EP1430052A2 - Imidazo 1, 2-a]-5, 6, 7, 8- tetrahydropyridin-8-ones substituees, leur procede de production et leur utilisation pour la production d'imidazo 1, 2-a] pyridines - Google Patents

Imidazo 1, 2-a]-5, 6, 7, 8- tetrahydropyridin-8-ones substituees, leur procede de production et leur utilisation pour la production d'imidazo 1, 2-a] pyridines

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Publication number
EP1430052A2
EP1430052A2 EP02776963A EP02776963A EP1430052A2 EP 1430052 A2 EP1430052 A2 EP 1430052A2 EP 02776963 A EP02776963 A EP 02776963A EP 02776963 A EP02776963 A EP 02776963A EP 1430052 A2 EP1430052 A2 EP 1430052A2
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EP
European Patent Office
Prior art keywords
alkyl
imidazo
group
amino
tetrahydropyridin
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EP02776963A
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German (de)
English (en)
Inventor
Hagen Weigl
Klaus Ebel
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BASF SE
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BASF SE
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    • 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
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the invention relates to substituted imidazo [1,2-a] -5,6,7, 8-tetrahydropyridin-8-ones, processes for their preparation and their use for the preparation of imidazo [1,2-a] pyridines.
  • Imidazo [1,2-a] pyridines represent an economically extremely interesting class of compounds in the field of pharmaceuticals, crop protection agents and cosmetics.
  • Imidazo [1,2-a] pyridines are mainly used for the prevention and treatment of various diseases, such as gastrointestinal diseases, cancer or diseases of the central nervous system.
  • diseases such as gastrointestinal diseases, cancer or diseases of the central nervous system.
  • the preparation and use of such compounds is described.
  • gastrointestinal diseases such as gastric ulcers (Kaminski JJ et al.
  • Solimidine® (Zolimidine ® also Zoliridine ®; 2 [4-methyl sulfonyDphenyl] imidazo [1,2-a] pyridine) to call.
  • kardiotoni- ULTRASONIC drug is also of the cAMP phosphodiesterase inhibitor oprinone® to call (Olprinone ®, 1,2-dihydro-5-imidazo [1, 2-a] - pyridin-6-yl-6-methyl-2-oxo-3 -pyridine carbonitrile).
  • Imidazo [1, 2-a] pyridines are also used in non-benzodiazepine hypnotics such as zolpidem (N, N, 6-trimethyl-2-p-tolyl-imidazo [1,2a] -pyridine-3-acetamide).
  • zolpidem N, N, 6-trimethyl-2-p-tolyl-imidazo [1,2a] -pyridine-3-acetamide.
  • curare mimetic is further Fazadinium- bromide to give (Fazadon ®; 1, l'-azobis [3-methyl-2-phenyl-imidazo [1,2-a] pyridiniumdibromid).
  • Alpidem® is also known as an anxiolytic (Ananxyl®, 6-chloro-2- (4-chlorophenyl) - N, N-dipropyl-imidazo [1,2-a] yridine-3-acetamide).
  • Minodronic Acid (YM-529) is evaluated in clinical studies (1-hydroxy-2-imidazo [1, 2-a] pyridin-3-ylethylidene bisphosphonic acid).
  • imidazo [1, 2a] pyridines are in clinical trials as promising bradikinin (BK) B2 receptor antagonists (8- [[3- (N-acylglycl-N-methylamino) -2, 6-dichlorobenzyl] oxy] 3- halo-2-methylimidazo- [1, 2-a] pyridines; Abe Y et al. (1998) J Med Chem 41: 564-578).
  • imidazo [1,2a] pyridines also go into nucleoside analogues which are used as antiviral therapeutics or in cancer therapy (chemotherapy) (Pan SF et al. (1998) Tetrahedron Letters 39: 8191-8194).
  • interleukin-6 inhibitors for example 2,3,7,8-tetrahydro-4-aryl-1H-cyclopent [e] imidazo [1,2-a] - pyridine-5 (6H) - on; Tagat J et al. (1995) Bioorg. Med. Chem. Lett. 5 (18): 2143-2146).
  • Imidazo [1,2-a] pyridines are used in cosmetics, for example, as coupling components in oxidative hair colorants (EP 0 930 062).
  • Imidazo [1,2-a] pyridines are also interesting building blocks in crop protection products.
  • Herbicides such as sulfosulfuron ® (Maverick ®, 1- (2-ethylsulphonyl-imidazo [l, 2-a] pyridin-3-yl-sulfonyl) -3- (4,6-demethoxypyrimidin-2-yl) -harnstof) or imazosulfuron ® (Takeoff ® , 1- (2-chloro-imidazo [1,2-a] pyridin-3-yl-sulfonyl) -3- (4,6-dimethoxypyrimidin-2-yl) urea) include this grouping.
  • WO 98/42707 outlines the preparation of pharmaceuticals based on imidazo- [1,2a] -tetrahydropyridin-8-ones in the context of a hypothetical synthesis process (p. 16 / scheme 8). However, the application does not contain any technical teaching on how these connections are technically accessible.
  • the task was to provide new starting materials and processes for the preparation of imidazo [1,2a] pyridines.
  • a first object of the invention relates to processes for the preparation of imidazo- [1, 2a] -5, 6, 7, 8-tetrahydropyridin-8-ones, characterized in that
  • the reaction can take place thermally at temperatures above 100 ° C., preferably at temperatures from 100 to 300 ° C., particularly preferably at temperatures from 150 to 250 ° C., very particularly preferably at temperatures from 190 to 220 ° C.
  • the reaction can be carried out without any additional activation or else by activation by adding bases, acids or catalysts.
  • the activation is preferably base-catalyzed.
  • Preferred bases are potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, DBU (1,5-diaza-bicyclo [5.4.0] undecylene-5), trialkylamines, LDA (lithium diisopropyl amide) and Hunig base (diisopropylethylamine).
  • the reaction of the imidazoles can be carried out with equimolar amounts of butyrolactone or an excess of one of the two starting materials - imidazole or ⁇ -butyrolactone.
  • the excess can be at least 20 mol%, preferably at least 50 mol%, particularly preferably at least 100 mol%, very particularly preferably at least 500 mol%.
  • the preferred range of excess is between 300 mol% and 500 mol%.
  • the reaction is preferably carried out with an excess of ⁇ -butyrolactone, which simultaneously serves as a solvent and for trapping the water of reaction.
  • the excess ⁇ -butyrolactone can possibly be partially or completely distilled off together with the water of reaction formed during or after the reaction.
  • the isolated yield can be increased if part of the butyrolactone is distilled off during or after the reaction.
  • solvents such as, for example, toluene or xylene
  • toluene or xylene can be added to the reaction mixture, which, for example in the function of a tractor, promote the removal of the water of reaction.
  • the reaction can be carried out at normal pressure, elevated or reduced pressure.
  • the pressure can be kept constant during the reaction or else can be modulated, for example for the purpose of distilling off a solvent.
  • the reaction is preferably carried out at normal pressure.
  • the response time depends on the speed of implementation. For example, it can be approximately 12 hours.
  • imidazo- [1,2a] -5, 6,7, 8-tetrahydropyridin-8-one can then be precipitated, for example, by cooling the batch and separated by solid / liquid separation (“suction”).
  • the invention 6 7 relates to methods for the preparation of imidazo [1,2-a] -5, 8-tetrahydro- pyridin-8-ones of the formula Ia or Ib, "characterized in that
  • Suitable substituents on the imidazole and / or butyrolactone which are used in the process according to the invention are preferably those which meet the conditions of the invention
  • Educts are preferably used which decompose under the reaction conditions by a maximum of 50%, preferably a maximum of 20%, particularly preferably a maximum of 10%.
  • the starting materials or individual substituents thereof used in the process according to the invention can be derivatized for the period of the reaction in the manner familiar to those skilled in the art or modified by known protective groups in order to improve the stability of the compounds under the conditions of the process according to the invention to increase.
  • Preferred derivatization or modification methods are oxidation, reduction, 0-, S- or N-alkylation or acylation, such as esterification, etherification or acetal formation.
  • hydroxyl groups can be protected by introducing protective groups such as trityl, tert-butyldimethylsilyl, tert-butyloxycarbonyl (BOC), THP ether or benzyl groups.
  • Carbonyl groups can be protected by acetal formation.
  • Thiols as thioesters or thioethers; Amines as carbamates, " amides or benzylamines.
  • the invention further relates to substituted imidazo- [1,2a] - 5,6, 7, 8-tetrahydropyridin-8-one described by the general formula Ia or Ib or salts thereof with the proviso that
  • Rl, R2 and all radicals R3 do not simultaneously represent hydrogen, or
  • R1, R2 or each R3 can in each case and independently of one another be selected from the group consisting of hydrogen, halogen, hydroxy, cyano, isocyano, thiocyano, amino, nitroso, nitro, carbonyl, alkylcarbonyl, sulfonate, alkylsulfonyl, sulfonamide, Sulfonylurea, carboxyl, alkylcarboxyl, substituted or unsubstituted, branched or unbranched or cyclic alkyl, alkenyl, alkynyl, substituted or unsubstituted aryl or heteroaryl.
  • R 1, R 2 or each R 3 are in each case selected independently and independently of one another from the group consisting of hydrogen, hydroxyl, halogen, cyano, thiocyanato, branched or unbranched, optionally substituted C ⁇ -C 6 -alkyl, ' C 2 -C 6 -Alkenyl, C -C 6 -alkynyl, C 3 -C -cycloalkyl, C 3 -C 6 -alkadienyl, hydroxy-Ci-Cg-alkyl, halo -CC-C 6 alkyl, Ci-C ⁇ -alkoxy, C 2 -C 6 -alkenyl-oxy, C -C 6 -alkynyloxy, Ci-Cg-alkyl-oxy-Ci-Cg-alkyl, Ci-C ⁇ -alkyl-oxy-C 2 -C 6 -alkenyl, C ⁇ -C 6 - Alkyl-oxy-C 2 -C 6
  • R1 and R2 can preferably also form a ring system together, so that a bicyclic imidazole is used and a tricyclic imidazo- [1, 2a] -5, 6, 7, 8-tetrahydropyridin-8-one is obtained.
  • one of the starting materials used contains a chirality center
  • one of the two enantiomers is preferably used in the reaction.
  • the halogen is fluorine
  • b) -C 6 alkyl is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, 1-methyl-propyl, 2nd -Methyl-propyl, n-pentyl, iso-pentyl, n-hexyl and iso-hexyl. Most preferred are methyl, ethyl, n-propyl and iso-propyl.
  • C 2 -C 6 alkenyl is selected from the group consisting of ethenyl, 1-propenyl, 2-propenyl, n-1- (or 2 or 3) -butenyl, iso-butenyl, nl- (or 2 or 3 or 4) pentenyl, iso-pentenyl, n-1- (or 2 or 3 or 3 or 5) -hexenyl and iso-hexenyl. Most preferred are ethenyl, 1-propenyl and 2-propenyl.
  • C 3 -C 6 alkadienyl is selected from the group consisting of 1,2-propadienyl, n-butadien-1, 3-yl, n-butadien-l, 2-yl, n-butadiene-2,3 -yl, iso-butadienyl, n-pentadienyl, iso-pentadienyl, n-hexadienyl and iso-hexadienyl. Most preferred are 1,2-propadienyl and n-butadien-1,3-yl.
  • C -C 6 -alkynyl is selected from the group consisting of ethynyl, 1-propynyl, 2-propynyl, n-butyn-1-yl, n-butyn-2-yl, n-butyn-3-yl, l -Methyl-propin-2-yl, n-pentyn-1-yl, isopentinyl, n-hexynyl, iso-hexynyl Most preferred are ethynyl, 1-propynyl and 2-propynyl.
  • C 3 -C -cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexyl.
  • R1 and R2 can preferably also form a ring system together, so that a bicyclic imidazole is used and a tricyclic imidazo- [1, 2a] -5, 6, 7, 8-tetrahydropyridin-8-one is obtained.
  • R1 and R2 preferably form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexyl ring system.
  • Halo-C ⁇ -Cg-alkyl is selected from the group consisting of halomethyl, haloethyl, n-halopropyl, iso-halopropyl, n-halobutyl, tert-halobutyl, halo-1-methyl-propyl, halo-2-methyl- propyl, n-halopentyl, iso-halopentyl, n-halohexyl and iso-halohexyl.
  • Halomethyl, haloethyl, n-halopropyl and iso-halopropyl are most preferred.
  • the halogen is preferably fluorine. Most preferred is trifluoromethyl.
  • Hydroxy-Ci-C ß- alkyl is selected from the group consisting of hydroxymethyl, hydroxyethyl, n-hydroxypropyl, iso-hydroxypropyl, n-hydroxybutyl, tert-hydroxybutyl, hydroxy-1-methyl-propyl, hydroxy-2-methyl -propyl, n-hydroxypentyl, iso-hydroxypentyl, n-hydroxyhexyl and iso-hydroxyhexyl. Most preferred are hydroxymethyl, hydroxyethyl, n-hydroxypropyl and iso-hydroxypropyl.
  • Ci-Cg-alkoxy is selected from the group consisting of
  • CC 6 _alkenyloxy is selected from the group consisting of ethenoxy, n-propenyloxy, isopropenyloxy, n-butenyloxy and sekiButenyloxy.
  • C 2 -Cg_alkynyloxy is selected from the group consisting of ethynyloxy, n-propynyloxy, isopropynyloxy, n-butynyloxy and sec-butynyloxy.
  • C ⁇ -Cg_Alkyl-oxy-C ⁇ -C 6 alkyl is selected from the group consisting of methoxymethyl, ethoxymethyl, propoxymethyl, methyloxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl and propoxypropyl.
  • m) -C-C 5 _Alkyl-oxy-C-Cg-alkenyl is selected from the group consisting of methyloxyethenyl, ethoxyethenyl, propoxy-ethenyl, methoxypropenyl, ethoxypropenyl and propoxypropenyl.
  • n) -C 6 -Alkyloxy-CC 6 -alkynyl is selected from the group consisting of methyloxyethynyl, ethoxyethynyl, propoxyethynyl, methoxypropynyl, ethoxypropynyl and propoxypropynyl.
  • C -C 6 alkenyloxy-C ⁇ -Cg-alkyl is selected from the group consisting of ethenoxymethyl, propenoxymethyl, ethenoxyethyl, propenoxyethyl, ethenoxypropyl and propenoxypropyl.
  • C ⁇ -Cg_Alkyl-oxy-C 2 -C 6 alkynyl is selected from the
  • Cyano-Ci-Cg-alkyl is selected from the group consisting of cyanomethyl (acetonitrile), cyanoethyl, n-cyanopropyl, iso- cyanopropyl, n-cyanobutyl, tert-cyanobutyl, cyano-1-methyl-propyl, cyano-2 -methyl-propyl, n-cyanopentyl, iso-cyano-pentyl, n-cyanohexyl and iso-cyanohexyl. Most preferred are cyanomethyl (acetonitrile), cyanoethyl, n-cyanopropyl and iso-cyanopropyl.
  • Isocyano-Ci-Cg-alkyl is selected from the group consisting of isocyanomethyl, isocyanoethyl, n-isocyanopropyl, iso-isocyanopropyl, n-isocyanobutyl, tert-isocyanobutyl, iso-cyano-1-methyl-propyl, isocyano-2- methyl-propyl, n-isocyano-pentyl, iso-isocyanopentyl, n-isocyanohexyl, iso-isocyano-hexyl. Most preferred are isocyanomethyl, isocyanoethyl, n-isocyanopropyl and iso-isocyanopropyl.
  • amino-Ci-Cg-alkyl is selected from the group consisting of aminomethyl, aminoethyl, n-aminopropyl, iso-aminopropyl, n-aminobutyl, tert-aminobutyl, amino-1-methyl-propyl, amino-2-methyl propyl, n-aminopentyl, iso-aminopentyl, n-aminohexyl, iso-aminohexyl. Most preferred are aminomethyl, aminoethyl, n-aminopropyl and iso-aminopropyl.
  • Amino-CC 6 -alkynyl is selected from the group consisting of aminoethynyl, 1-amino-1-propynyl, l-amino-2-propynyl, n-1-amino-butyn-l-yl, nl-amino-butyne -2-yl, n-1-amino-butyn-3-yl, l-amino-3-methyl-propyn-1-yl, n-1-amino-pentynyl, n-1-amino-hexynyl. Most preferred are aminoethynyl, 1-amino-l-propynyl and l-amino-2-propynyl.
  • C ⁇ -Cg_Alkylcarboxyl is selected from the group consisting of methylcarboxyl, ethylcarboxyl and propylcarboxyl.
  • C 3 -C 6 cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, imidazole and piperidine.
  • Ci-Cg-alkylsulfonyl is selected from the group consisting of methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, (1-methyl-propyl) sulfon , 2-methyl-propylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, n-hexylsulfonyl and iso-hexylsulfonyl. Most preferred are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl and iso-propylsulfonyl.
  • the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -Butyl, tert-butyl, 1-methyl-propyl, 2-methyl-propyl, n-pentyl, isopentyl, n-hexyl and iso-hexyl, particularly preferably from the group consisting of methyl, ethyl, n- Propyl and isopropyl.
  • Both substituents are very particularly preferably identical with regard to the disubstituted N, N- (C ⁇ -C-alkyl) sulfonamides.
  • y) sulfonylurea can be substituted or unsubstituted, preferably substituted.
  • the substitution can include substituted or unsubstituted alkyls or aryls or heteroaryls.
  • L-Sulfonyl-3 (4, 6-dimethoxypyrimidin-2-yl) urea is very particularly preferred.
  • Aryl is selected from the group consisting of substituted and unsubstituted benzyl, substituted and unsubstituted naphthyl, very particularly preferred are phenyl, tolyl, xylyl, 1-naphthyl, 2-naphthyl, 1-anthryl and 2-anthryl ,
  • Heteroaryl is selected from the group consisting of substituted and unsubstituted aromatic heterocycle, substituted and unsubstituted aromatic or partially aromatic heterobicyclic, the heterocycles being 5 or 6-membered rings and up to 3 heteroatoms selected from the group N, 0, S can contain.
  • the process according to the invention is carried out starting from imidazoles which each have a substitution different from hydrogen in position * 4 and position 5.
  • the process according to the invention is carried out starting from imidazoles, each of which has an identical substitution different from hydrogen in position 4 and position 5.
  • This embodiment is particularly advantageous since only one product is formed and the compounds of the general formulas Ia and Ib correspond. Since the yields on the desired product are particularly good here, this embodiment can be realized in an economically particularly advantageous manner.
  • the substituted imidazo- [1,2a] -5, 6, 7, 8-tetrahydropyridin-8-ones according to the invention preferably comprise those which each have a substitution different from hydrogen in position 2 and position 3. These substitutions in positions 2 and 3 which are different from hydrogen are very particularly preferably identical.
  • R3 H
  • ⁇ -Butyrolactone and 4,5-dimethylimidazole or derivatives or modifications of the aforementioned are used.
  • 2, 3-Dimethyl-imidazo [1, 2-a] - 5,6,7, 8-tetrahydropyridin-8-one is formed.
  • ⁇ -Butyrolactone and f4-methylimidazole (or alternatively 5-methylimidazole) are used.
  • ⁇ -Butyrolactone and 4-acetonitrile-5-methylimidazole or 5-acetonitrile-4-methylimidazole or derivatives or modifications of the aforementioned are used.
  • R3 methyl in position 6 of the ImidazopyrimidonsySterns "or ß-position of the ⁇ -butyrolactone, are used
  • R2 4-methylphenyl
  • R N, N-dimethylacetamide.
  • R2 chlorine
  • Rl sulfonyl-3- (4, 6-dimethoxypyrimidin-2-yl) urea).
  • ⁇ -Butyrolactone and: (4-ethylsulfonylimidazol-5-yl-sulfonyl) -3- (4, 6-dimethoxy-pyrimidin-2-yl) -urea or (5-ethylsulfonylimidazol-4-yl-sulfonyl) -3 are used - (4, 6-dimethoxypyrimidin-2-yl) urea or derivatives, precursors or modifications of the aforementioned.
  • the sulfonylurea side chain is preferably built up only after the reaction of imidazole and ⁇ -butyrolactone.
  • 1- (2-Ethylsulfonyl-imidazo- [1,2-a] -5,6,7, 8-tetrahydropyridin-8-one-3-yl-sulfonyl) -3- (4, 6-dimethoxypyrimidin-2) is formed -yl) urea and l- (3-ethylsulfonylimidazo [1, 2-a] -5,6,7, 8-tetrahydropyridin-8-one-2-ylsulfonyl) -3- (4, 6-dimethoxypyrimidin-2-yl) urea, where 1- (2-ethylsulfonylimidazo [1, 2-a] -5,6,7, 8-tetrahydropyr
  • the amino function can be protected in the form of an amide.
  • the hydroxy function can be protected in the form of an ester.
  • the amino function can be in the form of an amide
  • the carbonyl function can be protected in the form of an acetal 0.
  • imidazoT-4-acetate available, for example, from SIGMA-ALDRICH
  • esters of this compound can also be used, which are reductively converted to formyl after the reaction - if appropriate after saponification.
  • R2 H. 5-formylimidazole or 4-formylimidazole and ⁇ -methyl- ⁇ -butyrolactone or derivatives or modifications of the aforementioned are used.
  • the carbonyl function can be protected in the form of an acetal.
  • R3 H
  • R3 H
  • 4,5- (N, N-diethylamino) carbonylimidazole and ⁇ -butyro-lactone or derivatives or modifications of the aforementioned are used.
  • 2, 3- (N, N-diethylamino) carbonyl-imidazo [1,2-a] - 5,6,7, 8-tetrahydropyridin-8-one is formed.
  • Derivatives and modifications in relation to the above-mentioned starting materials for the production of the preferred imidazo [1,2-a] -5, 6,7, 8-tetrahydropyridin-8-one means, for example, such chemical changes that increase the stability of the starting materials under the reaction conditions grant the inventive method.
  • a carbonyl or formyl group can be protected in the form of an acetal.
  • Substituted ⁇ -butyrolactones are accessible in the manner familiar to the person skilled in the art, inter alia from substituted 1,4-butanediols or substituted tetrahydrofurans. Common synthetic processes are described, among others, in Houben-Weyl "Methods of Organic Chemistry” Volume 6/2 Oxygen Compounds I Part 2; Author H. Kröper; Pp. 571ff, 1963. Substituted ⁇ -butyrolactones can be obtained, for example, from tetrahydrofurans or substituted ⁇ -halogenated butyric acid derivatives, such as 4-bromobutyric acid.
  • ⁇ -butyrolactones or ⁇ -butyrolactones derived or derivatized from these by synthetic steps known to the person skilled in the art can be used, which (for the games can be purchased commercially from SIGMA-ALDRICH or FLUKA):
  • Pantolactone (2-hydroxy-3, 3-dimethyl- ⁇ -butyrolactone) ⁇ -acetyl- ⁇ -methyl- ⁇ -butyrolactone ⁇ -phenyl- ⁇ -trifluoromethyl- ⁇ -butyrolactone ⁇ -benzylidene- ⁇ -butyrolactone ⁇ ⁇
  • Another object of the invention relates to the use of the imidazo [1,2a] -5, 6, 7, 8-tetrahydropyridin-8-ones of the formula Ia or Ib according to the invention for the preparation of imidazo [1, 2a] pyridines, preferably according to the general formula IV, and of compounds of the general formula V and their preliminary or intermediate stages.
  • A is 0 or NH
  • R4 is substituted or unsubstituted, branched or unbranched -C-Cg-alkyl, C 2 -Cg-alkenyl, C-Cg-alkynyl, C 3 -C 7 -cycloalkyl, C 3 -Cg-alkadienyl, halo-C ⁇ -C 6 -alkyl,
  • R5a and R5b is selected from the group consisting of hydrogen, hydroxyl, -CC 6 alkoxy, Ci-Cg-alkoxy-Ci-Cg-alkoxy, Ci-Cg-alkylcarbonyloxy. R5a and R5b together can also be oxygen (oxo group), and
  • R6a and R6b is selected from the group consisting of hydrogen, hydroxyl, Ci-Cg-alkoxy, Ci-Cg-alkoxy-Ci-Cg-alkoxy, Ci-Cg-alkylcarbonyloxy, wherein at least one of the radicals R6a or R6b is hydrogen is.
  • R6a and R6b together can also be oxygen (oxo group)
  • R7 is hydrogen, halogen, Ci-Cg-alkyl, C ⁇ -Cg-alkoxy,
  • R8 is hydrogen, halogen, Ci-Cg-alkyl, C ⁇ -Cg_alkoxy or salts thereof.
  • 5, 6, 7, 8-tetrahydropyridin-8-one can be formed by reaction with alkyl or arylamines to form the base of the ship.
  • the amine is preferably used in excess and the reaction is carried out under acidic catalysis, for example with p-toluenesulfonic acid (as described, for example, in: Organikum, Deutscher Verlag dermaschineen (1990), Chapter 7.1.1).
  • the Schiff's bases (enamines) obtained can then be converted to substituted 8-amino-imidazo [1,2a] pyridines according to Reaction Scheme A (II) by oxidative aromatization.
  • imidazo [1,2-a] -5,6,7, 8-tetrahydropyridin-8-one can be converted to ' imidazo [1,2a] pyridines by reaction with ammonia and subsequent oxidative aromatization, and the preferred compounds by reaction, for example obtained with haloalkylene or arylene (Scheme A (I)).
  • 8-Hydroxy-imidazo [1, 2a] pyridines are directly accessible through oxidative aromatization.
  • Oxidative aromatization can be achieved, for example, by reaction with 2,3-dichloro-5, 6-dicyanobenzoquinone (DDQ) in the manner familiar to the person skilled in the art (review article: Walker D. et al. (1967) Chem. Rev. 67: 153-195 ). Bromination and subsequent HBr cleavage can be used as a further flavoring variant.
  • DDQ 2,3-dichloro-5, 6-dicyanobenzoquinone
  • reaction scheme A (I) or B The reactions of 8-hydroxy-imidazo [1,2a] pyridines or 8-amino-imidazo [1,2a] pyridines according to reaction scheme A (I) or B are carried out using hydroxy- or haloalkylene or -arylene - optionally after in situ Derivatization or activation - is described for example in US 6,124,313, EP 0 033 094, EP 0 308 917 or EP 0 268 989.
  • 2,3-dimethyl-imidazo [1,2-a] -5, 6, 7, 8-tetra-hydropyridin-8-one can be reacted with alkyl or aryl halides, preferably alkyl or aryl bromides, and then aromatized by oxidation to 2, 3-dimethyl-8-alkyl / aryloxy-imidazo- [1, 2-a] pyridines.
  • 2-methyl-3-acetonitrile-imidazo [1,2-a] pyridin-8-one can be converted into 2-methyl-8- (phenylmethoxy) imidazo [1,2-a] by reaction with bromomethylbenzene and subsequent aromatization by oxidation.
  • - Pyridine-3-acetonitrile are implemented.
  • the compound is known under the name SCH-28080 and acts as an inhibitor of gastric H +, K + -ATPase.
  • N, N, 6-trimethyl-2- (4-methylphenyl) imidazo [1,2-a] -5,6,7,8-tetrahydropyridin-8-one-3-acetamide can be reduced by reducing the oxo Group and subsequent elimination and aromatization to N, N, 6-trimethyl-2- (4-methylphenyl) imidazo [1,2-a] pyridine-3-acetamide.
  • the compound is commercially available under the name Zolpidem (Arabia ® ) as a non-benzodiazepine benzodiazepine agonist.
  • 3-Amino-2-methyl-imidazo [1,2-a] -5,6,7, 8-tetrahydropyridin-8-one can be converted to 3-amino-2-methyl- by reaction with, for example, phenylmethylbromide and subsequent aromatization by oxidation.
  • 8— (phenylmethoxy) imidazo [1,2-a] pyridine can be reacted.
  • a reaction with 2-phenylethylmagnesium bromide leads to 3-amino-2-methyl-8- (2-phenylethyl) imidazo [1,2-a] pyridine after subsequent elimination of the hydroxy group and aromatization.
  • 3-formylimidazo [1,2-a] -5,6,7, 8-tetrahydropyridin-8-one can be converted to 3-formyl-8-methylimidazo [1,2.
  • methylmagnesium bromide followed by aromatization with elimination of the hydroxy group -a] pyridine are implemented.
  • This compound is suitable as an intermediate for the production of C-nucleoside analogs (as described in Pan SF et al. (1998) Tetrahedron Letters 39: 8191-8194).
  • 3-Formyl-7-methyl-imidazo [1,2-a] -5,6,7, 8-tetrahyropyridin-8-one can be reduced to 3-formyl-7-methyl after reduction of the keto group and subsequent aromatization with elimination of the hydroxy group -imidazo- [1, 2-a] pyridine are implemented.
  • This compound is suitable as an intermediate for the production of C-nucleoside analogs (as described in Pan SF et al. (1998) Tetrahedron Letters 39: 8191-8194).
  • Preferred compounds of the general formula V are mentioned in 5 WO 98/42707.
  • the compounds according to the invention 3-formyl-2-methylimidazo [1,2-a] -5, 6, 7, 8-tetrahydropyridin-8-one, 3-hydroxymethyl-2-methylimidazo [1, 2-a] -5,6,7,8-tetrahydropyridin-8-one or 2,3-dimethyl-imidazo [1, 2-a] -5,6,7,8-tetrahydropyridin-8-one according to reaction scheme C. be converted to one of the following 0 connections: ⁇ ⁇
  • the formyl group is preferably used as acetal in a protected manner.
  • the two isomeric reaction products were isolated by bulb tube distillation of the bottom at 180 ° C. and 0.4 mbar. 4.5 g (0.03 mol; 20% of the theoretical maximum yield) of 2-methylimidazo [1, 2a] -5, 6, 7, 8-tetrahydropyridin-8-one and 3-methylimidazo [1,2a ] -5, 6,7, 8-tetrahydropyridin-8-one in the ratio of approx. 1: 1 (according to NMR) as a light oil 5 .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de production d'imidazo-[1m 2-a]-5,6,7,8-tétrahydropyridin-8-ones consistant à faire réagir des η-butyrolactones avec des Imidazols. L'invention concerne également de nouvelles imidazo[1,2-a]-5,6,7,8-tetrahydropyridin-8-ones et leur utilisation pour la production d'imidazo[1,2-a]pyridines.
EP02776963A 2001-09-14 2002-09-03 Imidazo 1, 2-a]-5, 6, 7, 8- tetrahydropyridin-8-ones substituees, leur procede de production et leur utilisation pour la production d'imidazo 1, 2-a] pyridines Withdrawn EP1430052A2 (fr)

Applications Claiming Priority (3)

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DE10145457 2001-09-14
DE10145457A DE10145457A1 (de) 2001-09-14 2001-09-14 Substituierte Imidazo[1,2-a]-5,6,7,8-tetrahydropyridin-8-one, Verfahren zu ihrer Herstellung, sowie deren Verwendung zur Herstellung von Imidazo[1,2,-a]pyridinen
PCT/EP2002/009813 WO2003024963A2 (fr) 2001-09-14 2002-09-03 Imidazo [1, 2-a]-5, 6, 7, 8- tetrahydropyridin-8-ones substituees, leur procede de production et leur utilisation pour la production d'imidazo [1, 2-a] pyridines

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DE (1) DE10145457A1 (fr)
HU (1) HUP0401991A3 (fr)
WO (1) WO2003024963A2 (fr)

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WO2008156314A2 (fr) * 2007-06-20 2008-12-24 Lg Electronics Inc. Procédé de réception d'information de système efficace
US8687565B2 (en) * 2007-09-20 2014-04-01 Lg Electronics Inc. Method of effectively transmitting radio resource allocation request in mobile communication system
US8992897B2 (en) 2010-01-06 2015-03-31 Elc Management Llc Skin lightening compositions
US8722026B2 (en) 2010-01-06 2014-05-13 Elc Management, Llc Skin lightening compositions

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DE10145457A1 (de) 2003-04-03
HUP0401991A3 (en) 2005-11-28
WO2003024963A3 (fr) 2003-09-12
CA2459960A1 (fr) 2003-03-27
JP2005504079A (ja) 2005-02-10
WO2003024963A2 (fr) 2003-03-27
HUP0401991A2 (hu) 2005-01-28
US7196196B2 (en) 2007-03-27
US20050020620A1 (en) 2005-01-27

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