc.), (iii) C,.., haloalkyl (e.g.
  • C,_._, haloalkoxy e.g. trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy
  • C,. . , alkoxy e.g. methoxy, ethoxy, propoxy, isopropoxy, etc.
  • C, . _, alkylthio e.g.
  • the "aryl” may have 1 to 4 (preferably 1 or 2 ) substituent groups such as those mentioned above in substitutable positions on the aryl.
  • the aryl having oxo group(s) includes benzoquinonyl , naphthoquinolyl , anthraquinonyl , etc .
  • acyl in this specification includes acyl derived from carboxylic acid, such as alkoxy- carbonyl, alkyl-carbamoyl and alkanoyl .
  • alkoxy-carbonyl includes C ⁇ _ 6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert- butoxycarbonyl, pentyloxycarbonyl. isopentyloxycarbonyl, neopentyloxycarbonyl , tert- pentyloxycarbonyl , etc .
  • alkyl-carbamoyl includes N-mono-C ⁇ - 6 alkyl- carbamoyl such as N-methylcarbamoyl, N-ethylcarbamoyl , N-propylcarbamoyl, N-butylcarbamoyl, etc.; N,N-di-C 1-6 alkyl-carbamoyl such as N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N- dibutylcarbamoyl, N-ethyl-N-methylcarbamoyl, etc.; and 4- to 6-membered cyclic carbamoyl formed jointly by two alkyl moieties, such as 1-azetidinylcarbonyl , morpholinocarbonyl, 1-pyrrolidinylcarbonyl , 1- piperidinocarbony
  • alkanoyl includes C_. 10 alkanoyl such as formyl and C ⁇ _ 9 alkyl-carbonyl (e.g. acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl , etc . ) .
  • acyl group further may be substituted by 1 to 3 substituents such as the substituent groups on the above-mentioned alkyl group.
  • the protective group of the "optionally protected carboxyl group” in this specification includes an optionally substituted C 1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl and silyl group, etc., each of which may be substituted by 1 to 3 substituents selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), formyl, C ⁇ _ 6 alkyl-carbonyl (e.g. acetyl, propionyl, butyryl, etc.) and nitro, etc.
  • halogen e.g. fluorine, chlorine, bromine, iodine, etc.
  • C ⁇ _ 6 alkyl-carbonyl e.g. acetyl, propionyl, butyryl, etc.
  • nitro etc.
  • a hydrogen atom or an optionally substituted hydrocarbon residue is preferable.
  • the optionally substituted hydrocarbon residue C,_ 6 alkyl group is preferable and C 1-3 alkyl, especially methyl, is most preferred.
  • carboxyl group or C _ 6 alkoxy-carbonyl group is preferable.
  • leaving group X a halogen atom is preferable .
  • salts are salts with inorganic acids (e.g. hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.) and salts with organic acids (e.g. acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, etc.).
  • the present compounds may form physiologically acceptable salts with inorganic bases
  • organic bases e.g. tri-C ⁇ _ 3 alkylamines such as triethylamine
  • the starting compounds for the synthesis of the compound i.e. the compound (II), (II') or (IV), may also be used in the salt form such as the above salt, but the kind of salt is not limited unless it is detrimental to the reaction.
  • the present compounds and the starting compounds may contain a double bond within the molecule.
  • Two kinds (Z and E) of stereoisomers and the mixtures thereof fall within the scope of the present compound and the starting compounds.
  • present compounds and the starting compounds may also assume enol- and keto-forms with respect to the oxo group, the respective forms as well as mixtures thereof fall within the scope of the present compounds and teh starting compounds.
  • Some species of the present compounds and the starting compounds have asymmetric carbon within the molecule. And two kinds (R and S) of stereoisomers and the mixtures thereof fall within the scope of the present compounds and the starting compounds .
  • the present compound (I) or a salt thereof can be produced by the following process.
  • hexamethylenetetramine is used in a proportion of one equivalent to a large excess, preferably about 1 to 10 equivalents, relative to the compound (II) or a salt thereof.
  • the acid which can be used in this reaction includes an inorganic acid (e.g. hydrochloric acid, sulfuric acid, boric acid, etc.) or an organic acid (e.g. acetic acid, trifluoroacetic acid, formic acid, methanesulfonic acid, etc.).
  • the preferable acid is acetic acid or boric acid.
  • the acid is used in a proportion of one equivalent to a large excess, preferably about 1 to 50 equivalents .
  • the reaction temperature may range from about 0°C to 200°C, preferably about 50°C to 150°C.
  • the solvent which can be used in the reaction includes halogenated hydrocarbons (e.g. methylene chloride, chloroform, dichloroethane, etc.), ethers (e.g. diethyl ether, tetrahydrofuran, etc.), esters (e.g. methyl acetate, ethyl acetate, etc.), protic solvents (e.g. methanol, ethanol, etc.) and aprotic polar solvents (e.g. acetonitrile etc.).
  • the solvent may contain water.
  • acetic acid which doubles as an acid and a solvent is used.
  • the reaction time may range from generally about 10 minutes to 24 hours, and preferably about 1 to 15 hours.
  • the compound of the formula (III) can be produced by the following process:
  • the compound of the formula (III) can also be produced by the following process:
  • the reaction from the compound (II') to the compound (I') is one mode of the reaction from the compound (II) to the compound (I).
  • the compound (I') can, for example, be used as an intermediate for producing the compound (III).
  • the compound (I') is reacted with a compound of the formula: HS-CH Z -R (V) or a salt thereof (wherein all symbols of the same meanings as defined hereinbefore; preferably thioglycolate ester or the like) in a proportion of one equivalent to a large excess, preferably about 1 to 10 equivalents.
  • the base which can be used in this reaction may, for example, be an inorganic base (e.g. potassium carbonate, sodium carbonate, etc.), an organic base (e.g.
  • the proportion of the base may range from one equivalent to a large excess, preferably about 1 to 5 equivalents .
  • the reaction temperature may be a range from about -70°C to 200°C, preferably about 0°C to 200°C, more preferably about 0°C to 100°C.
  • the solvent which can be used in this reaction includes halogenated hydrocarbons (e.g. methylene chloride, chloroform, dichloroethane, etc.), ethers (e.g. diethyl ether, tetrahydrofuran, etc.), esters (e.g. methyl acetate, ethyl acetate, etc.), protic solvents (e.g. acetic acid, methanol, ethanol, etc.), aprotic polar solvents (e.g. N,N- dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.).
  • the reaction time may range from about 10 minutes to 24 hours, and preferably about 1 to 10 hours .
  • any starting material compound has an amino group, a carboxyl group and/or a hydroxyl group as a substituent
  • such functional group or groups may be previously blocked or masked using protective groups which are conventionally used in peptide chemistry and the objective compound can then be obtained by eliminating the protective group or groups after the intended reaction.
  • the protective group that can be used for the amino function includes C ⁇ _ 6 alkyl-carbonyl (e.g. formyl, methylcarbonyl , ethylcarbonyl, etc.), phenylcarbonyl , C x _ 6 alkyl oxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl (e.g. benzoxycarbonyl etc.), C 7 _ 10 aralkyl (oxy)carbonyl (e.g. benzyloxycarbonyl etc.), trityl, phthaloyl, etc., each of which may be substituted.
  • the substituent group includes halogen (e.g.
  • the protective group that can be used for the carboxyl function includes C 1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl, etc., each of which may be substituted.
  • the substituent group includes halogen (e.g.
  • the protective group that can be used for the hydroxyl function includes C ⁇ _ 6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C 7 _ 10 aralkyl (e.g. benzyl etc.), C ⁇ _ 6 alkyl- carbonyl (e.g.
  • substituent group present includes halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), C,_ 6 alkyl, phenyl, C 7 _ 10 aralkyl, nitro, etc.
  • the number of substituents may range from 1 to about 4.
  • Removal of such protective groups can be carried out by techniques either known per se or analogous to known techniques.
  • a method using an acid or a base, reductive deprotection, and a technique using any of ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc. can be mentioned.
  • the compound (III) obtained by any of the above processes can be isolated and purified by the conventional procedures such as recrystallization, distillation, chromatography, etc.
  • the thus- obtained compound (III) is the free compound, it can be converted to a salt by a per se known procedure or an analogous procedure (e.g. neutralization).
  • the product compound is a salt, it can be converted to either the free compound or a different salt by the per se known procedure or an analogous procedure .
  • the compound (III) is an optically active compound, it can be fractionated into the S- and R-compounds by the conventional optical resolution technology.
  • the starting compounds for the compound (III) or salt of the present invention may be salts and the kind of salt is not critical as long as the reaction involved proceeds successfully.
  • compound (III) can be used as an intermediate for producing a fused imidazopyridine derivative useful for prophylaxis and/or treatment of hyperlipemia.
  • a useful medicine such as N-[ l-( 3-phenylpropan-l- yl )piperidin-4-yl ] -5-thia-l , 8b-diazaacenaphthylene-4- carboxamide (hereinafter it is sometimes called "Compound A”) is obtained, by the manner described in the Reference Examples which are shown below, or an analogous method thereto.
  • the Compound A and its salt of the present invention have an excellent LDL receptor up-regulating, lipids-lowering and blood sugar-lowering activity, and are of low toxicity. Therefore, the Compound A or a salt thereof can be safely used in mammals (e.g. mouse, rat, hamster, rabbit, cat, dog, bovine, horse, sheep, monkey, man, etc.) as a prophylactic and therapeutic agent for atherosclerotic diseases, hyperlipemia
  • diabetes hyperlipidemia
  • diabeties and diabetic complications diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, arrhythmia, peripheral vascular disease, thrombosis, disorders of pancreas, sequelae of myocardial infarction, valvular disease of the heart, and other diseases.
  • the Compound A and its salt have cholesterol and triglyceride lowering activities . These biological properties suggest that the Compound A and its salt are particularly suited for the therapy and prophylaxis of hyperlipemia (particularly hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia) and the associated atherosclerotic vascular lesions and secondary diseases (e.g. coronary artery disease, ischemic diseases of the brain, aneurysm, cerebral arteriosclerosis, peripheral arteriosclerosis, intermittent claudication, gangrene) .
  • hyperlipemia particularly hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia
  • atherosclerotic vascular lesions and secondary diseases e.g. coronary artery disease, ischemic diseases of the brain, aneurysm, cerebral arteriosclerosis, peripheral arteriosclerosis, intermittent claudication, gangrene
  • the Compound A and its salt have lipids-lowering activity and blood sugar-lowering activity in diabetic fatty rats, they are expected to ameliorate insulin resistance.
  • the Compound A and its salt are particularly suited for the treatment or prevention of hyperglycemia and its secondary diseases such as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic vascular diseases, etc. or insulin resistance and its associated diseases such as hypertension and impaired glucose tolerance, and even such secondary diseases as diseases of the heart, ischemic diseases of the brain, intermittent claudication, gangrene, etc.
  • the dosage of the Compound A is dependent on the route of administration, patient's clinical status, age and body weight, and other factors but when it is to be administered orally to an adult patient, for example as a therapeutic agent for arteriosclerosis, a hypoglycemic agent, or a therapeutic agent for diabetic complications, the recommended daily dosage in terms of the Compound A or a salt thereof is 0.2 to 50 mg/kg, preferably 0.5 to 30 mg/kg, which dosage is to be administered in one to a few divided doses.
  • the route of administration may be whichever of the oral route and a non-oral route .
  • the present invention provides a method for easily and efficiently producing in a high yield a 3- formylimidazopyridine derivative and the intermediate being useful for producing a fused imidazopyridine derivative, i.e., a 5-thia-l,8b-diazaacenaphthylene derivative, which is useful for prophylaxis and/or treatment of hyperlipemia.
  • room temperature means 0 to +30 °C
  • ratio of solvents indicated in the description of the purification procedure by silica gel column chromatography is by volume (v/v)
  • symbols used in the description of NMR data have the following meanings. s singlet d doublet t triplet quint quintet m multiplet br broad
  • a suspension of 5-thia-l, 8b-diazaacenaphthylene-4- carboxylic acid (1.2 g) , 4-amino-l- ( 3-phenylpropan-l- yl)piperidine dihydrochloride (1.5 g) , triethylamine (1.5 ml), 1-hydroxy-lH-benzotriazole monohydrate (0.8 g) , and l-ethyl-3-( 3-diethylaminopropyl)carbodiimide hydrochloride (1.0 g) in N,N-dimethylformamide (15 ml) was stirred at 50°C for 2 hours.

Landscapes

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

Abstract

3-Formylimidazopyridine derivatives (I and I') and/or 5-thia-1,8b-diazaacenaphthylene derivatives (III), which are useful as intermediates for producing a fused imidazopyridine derivatives being useful for prophylaxis and/or treatment of hyperlipemia, as shown, can be produced easily and efficiently in a high yield. In formula (1), rings Q, Q' and Q'' are optionally substituted pyridine rings, R1 is hydrogen, a halogen atom, an optionally substituted hydroxyl, an optionally substituted hydrocarbon residue or an acyl group, R2 is an optionally substituted carboxyl, and X is a leaving group.

Description

DESCRIPTION Imidazopyridine Derivatives and Their Production
TECHNICAL FIELD The present invention relates to imidazopyridine derivatives, which are useful as an intermediate for producing fused imidazopyridine derivatives which are useful for prophylaxis and/or treatment of hyperlipemia, and to a method for producing imidazopyridine derivatives or fused imidazopyridine derivatives .
BACKGROUND ART It has been reported that formylation at the 3- position of the imidazopyridine ring is carried out under strong acidic conditions in the presence of, for example, phosphoryl chloride-N,N-dimethylformamide or oxaryl chloride-N,N-dimethylformamide, or under basic conditions in the presence of, for example, n- butyllithium-N,N-dimethylformamide (Journal of
Medicinal Chemistry, 13, 1048(1970), European Patent Application Publication No. 92459, Journal of Organic Chemistry, J33_, 1638(1968)). However, the controls of these reactions are difficult. It has been found that intermediates for preparing novel fused imidazopyridine derivatives, 5-thia-l,8b- diazacenaphthylene-4-carboxylic acid derivatives possessing an excellent LDL receptor up-regulating, blood-lipids lowering, blood-sugar lowering and diabetic complication-ameliorating action, can be produced by the reaction of imidazopyridine derivatives and phosphoryl chloride-N,N-dimethylformamide. However, more easy and efficient and industrially feasible method is desired. DISCLOSURE OF INVENTION The present inventor found a method for easily and efficiently producing the derivatives by reacting imidazopyridine derivatives with hexamethylenetetramine, to produce 3- formylimidazopyridine derivatives and/or fused imidazopyridine derivatives. The present inventor conducted a further study based on these findings and has completed the present invention. The present invention is directed to:
(1) a method for producing a compound of the formula:
Figure imgf000004_0001
wherein ring Q is an optionally substituted pyridine ring, R is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon residue or an acyl group, or a salt thereof , which comprises reacting a compound of the formula:
Figure imgf000004_0002
wherein the ring Q and R have the same meaning as defined above, or a salt thereof, with hexamethylenetetramine, (2) the method according to the item (1), wherein R is a hydrogen atom,
( 3 ) the method according to the item ( 1 ) , wherein a compound of the formula:
Figure imgf000005_0001
wherein the ring Q' is an optionally substituted pyridine ring, R is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon residue or an acyl group, X is a leaving group, or a salt thereof, is produced by reacting a compound of the formula:
Figure imgf000005_0002
wherein the ring Q', R and X have the same meaning as defined above, or a salt thereof, with hexamethylenetetramine,
( 4 ) the method according to the item ( 3 ) , wherein the ring Q' is unsubstituted, and R is a hydrogen atom,
(5) the method according to the item (3), wherein X is a halogen atom,
( 6 ) the method according to the item ( 3 ) , wherein the ring Q' is unsubstituted, R is a hydrogen atom and X is a halogen atom,
(7) a method for producing a compound of the formula:
Figure imgf000005_0003
wherein the ring Q" is an optionally substituted pyridine ring, R is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally ι substituted hydrocarbon residue or an acyl group, R is an optionally protected carboxyl group, or a salt thereof, which comprises reacting a compound of the formula:
Figure imgf000006_0001
wherein the ring Q", R and R have the same meaning as defined above, or a salt thereof, with hexamethylenetetramine ,
( 8 ) the method according to the item ( 7 ) , wherein the ring Q" is unsubstituted and R is a hydrogen atom, (9) a compound of the formula:
Figure imgf000006_0002
wherein the ring Q' is an optionally substituted pyridine ring, R is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon residue or an acyl group, X is a leaving group, or a salt thereof, (10) the compound according to the item (9), wherein the ring Q' is unsubstituted and R is a hydrogen atom,
(11) the compound according to the item (9), wherein X is a halogen atom,
(12) the compound according to the item (9), wherein the ring Q' is unsubstituted, R is a hydrogen atom and X is a halogen atom,
(13) a method for producing a compound of the formula:
Figure imgf000007_0001
wherein the ring Q" is an optionally substituted pyridine ring, R is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon residue or an acyl group, R is an optionally protected carboxyl group, or a salt thereof, which comprises reacting a compound of the formula:
Figure imgf000007_0002
wherein ring Q' is an optionally substituted pyridine ring, R has the same meaning as defined above, and X is a leaving group, or a salt thereof, with a compound of the formula:
HS-CH2-R2 (V) wherein R ,2 has the same meaning as defined above, (14) the method according to the item (13), wherein the rings Q' and Q" are unsubstituted and R is a hydrogen atom.
(15) the method according to the item (13), wherein X is a halogen atom, and (16) the method according to the item (13), wherein the ring Q' and Q" are unsubstituted, R1 is a hydrogen atom and X is a halogen atom.
The "substituent" on rings Q, Q' and Q" includes
(i) nitro, (ii) hydroxy, (iii) cyano, (iv) carbamoyl, (v) mono- or di-Cι__, alkyl-carbamoyl (e.g. N- methylcarbamoyl, N-ethylcarbamoyl , N,N- dimeth lcarbamoyl, N,N-diethylcarbamoyl , etc.), (vi) carboxy, (vii) C,_4 alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl , isopropoxycarbonyl, etc.), (viii) sulfo, (ix) halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), (x) Ci.ή alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, etc.), (xi) phenoxy, naphthoxy, benzyloxy, (xii) halophenoxy (e.g. o-, m- or p-chlorophenoxy, o-, m- or p-bromophenoxy, etc.), (xiii) C,_4 alkylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc), (xiv) mercapto, (xv) phenylthio, (xvi) pyridylthio, (xvii) C,.., alkylsulfinyl (e.g. methylsulfinyl, ethylsulfinyl, etc.), phenylsulfinyl, (xviii) Ci- alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl, etc.), phenylsulfonyl , (xix) amino, (xx) Cι_3 acylamino (e.g. acetylamino , propionylamino, etc.), (xxi) mono- or di-Cι__, alkylamino (e.g. methylamino, ethylamino, dimethylamino, diethylamino , etc.), (xxii) Cι_4 alkyl (e.g. methyl, ethyl, propyl , isopropyl, etc.) and (xxiii) Cι__, haloalkyl (e.g. trifluoromethyl, trichloromethyl, 2,2 ,2-trifluoroethyl , etc.) and (xxiv) a leaving group.
As the leaving group, mention is made of halogen (e.g. chlorine, bromine, iodine, fluorine, etc.), sulfonyloxy groups (e.g. ethanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy) .
Rings Q, Q' and Q" may have 1 to 3 such substituents in substitutable positions. The "halogen" in this specification means fluorine, chlorine, bromine, iodine, etc.
The substituent group on the "optionally substituted hydroxy group" in this specification includes (i) Cι_6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), (ii) phenyl , (iii) C7.10 aralkyl (e.g. benzyl, etc.), (iv) for yl, (v) C,_6 alkyl-carbonyl (e.g. methylcarbonyl , ethylcarbonyl, etc.), (vi) phenyloxycarbonyl, (vii) C7.10 aralkyloxy- carbonyl (e.g. benzyloxycarbonyl , etc.), (viii) pyranyl, (ix) furanyl and (x) silyl, each of which may be substituted. The substituent group which may be substituted on these groups includes halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), C^ alkyl (e.g. methyl, ethyl, propyl, isopropyl, etc.), phenyl , C7.10 aralkyl (e.g. benzyl etc.), nitro, etc. and the number of substituents may range from 1 to 4.
The "hydrocarbon group" in the term "optionally substituted hydrocarbon group" in this specification means alkyl, alkenyl, aralkyl, aryl, etc. The "alkyl" includes "straight-chain or branched Cι_15 alkyl" such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl , octyl, nonyl , decyl, undecyl, tridecyl , tetradecyl, pentadecyl , etc., preferably Cι_6 alkyl, and "C3_8 cycloalkyl" such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
The substituent groups which may be substituted on said "straight-chain or branched Cι_15 alkyl and C3_8 cycloalkyl" include (i) nitro, (ii) hydroxy, (iii) cyano, (iv) carba oyl, (v) mono- or di-Ci., alkyl- carbamoyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, etc.), (vi) carboxy, (vii) C,_4 alkoxy-carbonyl (e.g. methoxycarbonyl , ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, etc.), (viii) sulfo, (ix) halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), (x) Cι__, alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, etc.), (xi) phenoxy, (xii) halophenoxy (e.g. o-, m- or p-chlorophenoxy, o-, m- or p-bromophenoxy, etc.), (xϋi) C,._, alkylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc), (xiv) mercapto, (xv) phenylthio, (xvi) pyridylthio, (xvii) (_:,__, alkylsulfinyl (e.g. methylsulfinyl , ethylsulfinyl , etc.), (xviii) Cι__, alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl, etc.), (xix) amino, (xx) Cι_3 alkanoylamino (e.g. acetylamino, propionylamino, etc.), (xxi) mono- or di-Cι__, alkylamino (e.g. methylamino, ethylamino, dimethylamino, diethylamino, etc.), (xxii) 4- to 6-membered cyclic amino (e.g. 1-azetidinyl, 1- pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, etc.), (xxiii) C,_3 alkanoyl (e.g. formyl, acetyl, etc.), (xxiv) benzoyl and (xxv) 5- to 10-membered heterocyclic group (e.g. 2- or 3-thienyl; 2- or 3-furyl; 3-, 4- or 5-pyrazolyl; 2-, 4- or 5- thiazolyl; 3-, 4- or 5-isothiazolyl; 2-, 4- or 5- oxazolyl; 1,2,3- or 1 , 2 , 4-triazolyl; 1H- or 2H- tetrazolyl; 2-, 3- or 4-pyridyl; 2-, 4- or 5- pyrimidinyl; 3- or 4-pyridazinyl; quinolyl; isoquinolyl; indolyl; etc.). The "alkyl" may have 1 to 5 (preferably 1 to 3 ) substituents in the substitutable positions on the alkyl.
Preferred examples of the "alkyl" are straight- chain or branched C^g alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. The substituent group which may be substituted on the "Cx_6 alkyl" includes said halogen, x_^ alkoxy, hydroxy, C,__, alkoxy-carbonyl, carboxy, carbamoyl, mono- or di-C1-ή alkyl-carba oyl , pyridylthio, etc. The number of substituents may range from 1 to 3.
The "alkenyl" includes "C2-ι8 alkenyl" such as vinyl, allyl, isopropenyl, 3-butenyl, 3-octenyl, 9- octadecenyl, etc. The substituent groups which may be substituted on the "alkenyl" are of the same groups as the substituent groups of said "alkyl". The number of substituent groups may range from 1 to 3. Preferred examples of the "alkenyl" are C2_6 alkenyl groups such as vinyl, allyl, 2-butenyl, 3-butenyl, etc. The substituent groups which may be substituted on said "C2-6 alkenyl" are of the same groups as the substituent groups of said "C,_6 alkyl". The number of substituent groups may range from 1 to 3.
The "aralkyl" includes C7_16 aralkyl, typically, phenyl-Cι_6 alkyl such as benzyl, phenethyl, 3- phenylpropyl, 4-phenylbutyl , etc. and naphthyl-C,_6 alkyl such as ( 1-naphthyl )methyl , 2-( 1-naphthyl) ethyl , etc .
The substituent groups which may be substituted on said "aralkyl" include (i) halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), (ii) Cι__, alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, etc.), (iii) C2-.6 alkenyl (e.g. vinyl, allyl, 2-butenyl, 3-butenyl, etc.), (iv) C,_3 alkanoyl (e.g. formyl, acetyl, etc.), (v) CL^ alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, etc.), (vi) nitro, (vii) cyano, (viii) hydroxy, (ix) C^z, alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, etc.), (x) carbamoyl, (xi) mono- or di-C,._, alkyl-carbamoyl (e.g. N-methylcarbamoyl, N- ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, etc.) and (xii) mono- or di-Cz-,, alkenyl-carbamoyl (e.g. N-vinylcarbamoyl etc.). The "aralkyl" may have 1 to 4 (preferably 1 to 3 ) substituent groups such as those mentioned above in substitutable positions on the aralkyl.
The "aryl" includes aromatic monocyclic, dicyclic or tricyclic C6_,_, aryl such as phenyl, 1-naphthyl, 2- naphthyl, phenanthryl, anthryl, etc. Preferred is phenyl . The substituent groups which may be substituted on said "aryl" include (i) halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), (ii) C,__, alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, etc.), (iii) C,.., haloalkyl (e.g. trifluoromethyl , 2,2,2- trifluoroethyl, trichloromethyl, etc.), (iv) C,_._, haloalkoxy (e.g. trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy) , (v) C,.., alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, etc.), (vi) C,._, alkylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), (vii) hydroxy, (viii) carboxy, (ix) cyano, (x) nitro, (xi) amino, (xii) mono- or di-C__, alkylamino (e.g. methylamino, ethylamino, dimethylamino, diethylamino, etc.), (xiii) formyl, (xiv) mercapto, (xv) C,_5 alkyl-carbonyl (e.g. acetyl, propionyl, butyryl , hexanoyl , etc.), (xvi) (_.!__, alkoxy- carbonyl (e.g. methoxycarbonyl , ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, etc.), (xvii) sulfo, (xviii) Cι__, alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl, etc.), (xix) carbamoyl, (xx) mono- or di-C,_4 alkyl-carbamoyl (e.g. N-methylcarbamoyl, N- ethylcarbamoyl, N,N-dimethylcarbamoyl , N,N- diethylcarbamoyl, etc.), (xxi) oxo and (xxii) thioxo . The "aryl" may have 1 to 4 (preferably 1 or 2 ) substituent groups such as those mentioned above in substitutable positions on the aryl. The aryl having oxo group(s) includes benzoquinonyl , naphthoquinolyl , anthraquinonyl , etc .
The term "acyl" in this specification includes acyl derived from carboxylic acid, such as alkoxy- carbonyl, alkyl-carbamoyl and alkanoyl .
The "alkoxy-carbonyl" includes Cι_6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert- butoxycarbonyl, pentyloxycarbonyl. isopentyloxycarbonyl, neopentyloxycarbonyl , tert- pentyloxycarbonyl , etc .
The "alkyl-carbamoyl" includes N-mono-Cι-6 alkyl- carbamoyl such as N-methylcarbamoyl, N-ethylcarbamoyl , N-propylcarbamoyl, N-butylcarbamoyl, etc.; N,N-di-C1-6 alkyl-carbamoyl such as N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N- dibutylcarbamoyl, N-ethyl-N-methylcarbamoyl, etc.; and 4- to 6-membered cyclic carbamoyl formed jointly by two alkyl moieties, such as 1-azetidinylcarbonyl , morpholinocarbonyl, 1-pyrrolidinylcarbonyl , 1- piperidinocarbonyl, 1-piperazinylcarbonyl , ( 1- piperazinylcarbonyl ) , etc.
The "alkanoyl" includes C_.10 alkanoyl such as formyl and Cι_9 alkyl-carbonyl (e.g. acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl , etc . ) .
The "acyl group" further may be substituted by 1 to 3 substituents such as the substituent groups on the above-mentioned alkyl group.
The protective group of the "optionally protected carboxyl group" in this specification includes an optionally substituted C1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl and silyl group, etc., each of which may be substituted by 1 to 3 substituents selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), formyl, Cι_6 alkyl-carbonyl (e.g. acetyl, propionyl, butyryl, etc.) and nitro, etc. As the rings Q, Q' and Q", the unsubstituted ones are preferable.
As the group R , a hydrogen atom or an optionally substituted hydrocarbon residue is preferable. As the optionally substituted hydrocarbon residue, C,_6 alkyl group is preferable and C1-3 alkyl, especially methyl, is most preferred.
As the optionally protected carboxyl group, carboxyl group or C _6 alkoxy-carbonyl group is preferable. As the leaving group X, a halogen atom is preferable .
The salt of the present compounds, i.e. compounds
(I), (I'), or (III), includes salts are salts with inorganic acids (e.g. hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.) and salts with organic acids (e.g. acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, etc.). Furthermore, in cases where the present compounds contains an acidic group such as carboxyl, the present compounds may form physiologically acceptable salts with inorganic bases
(e.g. alkali metal or alkaline earth metal elements such as sodium, potassium, calcium, magnesium, etc., or ammonia) or organic bases (e.g. tri-Cι_3 alkylamines such as triethylamine) .
The starting compounds for the synthesis of the compound, i.e. the compound (II), (II') or (IV), may also be used in the salt form such as the above salt, but the kind of salt is not limited unless it is detrimental to the reaction.
The present compounds and the starting compounds may contain a double bond within the molecule. Two kinds (Z and E) of stereoisomers and the mixtures thereof fall within the scope of the present compound and the starting compounds.
While the present compounds and the starting compounds may also assume enol- and keto-forms with respect to the oxo group, the respective forms as well as mixtures thereof fall within the scope of the present compounds and teh starting compounds.
Some species of the present compounds and the starting compounds have asymmetric carbon within the molecule. And two kinds (R and S) of stereoisomers and the mixtures thereof fall within the scope of the present compounds and the starting compounds .
The present compound (I) or a salt thereof can be produced by the following process.
hexamethylenetetramine
Figure imgf000015_0001
fr
(ID CHO
(I)
wherein all symbols are of the same meanings as defined hereinbefore.
In the above reaction, hexamethylenetetramine is used in a proportion of one equivalent to a large excess, preferably about 1 to 10 equivalents, relative to the compound (II) or a salt thereof. The acid which can be used in this reaction includes an inorganic acid (e.g. hydrochloric acid, sulfuric acid, boric acid, etc.) or an organic acid (e.g. acetic acid, trifluoroacetic acid, formic acid, methanesulfonic acid, etc.). The preferable acid is acetic acid or boric acid. The acid is used in a proportion of one equivalent to a large excess, preferably about 1 to 50 equivalents . The reaction temperature may range from about 0°C to 200°C, preferably about 50°C to 150°C. The solvent which can be used in the reaction includes halogenated hydrocarbons (e.g. methylene chloride, chloroform, dichloroethane, etc.), ethers (e.g. diethyl ether, tetrahydrofuran, etc.), esters (e.g. methyl acetate, ethyl acetate, etc.), protic solvents (e.g. methanol, ethanol, etc.) and aprotic polar solvents (e.g. acetonitrile etc.). The solvent may contain water. Preferably, acetic acid which doubles as an acid and a solvent is used. The reaction time may range from generally about 10 minutes to 24 hours, and preferably about 1 to 15 hours.
The compound of the formula (III) can be produced by the following process:
hexamethylenetetramine
Figure imgf000016_0001
Figure imgf000016_0002
wherein all the symbols have the same meanings as defined above. The reaction is carried out in a similar manner as those mentioned above where hexamethylenetetramine is employed.
The compound of the formula (III) can also be produced by the following process:
^^ __ hexamethylenetetramine
Figure imgf000016_0003
(Ilϋ wherein all symbols are of the same meanings as defined hereinbefore .
The reaction from the compound (II') to the compound (I') is one mode of the reaction from the compound (II) to the compound (I). The compound (I') can, for example, be used as an intermediate for producing the compound (III).
With respect to the production of the compound (III) or a salt thereof, the compound (I') is reacted with a compound of the formula: HS-CHZ-R (V) or a salt thereof (wherein all symbols of the same meanings as defined hereinbefore; preferably thioglycolate ester or the like) in a proportion of one equivalent to a large excess, preferably about 1 to 10 equivalents. The base which can be used in this reaction may, for example, be an inorganic base (e.g. potassium carbonate, sodium carbonate, etc.), an organic base (e.g. triethylamine, pyridine, dimethylamine, 1 , 8-diazabicyclo[5.4.0 ] -7- undecene, etc.), an alcoholate (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), an organometallic reagent (e.g. n-butyllithium etc.), sodium hydride, or sodium amide. The proportion of the base may range from one equivalent to a large excess, preferably about 1 to 5 equivalents . The reaction temperature may be a range from about -70°C to 200°C, preferably about 0°C to 200°C, more preferably about 0°C to 100°C. The solvent which can be used in this reaction includes halogenated hydrocarbons (e.g. methylene chloride, chloroform, dichloroethane, etc.), ethers (e.g. diethyl ether, tetrahydrofuran, etc.), esters (e.g. methyl acetate, ethyl acetate, etc.), protic solvents (e.g. acetic acid, methanol, ethanol, etc.), aprotic polar solvents (e.g. N,N- dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.). The reaction time may range from about 10 minutes to 24 hours, and preferably about 1 to 10 hours .
In the above reactions according to the present invention and the reactions for synthesizing the starting compounds used there, where any starting material compound has an amino group, a carboxyl group and/or a hydroxyl group as a substituent, such functional group or groups may be previously blocked or masked using protective groups which are conventionally used in peptide chemistry and the objective compound can then be obtained by eliminating the protective group or groups after the intended reaction.
The protective group that can be used for the amino function includes Cι_6 alkyl-carbonyl (e.g. formyl, methylcarbonyl , ethylcarbonyl, etc.), phenylcarbonyl , Cx_6 alkyl oxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl (e.g. benzoxycarbonyl etc.), C7_10 aralkyl (oxy)carbonyl (e.g. benzyloxycarbonyl etc.), trityl, phthaloyl, etc., each of which may be substituted. The substituent group includes halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), Cι_6 alkyl-carbonyl (e.g. methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro, etc. The number of substituents may range from 1 to about 3. The protective group that can be used for the carboxyl function includes C1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl, etc., each of which may be substituted. The substituent group includes halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), C 6 alkyl-carbonyl (e.g. formyl, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro, etc. The number of substituents may range from 1 to about 3. The protective group that can be used for the hydroxyl function includes Cι_6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C7_10 aralkyl (e.g. benzyl etc.), Cι_6 alkyl- carbonyl (e.g. formyl, methylcarbonyl, ethylcarbonyl, etc.), phenyloxycarbonyl, C7.10-aralkyloxy-carbonyl (e.g. benzyloxycarbonyl etc.), pyranyl, furanyl, silyl, etc., each of which may be substituted. The substituent group present includes halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), C,_6 alkyl, phenyl, C7_10 aralkyl, nitro, etc. The number of substituents may range from 1 to about 4.
Removal of such protective groups can be carried out by techniques either known per se or analogous to known techniques. By way of illustration, a method using an acid or a base, reductive deprotection, and a technique using any of ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc. can be mentioned.
The compound (III) obtained by any of the above processes can be isolated and purified by the conventional procedures such as recrystallization, distillation, chromatography, etc. When the thus- obtained compound (III) is the free compound, it can be converted to a salt by a per se known procedure or an analogous procedure (e.g. neutralization). Conversely when the product compound is a salt, it can be converted to either the free compound or a different salt by the per se known procedure or an analogous procedure . Furthermore, when the compound (III) is an optically active compound, it can be fractionated into the S- and R-compounds by the conventional optical resolution technology.
The starting compounds for the compound (III) or salt of the present invention may be salts and the kind of salt is not critical as long as the reaction involved proceeds successfully.
Thus obtained compound (III) can be used as an intermediate for producing a fused imidazopyridine derivative useful for prophylaxis and/or treatment of hyperlipemia. For example, from 5-thia-l,8b- diazaacenaphthylene-4-carboxylic acid or its ester, a useful medicine such as N-[ l-( 3-phenylpropan-l- yl )piperidin-4-yl ] -5-thia-l , 8b-diazaacenaphthylene-4- carboxamide (hereinafter it is sometimes called "Compound A") is obtained, by the manner described in the Reference Examples which are shown below, or an analogous method thereto.
The Compound A and its salt of the present invention have an excellent LDL receptor up-regulating, lipids-lowering and blood sugar-lowering activity, and are of low toxicity. Therefore, the Compound A or a salt thereof can be safely used in mammals (e.g. mouse, rat, hamster, rabbit, cat, dog, bovine, horse, sheep, monkey, man, etc.) as a prophylactic and therapeutic agent for atherosclerotic diseases, hyperlipemia
( hyperlipidemia) , diabeties and diabetic complications, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, arrhythmia, peripheral vascular disease, thrombosis, disorders of pancreas, sequelae of myocardial infarction, valvular disease of the heart, and other diseases.
The Compound A and its salt have cholesterol and triglyceride lowering activities . These biological properties suggest that the Compound A and its salt are particularly suited for the therapy and prophylaxis of hyperlipemia (particularly hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia) and the associated atherosclerotic vascular lesions and secondary diseases (e.g. coronary artery disease, ischemic diseases of the brain, aneurysm, cerebral arteriosclerosis, peripheral arteriosclerosis, intermittent claudication, gangrene) .
Furthermore, because the Compound A and its salt have lipids-lowering activity and blood sugar-lowering activity in diabetic fatty rats, they are expected to ameliorate insulin resistance. In consideration of these biological properties, the Compound A and its salt are particularly suited for the treatment or prevention of hyperglycemia and its secondary diseases such as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic vascular diseases, etc. or insulin resistance and its associated diseases such as hypertension and impaired glucose tolerance, and even such secondary diseases as diseases of the heart, ischemic diseases of the brain, intermittent claudication, gangrene, etc.
The dosage of the Compound A is dependent on the route of administration, patient's clinical status, age and body weight, and other factors but when it is to be administered orally to an adult patient, for example as a therapeutic agent for arteriosclerosis, a hypoglycemic agent, or a therapeutic agent for diabetic complications, the recommended daily dosage in terms of the Compound A or a salt thereof is 0.2 to 50 mg/kg, preferably 0.5 to 30 mg/kg, which dosage is to be administered in one to a few divided doses. The route of administration may be whichever of the oral route and a non-oral route .
The present invention provides a method for easily and efficiently producing in a high yield a 3- formylimidazopyridine derivative and the intermediate being useful for producing a fused imidazopyridine derivative, i.e., a 5-thia-l,8b-diazaacenaphthylene derivative, which is useful for prophylaxis and/or treatment of hyperlipemia.
BEST MODE FOR CARRYING OUT THE INVENTION The following examples and reference examples are intended to describe the present invention merely in further detail and should by no means be construed as defining the scope of the invention. In these reference examples and examples, the term "room temperature" means 0 to +30 °C, the ratio of solvents indicated in the description of the purification procedure by silica gel column chromatography is by volume (v/v) , and the symbols used in the description of NMR data have the following meanings. s singlet d doublet t triplet quint quintet m multiplet br broad
Hz Hertz
CDC13 : deuteriated chloroform
DMSO- D6: deuteriated dimethyl sulfoxide
Reference Example 1
Production of ethyl imidazo[ 1, 2-a]pyridin-5-ylthio- acetate:
Figure imgf000022_0001
H115
To a solution of 100.55 g (669.4 mM) of imidazo[l,2-a]pyridine-5-thiol and 112 ml (803 mM) of triethylamine in 500 ml of ethanol was added 81.7 ml (736 mM) of ethyl bromoacetate at room temperature and the mixture was stirred at room temperature for 2 hours. The solvent was then distilled off under reduced pressure and ethyl acetate was added to the residue. The resulting precipitate (triethylamine hydrochloride) was filtered off and washed with ethyl acetate. The filtrate and washed were pooled, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate = 1:1 to ethyl acetate) to provide the title compound.
Brown liquid. Yield 132.34 g (84%)
*H-NMR (CDC13, 200 MHz) δ: 1.169 (3H, t, 7.1 Hz), 3.678 (2H, s), 4.122 (2H, q, 7.1 Hz), 7.066 (1H, dd, 1.5
Hz, 6.9 Hz), 7.160 (1H, dd, 7.0 Hz, 8.8 Hz), 7.642 (1H, ddd, 0.7 Hz, 1.5 Hz, 8.8 Hz), 7.724 (1H, d, 1.0 Hz), 7.919 (1H, d, 0.6 Hz).
IR (neat): 3390, 2983, 1734, 1487, 1294, 1180, 1147, 1026, 783, 739 cm"1.
Example 1
Production of 5-chloro-3-formylimidazo [ 1 ,2-a]pyridine:
Figure imgf000023_0001
A solution of 5-chloroimidazo [ 1 , 2-a]pyridine (997 mg) and hexamethylenetetramine (1.8 g) in acetic acid (10 ml) was stirred at 90°C for 5 hours. After the reaction mixture was allowed to cool, ethyl acetate- tetrahydrofuran (4/1; 200 ml) was added and the mixture was washed with saturated aqueous solution of sodium chloride. The organic layer was neutralized with 2N- aqueous solution of sodium hydroxide, dried over MgSO_,, and concentrated. The resulting crystals were rinsed with diethyl ether to provide the title compound (440 mg, 37%). *H-NMR (300 MHz, CDC13) δ: 7.20 (d, J=7.4 Hz, 1H) , 7.44 (dd, J=7.4, 8.9 Hz, 1H) , 7.76 (d, J=8.9 Hz, 1H) ,
8.50 (s, 1H) , 10.71 (s, 1H) . Example 2
Production of ethyl 5-thia-l, 8b-diazaacenaphthylene-4- carboxylate :
Figure imgf000024_0001
.
To a solution of ethyl imidazo[ 1, 2-a]pyridin-5- ylthioacetate (11.8 g) in acetic acid (120 ml) was added hexamethylenetetramine (14.0 g) and the mixture was reacted at 90 °C for 10 hours. After this reaction mixture was allowed to cool, ethyl acetate (360 ml) was added and the mixture was washed with water. The organic layer was neutralized with 30% aqueous solution of sodium hydroxide under ice-cooling and washed again with water. The organic layer was concentrated and n- hexane (100 ml) was added to the crystalline residue, followed by 1 hour of stirring at room temperature. The crystals were collected by filtration and dried to provide the title compound (9.6 g, 78%). ^-NMR (300 MHz, CDC13) δ: 1.30 (t, J=7.1 Hz, 3H) , 4.22 (q, J=7.1 Hz, 2H), 5.70 (m, 1H) , 6.55-6.64 (m, 2H), 6.80 (s, 1H), 7.01 (s, 1H) . Example 3 Production of ethyl 5-thia-l , 8b-diazaacenaphthylene-4- carboxylate:
Figure imgf000024_0002
.
A solution of 5-chloro-3-formylimidazo[l,2- ajpyridine (448 mg) , ethyl thioglycolate (0.36 ml), and sodium ethoxide (210 mg) in ethanol (10 ml) was refluxed with stirring for 3 hours . The mixture was then allowed to cool and concentrated. The residue was diluted with ethyl acetate (10 ml) and extracted with lN-hydrochloric acid. The aqueous layer was neutralized with IN-NaOH/water and extracted with ethyl acetate, and the organic layer was washed with water and concentrated. The resulting crystals were collected, rinsed with diisopropyl ether (20 ml), and dried to provide the title compound (430 mg, 65%). Reference Example 2
Production of 5-thia-l, 8b-diazaacenaphthylene-4- carboxylic acid:
Figure imgf000025_0001
To a suspension of 2.2 g of ethyl 5-thia-l, 8b- diazaacenaphthylene-4-carboxylate in methanol (6.6 ml) was added lN-aqueous solution of sodium hydroxide (13 nil), and the mixture was stirred at room temperature for 2 hours. This reaction mixture was adjusted to pH 5 with lN-hydrochloric acid under ice-cooling. Then, the mixture was stirred at room temperature for 1 hour. The resulting crystals were collected by filtration and dried to provide 5-thia-l, 8b-diazaacenaphthylene-4- carboxylic acid (1.8 g, 94%).
^-NMR (200 MHz, DMSO-d6) δ: 5.97 (1H, dd, J=6.6, 1.2 Hz), 6.57-6.73 (2H, m) , 6.88 (1H, s), 7.12 (1H, s). Reference Example 3
Production of N- [ 1- ( 3-phenylpropan-l-yl )piperidin-4- yl ] -5-thia-l , 8b-diazaacenaphthylene-4-carboxamide :
Figure imgf000026_0001
( i ) Process (A)
A suspension of 5-thia-l, 8b-diazaacenaphthylene-4- carboxylic acid (1.2 g) , 4-amino-l- ( 3-phenylpropan-l- yl)piperidine dihydrochloride (1.5 g) , triethylamine (1.5 ml), 1-hydroxy-lH-benzotriazole monohydrate (0.8 g) , and l-ethyl-3-( 3-diethylaminopropyl)carbodiimide hydrochloride (1.0 g) in N,N-dimethylformamide (15 ml) was stirred at 50°C for 2 hours. After spontaneous cooling, water was added and this reaction mixture was diluted with water and extracted with ethyl acetate/tetrahydrofuran (4/1; 90 ml) . The organic layer was washed with lN-aqueous solution of sodium hydroxide (10 ml) and water (30 ml) and concentrated. The resulting crystals were rinsed with diisopropyl ether (20 ml) and dried to provide the title compound (2.0 g, 95%) . (ii) Process (B) To a suspension of 5-thia-l, 8b- diazaacenaphthylene-4-carboxylic acid (10 g) and N,N- dimethylformamide (1.8 ml) in tetrahydrofuran (100 ml) was added oxalyl chloride (8 ml) dropwise with ice- cooling. Then, at room temperature, the mixture was stirred for 24 hours. This reaction mixture was concentrated and dissolved in N,N-dimethylformamide (40 ml) .
To a solution of 4-amino-l-( 3-phenylpropyl ) piperidine dihydrochloride (13.4 g) , 1,8- diazabicyclo[5.4.0 ] -7-undecene (13.7 ml), triethylamine (25.6 ml), and N,N-dimethylformamide (60 ml) was added the solution prepared above under ice-cooling using care not to allow the temperature to rise beyond 10°C. The mixture was then stirred at room temperature for 1.5 hours. This reaction mixture was diluted with water (400 ml) and extracted with ethyl acetate/tetrahydrofuran (4/1; 200 ml). The organic layer was washed with lN-aqueous solution of sodium hydroxide (100 ml) and water (300 ml) and concentrated. The resulting crystals were rinsed with diisopropyl ether (20 ml) and dried to provide the title compound (12.9 g, 67%) .
XH-NMR (300 MHz, CDCl3) δ: 1.45-1.53 (2H, ) , 1.69-1.83 (2H, m), 1.85-1.92 (2H, m) , 1.96-2.08 (2H, ) , 2.33-2.38 (2H, m) , 2.60-2.65 (2H, m) , 2.81-2.85 (2H, m), 3.79-3.82 (1H, ) , 5.53 (1H, d, J=7.8 Hz), 5.78 (1H, d, J=6.6 Hz), 6.59-6.69 (3H, m) , 7.05 (1H, s), 7.16-7.19 (3H, m) , 7.25-7.30 (2H, m).

Claims

1. A method for producing a compound of the formula:
Figure imgf000028_0001
wherein ring Q is an optionally substituted pyridine ring, R is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon residue or an acyl group, or a salt thereof, which comprises reacting a compound of the formula:
Figure imgf000028_0002
wherein the ring Q and R have the same meaning as defined above, or a salt thereof, with hexamethylenetetramine .
2. The method according to Claim 1, wherein R is a hydrogen atom.
3. The method according to Claim 1, wherein a compound of the formula:
Figure imgf000028_0003
wherein the ring Q' is an optionally substituted pyridine ring, R is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon residue or an acyl group, X is a leaving group, or a salt thereof, is produced by reacting a compound of the formula:
Figure imgf000029_0001
wherein the ring Q', R and X have the same meaning as defined above, or a salt thereof with hexamethylenetetramine .
4. The method according to Claim 3, wherein the ring Q' is unsubstituted, and R is a hydrogen atom.
5. The method according to Claim 3, wherein X is a halogen atom.
6. The method according to Claim 3, wherein the ring Q' is unsubstituted, R is a hydrogen atom and X is a halogen atom.
7. A method for producing a compound of the formula:
Figure imgf000029_0002
wherein ring Q" is an optionally substituted pyridine ring, R is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally
2 substituted hydrocarbon residue or an acyl group, R is an optionally protected carboxyl group, or a salt thereof, which comprises reacting a compound of the formula:
Figure imgf000030_0001
wherein the ring Q", R and R have the same meaning as defined above, or a salt thereof, with hexamethylenetetramine .
8. The method according to Claim 7 , wherein the ring Q" is unsubstituted and R is a hydrogen atom.
9. A compound of the formula:
Figure imgf000030_0002
wherein the ring Q' is an optionally substituted pyridine ring, R is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon residue or an acyl group, X is a leaving group, or a salt thereof.
10. The compound according to Claim 9, wherein the ring Q' is unsubstituted and R is a hydrogen atom.
11. The compound according to Claim 9, wherein X is a halogen atom.
12. The compound according to Claim 9, wherein the ring Q' is unsubstituted, R is a hydrogen atom and X is a halogen atom.
13. A method for producing a compound of the formula:
Figure imgf000031_0001
wherein ring Q" is an optionally substituted pyridine ring, R is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl gorup, an optionally
2 substituted hydrocarbon residue or an acyl group, R is an optionally protected carboxyl group, or a salt thereof, which comprises reacting a compound of the formula:
Figure imgf000031_0002
wherein ring Q' is an optionally substituted pyridine ring, R has the same meanings as defined above, and X is a leaving group, or a salt thereof, with a compound of the formula:
HS-CHz-R2 (V) wherein R .2 has the same meaning as defined above.
14. The method according to Claim 13, wherein the rings Q' and Q" are unsubstituted and R is a hydrogen atom.
15. The method according to Claim 13, wherein X is a halogen atom.
16. The method according to Claim 13, wherein the ring Q' and Q" are unsubstituted, R is a hydrogen atom and
X is a halogen atom.
PCT/JP1997/004532 1996-12-11 1997-12-10 Imidazopyridine derivatives and their production WO1998025926A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU54099/98A AU5409998A (en) 1996-12-11 1997-12-10 Imidazopyridine derivatives and their production

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/330802 1996-12-11
JP33080296 1996-12-11

Publications (1)

Publication Number Publication Date
WO1998025926A1 true WO1998025926A1 (en) 1998-06-18

Family

ID=18236724

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1997/004532 WO1998025926A1 (en) 1996-12-11 1997-12-10 Imidazopyridine derivatives and their production

Country Status (2)

Country Link
AU (1) AU5409998A (en)
WO (1) WO1998025926A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8835441B2 (en) 2005-05-20 2014-09-16 Amgen Inc. Heterobicyclic metalloprotease inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0092459A2 (en) * 1982-04-21 1983-10-26 Synthelabo Imidazo(1,2-a)pyridines, their preparation and therapeutical use
EP0368158A1 (en) * 1988-11-07 1990-05-16 Byk Gulden Lomberg Chemische Fabrik GmbH Imidazo pyridines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0092459A2 (en) * 1982-04-21 1983-10-26 Synthelabo Imidazo(1,2-a)pyridines, their preparation and therapeutical use
EP0368158A1 (en) * 1988-11-07 1990-05-16 Byk Gulden Lomberg Chemische Fabrik GmbH Imidazo pyridines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF MEDICINAL CHEMISTRY, vol. 13, no. 6, November 1970 (1970-11-01), pages 10481051, XP002059938 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8835441B2 (en) 2005-05-20 2014-09-16 Amgen Inc. Heterobicyclic metalloprotease inhibitors

Also Published As

Publication number Publication date
AU5409998A (en) 1998-07-03

Similar Documents

Publication Publication Date Title
CA1288431C (en) N9-cyclopentyl-substituted adenine derivatives
JP2528218B2 (en) Pyrimidine derivative
US4933447A (en) Quinoline derivatives
EP1539696A2 (en) Process for preparing quinolin antibiotic intermediates
US20080081811A1 (en) Selective Inhibitors Against Cdk4 and Cdk6 Having Aminothiazole Skeleton
NZ228766A (en) 1,3-disubstituted pyrrolidines and pharmaceutical compositions thereof
WO2011075334A1 (en) Pyrrolo[2,3-d]pyrimidine compounds
BG107460A (en) Benzimidazole derivatives, preparation and therapeutic use thereof
WO2009082134A2 (en) Dipeptidyl peptidase-iv inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as active agent
Rewcastle et al. Potential antitumor agents. 63. Structure-activity relationships for side-chain analogs of the colon 38 active agent 9-oxo-9H-xanthene-4-acetic acid
JPH0867670A (en) Use of substituted 4-phenyl-6-aminonicotinic acid derivativeas drug
JPH11509541A (en) Novel galantamine derivative, method for producing the same, use thereof as a medicament, and pharmaceutical composition containing the same
EP0768311B1 (en) Pyrrolocarbazole derivatives
JP3107784B2 (en) Acid addition salts of optically active piperidine derivatives and their preparation
KR900004125B1 (en) Process for preparing phenyl piperazine derivatives
EP2297148B1 (en) Novel derivatives of (bridged piperazinyl)-1-alcanone and use thereof as p75 inhibitors
EP0594883B1 (en) Imidazo(1,2-c) quinazoline derivatives as antihypertensives and anti dysurics
JP4652647B2 (en) Ceramide analogues, methods for their preparation and their use as antitumor agents
CA2141366A1 (en) Treatment of heart rhythm disorders by administration of 3-phenylsulfonyl-3,7-diazabicyclo[3.3.1]nonane compounds
WO1998025926A1 (en) Imidazopyridine derivatives and their production
IL103229A (en) Imidazolylmethyl-pyridine derivatives their preparation and pharmaceutical compositions containing them
ES2912409T3 (en) Intermediates and processes for the preparation of linagliptin and its salts
EP0201085A2 (en) 6-Phenyl-1,2,3,4,4a,5,6,10b-octahydrobenz(h) isoquinolines
EP0646116B1 (en) Process and intermediates for bis-aza-bicyclic anxiolytic agents
AU2005282572A1 (en) Fibrate compounds having PPAR agonist activity

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AU AZ BA BB BG BR BY CA CN CU CZ EE GE HU ID IL IS KG KR KZ LC LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK SL TJ TM TR TT UA US UZ VN YU AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase