WO1997032854A1 - Derives de 2-sulfinylnicotinamide, intermediaire de ces derives, procede pour produire ces derives et composition medicinale contenant ces derives comme ingredient actif - Google Patents

Derives de 2-sulfinylnicotinamide, intermediaire de ces derives, procede pour produire ces derives et composition medicinale contenant ces derives comme ingredient actif Download PDF

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WO1997032854A1
WO1997032854A1 PCT/JP1996/000512 JP9600512W WO9732854A1 WO 1997032854 A1 WO1997032854 A1 WO 1997032854A1 JP 9600512 W JP9600512 W JP 9600512W WO 9732854 A1 WO9732854 A1 WO 9732854A1
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group
hydrogen atom
alkyl group
alkoxy
pyridyl
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PCT/JP1996/000512
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English (en)
Japanese (ja)
Inventor
Yoshinori Nishikawa
Hideo Terauchi
Akihiko Tanitame
Keiko Tada
Masanobu Komiya
Keiji Nakamura
Yukio Tominaga
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Dainippon Pharmaceutical Co., Ltd.
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Priority to PCT/JP1996/000512 priority Critical patent/WO1997032854A1/fr
Priority to AU48451/96A priority patent/AU4845196A/en
Publication of WO1997032854A1 publication Critical patent/WO1997032854A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a method for producing a 2-sulfinylnicotinamide derivative, an intermediate thereof, a 2-sulfinylnicotinamide derivative, and a pharmaceutical composition containing the compound as an active ingredient.
  • the present invention relates to a novel 2-sulfinylnicotinamide derivative having a gastric acid secretion inhibitory action based on an inhibitory action of ⁇ +, K + -ATPase (proton pump) and a novel intermediate 2-mercaptonicotinamide derivative, And a therapeutic agent for peptic ulcer, comprising a 2-sulfinylnicotinamide derivative as an active ingredient.
  • Ri is halogen, cyano, nitro, amino, alkylamino, aminoamino, alkyl, aralkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, arylthio, alkylsulfini Le, ⁇ Li one Rusurufieru, ⁇ reel sulfonyl, halogenoalkylthio, halo genomic alkylsulfinyl, halogenoalkyl alkylsulfonyl or optionally substituted with Karubonirua reel C i ⁇ c 8 - alkyl, Ararukiru, Teroari Ichiru group to Ariru or Represents
  • X represents 0 or 1 N (R 3) —
  • R 2 represents C i-(: 5 —alkyl, aralkyl, alkenyl or alkynyl,
  • R 3 represents a hydrogen atom or alkyl, or R 1 and R 3 together with an adjacent N atom can include 0 or N as an additional heteroatom, and optionally C 1-(: 4 Represents a 5- or 6-membered heterocyclic ring which may be substituted with alkyl,
  • R 4 represents hydrogen, halogen, optionally substituted alkyl, halogenoalkyl, cyano, nitro, amino, aminoacyl, phenyl, alkoxy, aryloxy, thioalkyl and arylthio.
  • Japanese Unexamined Patent Publication No. 5-221994 discloses that a nicotinic acid anilide derivative represented by the following formula is used for the fungus Botrytis (Botrytis). Germicidal activity, and is described as having a significant effect on its control.
  • Ri is halogen, methyl, trifluoromethyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl
  • R 2 represents alkyl, alkenyl, alkoxy, or the like which may be optionally substituted with halogen.
  • proton pump inhibitors also have some disadvantages, such as affecting drug metabolism, and are not always satisfactory.
  • proton pump inhibitors are under development, but most of them have the basic skeleton of benzimidazole or imidazole as well as existing proton bomb inhibitors. Therefore, it has a completely different basic skeleton from the existing and under development proton pump inhibitors, and has a similar mechanism of action to existing proton pump inhibitors, namely, after being taken into the acidic site of gastric parietal cells, Compounds that undergo a structural change to the active form to exert a proton pump inhibitory action may be able to compensate for the shortcomings of existing and developing proton pump inhibitors.
  • the present inventors have conducted intensive studies, and as a result, the 2-sulfinylnicotinamide derivative represented by the formula (I) described below shows a strong proton pump inhibitory action under acidic conditions and is excellent in vivo.
  • the present invention was found to exhibit a gastric acid secretion inhibitory action,
  • the present invention relates to a novel 2-sulfinylnicotine having an excellent gastric acid secretion inhibitory action
  • An object is to provide an amide derivative.
  • Another object of the present invention is to provide a method for producing the compound.
  • an object of the present invention is to provide a pharmaceutical composition containing the compound.
  • an object of the present invention is to provide a novel intermediate which can be used for producing the compound.
  • Ri represents a group represented by the following formula (A), (B) or (C),
  • Ri i is a hydrogen atom, a Ci-C 3 alkyl group, a hydroxy (Ci-C 3 ) alkyl group, a C 2 -C 5 alkanoyloxy (Ci-C 3 ) alkyl group, a methoxy (Ci-C 3 (: 3 ) means an alkoxymethyl group, an aminomethyl group, a mono- or di-substituted aminomethyl group, an amino group or a mono- or di-substituted amino group; R i 2 represents a hydrogen atom or a C i Cg alkyl group,
  • R 1 3 is a hydrogen atom or a C i Cs alkyl group
  • R 14 and R 15 represents a hydrogen atom, the other represents a C i-C 3 alkoxy group or a mono- or di-substituted amino group,
  • R 16 represents a C 3 -C 3 alkyl group
  • R 2 represents a hydrogen atom, C i- (: 3 alkyl group, amino group or mono- or di-substituted amino group,
  • R 3 represents a hydrogen atom or a halogen atom
  • R 4 represents a hydrogen atom or a C 3 alkyl group
  • R 5 is a C-C 3 alkoxy group, a halogeno ((: ⁇ -ji) alkoxy group, a hydroxy
  • R 6 represents a hydrogen atom or a C-C 3 alkyl group
  • R 7 represents a C to C alkoxy group
  • R 8 represents a hydrogen atom
  • R 9 represents a hydrogen atom, a Ci Cs alkyl group or a C 1 to (: 3 alkoxy group, and (ii) when R 4 is a C i Cs alkyl group,
  • R5, R6, R8 and R9 represent a hydrogen atom
  • R 7 represents a C i -C 3 alkoxy group.
  • the present invention also provides a compound of formula (II) useful as an intermediate of the compound of formula (I) (hereinafter sometimes referred to as “intermediate of the present invention”).
  • R R2, R 3: R 4, R 5, R 6, R 7, R 8 and R 9 mean the same as described above.
  • the compound in which R 1 in the formula (I) is a group represented by the formula [C] forms an acid addition salt.
  • the acid addition salt include pharmaceutically acceptable acid addition salts, such as oxalate, maleate, fumarate, lactate, lingate, citrate, tartrate, benzoate, and the like.
  • Organic acid salts such as methanesulfonate are mentioned. Since the compound of formula (I) and the acid addition salt thereof may exist as a hydrate and Z or a solvate, these hydrates and / or solvates are also included in the present invention.
  • the compound of the formula (II) which is an intermediate of the present invention also forms an acid addition salt with the compound of the formula (II) wherein R 1 is a group represented by the formula [c].
  • the acid addition salt include the pharmaceutically acceptable acid addition salts described above.
  • the compound of the formula (I) has a sulfinyl group, at least two kinds of stereoisomers can exist.
  • Compounds of formula (I) may optionally have one asymmetric carbon atom, in which case there may be four stereoisomeric forces 5 '. These stereoisomers, their mixtures and racemates are included in the compounds of the present invention.
  • compounds of formula (II) having one asymmetric carbon atom two stereoisomers may exist.
  • these stereoisomers, their mixtures and racemates are included in the intermediates of the present invention.
  • the compound of the formula (I) is taken up by the secretory tubule of the gastric parietal cell, and the group represented by the following formula R is eliminated.
  • Ci-C3 alkyl group examples include methyl, ethyl, propyl, and isopropyl.
  • C!-(: 3 alkoxy group) examples include methoxy, ethoxy, propoxy, and isopropoxy.
  • Halogen atom means fluorine, chlorine, bromine, and iodine; Chlorine and bromine are preferred.
  • Halogeno (C i ⁇ C alkoxy group) refers to a group substituted with 1 to 3 halogen atoms.
  • C! -C3 alkoxy group for example, chloromethoxy, bromomethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-fluoroethoxy. , 3-chloropropoxy.
  • Specific examples of the “hydroxy (C 2 -C 3 ) alkoxy group” include 2-hydroxyethoxy and 3-hydroxypropoxy.
  • rc Cg alkoxy ((: ⁇ alkoxy group) include methoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, and 3-propoxypropoxy.
  • the “mono- or di-substituted amino group” and the mono- or di-substituted amino moiety mean a group or a moiety represented by the following formula [D].
  • R 17 represents a hydrogen atom or a C] to C 3 alkyl group
  • R 18 represents a c! Cs alkyl group or a hydroxy (C i to C 3 ) alkyl group
  • R your and R 18 may form a 5- to 7-membered hetero atom with an adjacent nitrogen atom
  • the heterocyclic ring may further form a group NR ie (R 16 is a C 1-(: 3 alkyl group) ) May be replaced by a force interrupted by, or by a hydroxy group.
  • Specific examples of the group represented by the above formula [D] include methylamino, ethylamino, propylamino, isopropylamino, 2- (dimethylamino) ethylamino, dimethylaminoethylmethylamino, isopropylmethylamino, and ethylamino.
  • Mino (2-hydroxyxethyl) methylamino, 1-pyrrolidinyl, piberidino, 4-hydroxypiperidino, 1-piperazinyl, 4-methyl-11-piperazinyl, morpholino.
  • the “mono- or di-substituted aminomethyl group” means a methyl group substituted by a group represented by the above formula [D], and specific examples include methylaminomethyl, dimethylaminomethyl, (4-methyl 1-piperazinyl) methyl and (2-hydroxyethyl) methylaminomethyl.
  • more preferred compounds include those represented by the formula (A), wherein R ii is a Ci-C 3 alkyl group, a hydroxymethyl group, a C 2 -C 5 alkanoyloxymethyl group or a dialkyl group.
  • R 12 is a hydrogen atom or a c to C 3 alkyl group
  • R 13 is a hydrogen atom
  • R 14 is c 1 to ( :? a 3 alkoxy group, or an R 1 5 force ⁇ hydrogen atom, or an R 1 4 forces hydrogen atom
  • R 15 is di
  • R i represents a group represented by the following formula [ ⁇ '] or [ ⁇ '];
  • R ii represents a methyl group, a hydroxymethyl group, a C 2 -C 5 alkanoyloxymethyl group or a dimethylamino group
  • R 12 ′ represents a hydrogen atom or a methyl group
  • R 15' R 14 or is a hydrogen atom, or 'a is hydrogen atom, R 15' R 1 4 means Jimechiruamino group.
  • particularly suitable compounds include the following compounds.
  • the compound of the formula (I) can be produced by oxidizing the compound of the formula (II).
  • substituents when showing the structure of each compound, the following substituents,
  • This reaction is carried out by reacting the compound of the formula (II) with an oxidizing agent in a suitable solvent.
  • an oxidizing agent suitable for oxidizing a thio group to a sulfinyl group is used, for example, 3-chloroperbenzoic acid, perbenzoic acid, monoperphthalic acid, peracetic acid, trifluoroperacetic acid, and peroxide. Hydrogen, sodium periodate, sodium benzene, and 3-methyl sodium benzene.
  • the amount of the oxidizing agent to be used is usually about 0.9 to about 2 equivalents based on the type of the compound of the formula (II) or the desired force s , which depends on the type of the compound of the formula (I), the compound UI). It is.
  • the solvent include halogenated hydrocarbons such as methylene chloride salt, methyl form, ethers such as tetrahydrofuran and dioxane, alcohols such as methanol and ethanol, and aromatics such as benzene and toluene. Group hydrocarbons, acetonitrile, and water. These solvents are used alone or in combination of two or more.
  • the reaction temperature is usually about -50 to about 1 O :, preferably about 140 to about 5.
  • the basicity of those groups is considered. It is preferable to carry out the main oxidation reaction while suppressing the temperature.
  • Specific methods for suppressing basicity include, for example, a method in which the present oxidation reaction is performed in the presence of hydrochloric acid, and a method in which a borane-tetrahydrofuran complex is actuated to form a complex with borane.
  • the borane complex after the completion of the reaction is suitably carried out by heating to reflux in an alcohol such as methanol using sodium carbonate, for example.
  • the compound of the formula (II), which is an intermediate of the present invention can be produced, for example, by the following production method (a-1), production method (a-2) or production method (a-3) shown in Chart 1.
  • R la is the same as R 1 described above except that R 11 in the formula (A) is a group other than an aminomethyl group, and R 1, R 2, R 3, R 12, R 13 and
  • R represents the same as described above, X and Y each represent a halogen atom, and n represents 0 or 1.
  • the compound of the formula (IV) or its reactive derivative in the chart 1 and the formula (V) The reaction with the compound of formula (I) is usually carried out in a suitable solvent.
  • Examples of the reactive derivative of the compound of the formula (IV) include an active ester, an acid anhydride, and an acid halide (particularly, acid chloride).
  • Specific examples of the active ester include p-nitrophenyl ester, N-hydroxysuccinic acid imidester, and N-hydroxyphthalimid ester.
  • As the acid anhydride a symmetrical acid anhydride or a mixed acid anhydride is used.
  • Specific examples of the mixed acid anhydride include a mixed acid with an alkyl carbonate such as ethyl ethyl carbonate or isobutyl carbonate.
  • Anhydrides, mixed anhydrides with alkanoic acids such as isovaleric acid and vivalic acid can be mentioned.
  • the solvent to be used should be appropriately selected according to the type of the starting compound, etc., for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as getyl ether, tetrahydrofuran, dioxane, and methylene chloride.
  • Aroma hydrocarbons such as benzene, toluene, and xylene
  • ethers such as getyl ether, tetrahydrofuran, dioxane, and methylene chloride.
  • Halogenated hydrocarbons such as chloroform, ethyl acetate, acetonitrile, pyridine, dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, ethylene glycol, and water. Used in combination of two or more. This reaction is carried out in the presence of a base, if necessary.
  • the base include alkali metal carbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate, sodium carbonate and sodium carbonate, and potassium carbonate.
  • Organic bases such as triethylamine, diisopropylethylamine and N-methylmorpholine.
  • the reaction temperature varies depending on the kind of the starting compound used, etc., usually about 130 to about 100, preferably about 110 to about 80.
  • the compound of the formula (IV) and / or the compound of the formula (V) When present, the compound is reacted in the form of a group that can be easily converted to those groups or in a protected form according to a conventional method, and then the group in the product is converted to the target group. Is preferred.
  • formula (II) when obtaining a compound in which a hydroxy group is present in R, a compound in which a monosubstituted amino group is present in R 1, and / or a compound in which R 2 is a monosubstituted amino group, After performing this reaction using a compound of the formula (IV) in which these groups are protected, it is preferable to remove the protecting groups in the product according to a conventional method.
  • R 1 represents an amino group, a force of a substituted amino group such as Ci ⁇ (: 3 alkylamino group, di (C ⁇ C 3 ) alkylamino group), and / or R 2 Is a substituted amino group such as an amino group, a C 3 -C 3 alkylamino group, or a di (CiCalkylamino group), the corresponding halogeno compound is obtained by this reaction, and then ammonia, C 1- (: 3 alkylamine, di
  • (C i -C 3 ) It can be produced by reacting an alkylamine or the like.
  • Formula 1-hydroxy 3 R 1 is at the 2-position in (II)) alkyl or
  • the 1- (C 2 -C 5 ) alkanoyloxy (4-pyridyl group having a C ⁇ C ⁇ alkyl compound is compound (IV) or its reactive derivative at the 2-position (( ⁇
  • the product After reacting 4-aminopyridine-1-N-oxide having 3 alkyl groups by this reaction, the product is catalytically reduced with palladium carbon, platinum oxide, Raney nickel, etc. Alternatively, it can be produced by subjecting the compound to a reduction reaction with phosphorus trichloride, phosphorus pentachloride, triphenylphosphine, triethyl phosphite, sodium borohydride or lithium aluminum hydride.
  • the starting compound represented by the formula (V) is commercially available or can be produced by a method known per se, for example, by referring to the following textbooks and documents.
  • the starting compound represented by the formula (IV) can be produced, for example, by the method shown in Chart 2 below.
  • R 2 R 3 and R have the same meanings as described above, one of Y, and ⁇ represents a mercapto group, and the other represents a halogen atom.
  • reaction between the compound of the formula (VIII) and the compound of the formula (IX) can be carried out in the same manner as in the production method (a-2) described below.
  • the reaction temperature varies depending on the type of the starting compound and the like, but is usually about 20 to about 150, preferably about 801: to about 120.
  • the leaving group R is 2,4-dimethoxybenzyl, 2,4,
  • a compound having a strong electron donating group such as 6-trimethoxybenzyl, 2,4-dimethoxy-3-methylbenzyl or 1- (4-methoxyphenyl) ethyl
  • the compound represented by the formula (VIII) A compound in which Y ′ is a mercapto group and a compound in which Z is a hydroxy group in the formula (IX) (J. Org. Chem., ⁇ 13013 (1992); Japanese Patent Application Laid-Open No.
  • reaction temperatures are usually from about 0 to about 30.
  • R is a 4-methoxy (2-methoxymethoxy) benzyl group or a 4-methoxy ([2-methoxyethoxy) ethoxy] alkoxyalkoxy or methoxyalkoxyalkoxy group such as a benzyl group
  • the corresponding hydroxyalkoxy compound such as a compound in which R is 2—hydroxyethoxy-14-methoxybenzyl group in the formula (IV) is added to a base in an appropriate solvent.
  • a halogenoalkane or a halogenoalkylalkyl ether in the presence of Specific examples of the solvent, Tet Rahi Dorofuran, methylene chloride, black hole Holm, toluene, dimethylformamidine de, N- Mechirupirori Don force ?, Exemplary bases, Toryechiruami down, Jie isopropyl E chill ⁇ Mi emissions , Sodium hydride and potassium carbonate.
  • the reaction temperature is usually about 0 to about 3O.
  • the starting compound in which Y ′ is a mercapto group in the formula (VIII) is commercially available or is produced according to the method described in Eur. J. Med. Chem.- Chim. Ther., 20, 61 (1985). can do.
  • the raw material compound in which Y ′ is a halogen atom can be commercially available or can be produced by the method described in Reference Example 9.
  • the starting compound in which Z is a halogen atom in the formula (IX) is commercially available Or a method according to the method described in JP-A-58-77841.
  • the starting compound in which ⁇ is a mercapto group can be produced according to the method described in Reference Example 25 below.
  • the reaction between the compound of the formula (VI) and the compound of the formula (VII) in Chart 1 is usually performed in a suitable solvent in the presence of a base.
  • a base include alkali carbonates such as sodium carbonate and potassium carbonate, quaternary hydroxyammonium such as tetrabutylammonium hydroxide, benzyltriethylammonium hydroxide, sodium methoxide, and sodium ethoxide.
  • alkali metal hydrides such as sodium hydride and potassium hydride.
  • the solvent to be used should be appropriately selected according to the starting compound, the type of base, etc., for example, methylene chloride, acetone, acetonitrile, methanol, ethanol, isopropyl alcohol, diglyme, dimethylformamide, N-methylpyrrolidone and These mixtures are mentioned.
  • the reaction temperature varies depending on the type of the starting compound used and the like, and is usually about 30 to about 150, preferably about 80 X to about 120 X :.
  • the starting compound represented by the formula (VII) is the same as the compound in which Z is a mercapto group in the formula (IX) in Chart 2 described above, and the production method thereof has already been described.
  • the starting compound represented by the formula (VI) can be produced in the same manner as in the production method (a-1) except that the compound (VIII) is used in place of the compound (IV) as one of the starting materials, Can be produced by reacting
  • R i is the formula [A]
  • R 11 is an aminomethyl group, a mono- or di-substituted aminomethyl group, an amino group or a mono- or di-substituted amino group.
  • R 19 represents an amino group or a mono- or di-substituted amino group, and R 2, R 3, R 12, R 13, R and n have the same meanings as described above.
  • R 19 represents a phthalimid group or a mono- or di-substituted amino group.
  • R 19 is a phthalimid group
  • the product is further reacted.
  • This reaction is performed in a suitable solvent in the presence of a base.
  • the solvent include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran and dioxane, alcohols such as methanol and ethanol, and aromatics such as benzene and toluene. Group hydrocarbons, acetonitrile, acetone, pyridine, dimethylformamide, and water. These solvents are used alone or in combination of two or more.
  • the reaction temperature is usually about 0 to about 20 °, preferably about 10 to about 10 ox :.
  • the base those described in the above-mentioned production method (a) can be used as they are.
  • R 19 is a phthalimid group
  • the hydrolysis can be carried out according to a conventional method, for example, by contacting with water in a suitable solvent under basic conditions.
  • a suitable solvent for example, alcohols such as methanol, ethanol, and isopropanol, dioxane, water, or a mixture thereof is used.
  • the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, sodium carbonate, and aluminum carbonate such as lithium carbonate.
  • the reaction temperature is usually about 20 ° C to 1 oot :.
  • the decomposition reaction using hydrazine is carried out, for example, in an alcohol such as methanol, ethanol, or isopropanol, or in a solvent such as tetrahydrofuran, acetate nitrile, acetone, or dimethylformamide in the presence of hydrazine at about 30. Done at ⁇ 8 ot :.
  • the compound of the formula (1-1) may be obtained by using a commercially available compound or a raw material compound produced by a method known per se, using the production method (a-1) or (a-2) and the production method
  • the compound of formula (III) can be prepared by reacting the compound of formula (I) in a suitable solvent under acidic conditions. It can be manufactured by responding.
  • a suitable solvent for example, alcohols such as methanol, ethanol, and isopropanol, dioxane, water, or a mixture thereof is used.
  • Specific examples of the acid include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as formic acid and acetic acid.
  • the reaction temperature is usually about 20 to about 100.
  • the compound produced by each of the above production methods is isolated and purified by a conventional method such as chromatography, recrystallization, and reprecipitation.
  • a conventional method such as chromatography, recrystallization, and reprecipitation.
  • the compound (I) of the present invention is shown in the following Example No., omeprazole (compound A) was used as a control compound, and the following compound was used as a closed-ring form (III).
  • the ⁇ +, ⁇ + - ⁇ ase inhibition activity of the test compound was measured both under the condition without acid treatment and after the acid treatment.
  • a microsomal fraction was prepared from pig fundic gland and used as an enzyme preparation in this test.
  • ⁇ +, ⁇ + For measurement of ATPase activity, 50 mM Tris-HCl (pH 7.4), 4 mM magnesium chloride, 5 // g / m 1 gramicidin, 2 mM ATP (adenosine triphosphate) '2 sodium, test The reaction was performed in a 1.Oml reaction solution containing or not containing the compound and 20 mM potassium chloride.
  • an enzyme preparation (10-20 / g protein) and a test compound were reacted at 37 for 30 minutes, followed by addition of a substrate, ATP ⁇ 2 sodium, for 20 minutes. The reaction was then stopped by adding 1 ml of 16% triclomouth acetic acid solution and centrifugation
  • the concentration of inorganic phosphorus in the supernatant was determined according to the method of Sanui [Anal. Biochem., 60,489-504 (1974)].
  • H + and K + -ATPase activity values were determined from the difference between the activities in the presence and absence of potassium chloride.
  • the inhibition rate was determined from the control activity value and the activity value at each concentration of the test compound, and the 50% inhibitory concentration (IC 50 ) was calculated.
  • the acid treatment was performed by reacting the test compound in 0.1 N hydrochloric acid at 37 for 30 minutes. After the acid treatment, the same amount of 100 mM Tris-HCl buffer (pH 7.5) was added to the solution containing the test compound, and the H +, K +-ATPase inhibitory activity was measured in the same manner as described above.
  • test compound was used after dissolving in dimethyl sulfoxide, and the final concentration of dimethyl sulfoxide in the enzyme reaction was 1%.
  • Example 1 Means the compound of Example 1 (hereinafter also means the compound of Example).
  • Compound ⁇ which is a closed ring, exhibited strong proton pump inhibitory activity under untreated conditions, and this inhibitory activity was not changed by acid treatment.
  • the tested compounds of the present invention exhibited the expression or enhancement of the proton pump inhibitory activity after the acid treatment as compared with the untreated condition.
  • parietal cells isolated from the heron fundic gland were used in this test according to the method of Fryklund et al. [Biochem. Pharmacol., 33, 273-280 (1984)].
  • the acid-forming ability of parietal cells was determined from the incorporation of [14C] -aminopirin into cells according to the method of Nagaya et al. Pharmacol. Exp. Ther., 24 ⁇ 1289-1295 (1989)].
  • the inhibition rate was determined from the incorporation amount of [14 C] -aminopyrine into cells in the control and the incorporation amount at each concentration of the test compound, and the 50% inhibition (IC 50 ) was calculated. Table 2 shows the results. Table 2
  • Example 1 Means the compound of Example 1 (hereinafter also means the compound of Example). As is evident from Table 2, most of the tested compounds (I) of the present invention exhibited acid formation inhibitory activity in isolated wall cells equivalent to that of omebrazole (compound A). The remaining compounds also showed a distinct but weaker acid formation inhibitory activity than omebrazole.
  • Test Example 3 Inhibition of gastric acid secretion by pyloric ligation rat (in vivo)
  • test compound (3 O mg / kg) was administered subcutaneously, and three hours later, the stomach was removed and gastric juice was collected, and the volume and acid concentration were measured. Acid concentration was calculated from the amount of sodium hydroxide required for neutralization (pH 7.0), and gastric acid excretion was expressed as the product of the solution volume and the acid concentration.
  • the test compound is dissolved or suspended in 0.5% tragacanth suspension for intraduodenal administration, and glycerol formal for intravenous administration.
  • the inhibition rate (%) was determined from the gastric acid excretion in the control group and the gastric acid excretion in each of the groups administered with each dose of the test conjugate. Table 3 shows the results.
  • Example 1 Refers to the compound of Example 1 (hereinafter also referred to as the compound of Example). : Only the compounds of Examples 1 5 2 7 and 4 7 were administered intravenously. All compounds were administered intraduodenally.
  • microsomal fraction was purified from rat liver according to the method of Reiners et al. [Anal. Biochem., Breath 317-324 (1990)], and this fraction was used as an enzyme preparation for 7_ethoxycoumarin-0-deacetyl. The inhibitory effect of the compounds on the activation activity was measured.
  • This activity was measured using 10 mM tris-HCl ( ⁇ 7.8), 1 mM NADP (/? _ Nicotinamide adenosine dinucleotide phosphate), 5 mM magnesium sulfate, 6 mM glucose-16-phosphate, 0 mM
  • the reaction was performed in a 1.0 ml reaction solution containing 2 mg / ml ⁇ serum albumin, 2 units / ml glucose-16-phosphate dehydrogenase, and 0.1 mM 7-ethoxycoumarin.
  • the enzyme preparation (about 8 Og protein) and the test compound were allowed to stand at 37 for 10 minutes, and then 7-ethoxycoumarin as a substrate was added and reacted for 20 minutes. Then, the reaction was stopped by adding 0.5 ml of a cooled 5% trichloroacetic acid solution. After removing the precipitated protein by centrifugation (3,000 rpm, 10 minutes), add 1.8 ml of 1.6 M glycine solution (pH 10.3) to 0.9 ml of the supernatant, and perform fluorescence detection (excitation wavelength 365 7-Hydroxycoumarin was quantified by nm, fluorescence wavelength 455 nm).
  • the 7-ethoxycoumarin-0-deethylation activity value was determined from the amount of 7-hydroxycoumarin produced by the reaction.
  • the inhibitory rate was determined from the control activity value and the activity value at each test compound, and the 50% inhibitory concentration (IC 50 ) was calculated.
  • the test compound used in this test was dissolved in dimethylformamide and used, and the final concentration of dimethylformamide in the reaction solution was 0.1%. Table 4 shows the results. Table 4
  • Test Example 5 Acute toxicity
  • Acute toxicity tests were performed on the compounds of Examples 1, 2, 10, 17, and 69a using six Std-ddy male mice (body weight, 26 to 31 g) in each group.
  • 2% carbonic acid Test compound 3 O OmgZkg or lOOOmgZkg suspended in 1% carboxymethylcellulose (CMC) containing sodium hydrogen was administered orally, and death was observed for 7 days after administration.
  • the compound of the present invention represented by the formula (I) has a strong gastric acid secretion inhibitory action, mainly based on the inhibitory action of protonpump, and has a low toxicity. It can be used for the treatment and prevention of peptic ulcers such as gastric cysts, duodenal ulcers, reflux esophagitis, Zollinger-Ellison syndrome, anastomotic gastric ulcers, gastritis and related diseases and symptoms.
  • peptic ulcers such as gastric cysts, duodenal ulcers, reflux esophagitis, Zollinger-Ellison syndrome, anastomotic gastric ulcers, gastritis and related diseases and symptoms.
  • the administration route of the compound (I) of the present invention may be any of oral administration, parenteral administration and rectal administration, but oral administration is preferred.
  • the compound (I) of the present invention is usually administered in the form of a preparation prepared by mixing with a preparation carrier.
  • a preparation carrier a substance that is commonly used in the pharmaceutical field and that does not react with the compound of the present invention is used.
  • lactose glucose, mannitol, dextran, starch, partially alpha-monostarch, sucrose, magnesium metasilicate aluminate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, Carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum Arabic, hydroxypropylcellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid , Sodium alginate, Light caffeic anhydride, Magnesium stearate-talc, Carboxyvinyl polymer, Titanium oxide, Sorbi Examples include tan
  • Dosage forms include tablets, capsules, granules, powders, syrups, opacifiers, suppositories, injections and the like. These preparations are prepared according to a conventional method. In the case of liquid preparations, they may be dissolved or turbid in water or other suitable medium at the time of use. Tablets and granules may be coated by well-known methods.
  • preparations can contain the compound of the present invention in an amount of 0.5% or more, preferably 10 to 70%.
  • preparations may also contain other therapeutically active ingredients, for example, protective factor enhancers such as teprenone and sulpiride. It can also be used in combination with the above-mentioned protective factor enhancer.
  • Ph-2,4,6- (OMe) 3 is a 2,4,6-trimethoxyphenyl group
  • Ph-2-OCH 2 OMe-4-OMe is 2- represents a 4-methoxymethoxy group.
  • Example 1 Same as Example 1 except that 2-([2,4-dimethoxybenzyl) thio] —N— (2,6-dimethyl-4-pyridyl) nicotinamide in Example 1 was replaced with the corresponding raw material compound To give the compounds shown in Table 5 below.
  • Example 10 was repeated using the corresponding starting compound instead of 2-[(2,4-dimethylmethoxybenzyl) thio] -N- (2-dimethylamino-4-pyridyl) nicotinamide in Example 10.
  • the reaction and treatment are performed in the same manner to obtain the compounds shown in Table 6 below.
  • N— (2-dimethylamino-1-pyridyl) -1-2-[[2- (2-hydroxylethoxy) -14-methoxybenzyl] sulfinyl] nicotinamide 2-[(2 , 4 dimethoxybenzyl) thio] —N— (2-dimethylamino-41-pyridyl) nicotinamide instead of N— (2-dimethylamido)
  • Example 7 Same as Example 1 except that 2-[(2,4-dimethoxybenzyl) thio] -N- (2,6-dimethyl-4'-pyridyl) nicotinamide used in Example 1 was replaced with the corresponding starting compound. To give the compounds shown in Table 7 below. Table 7
  • the residue is subjected to basic silica gel column chromatography, eluted and purified with n-hexane monochloroform (1: 1), and the residue is recrystallized from acetonitrile to obtain 0.8 g of the desired product.
  • Example 3 Example 2 was repeated using the corresponding raw material compound instead of 2 — [(2,4-dimethoxybenzyl) thio] —N— (4-methoxy-3-pyridyl) nicotinamide in Example 2. The reaction and treatment were carried out in the same manner as in 2 to obtain the compounds shown in Table 8 below.
  • Example 2 was repeated except that 2-[(2,4-dimethoxybenzyl) thio] —N— (2,6 dimethyl-1-41-pyridyl) nicotinamide in Example 1 was replaced with the corresponding starting material. The same reaction and treatment are performed to obtain the compounds shown in Table 9 below.
  • Example 1 Using 2-([2,4-dimethoxybenzyl) thio] -N- (2,6-dimethyl-4-pyridyl) nicotinamide in Example 1 instead of the corresponding starting compound, the reaction was carried out in the same manner as in Example 1. ⁇ Treat to obtain the compound shown in Table 11 below.
  • the reaction mixture was reduced under reduced pressure, and the residue was subjected to medium pressure ram chromatography using Diaion CHP-20P (trademark) [high-porous polystyrene resin (75 to 150 m), Mitsubishi Kasei].
  • Diaion CHP-20P trademark
  • high-porous polystyrene resin 75 to 150 m
  • Mitsubishi Kasei Mitsubishi Kasei
  • Example 69 (a) The corresponding compounds are reacted and treated in the same manner as in Example 69 (a) to obtain the following compounds.
  • Example 7 After diastereomer A was eluted by chromatography in 5, elution was carried out with a mixture of chloroform-methanol (10: 1), the eluate was reduced under reduced pressure, and the residue was recovered from getyl ether. Recrystallization affords 0.72 g of the desired product.
  • Example 7 The corresponding raw material compound was used in place of 2,6-dimethyl-1-4- [2-[(2,4-dimethoxybenzyl) thio] nicotinylylamino] pyridine-N-oxide in Example 9. The reaction is performed in the same manner as in 79 to obtain the compound shown in Table 13 as crystals.
  • Example 88 Using the corresponding starting compounds in place of the 4-amino-12-dimethylaminopyridine in Example 88, the reaction and treatment were carried out in the same manner as in Example 88 to obtain the compounds shown in Table 14.
  • the compounds of Examples 89 and 90 are crystals, and the other compounds are oils.o Table 14
  • Example 95 Same as Example 95 except that the corresponding raw material compound was used instead of 4- [2-[(2,4-dimethoxybenzyl) thio] nicotinoylamino] -2-methylpyridine-1-N-oxide in Example 95 to give the compound shown in Table 15 below.
  • the compound of Example 96 was a crystal, and the other compounds were oils. Table 15
  • Example 95 The same procedure as in Example 95 was carried out except that propionic anhydride was used instead of acetic anhydride in Example 95, to obtain the desired product as an oil.
  • Example 102 In place of N- (2-acetoxymethyl-14-pyridyl) -1-[(2,4-dimethoxybenzyl) thio] nicotinamide in Example 102, the corresponding raw material compound was used. In the same manner, the reaction was carried out, and the compound represented by the following Table 16 was referred to as the mouth.
  • Example 110 Using the corresponding starting compounds in place of 4-methoxy-13-aminopyridine in Example 110, the reaction was carried out in the same manner as in Example 110 to obtain the compounds represented by the following Table 17 as crystals. .
  • Example 114 The reaction and treatment were carried out in the same manner as in Example 114 using methylamine in place of the aqueous ammonia in Example 114 to obtain the desired product as an oil.
  • Example 116 Using 2-methylaminoethanol in place of 2-aminoethanol in Example 116, the reaction and treatment were carried out in the same manner as in Example 116 to obtain the desired product as an oil.
  • Example 1 Compound of 1 2 2-[(2,4-Dimethoxybenzyl) thio] _ 6— [N- (2-hydroxyxethyl) methylamino] 1 N— (4-pyridyl) nicotinamide 1. O g A mixture consisting of 3.Om 3 of acetic anhydride and 3.Oml of pyridine is stirred at room temperature for 12 hours. After concentrating the solvent under reduced pressure, extract twice with 100 ml of chloroform. The extract is washed twice with 5 Om 1 of saturated saline, dried over magnesium sulfate, and then dried. The residue was subjected to silica gel column chromatography, and eluted with chloroform-methanol (50: 1). Purification gave 0.65 g of the desired product as an oil.
  • Example 1 6-Chloro-2-([2,4 dimethylbenzyl) thio] -N- (4-pyridyl) nicotinamide in place of 6-Chloro-2-([2,4 -Dimethoxybenzyl) thio] -1-5-N- (4-pyridyl) nicotinamide was reacted and treated in the same manner as in Example 119 to obtain the desired product as crystals.
  • Example 120 4-Piberidinol was used in place of N-methylethanolamine in Example 120, and the reaction was carried out in the same manner as in Example 120 to obtain the desired product as crystals.
  • Example 13-1 The reaction was carried out in the same manner as in Example 13-1, except that the corresponding starting compound was used in place of 2-[(2,4-dimethoxybenzyl) thio] nicotinic acid in Example 131, and the reaction was treated. Is obtained.
  • Example 132 was a crystal, and the other compounds were oils.
  • Example 13 instead of 4-aminoviridine in 31-1, 3-amino-6- (4-methyl-1-piperazinyl) pyridine synthesized according to the method described in JP-A-57-48967 was used. The reaction and treatment were conducted in the same manner as in 131 to obtain the desired product as an oil.
  • Example 120 Using 4-methyl-1-piperazine instead of N-methylethanolamine in Example 120, the reaction and treatment were carried out in the same manner as in Example 120 to obtain the desired product as an oil.
  • the extract is washed with water, dried over magnesium sulfate, and concentrated.
  • the residue is purified by silica gel column chromatography.
  • the residue was purified by elution with chloroform-methanol (10: 1) and purified to give 4.2 g of the desired product as an oil.
  • Example 1 In place of 2-[(2,4-dimethoxybenzyl) thio] nicotinic acid in 31, 2-[[1- (4-Methoxyphenyl) ethyl] thio] nicotinic acid was used. The reaction is carried out in the same manner as 31 to obtain the desired product as an oil.
  • Example 9 In place of 4- [2-((2,4-dimethoxybenzyl) thio] nicotinoylamino] -1-methylpyridine-1-N-oxide in 5, 4-[[2- [1-(4- [Methoxyphenyl) ethyl] thio] nicotinylamino] -12-methylpyridine-1-N-oxide was reacted and treated in the same manner as in Example 95 to obtain the desired product as an oil.
  • the extract is extracted twice with 100 ml of chloroform, washed twice with 20 ml of saturated saline, dried over magnesium sulfate and concentrated. The residue is subjected to silica gel column chromatography, and eluted and purified with chloroform-methanol (40: 1) to obtain 3.2 g of the desired product.
  • the starting compound 4-amino-2-methylpyridine-1-N-oxide is synthesized according to the method described in 0.0. C. 26 2740 (1961).
  • the starting compound 4-amino-13-methylpyridine-1-N-oxide is synthesized according to the method described in Pharmaceutical Journal, 75, 292 (1955).
  • the starting compound 4-amino-12-methylpyridine-1-N-oxide is synthesized according to the method described in J.O.C., 26, 2740 (1961).
  • the desired product is obtained by reaction and treatment using 2,5-dimethylviridine according to the method described in Pharmaceutical Journal, 2 292 (1955).
  • Example 147 The same procedure as in Example 147 was carried out using N- (2-bromo-14-pyridyl) -12-cloniconicotinamide to obtain the desired product.
  • the starting compound 2,6-dichloro-5-fluoronicotinic acid is synthesized according to the method described in Japanese Patent Application Laid-Open No. 172753/1986.
  • the starting compound 2,4,6-trimethoxybenzyl alcohol is synthesized according to the method described in J. Org. Chem., 513013 (1992).
  • the starting compound 11- (4-methoxyphenyl) ethyl alcohol is synthesized according to the method described in JP-A-58-77841.
  • the target product is obtained by reacting and treating in the same manner as in Reference Example 19 except that butyl bromide is used in place of the acetic acid 2-chloroethyl ester of Reference Example 19.
  • the extract is washed twice with 30 ml of saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. 400 ml of methanol and 60 ml of a 1 N aqueous solution of sodium hydroxide are added to the residue, and the mixture is heated under reflux with stirring for 1 hour. After cooling, neutralize with 1 N hydrochloric acid and compress under reduced pressure. The residue is extracted twice with 200 ml of chloroform, and the extract is washed twice with 40 ml of saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 7.4 g of the desired product.
  • Example 1 was repeated using the corresponding nicotinamides in place of 2-([2,4-dimethoxybenzyl) thio] —N— (2,6-dimethyl-14-pyridyl) nicotinamide in Example 1.
  • the reaction is performed in the same manner as described above to obtain the following compound.
  • the above components are mixed, granulated, and compression-molded to prepare a tablet core of 150 mg per tablet and 1,000 tablets. Then, use methacrylic acid 'acrylic acid. Copolymer, polyethylene glycol 6000, twin 80 and talc. The skin is coated according to the usual method to make enteric-coated tablets.
  • the above components are mixed and granulated to prepare a 10% powder.
  • the compound of the present invention represented by the formula (I) has an excellent gastric acid secretion inhibitory action based on a proton pump inhibitory action and has a low toxicity, and therefore, as a therapeutic agent for peptic ulcer, gastric ulcer, duodenal ulcer, reflux It can be used for the prevention and treatment of esophagitis, Zollinger-miison syndrome, anastomotic ulcer, gastritis, etc. Further, the intermediate of the present invention represented by the formula (II) is useful as a synthetic intermediate for the compound of the formula (I).

Abstract

Cette invention se rapporte à des dérivés de 2-sulfinylnicotinamide représentés par la formule générale (I), qui ont une excellente action de suppression de la sécrétion de l'acide chlorhydrique gastrique et qui sont utiles comme remède contre l'ulcère peptique, ou à des sels d'addition d'acide de ces dérivés, qui sont acceptables sur le plan pharmaceutique. Dans la formule (I), R1 représente un groupe représenté par la formule générale [A], [B] ou [C], et les autres substituants R?2, R3, R4, R5, R6, R7, R8, R9, R11, R12, R13, R14, R15 et R16¿ sont chacun définis dans les pièces descriptives de l'invention.
PCT/JP1996/000512 1996-03-04 1996-03-04 Derives de 2-sulfinylnicotinamide, intermediaire de ces derives, procede pour produire ces derives et composition medicinale contenant ces derives comme ingredient actif WO1997032854A1 (fr)

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AU48451/96A AU4845196A (en) 1996-03-04 1996-03-04 2-sulfinylnicotinamide derivatives, intermediate thereof, process for producing 2-sulfinylnicotinamide derivatives, and medicinal composition containing the same as active ingredient

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6492396B2 (en) 2000-05-16 2002-12-10 Cephalon, Inc. Substituted thioacetamides
US6852739B1 (en) 1999-02-26 2005-02-08 Nitromed Inc. Methods using proton pump inhibitors and nitric oxide donors
US6919367B2 (en) 2000-05-16 2005-07-19 Cephalon, Inc. Substituted thioacetamides
US7211590B2 (en) 2002-08-01 2007-05-01 Nitromed, Inc. Nitrosated proton pump inhibitors, compositions and methods of use
WO2009105568A1 (fr) 2008-02-20 2009-08-27 The Curators Of The University Of Missouri Composition comprenant une combinaison d'oméprazole et de lansoprazole, et un agent tampon, et ses méthodes d'utilisation
EP2486910A2 (fr) 2006-10-27 2012-08-15 The Curators Of The University Of Missouri Appareil comprenant plusieurs chambres et une tête de distribution

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05221994A (ja) * 1991-11-22 1993-08-31 Basf Ag 酸アニリド誘導体およびこれを使用するボトリティス菌の防除方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05221994A (ja) * 1991-11-22 1993-08-31 Basf Ag 酸アニリド誘導体およびこれを使用するボトリティス菌の防除方法

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6852739B1 (en) 1999-02-26 2005-02-08 Nitromed Inc. Methods using proton pump inhibitors and nitric oxide donors
US7332505B2 (en) 1999-02-26 2008-02-19 Nitromed, Inc. Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use
US6492396B2 (en) 2000-05-16 2002-12-10 Cephalon, Inc. Substituted thioacetamides
US6919367B2 (en) 2000-05-16 2005-07-19 Cephalon, Inc. Substituted thioacetamides
USRE39575E1 (en) * 2000-05-16 2007-04-17 Cephalon, Inc. Substituted thioacetamides
US7268132B2 (en) 2000-05-16 2007-09-11 Cephalon, Inc. Substituted thioacetamides
US7211590B2 (en) 2002-08-01 2007-05-01 Nitromed, Inc. Nitrosated proton pump inhibitors, compositions and methods of use
EP2486910A2 (fr) 2006-10-27 2012-08-15 The Curators Of The University Of Missouri Appareil comprenant plusieurs chambres et une tête de distribution
WO2009105568A1 (fr) 2008-02-20 2009-08-27 The Curators Of The University Of Missouri Composition comprenant une combinaison d'oméprazole et de lansoprazole, et un agent tampon, et ses méthodes d'utilisation

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