WO1997032854A1 - 2-sulfinylnicotinamide derivatives, intermediate thereof, process for producing 2-sulfinylnicotinamide derivatives, and medicinal composition containing the same as active ingredient - Google Patents

Abstract

2-Sulfinylnicotinamide derivatives represented by general formula (I), having an excellent effect of suppressing gastric hydrochloric acid secretion, and are useful as a remedy for peptic ulcer, or pharmaceutically acceptable acid-addition salts thereof. In said formula, R1 represents a group represented by the general formula [A], [B] or [C] and other substituents R?2, R3, R4, R5, R6, R7, R8, R9, R11, R12, R13, R14, R15 and R16¿ are each as defined in the specification.

Description

 Specification

TECHNICAL FIELD 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 Η +, 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.

Branch surgery

Tetrahedron Letters, 2153-156 (1992) states that 2- (benzyl) sulfinyl-N- (phenyl) nicotinamide and 2- (benzyl) sulfinyl-N- (4-methoxyphenyl) nicotinamide each contain 2 - phenylene Lou and 2- (4-menu Tokishifue sulfonyl) one [5, 4-b] force may be used as a synthetic intermediate one pyridinium Doisochiazoron disclosed ^s, with respect to its own efficacy Is not described at all.

 JP-A-5-32631 (= EP-A-48025) discloses a 2-mercaptonicotinic acid derivative represented by the following formula, which is useful as an internal parasite control agent. It is stated that

(In the formula, 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 (= US Pat. No. 5,339,955) 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.

 (Wherein 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. )

In recent years, the number of peptic ulcer patients such as gastric ulcer and duodenal ulcer has increased due to the complication of social life and the advent of an aging society. Excess gastric secretion has been considered as a major growth factor for peptic潰癌, Hisuta Mi emissions H ₂ receptor antagonists in the treatment, anticholinergic agents, Gastric acid secretion inhibitors such as Η +, K +-ATPase (hereinafter sometimes referred to as “proton pump”) inhibitors are used. Currently available proton pump inhibitors are omebrazole (see, for example, Merck Index, 1st edition, 6800 (1989)) and lansobrazole (for example, Drugs Fut., 14, 625 (1989); ibid. 665 (1991). Reference]. All of these are 2-sulfinylbenzimidazole derivatives, which are enzymes involved in the final stage of gastric acid secretion, after being taken up by acidic sites (secretory tubules) of gastric parietal cells, undergoing a structural change to an active form by acid. It is said that the enzyme reacts with a cysteine residue of a proton pump to inactivate the enzyme. This mechanism of action is thought to lead to the strong gastric acid secretion inhibitory effect of these drugs, high tissue selectivity and, consequently, few side effects.

 However, existing proton pump inhibitors also have some disadvantages, such as affecting drug metabolism, and are not always satisfactory. At present, several types of 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.

Disclosure of the invention

 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,

7C completed

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. Furthermore, an object of the present invention is to provide a pharmaceutical composition containing the compound. Furthermore, an object of the present invention is to provide a novel intermediate which can be used for producing the compound. These and other objects and advantages will be apparent to those skilled in the art from the description below.o

 According to the present invention, there is provided a 2-sulfinylnicotinamide derivative represented by the following formula (I) or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutical composition containing the same.

 Wherein Ri represents a group represented by the following formula (A), (B) or (C),

 [A] [B] [C]

Here, 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,

One of 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,

 (i) When R is a hydrogen atom,

R 5 is a C-C ₃ alkoxy group, a halogeno ((: 丄 -ji) alkoxy group, a hydroxy

A (C ₂ -C ₃ ) alkoxy group, a C! Cs alkoxy (C i Cs) alkoxy group or a (j-j ^ alkoxy (C ^ C alkoxy (C ₂ -C ₃ ) alkoxy group)

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”).

 (Wherein, 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. Examples of 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]. Examples of the acid addition salt include the pharmaceutically acceptable acid addition salts described above. Expression

 Since the compound of (II) and the acid addition salt thereof may exist as a hydrate and / or a solvate, these hydrates and / or solvates are also included in the present invention.

Since 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. In the case of compounds of formula (II) having one asymmetric carbon atom, two stereoisomers may exist. Thus, 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.

(In the formula, R 4, R 5, R 6, R 7, R 8 and R 9 have the same meanings as described above.) The compound is converted into a compound represented by the following formula (III) to inhibit the proton pump inhibitory action. It is considered to be expressed. Depending on the kind of the compound is sometimes compound of formula (I) per se exhibits a proton Bonn flop inhibitory action force, even in this case, are generated force ^s' confirmation of the compound of formula (III) after acid treatment Therefore, after being taken into the secretory canaliculus, the formula

It is considered that the compound is converted into the compound (III) to exhibit a proton pump inhibitory action.

(Wherein, R i: R ² and R 3 mean the same as described above.)

 The terms used in this specification are described below.

Specific examples of the "Ci-C3 alkyl group" include methyl, ethyl, propyl, and isopropyl. Specific examples of “C!-(: ₃ alkoxy group) 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. Specific examples of rc Cg alkoxy ((: じ alkoxy group) include methoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, and 3-propoxypropoxy. Specific examples of “((: 丄 -di) alkoxy (C i Cs) alkoxy (C _2- (: ₃ ) alkoxy group”) include 2-methoxyethoxyethoxy, 2- (2-methoxyethoxy). Ethoxy, 2- (2-ethoxyethoxy) ethoxy, 2- (methoxymethoxy) propoxy, 3- (2-methoxyethoxy) propoxy 0

 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].

 -N (R I?) (R 18) (D)

[Wherein, 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, or R your and R 18 may form a 5- to 7-membered hetero atom with an adjacent nitrogen atom, and 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.

. Specific examples of the "human Dorokishi (Ci C alkyl group", the human Dorokishimechi Le, 1-arsenide Dorokishechiru include 1 over hydroxycarboxylic propyl "C 2 to C ₅ alkanoyloxy Noi Ruo carboxymethyl (C i to (: ₃ ) Specific examples of the `` alkyl group '' include acetoxmethyl, propionyloxymethyl, butyryloxymethyl, norreloxymethyl, 1-acetoxicetyl, 1-propionyloxyxethyl, and 1-acetoxipyl pill. .

Among the compounds of the present invention represented by the formula (I), compounds wherein R i is the formula [A] or [B] and R ⁴ is a hydrogen atom are preferred.

Among them, 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.

(C) to C ₃ ) an alkylamino group, R 12 is a hydrogen atom or a c to C ₃ alkyl group, R 13 is a hydrogen atom, and in the formula (B), R 14 is c 1 to ( :? a ₃ alkoxy group, or an R 1 5 force ί hydrogen atom, or an R 1 4 forces hydrogen atom, R 15 is di

Compounds that are (C i -C ₃ ) alkylamino groups are exemplified. Among these compounds, more preferred compounds include those in which R ⁵ and R ⁷ are the same or different and each is a methoxy group or an ethoxy group, and R 6, R ⁸ and R ⁹ are hydrogen atoms. . Still more preferred compounds among the compounds of the present invention (I), and a 2-sulfinyl nicotinamidine de derivative represented by the following formula (1,) _c

 (Wherein, R i, represents a group represented by the following formula [Α '] or [Β'];

 [Α '] [Β']

Here, 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,

'The eyes butoxy group, R 15' R 14 or is a hydrogen atom, or 'a is hydrogen atom, R 15' R 1 ⁴ means Jimechiruamino group. )

 Specific examples of particularly suitable compounds include the following compounds.

 2-[(2,4-Dimethoxybenzyl) sulfinyl] — N— (2-Methyl-1-4-pyridyl) nicotinamide,

 2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— (2,5-Dimethyl-1-41-pyridyl) nicotinamide,

2 — [(2,4-dimethoxybenzyl) sulfinyl] 1 N— (3-methyl-2-dimethylamino 1-41 pyridyl) nicotinamide, N— (2-acetoxymethyl-4-pyridyl) -1-2 — [(2,4-dimethoxybenzyl) sulfinyl] nicotinamide,

 N- (2-Acetoxymethyl-3-methyl-4-pyridyl) -1-2-[(2,4-Dimethoxybenzyl) sulfinyl] nicotinamide,

 N— (6-acetoxymethyl-2-methyl-14-pyridyl) 1 2— [(2, 4

—Dimethoxybenzyl) sulfinyl] nicotinamide,

 2 — [(2,4-Dimethoxybenzyl) sulfinyl] 1 N— (2—Propionyloxymethyl_4-pyridyl) nicotinamide,

 N— (2-butyryloxymethyl-1-4-pyridyl) 1-2 — [(2,4-dimethoxybenzyl) sulfinyl] nicotinamide,

 2 — [(2,4-Dimethoxybenzyl) sulfinyl] 1 N— (2—valeryloxymethyl-1-41 pyridyl) nicotinamide,

 2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— (2-Methyl-6-propionyloxymethyl-4-pyridyl) nicotinamide,

 2 — [(2,4-Dimethoxybenzyl) sulfinyl] -1-N— (2-hydroxymethyl-4-pyridyl) nicotinamide,

 2-[(2,4-Dimethoxybenzyl) sulfinyl] -N- (2-Hydroxymethyl-3-methyl-1-4-pyridyl) nicotinamide,

 2 — [(2,4-Dimethoxybenzyl) sulfinyl] -1-N— (6-hydroxymethyl-2-methyl-1-4-pyridyl) nicotinamide,

 2 — [(2,4-Dimethoxybenzyl) sulfinyl] -1-N— (4-Methoxy-13-pyridyl) nicotinamide, and

 2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— (6-dimethylamino-3-pyridyl) nicotinamide.

Specific examples of the most preferable compounds include the following compounds. 2 — [(2,4-Dimethoxybenzyl) sulfinyl] 1 N— (2,6-Dimethyl-4-4-pyridyl) nicotinamide, and

 2-[(2,4-Dimethoxybenzyl) sulfinyl] —N— (2-Dimethylamino-4-pyridyl) nicotinamide.

 Specific examples of the compound included in the compound (I) of the present invention include the following compounds in addition to the compounds of Examples described later.

 2 — [(2,4-Dimethoxybenzyl) sulfinyl] _ 6—Dimethylamino-N- (2-Methyl-1-pyridyl) nicotinamide,

 2 — [(2,4-Dimethoxybenzyl) sulfinyl] —6-dimethylamino—N— (2,5-dimethyl-1-pyridyl) nicotinamide,

 N— (2-ethyl-6-methyl-4-pyridyl) -1-2-[(2,4-dimethoxybenzyl) sulfinyl] nicotinamide,

 2 — [(2,4-Dimethoxybenzyl) sulfinyl] —6-dimethylamino—N— (2-hydroxymethyl-13-methyl-4-pyridyl) nicotinamide, 2-[(2,4-dimethoxybenzyl) sulfinyl ] —6-Dimethylamino

— N— (4-Methoxy-3-pyridyl) nicotinamide,

 2 — [(2,4-Dimethoxybenzyl) sulfinyl] 1 N— (2,3,6—trimethyl-1-pyridyl) nicotinamide,

 N- (2-butyryloxymethyl-3-methyl-4-pyridyl) 1 2—

 [(2,4-Dimethoxybenzyl) sulfinyl] nicotinamide,

 2 — [(2-ethoxy-4-methoxybenzyl) sulfinyl] 1 N— (2—dimethylamino-4-pyridyl) nicotinamide,

 6-dimethylamino-N- (2,6-dimethyl-4-pyridyl) 1-2-[[1- (4-methoxyphenyl) ethyl ニ ル sulfinyl] nicotinamide,

6-Dimethylamino 2 -— [[1 _ (4-Methoxyphenyl) ethyl 1 Sulfini _N— (4-Methoxy-3-pyridyl) nicotinamide,

 N— (2-acetoxymethyl-1-3-methyl-14-pyridyl) 1 2— [[1— (4

—Methoxyethoxy) ethyl] sulfinyl] nicotinamide,

 N- (2-butyryloxymethyl-4-pyridyl) -1-2-[[1- (4-methoxyphenyl) ethyl] sulfinyl] nicotinamide,

 N- (2-dimethylamino-4-pyridyl) -1-2-[[1- (4-methoxyphenyl) ethyl] sulfinyl] nicotinamide,

 N— (2-hydroxymethyl-3-methyl-14-pyridyl) 1-2 — [[1- (4-methoxyphenyl) ethyl] sulfinyl] nicotinamide,

 2 — [[1— (4-Methoxyphenyl) ethyl] sulfinyl] -1-N— (4-Methoxy-3-pyridyl) nicotinamide, and

 N- [4-(4-Methyl-1-piperazinyl) phenyl] -1-[[1- (4-Methoxyphenyl) ethyl] sulfinyl] nicotinamide.

 Hereinafter, the method for producing the compound of the present invention will be described.

 Law (a)

 The compound of the formula (I) can be produced by oxidizing the compound of the formula (II). In the following description, when showing the structure of each compound, the following substituents,

Is represented by the R group as defined above. For example, compound (II) has the following formula

(Π)

(式中、 R i、 R 2、 R 3および Rは前掲に同じものを意味する。 ） で表される。

(Wherein, R i, R 2, R 3 and R have the same meanings as described above.)

This reaction is carried out by reacting the compound of the formula (II) with an oxidizing agent in a suitable solvent. As the oxidizing agent, 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. Specific examples of 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.

In the case of using a compound having a relatively strongly basic substituent (for example, a 4-methyl-1-piperazinyl group) in the groups R 1 and / or R ² in the formula (II), 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. Can be 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.

When a compound having an asymmetric carbon atom in the formula (II), that is, a compound in which the carbon atom to which R ⁴ is bonded is asymmetric, is oxidized, the compound of the formula (I) is converted into two types of diastereomer. It is obtained as a mixture of polymers. Separation into each diastereomer can be performed by a conventional method such as chromatography.

 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.

Chart 1

 (IV) (V)

 Manufacturing method-1)

 (VI) (VII) (ID

(In the formula, 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. )

 Each production method will be described below.

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. When the compound of the formula (IV) itself is used, it is possible to use a compound such as dicyclohexyl carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N'-carbonyldiimidazole. The reaction is preferably performed in the presence of a suitable condensing agent.

 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. 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. Specific examples of 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.

In 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. For example, in 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. Further, in the formula (II), R 1 represents an amino group, a force of a substituted amino group such as Ci〜 (: ₃ alkylamino group, di (C ュ 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 ((^^

C ₃ ) After reacting 4-aminopyridine-N-oxide having alkyl with this method, the product is subjected to a transfer reaction with an acid anhydride (for example, propionic acetic anhydride, acetic anhydride) or the like, or It can be produced by reacting an alcohol form obtained by a transfer reaction with trifluoroacetic anhydride or an ester form obtained by the above transfer reaction with an alcohol form obtained by hydrolysis and a corresponding acid chloride. In the formula (II), the compound in which R 1 is a 4-pyridyl group having a C! To C ₃ alkyl group is the compound (IV) or a reactive derivative thereof and d

~ (: 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.

1) E. Klingsberg (ed.), "Pyridine and Its Derivatives Part Three", John Wiley & Sons, Inc., New York, p. 3-177 (1962); 2) PA Abramovitch (ed.), "Pyridine and Its Derivatives Supplement Part Three ", John Wiley & Sons, Inc., New York, p.41-255 (1974); 3) J. Am. Chem. Soc., 7 3100 (1951); 4) Chem. Pharm. Bull., Ϋ 963 (1965); 5) Rec. Trav. Chim., 2Q, 591 (1951); 6) Pharmaceutical Journal, 75, 292 (1955); 7) Roczniki Chem., 35, 475 (1961) ; 8) J. Orgm. Chem., 26, 2740 (1961); 9) J. Chem. Soc, 4516 (1954); 10) Rec. Trav. Chim., 83 (3), 249 (1964); 11 ) J. Chem. Soc. (C), 80 (1966).

 The starting compound represented by the formula (IV) can be produced, for example, by the method shown in Chart 2 below.

 Chart 2

(In the formula, R 2, R 3 and R have the same meanings as described above, one of Y, and Ζ represents a mercapto group, and the other represents a halogen atom.)

The 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. In the formula (IV), the leaving group R is 2,4-dimethoxybenzyl, 2,4, In order to obtain 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. 58-77841) ) In a suitable solvent such as tetrahydrofuran, acetone, acetonitrile, methanol, and ethanol using concentrated hydrochloric acid as a catalyst. Reaction temperatures are usually from about 0 to about 30.

In the formula (IV), 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 When a compound of the formula (IV) is obtained, 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. It is also suitably carried out by reacting 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. In the formula (VIII), 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. In formula (IX), the starting compound in which Ζ is a mercapto group can be produced according to the method described in Reference Example 25 below.

Production method (a-2):

 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. Specific examples of the base include alkali carbonates such as sodium carbonate and potassium carbonate, quaternary hydroxyammonium such as tetrabutylammonium hydroxide, benzyltriethylammonium hydroxide, sodium methoxide, and sodium ethoxide. And 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

 'Law (a-:

In the formula (II), the compound wherein R 1 is the formula [A] and R 11 is an aminomethyl group, a mono- or di-substituted aminomethyl group, an amino group or a mono- or di-substituted amino group is represented by the formula (II) The same reaction as in the following production method (b) using the compound of Can be produced.

碰 (b)

 In the formula (I), R i is the formula [A], and R 11 is an aminomethyl group, a mono- or di-substituted aminomethyl group, an amino group or a mono- or di-substituted amino group. )

(In the formula, 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.) The compound represented by the following formula (1-1)

 (In the formula, R 2, R 3, R 12, R 13, R, X and n mean the same as described above.)

The compound represented by the following formula (X)

 R 19-H (X)

 (In the formula, R 19 represents a phthalimid group or a mono- or di-substituted amino group.)

When R 19 is a phthalimid group, the product is further reacted. By hydrolysis or decomposition with hydrazine. This reaction is performed in a suitable solvent in the presence of a base. Specific examples of 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 :. As specific examples of the base, those described in the above-mentioned production method (a) can be used as they are. When a phthalimid group is introduced, the reaction proceeds smoothly when phthalimid potassium is used.

 When 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. As the solvent, for example, alcohols such as methanol, ethanol, and isopropanol, dioxane, water, or a mixture thereof is used. Specific examples of 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 :. In addition, 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

 It can be produced by combining the methods shown in (a).

Formula of the formula (I τ).

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. As the 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. Hereinafter, the results of pharmacological tests of a representative compound of the compound (I) of the present invention, a known proton pump inhibitor (omebrazole) and a closed-ring form (III) will be described, and the characteristics of the action of the compound of the present invention will be described.

 Among the test compounds, 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).

 Compound B: 2- (4-pyridyl) -1,3-oxoisothiazolo [5,4-b] pyridine [In the formula (III), Ri is a 4-pyridyl group, and R 2 and R 3 are both hydrogen atoms. A compound which is

 Compound C: 2- (2,6-dimethyl-4-pyridyl) -13-oxoisothiazo port [5,4-b] pyridine [In the formula (III), Ri is a 2,6-dimethyl-4-pyridyl group, R Compound in which both 2 and R 3 are hydrogen atoms)

Compound D: 2- (2-methyl-4-pyridyl) -13-oxoisothiazolo [5,4-b] pyridine [In the formula (III), R 1 is a 2-methyl-14-pyridyl group; Compound in which both ² and R 3 are hydrogen atoms)

Compound E: 2- (2-dimethylamino-4-pyridyl) 1,3-oxoisothiazolo [5,4-b] pyridine [In the formula (III), Ri is 2-dimethylamino —4—A compound in which R ² and R ³ are both hydrogen atoms with a pyridyl group] Test Example 1 —— H +, K +-ATPase inhibitory activity (in vitro) ——

 The Η +, Κ + -ΑΤΡase inhibition activity of the test compound was measured both under the condition without acid treatment and after the acid treatment.

 According to the method of Nagaya et al. FJ. Pharmacol. EXP. Ther .. 248.799-805-989) 1, a microsomal fraction was prepared from pig fundic gland and used as an enzyme preparation in this test. Η +, Κ + — 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.

 First, 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

 After that (3,000 rpm, 10 minutes), 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.

 The test compound was used after dissolving in dimethyl sulfoxide, and the final concentration of dimethyl sulfoxide in the enzyme reaction was 1%.

H +, K +-under both conditions (untreated and acid treated) of the test compound _C of ATP ase inhibiting activity (IC _{5 0)} shown in Table 1

 table 1

*: Means the compound of Example 1 (hereinafter also means the compound of Example). As is evident from Table 1, Compound で, which is a closed ring, exhibited strong proton pump inhibitory activity under untreated conditions, and this inhibitory activity was not changed by acid treatment. On the other hand, as is clear from Table 1, 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. The fact that the compound (I) of the present invention was converted to the compound (111) which was a closed form after the acid treatment, was that the compound (I) was treated under the same conditions as the acid treatment in Test Example 1. After that, when subjected to high performance liquid chromatography, it was confirmed that a new peak appeared at the elution position of the preparation of the compound (III).

 Ell L: Acid formation inhibitory activity in isolated parietal cells "n vitro"

 The 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)].

 2-4 x 106 cells / m1 parietal cells, 0.1 Ci / m1 [i4C] monoaminovirin, ImM dibutyryl cyclic AMP, 0.2% ゥ blood albumin, 25 mM Hepes (HEPES) —Earie's balanced salt solution containing sodium hydroxide (pH 7.4) Add 1.51 test compound dissolved in dimethyl sulfoxide to 1.5 ml, add 9 596 oxygen and 5% carbon dioxide In a mixed gas of 30 and 30 minutes. After completion of the reaction, the reaction solution was centrifuged (14,000 rpm, 1 minute) to obtain a cell pellet. After the cell sediment was lysed with a solubilizer for counting liquid scintillation (NCS (registered trademark), Amersham Co., Ltd.), radioactivity was measured with a liquid scintillation spectrometer.

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

*: 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)

 This test was performed according to the method of Satoh et al. [J. Pharmacol. Exp. Ther., 248, 806-815 (1989)].

 Five Std: Wistar male rats weighing about 200 g were used per group. After the rat was fasted for 17 hours, urine (1 g / kg, intraperitoneal administration) was opened under anesthesia, the pylorus was ligated, and then the test compound was administered into the duodenum or vein. Histamine dihydrochloride as an acid secretion stimulant 5 minutes after intravenous administration and 30 minutes after intraduodenal administration

(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.

 (glycerol formal).

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.

Table 3

実施例 1の化合物を意味する （以下同様に実施例の化合物を意味する） 。 ：投与経路は実施例 1 5 2 7および 4 7の化合物のみ静脈内投与で、 残りの 化合物は全て十二指腸内投与。

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.

 As is evident from Table 3, all of the tested compounds (I) of the present invention showed a significant gastric acid secretion inhibitory action at a dose of 10 mg / kg, and showed a gastric acid secretion inhibitory action almost equivalent to that of omebrazole. .

Test Example 4: Cytochrome P450 monooxygenase inhibitory activity (in vitro)

 In this test, the 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 (ρΗ7.8), 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 ゥ serum albumin, 2 units / ml glucose-16-phosphate dehydrogenase, and 0.1 mM 7-ethoxycoumarin.

 First, 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

 *: Means the compound of Example 1 (hereinafter also means the compound of Example). 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. 30 compounds at 30 Omg / kg; compounds of Examples 2, 17 and 69a each at 100 Omg / kg. As a result, no death occurred in any of the test compound administration groups.

 As described above, 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.

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 dosage of the compounds of the present invention, the kind of compound, administration method, different forces by the patient's symptoms ■ age, etc. ⁵ ', usually 0. 01~ 20 mg / kg / day, preferably 0. 1 ~ 5mg / kg / Day.

The compound (I) of the present invention is usually administered in the form of a preparation prepared by mixing with a preparation carrier. As the pharmaceutical 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. Specifically, for example, 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 fatty acid esters, sodium lauryl sulfate, glycerin, fatty acid glycerin esters, purified lanolin, glycerinated gelatin, polysorbate, macrogol, vegetable oil, wax, propylene glycol, water and the like.

 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.

 These preparations can contain the compound of the present invention in an amount of 0.5% or more, preferably 10 to 70%. These 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.

For the month of departure

 Hereinafter, the present invention is not limited to these examples, with reference to Reference Examples and Examples. The compounds were identified by elemental analysis values, mass spectra, IR spectra, NMR spectra, high performance liquid chromatography (HPLC), and the like.

 In order to simplify the description of the specification, the following abbreviations may be used in the examples and the tables in the examples.

 (Substituent)

 M e: methyl group

 E t: ethyl group

 P r: propyl group

 B u: butyl group

A c: acetyl group P h: phenyl group

(For example, in Table 11 in Examples below, Ph-2,4,6- (OMe) ₃ is a 2,4,6-trimethoxyphenyl group, and Ph-2-OCH ₂ OMe-4-OMe is 2- represents a 4-methoxymethoxy group.)

 (Recrystallization solvent)

 M: methanol

 T ： Truen

 AC: Acetonitrile

 AT: Acetone

 CF: Black mouth Holm

 HX: n-hexane

 I P: diisopropyl ether

 I PN: Isopropanol

 CNMR]

 s: heavy line

 d: Double line

 d d: Double double line

 J: Coupling constant

 Example 1

 2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— (2,6-dimethyl

4 Production of 4-pyridyl) nicotinamide:

2-[(2,4-Dimethoxybenzyl) thio] —4.8 g of N— (2,6-dimethyl_-4-pyridyl) nicotinamide is added to 20 m1 of methylene chloride and stirred at 0 with stirring. 3-Operoxybenzoic acid 2.5 g of methylene chloride solution 3 Om 1 was added dropwise and stirred at the same temperature for 3 minutes. 5 Oml of 10% aqueous sodium hydrogen carbonate solution was added to the reaction solution, Extract twice with 200 ml of black-mouthed form. The extract is dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (10: 1). After purification, the residue was crystallized from acetonitrile to give 4.2 g of the desired product.

Melting point 2 1 3— 2 1 4 Leak 2-9

 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.

 Table 5

 Solvate-melting point re-B says Example R2 R11 R12 R5

 Hydrate (V) solvent

2 H 2-Me H OMe 151-154 AT

3 H 3-Me H O e 2 / 5EtOH '151-154 AC

I / 4H ₂ 0

4 H 2-Me 5-Me OMe 1 / 4H ₂ 0 202-204 AT

5 H 2-Me 3-Me OMe 207-210 AT

6 H 2-Me 6-Me OEt 205-208 AC

7 NMe ₂ 2-Me 6-Me OMe 1 / 4H ₂ 0 171-173 AC

8 H 2-Et H OMe 183-185 AC

9 H 2-Pr H OMe 1 / 2H ₂ 0 160-162 AT Example 10

 Preparation of 2-[[2,4-Dimethoxybenzyl) sulfinyl-1-N- (2-dimethylamino-4-pyridyl) nicotinamide:

 2 — [(2,4-Dimethoxybenzyl) thio] -1-N— (2-dimethylamino-4-pyridyl) nicotinamide 28.2 g was added to 500 ml of methylene chloride, and the mixture was stirred at 45 ° C. 3 _ Black perbenzoic acid 1 After dropping 100 ml of methylene chloride solution of 3.6 g, stir at the same temperature for 3 minutes. To the reaction mixture is added 200 ml of a 10% aqueous sodium hydrogen carbonate solution, and the mixture is extracted twice with 200 ml of chloroform. The extract is dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (20: 1) and purified, and the residue was recrystallized from acetonitrile to obtain 12.8 g of the desired product.

Melting point 1 72— 1 74

Lonely 1 1 ~ 1 5

 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.

 Table 6

脑 11

脑 11

Production of 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) No 4-Ipyridyl) 1-2-[[2- (2-hydroxyethoxy) -14-methoxybenzyl] thio] nicotinamide Example: Reaction in the same manner as I0 The product is recrystallized from acetonitrile to obtain the desired 1/4 hydrate.

Melting point 1 99- 201

m 11

 Production of N- (2-acetoxymethyl-4-pyridyl) -1-2-[(2,4-dimethoxybenzyl) sulfinyl] nicotinamide:

 Add 3.8 g of N- (2-acetoxymethyl-4-pyridyl) 1-2-[(2,4-dimethoxybenzyl) thio] nicotinamide to 200 ml of methylene chloride and stir at 178 with 3-Drop-mouth perbenzoic acid 1.7 g of methylene chloride solution (50 ml) is dropped, and the mixture is stirred at the same temperature for 3 minutes. 50 ml of 1096 aqueous sodium hydrogencarbonate solution is added to the reaction solution, and the mixture is extracted twice with 100 ml of chloroform. The extract is dried over magnesium sulfate, concentrated under reduced pressure, the residue is subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (50: 1), and recrystallized from acetone Object 2. Obtain Og.

Melting point 180-182

Examples 18 to 31

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

2— [(2， 4ージメ トキシベンジル）スルフィエル]— N— （4ーメ トキシー 3 - ピリジル） ニコチンアミ ドの製造：

2 -— [(2,4-Dimethoxybenzyl) sulfiel] —N— (4-Methoxy-3-pyridyl) nicotinamide production:

 2 — [(2,4-Dimethoxybenzyl) thio] —N— (4-Methoxy-3-pyridyl) nicotinamide 3.4 g was added to methylene chloride 10 Om1 and the mixture was added at 0 ° C. Under stirring, 1.6 g of 3-chloroperbenzoic acid, 3 Om 1 of dimethyl chloride solution was added dropwise, and the mixture was stirred at the same temperature for 3 minutes. To the reaction mixture is added 3% of a 10% aqueous solution of sodium hydrogencarbonate, and the mixture is extracted twice with 50 ml of chloroform. After drying the extract with magnesium sulfate, reduce the pressure. 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.

Melting point 1 8 3— 1 8 5 t:

Example 3 3 to 3 5

 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.

 Table 8

実施例 R 1 水和物 融点 （ ） 再結晶溶媒

Example R monohydrate Melting point () Recrystallization solvent

33 6-OMe 1 / 4H ₂ 0 194-196 CF-M

34 6-NMe ₂ 164-165 AC

35 4-NMe ₂ 1 / 4H ₂ 0 219-221 AC

Well 3 ~

 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.

 Table 9

 Example R 1 Monohydrate Melting point (.C) Recrystallization solvent

36 NH ₂ 212-215 M

37 NHMe 215-218 AC

38 NH (CH ₂ CH ₂ OH) 1 / 2H ₂ 0 164-172 M

39 NMe (CH ₂ CH ₂ OH) 170-174 AC

Hin I 40-46

 In place of 2-[(2,4-dimethoxybenzyl) thio] -N- (2,6 dimethyl-4-pyridyl) nicotinamide in Example 1, the corresponding starting compound was used. To give the compounds shown in Table 10 below.

 Table 10

Example R2 R3 hydrate Melting point (V) Recrystallization solvent

40 NHMe H 1 / 4H ₂ 0 153-157 AC

41 solid e ₂ H 178-180 AC

42 NMe (CH ₂ CH ₂ OH) H 199-201 AC

43 NMe (CH ₂ CH ₂ OAc) H 141-144 AC

44 NMe ₂ F 168-171 M

45 NH ₂ F 3 / 4H ₂ 0 123-124 M

46 N) -OH H 172-174 AC

E. Italy "4 7-52

 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.

 Table 11

実施例 R2 R3 水和物 融点 (。C) 再結晶溶媒

Example R2 R3 hydrate Melting point (.C) Recrystallization solvent

47 NH ₂ H 3 / 4H ₂ 0 195-197 M

48 NHMe H 200-203 AC

49 NMe ₂ H 195-197 AC

50 NEt ₂ H 139-14] T

51 NMe (CH ₂ CH ₂ OH) H 1 / 2H ₂ 0 112-114 AC

52 NMe ₂ F 220-222 M

Continued 5 to fi 2

 A reaction was carried out in the same manner as in Example 1 except that 2-([2,4-dimethoxybenzyl) thio-N- (2,6 dimethyl-4-pyridyl) nicotinamide corresponding to the corresponding starting compound in Example 1 was used instead. · Treat to obtain the compounds shown in Table 12 below.

 Table 1 2

 Example R, hydrate Melting point (V) Recrystallization solvent

53 Ph-2,4- (OMe) ₂ 190-192 AC

54 Ph-2,4,6- (OMe) ₃ 182-185 AC

55 Ph-2,4- (OMe) ₂ -3-Me 1 / 4H ₂ 0 105-108 AC

56 Ph-2,4- (OMe) ₂ -6-Me 1 / 4H ₂ 0 195-198 AC

57 Ph-2,4- (OEt) ₂ 165-166 AC

58 Ph-2-OEt-4-OMe 200-202 AC

59 Ph-2-OCH ₂ OMe-4-OMe 189-191 AC

60 Ph-2-OCH ₂ CH ₂ F-4-OMe 163-164 AC

61 Ph-2-OCH ₂ CH ₂ OH-4-OMe 1 / 4H ₂ 0 182-184 AT

62 Ph-2-OCH ₂ CH ₂ OCH ₂ OMe-4-OMe 200-202 M 63-64

 The corresponding starting compounds were used and reacted and treated in the same manner as in Example 1 to obtain the following compounds.

 Dragon B 3)

 2-[(2,4-Dimethoxybenzyl) sulfinyl] -N_ (2-Methoxymethoxymethyl-1-4-pyridyl) nicotinamide '1/4 hydrate: mp 159- 16

 2V (recrystallized from acetonitrile)

2-[(2,4-Dimethoxybenzyl) sulfinyl] — 6-methyl-N—

 (4-Pyridyl) nicotinamide: Melting point 1 9 7-200 (acetonitrile power, Raraguchi Nichinichi)

 Five

 N- (2-Aminomethyl-4-pyridyl) 1-2-[(2,4-Dimethoxybenzyl) sulfinyl] nicotinamide ■ Preparation of 3 tetrahydrate:

 2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— (2-phthalimidometyl—4-pyridyl) nicotinamide 1.4 g and hydrazine hydrate 0.

33 g was added to 100 ml of methanol, and the mixture was heated to reflux while stirring for 1 hour. After cooling, the reaction mixture is reduced under reduced pressure. The residue was subjected to medium pressure ram chromatography using Diaion CHP-20P (trade name) (high bolus polystyrene resin (75-170 // m), Mitsubishi Kasei), and eluted with 20% acetonitrile. Methanol is added to the solution, the mixture is concentrated under reduced pressure, and the precipitated crystals are collected by filtration to obtain 0.25 g of the desired product. Melting point 1 6 9— 1 7 1

 Example B Β

2 — [(2,4-Dimethoxybenzyl) sulfinyl] —Ν— (2-Dimethylaminomethyl-4-pyridyl) nicotinamide: Add 0.5 g of 2-[(2,4-dimethoxybenzyl) sulfinyl] -N- (2-chloromethyl-14-pyridyl) nicotinamide and 12 ml of 50% aqueous dimethylamine solution to 50 ml of ethanol, and add room temperature. And stir for 5 hours. 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]. The residue was recrystallized from acetone to obtain 0.33 g of the desired dihydrate.

Melting point 1 5 5— 1 57

Example 67-68

 Using the corresponding starting compounds, the reaction and treatment were conducted in the same manner as in Example 66 to obtain the following compounds.

 Example B 7)

 2-[(2,4-Dimethoxybenzyl) sulfinyl] —N— [2- (4-Methyl-1-piperazinylmethyl) -14-pyridyl] nicotinamide '1/2 hydrate: melting point 1 49-1 1 521: (Recrystallized from acetonitrile)

 Example 6

 2-[(2,4-Dimethoxybenzyl) sulfinyl] —N— [2— [N— (2-hydroxyshethyl) methylamino] methyl-4-pyridyl] nicotinamide. — 1 5 1 (recrystallized from acetonitrile)

 脑 69

 2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— [4 -— (4-Methyl-1-piperazinyl) phenyl] nicotinamide Preparation:

(a) 2 — [(2,4-Dimethoxybenzyl) thio] —N— [4— (4-Methyl-1-piperazinyl) phenyl ;! Nicotinamide (11.4 g) was added to methylene chloride (400 ml), and 1 M borane-tetrahydrofuran complex was added to the reaction mixture with stirring under ice cooling. After adding 48 ml of the mixture, the mixture is stirred at the same temperature for 1 hour. To the reaction mixture was added dropwise a solution of 8.8 g of 3-chloroperbenzoic acid in 10 Om 1 of methylene chloride, followed by stirring at room temperature for 30 minutes. To the reaction solution is added a saturated aqueous solution of sodium hydrogencarbonate (10 Oml), and the mixture is extracted twice with 300 ml of chloroform. The extract is dried over magnesium sulfate, concentrated under reduced pressure, and methanol 30 OmI is added to the residue. Add 13 g of sodium carbonate to the mixture and heat to reflux for 3 hours. After concentrating the reaction mixture under reduced pressure, add 10 Om 1 of water and extract twice with 30 Om 1 of chloroform. The extract is dried over magnesium sulfate, and then dried under reduced pressure. The residue is subjected to silica gel column chromatography, and eluted and purified with chloroform-methanol (5: 1) to obtain an oil. Since this crystallizes soon, it is recrystallized from methanol to obtain the desired product, 2.Og.

Melting point 1 97-200

 (b) The above-mentioned product is treated with fumaric acid, and recrystallized from methanol to obtain the desired fumarate salt · 544 hydrate.

Melting point 1 74— 1 78

 (c) The above-mentioned product is treated with tartaric acid, and recrystallized from methanol to obtain the desired tartaric acid salt · monodihydrate.

Melting point 1 86— 1 89

 Shin I 70

 Preparation of 2-[(2,4-Dimethoxybenzyl) sulfinyl] _6-dimethylamino-N- [4- (4-Methyl-1-1-piperazinyl) phenyl] nicotinamide:

(a) In place of 2-[(2,4-dimethoxybenzyl) thio] -1-N- [4- (4- (methyl-1--1-piperazinyl) phenyl] nicotinamide in Example 69 (a), (2,4-Dimethoxybenzyl) thio-6-dimethylamino-1-N- [4- (4-methyl-1-piperazinyl) phenyl] nicotinamide was reacted in the same manner as in Example 65 (a) to give a product. The product is recrystallized from acetonitrile to Obtain 1/4 hydrate.

Melting point 1 1 3— 1 1 6 T:

 (b) The above product is treated with fumaric acid, recrystallized from methanol,

1 2 fumarate. 3/4 hydrate is obtained.

Melting point 1 1 0— 1 1 3

Well 7 1? Four

 The corresponding compounds are reacted and treated in the same manner as in Example 69 (a) to obtain the following compounds.

 (Example of 荬 荬 7 1)

 2-[(24-Dimethoxybenzyl) sulfinyl] -1-N- [6- (4-methyl-1-piperazinyl) -3-pyridyl] nicotinamide: melting point 200-202

(Reunited from Acetonitrile,

 B

2-[(2,4-Dimethoxybenzyl) sulfinyl] -1-6- (4-methyl-11-piperazinyl) -N- (4-pyridyl) nicotinamide 'monodihydrate: mp 172-174 In (recrystallized from acetonitrile)

2 — [(24-Dimethoxybenzyl) sulfinyl] -1-N— [2 -— (4-Methyl-1-piperazinyl) -1-4-pyridyl] nicotinamide '3-notetrahydrate: melting point 15 3-1 54 (Recrystallized from acetonitrile)

 Example 4)

2-[(2,4-Dimethoxybenzyl) sulfinyl] -1-5-fluoro-6- (4-methyl-1-piperazinyl) -N- (4-pyridyl) nicotinamide: mp 198-20C (recrystallized from methanol ) Harm case 7 5

 Preparation of 2-[[1- (4-Methoxyphenyl) ethyl] sulfinyl] —N— (4-pyridyl) nicotinamide (diastereomer A):

 2-[(2,4-Dimethoxybenzyl) thio] —N— (2,6-Dimethyl-4-pyridyl) nicotinamide in Example 1 was replaced with 2 — [[1- (4-Methoxyphenyl) ) Ethyl] thio] -N- (4-pyridyl) nicotinamide 4. Reaction with Og was carried out in the same manner as in Example 1 to obtain an oil containing diastereomers A and B. This was subjected to silica gel column chromatography, and eluted with a mixture of formaldehyde (25: 1). The eluate was concentrated under reduced pressure. The residue was recrystallized from acetonitrile to give the desired product 0.68 g of the product is obtained.

With a melting point of 232—23 7

Example 7

 Preparation of 2-[[1- (4-methoxyphenyl) ethyl] sulfinyl] —N— (4-pyridyl) nicotinamide (Diastereomer B):

 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.

Melting point 240-243

Example 77

 Production of N- (2-acetoxymethyl-4-pyridyl) -1-2-[[1- (4-methoxyphenyl) ethyl] sulfinyl] nicotinamide (diastereomer C):

Instead of 2-[(2,4-dimethoxybenzyl) thio] -1-N- (2,6-dimethyl-4-1-pyridyl) nicotinamide in Example 1, N- (2-acetoxymethyl-14-pyridyl) 1-2 — [[11- (4-methoxy) ethyl] thio] nicotine The amide is reacted and treated in the same manner as in Example 1 to obtain an oil containing diastereomers C and D. This is subjected to silica gel column chromatography, eluted with a mixture of chloroformumethanol (50: 1), the eluate is concentrated under reduced pressure, and the residue is recrystallized from toluene to obtain the desired product. With a melting point of 120-122

 m 7 S

 N- (2-Acetoxymethyl-4-pyridyl) -1-2-[[1- (4-Methoxyphenyl) ethyl] sulfinyl] nicotinamide (Diastereomer D) Production:

 After eluting diastereomer C by the chromatography of Example 77, elution was carried out with a mixture of chloroform-methanol (30: 1), the eluate was reduced under reduced pressure, and the residue was recrystallized from acetonitrile. Obtain the desired product.

Melting point 1 59— 16 11:

 79

 Preparation of 2 -— [(2,4-Dimethoxybenzyl) thio] —N— (2,6-dimethyl-14-pyridyl) nicotinamide:

 2,6-Dimethyl 4 -— [2 — [(2,4 dimethylbenzyl) thio] nicotinyl lumino] pyridine-N-oxide 7.0 g was added to 200 ml of methylene chloride, and trichloride was stirred at room temperature with stirring. After dropwise adding 3.4 g of phosphorus, the mixture is refluxed for 30 minutes. After cooling, 100 ml of a 10% aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the mixture is extracted twice with 10 ml of chloroform. The extract was dried over magnesium sulfate and dried, and the residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (20: 1). Purification was performed, and 4.8 g of the desired product was converted into an oil. obtain.

iH-NMR (DMSO-d ₆ ) δ: 2.40 (s, 6H), 3.72 (s, 3H), 3.79 (s, 3H), 4.32 (s, 2H), 6.43 (dd, J =

8.0Hz, J = 2.9Hz, lH), 6.54 (d, J = 2.9Hz, lH), 7.34 (s, 2H), 7.91 (dd,

J = 7.0Hz, J = 2.0Hz, lH), 8.63 (dd, J = 5.0Hz, J = 2.0Hz, lH), 10.62 (s, lH) Examples 80 to 87

 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.

 Table 13

実施例 88

Example 88

Production of 2 -— [(2,4-dimethoxybenzyl) thio] —N— (2-dimethylamino 4-pyridyl) nicotinamide: 27.9 g of 2-[(2,4 dimethylbenzyl) thio] nicotinic acid was added to 500 ml of dioxane, and 28 ml of oxalyl chloride was added dropwise while stirring, and the mixture was added at room temperature. Stir for 0 minutes. After the solvent was distilled off, dimethylformamide 500 ml and 4-amino-2-dimethylaminopyridine 1 synthesized according to the method described in Roczniki Chem. 35,475 (1961) [CA57,15066b (1962)] Add 7.6 g, add dropwise 18.1 ml of triethylamine while stirring under ice-cooling, and stir at room temperature for 2 hours. After concentrating the reaction mixture under reduced pressure, extract twice with 300 ml of chloroform, wash twice with 50 ml of saturated saline, dry with magnesium sulfate, and compress. The residue was subjected to silica gel column chromatography, and eluted with chloroform-methanol (40: 1) -purified to obtain 28.7 g of the desired product as an oil.

iH-NMR (DMSO-d ₆ ): 2.99 (s, 6H), 3.73 (s, 3H), 3.78 (s, 3H), 4.32 (s, 2H),

 6.43 (dd, J = 8.1Hz, J = 2.0Hz, lH), 6.54 (d, J = 2.0Hz, lH), 6.85 (dd, J = 5.6Hz,

J = 1.8Hz, lH), 7.03 (d, J = 1.9Hz, lH), 7.25 (d, J = 8.1Hz, lH), 7.26 (dd, J = 7.7Hz,

J = 5.0Hz, lH), 7.91 (dd, J = 7.7Hz, J = 1.9Hz, 1H), 7.97 (d, J = 5.6Hz, lH), 8.62 (dd,

J = 5.0Hz, J = 1.9Hz, l H), 10.49 (s, 1H)

Example 8 9 ~ 92

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 93

 2 — [(2,4-Dimethoxybenzyl) thio] —N— [2— (4-Hydroxy-1-piperidinyl) -1-4-pyridyl] nicotinamide production:

 2 — [(2,4-Dimethoxybenzyl) thio] —N— [2— (4-oxo-piperidino) -14-pyridyl] nicotinamide 0.9 g was added to 100 ml of methanol and stirred. While adding 64 mg of sodium borohydride!] And stirring at room temperature for 1 hour. 5.0 ml of acetone was added to the reaction mixture, the mixture was decompressed, extracted twice with 50 ml of black-mouthed form, washed twice with saturated diet fekl Oml, dried over magnesium sulfate, and shrunk. 0.87 g of the desired product is obtained as an oil.

Example 94

 Production of N— (2-Dimethylamino-1-4-pyridyl) 1-2 — [[2- (2-Hydroxyethoxy) -1-4-methoxybenzyl] thio] nicotinamide:

0.68 g of 2 -— [[2- (2-acetoxyethoxy) -14-methoxybenzyl] thio] -1-N— (2-dimethylamino-1-pyridyl) nicotinamide was added to 5 Oml of methanol. Add 28 ml of a 10% aqueous potassium carbonate solution with stirring, and stir at room temperature for 30 minutes. After concentrating the reaction mixture under reduced pressure, extract twice with 50 ml of black-mouthed form, wash twice with saturated diet lOm1, dry over magnesium sulfate, and compress. This gives 0.33 g of the desired product as an oil.

Example 9 5

 Preparation of N- (2-acetoxymethyl-4-pyridyl) -1-2-[(2,4-dimethoxybenzyl) thio] nicotinamide:

 Add 6.9 g of 4- [2-[(2,4-dimethoxybenzyl) thio] nicotinoylamino] -12-methylpyridine-N-methoxide to 300 ml of acetic anhydride, and add 90 T After stirring for 2 hours at:, concentrate under reduced pressure, add water and concentrate again under reduced pressure. After the residue is extracted twice with 200 ml of chloroform, the extract is washed twice with 30 ml of saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to gel column chromatography, eluted with chloroform-methanol (40: 1) and purified to obtain 4.3 g of the desired product as an oil.

iH-NMR (DMSO-d ₆ ) $: 2.10 (s, 3H), 3.73 (s, 3H), 3.77 (s, 3H), 4.31 (s, 2H), 5.10 (s, 2H), 6.43 (dd, J = 8.2Hz, J = 2.4Hz, lH), 6.54 (d, J = 2.4Hz, lH), 7.25 (d, J = 8.2Hz, lH), 7.28 (dd, J =

7.9Hz, J = 3.8Hz, lH), 7.62 (dd, J = 7.8Hz, J = 2.0Hz, lH), 7.64 (d, J = 2.0Hz, lH), 7.96 (dd, J = 7.9Hz, J = 1.4Hz, lH), 8.43 (d, J = 7.8Hz, lH), 8.64 (dd, J = 3.8Hz, J = 1.4Hz, lH), 10.84 (s, lH) Lonely 9 6〜1 0 0

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

 1 Ω l

 2 — [(2,4-Dimethoxybenzyl) thio] —N— (2-Methyl-16-propionyloxymethyl-14-pyridyl) Nicotinamide Preparation:

 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.

 麵 1 02

 Preparation of 2-[(2,4-dimethoxybenzyl) thio] -1-N- (2-hydroxymethyl-41-viridyl) nicotinamide:

Add 2.7 g of N- (2-acetoxymethyl- 4-pyridyl) -1-[(2,4-dimethoxybenzyl) thio] nicotinamide to 150 ml of methanol and add 0.1 N aqueous potassium carbonate solution Add 100 ml and stir at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure to 10 Om 1 and neutralized by adding 1 N hydrochloric acid under ice-cooling. The extract was extracted twice with 10 Om 1 and the extract was washed twice with a saturated diet K 3 Om 1, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 1.1 g of the desired product. Obtained as an oil. mlo 3〜 l ο 6

 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.

 Table 16

実麵 1 07

Actual 1 07

 2 -— [(2,4-Dimethoxybenzyl) thio] —N— (2-Propionyloxymethyl 4-pyridyl) Production of nicotinamide:

 3.0 g of 2-[(2,4-dimethoxybenzyl) thio] -1-N- (2-hydroxymethyl-4-pyridyl) nicotinamide and 0.74 g of propionyl chloride were added to 50 ml of pyridine, Stir at room temperature for 2 hours. After concentrating the reaction mixture under reduced pressure, extract twice with 50 ml of chloroform. The extract is washed twice with 10 ml of saturated saline, dried over magnesium sulfate, and then dried. The residue is applied to a silica gel column chromatography, and eluted with chloroform (50: 1) to give 2.53 g of the desired product as an oil.

iH-NMR (DMSO-d ₆ ) S 1.09 (t, J = 7.6Hz, 3H), 2.43 (q, J = 7.6Hz, 2H), 3.73 (s, 3H), 3.78 (s, 3H), 4.33 ( s, 2H), 5.13 (s, 2H), 6.44 (dd, J = 8.4Hz, J = 2.5Hz, lH), 6.55 (d, J = 2.5Hz, lH), 7.26 (d, J = 8.4Hz, lH), 7.29 (dd, J = 7.6Hz, J = 4.9Hz, lH), 7.62 (dd, J = 5.4Hz, J = 2.0Hz, lH), 7.68 (d, J = 2.0Hz, lH), 7.96 (dd, J = 7.6Hz, J = 1.8Hz, lH), 8.46 (d, J = 5.4Hz, lH), 8.65 (dd, J = 4.9Hz, J = 1.8Hz, lH), 10.84 (s, lH)

荬 Examples of 荬

 The corresponding compounds were reacted and treated in the same manner as in Example 107 to obtain the following compounds as oils.

 (Example 1 08)

 N- (2-butyryloxymethyl-4-pyridyl) _2 -— [(2,4-dimethoxybenzyl) thio] nicotinamide

(Example 109)

 2 — [(2,4-Dimethoxybenzyl) thio] -1-N— (2-norreloxymethyl)

4-pyridyl) nicotinamide Example 1 1 0

 2 — [(2,4-Dimethoxybenzyl) thio] -1-N— (4-Methoxy-3-pyridyl) nicotinamide production:

 2 — [(2,4-Dimethoxybenzyl) thionicotinic acid 6.3 g with dioxane 2

In addition to 00 ml, 6.3 ml of oxalyl chloride and 0.1 ml of dimethylformamide are added dropwise with stirring, and the mixture is stirred at room temperature for 30 minutes. After evaporating the solvent, 4.0 g of dimethylformamide and 4.0 g of 4-methoxy-3-aminoviridine synthesized according to the method described in J. Chem. Soc. 1954.4516 while stirring under water cooling. Add 4.6 g of triethylamine, and stir with heating at 8 for 4 hours. After decompression, the extract is extracted twice with 150 ml of black-mouthed form, washed twice with 30 ml of saturated food ^ 7K, dried over magnesium sulfate, and then reduced. The residue is subjected to silica gel column chromatography, and eluted with chloroform-methanol (80: 1). Purification gives 3.4 g of the desired product as crystals.

iH-NMR (DMSO-d ₆ ) δ: 3.73 (s, 3H), 3.78 (s, 3H), 3.85 (s, 3H), 4.30 (s, 2H), 6.44 (dd, J = 8.0Hz, J = 2.7Hz, lH), 6.55 (d, J = 2.7Hz, lH), 7.14 (d, J = 6.1Hz, lH), 7.26 (d, J = 8.0Hz, lH), 8.31 (d , J = 6.1Hz, lH), 8.61 (dd, J = 5.1Hz, J = 2.2Hz, lH), 8.68 (s, lH), 9.88 (s, lH)

荬 examples

 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. .

 Table 17

実施例 1 1

Example 1 1

 Production of N- (2-amino-4-pyridyl) -1-[(2,4-dimethoxybenzyl) thio] nicotinamide:

 N- (2-bromo-4-pyridyl) -2-[[(2,4-dimethoxybenzyl) thio] nicotinamide 6.0 g, copper (I) bromide 1.9 g, 28% aqueous ammonia 120 The mixture consisting of m 1 and methanol 5 Om 1 is heated in a sealed tube at 110 for 12 h. After the solvent is reduced under reduced pressure, the solution is extracted twice with 20 ml of form. The extract is washed twice with 50 ml of saturated saline, dried over magnesium sulfate and concentrated. The residue was subjected to gel chromatography on a silica gel gel column, and

Elution with (20: 1) • Purification to obtain 2.7 g of the desired product as an oil.

Example 1 1 5

2 — [(2,4-Dimethoxybenzyl) thio] —N— (2-Methylamino-4 Jill) Production of nicotinamide:

 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.

Well 1 1 β

 Preparation of 2 — [(2,4-Dimethoxybenzyl) thio] 1 N— [2— (2-hydroxy) ethyl amino-4-pyridyl] nicotinamide:

 2 _ [(2,4-Dimethoxybenzyl) thio] — N— (2-bromo-4-pyridyl) nicotinamide 5.0 g, copper (I) bromide 1.6 g, 2-aminoethanol 6 A mixture of 6 g and 200 ml of dimethylformamide is heated at 10 Ot: for 5 hours with stirring. After removing the solvent under reduced pressure, extract twice with 30 mL of form. The extract is washed twice with 10 mL of saturated saline, dried over magnesium sulfate and concentrated. The residue is subjected to silica gel column chromatography, eluted and purified with chloroform-formanol (15: 1), and recrystallized from methanol to obtain 0.42 g of the desired product as crystals.

Well 1 Ί 7

 2 -— [(2,4-Dimethoxybenzyl) thio] —N— [2— [N— (2-hydroxyethyl) methylamino] 1-4-pyridyl] nicotinamide:

 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.

 麵 1 1 8

 2 — [(2,4-Dimethoxybenzyl) thio] —6_methylamino-N— (4-pyridyl) nicotinamide production:

6—Chloro-2 -— [(2,4 dimethylbenzyl) thio] —N— (4-pyridyl) nicotinamide 1.5 (?, 30% methylamine in ethanol 2 Om Heat the mixture of ethanol 2 Om 1 in a sealed tube at 160 for 24 hours. After the reaction solution is cooled to room temperature, it is extracted twice with 100 ml of chloroform. The extract is washed twice with 5 Om 1 of saturated saline, dried over magnesium sulfate and concentrated. The residue is subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (15: 1), and recrystallized from methanol to obtain 1.4 g of the desired product.

Melting point 188-1 90

Example 1 1 9

 Preparation of 2-[(2,4-dimethoxybenzyl) thio]-6-dimethylamino-N- (4-pyridyl) nicotinamide:

 6-chloro-2- 1-[(2,4-dimethoxybenzyl) thio] -1-N- (4-pyridyl) nicotinamide 4.0 g, dimethylamine 50% aqueous solution 80 ml and ethanol 8 Oml The resulting mixture was heated to reflux for 10 hours while stirring. After completion of the reaction, the precipitated crystals are collected by filtration to obtain 3.85 g of the desired product as crystals.

Example 1 20

 2 — [(2,4-Dimethoxybenzyl) thio] —6— [N- (2-Hydroxyethyl) methylamino] 1-N— (4-pyridyl) nicotinamide Preparation:

6-Chloro-2-([2,4-dimethoxybenzyl) thio] -1-N- (4-pyridyl) nicotinamide 5.0 g, N-methylethanolamine 1.8 g, potassium carbonate A mixture consisting of 3.3 g of acetonitrile and 150 ml of acetonitrile is heated to reflux for 10 hours while stirring. After concentrating the solvent under reduced pressure, add 7 Oml of water and extract twice with 200 ml each of form. The extract is washed twice with 5 Om 1 of saturated saline, dried over magnesium sulfate, and then dried. The residue is subjected to silica gel column chromatography, eluted with chloroform-methanol (50: 1), and purified to obtain 4.3 g of the desired product as crystals. Example 1 2 1

 6— [N_ (2-acetoxitytyl) methylamino] 1-2 — [(2,4-dimethyloxybenzyl) thio] —N— (4-pyridyl) nicotinamide production:

 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.

Well ^ 1 2

 Preparation of 2-[(2,4-dimethoxybenzyl) thio] -1-6-dimethylamino 5-fluoro N- (4-pyridyl) nicotinamide:

 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.

Leakage I 1 3

 6-Amino-2-[[(2,4-dimethoxybenzyl) thio]-5-Fluoro-N- (4-Pyridyl) nicotinamide Preparation:

6-Chloro-2-[(2,4-dimethoxybenzyl) thio]-5-fluoro-N- (4-pyridyl) nicotinamide 4.lg, phthalimid potassium 7.Og and dimethylformamide 10 The mixture of Om 1 is heated and stirred at 100 for 5 hours. After the solvent was reduced under reduced pressure, 100 ml of a 10% aqueous sodium hydrogen carbonate solution was added. Extract twice with 200 ml of mouth form. The extract is washed twice with 70 ml of saturated saline, dried over magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted and purified with chloroform-form (100: 1) to obtain 0.7 g of the desired product.

With a melting point of 176-178

■ Example 1 4

 2-[(2,4-Dimethoxybenzyl) thio-6- (4-hydroxy-1-1-piridinyl) -1-N- (4-pyridyl) nicotinamide:

 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.

 Par 125

 Preparation of 6-amino-2-[(2,4-dimethoxybenzyl) thio-N- (2-dimethylamino-1-pyridyl) nicotinamide:

 2 — [(2,4-Dimethoxybenzyl) thio] —N— (2-Dimethylamino-14-pyridyl) -16-fluoronicotinamide 7.0 g was dissolved in dimethylformamide 70 ml. Then, 5.8 g of potassium phthalimid is added, and the mixture is heated and stirred with lOO: for 17 hours. After the solvent is reduced under reduced pressure, 100 ml of a 10% aqueous sodium hydrogen carbonate solution is added, and the mixture is extracted twice with 200 ml each of a porcelain form. The extract is washed twice with 70 ml of a saturated saline solution, dried over magnesium sulfate, and dried. The residue is subjected to silica gel column chromatography, eluted with chloroform-methanol (50: 1), and purified to obtain 1.2 g of the desired product as crystals.

卖 Example 1 2 ~〗 30

Using the corresponding 2-mercaptonicotinamide derivative and amines, the following compound is obtained by reaction and treatment in the same manner as in Example 119. (Example 26)

 2 — [(2,4-Dimethoxybenzyl) thio] 1 —— (2-Dimethylamino 4-pyridyl) -1 6-Methylaminonicotinamide: oil 2— [(2,4-Dimethoxybenzyl) 6) -Dimethylamino-1- (2-dimethylamino-4-pyridyl) nicotinamide: oil

 (Ex. 1 28)

 6-Jetylamino-1 2-— [(2,4-Dimethoxybenzyl) thio] — Ν— (2-dimethylamino-1-pyridyl) nicotinamide: oil

 (Example 1 29)

 2 — [(2,4-Dimethoxybenzyl) thio-〗 — (2-Dimethylamino-4-1pyridyl) 16- [Ν- (2-Hydroxitytyl) methylamino] nicotinamide

 2-[(2,4-dimethoxybenzyl) thio] -1-6-amino-N- (2-dimethylamino-4-pyridyl) -1-5-fluoronicotinamide: crystal

Continue 1 3 1

 2 — [(2,4-Dimethoxybenzyl) thio] —N— (4-Pyridyl) nicotinamide production:

In a mixture of 26 g of 2-[(2,4-dimethoxybenzyl) thio] nicotinic acid, 9.7 g of 4-amino viridine and 700 ml of tetrahydrofuran, 1-ethyl-3- (3-dimethyl) (Aminopropyl) Carposimid hydrochloride (20 g) is added, and the mixture is stirred at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure, and extracted twice with 30 mL of ethyl acetate. The extract is washed twice with 30 ml of saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue Elute with chloroform-methanol (30: 1) and purify to obtain 6.4 g of the desired product as an oil.

 ¾ Italy 11 32 2 ~! · Ί 8

 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.

 Table 18

^ ml 9

 2 -— [[2- (2-Hydroxyxetoxy) -1- 4-methoxybenzyl] thio] —N— (4-pyridyl) nicotinamide production:

N- (2-Acetoxymethyl-4-pyridyl) 1-2-[(2,4-dimethoxybenzyl) of Example 102 Instead of thiodinicotinamide, 2-[[2- (2-acetoxicetoxy) 0.8 g of 4- (methoxybenzyl) thio] —N— (4-pyridyl) nicotineamide was used. The reaction and treatment were carried out in the same manner as in Example 102 to obtain the desired product as an oil. . Mashi. Example 1 40 ~: 1 4 1

 The corresponding compounds were reacted and treated in the same manner as in Example 88 to obtain the following compounds as oils.

 2 — [[4-Methoxy-1 2— [2- (Methoxymethoxy) ethoxy] benzyl] thio] —N— (4-Pyridyl) nicotinamide

 (Μ 1 1)

 2 — [(2,4-Dimethoxybenzyl) thio] -1-N _ (2-Methoxymethoxymethyl—4-pyridyl) nicotinamide

Examples 142-243

 The following compounds were reacted and treated in the same manner as in Example 1331 using the corresponding starting compounds to obtain the following compounds.

 (Example 1 42)

 2 — [(2,4-Dimethoxybenzyl) thio] —6-Methyl-1-N— (4-pyridyl) nicotinamide: melting point 1 50_1 151 (recrystallized from methanol)

 (M LU

 2-[(2,4-Dimethoxybenzyl) thio] — N— [4-[(4-Methyl-1-1-piperazinyl) phenyl]] nicotinamide: mp 176-180 (recrystallized from acetate nitrile) ) Resolution 1 44

2 — [(2,4-Dimethoxybenzyl) thio] —6-dimethylaminomin N— [4 — [(4-Methyl-1-piperazinyl) phenyl]] Production of nicotinamide: Example 11 6-Chloro-2 -— [(2,4-dimethoxybenzyl) thio] —N— (4-pyridyl) nicotinamide instead of 6-chloro-2-([2,4-dimethoxybenzyl) thio] — N— [4— [(4-Methyl-1-1-piperazinyl) Hue [Nyl] nicotinamide was reacted and treated in the same manner as in Example 119 to obtain the desired product as an oil.

 Example 15

 2 — [(2,4-Dimethoxybenzyl) thio] —N— [6- (4-Methyl-1-piperazinyl) -1-pyridyl] Production of nicotinamide:

 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 1 46

 2-[(2,4-Dimethoxybenzyl) thio] -1-6- (4-methyl-1-piperazinyl) -1-N- (4-pyridyl) nicotinamide production:

 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.

 Example 1 47

 2 — [(2,4-Dimethoxybenzyl) thio] —N— [2— (4-Methyl-1-pyridinyl) -1-4-pyridyl] nicotinamide:

1.5 g of 60% sodium hydride was washed with getyl ether, 100 ml of tetrahydrofuran was added, and 4.0 g of 2,4-dimethoxybenzylthiol was added dropwise while stirring at 0. After 30 minutes, a mixture of 6.6 g of 2-N- [2- (4-methyl-1-piperazinyl) -4-pyridyl] nicotinamide and 100 ml of tetrahydrofuran is added. After heating under reflux with stirring for 2 hours, add to 70 ml of ice water, neutralize with dilute hydrochloric acid, and extract twice with 300 ml of ethyl acetate. 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.

 Fine 1 8

 Preparation of 2-[(2,4-dimethoxybenzyl) thio] -5-fluoro-6- (4-methyl-1-piperazinyl) -N- (4-pyridyl) nicotinamide:

 2-chloro-1-N- [2- (4-methyl-1-piperazinyl) —4-pyridyl] nicotinamide in Example 1 47 instead of 2-chloro-5-fluoro-6— (4-methyl-1-) The reaction and treatment were carried out in the same manner as in Example 147 using (piperazinyl) -N- (4-pyridyl) nicotinamide to obtain the desired product as an oil.

Example 1 49

 2 -— [[11- (4-Methoxyphenyl) ethyl] thio] —N— (4-pyridyl) nicotinamide production:

 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.

 MI 150

 Production of N- (2-acetoxymethyl-1-pyridyl) -1-2-[[1- (4-methoxyphenyl) ethyl] thio] nicotinamide:

 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.

 Shin 11

2,6-Dimethyl 4-1 [2-[(2,4-Dimethoxybenzyl) thio] nicotinoy Lumino] Preparation of pyridine-N-oxide:

 4.9 g of 2-[(2,4-dimethoxybenzyl) thio] nicotinic acid is added to 20 ml of dioxane, and 7.6 ml of oxalyl chloride and 0.1 ml of dimethylformamide are added with stirring. Add dropwise and stir at room temperature for 30 minutes. After distilling off the solvent, 200 ml of dimethylformamide and 4-amino-2,6-dimethylpyridine-1-N-oxide 1. synthesized according to the method described in Chem. Pharm. Bull. 13,963 (1965) 1. After adding 5 g, 2.6 ml of triethylamine was added dropwise under ice-cooling and stirring, followed by stirring at room temperature for 8 hours. After concentration under reduced pressure, 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 following compounds are reacted and treated in the same manner as above using the corresponding starting compounds to obtain the following compounds.

 (1) 4— [2 — [(2,4-Dimethoxybenzyl) thio] nicotinoylamino] —2-methylpyridine-N-oxide:

 The starting compound 4-amino-2-methylpyridine-1-N-oxide is synthesized according to the method described in 0.0. C. 26 2740 (1961).

 (2) 4— [2 — [(2,4-Dimethoxybenzyl) thio] nicotinoylamino] -1-methylpyridine-1-N-oxide:

 The starting compound 4-amino-13-methylpyridine-1-N-oxide is synthesized according to the method described in Pharmaceutical Journal, 75, 292 (1955).

 (3) 4- [2-[[(2,4-dimethoxybenzyl) thio] nicotinylamino] -1,2,1-dimethylpyridine-N-oxide

(4) 4- [2-[(2,4-dimethoxybenzyl) thio] nicotinoylamino j—2,3—dimethylpyridine-N-year-old oxide (5) 4- [2-[(2-ethoxy-4- 4-methoxybenzyl) thio] nicotinoylamino] -1,6-dimethylpyridine 1-N-oxide

 (6) 4— [2 -— [6-Fluoro (2,4-dimethoxybenzyl) thio] nicotinylamino] -1,2,6-dimethylviridine N-oxide

(7) 4 -— [2 -— [[(4-Methoxyphenyl) ethyl] thio] nicotinylamino] -1-methylpyridine-1-N-oxide

 (8) 4- [2- [6-Chloro (2,4-dimethoxybenzyl) thionicotinylamino]-2-methylpyridine-N-methyl oxide

 The starting compound 4-amino-12-methylpyridine-1-N-oxide is synthesized according to the method described in J.O.C., 26, 2740 (1961).

Participant example 2

 Preparation of 4-Amino-2,5-dimethylviridine-1-oxide · hydrochloride:

 The desired product is obtained by reaction and treatment using 2,5-dimethylviridine according to the method described in Pharmaceutical Journal, 2 292 (1955).

 Using the corresponding starting compounds, the reaction is similarly performed to obtain the following compounds.

 (1) 4-Amino-2-Methoxymethoxyviridine

 (2) 3-Amino-6- (4-methyl-1-piperazinyl) pyridine

I ^ I 3

2-[(2,4-Dimethoxybenzyl) thio]-Preparation of 6-Fluoronicotinic acid: 3.7 g of 60% sodium hydride was washed with geethylether, and the mixture was added with 50 ml of tetrahydrofuran and added with 0 ml. 6. Og of 2,4-dimethoxybenzylthiol is added dropwise with stirring. After 30 minutes, a mixture of 5.8 g of 2,6-difluoronicotinic acid and 50 ml of tetrahydrofuran is added. After heating and refluxing for 1 hour, add 70 ml of ice water and extract twice with 200 ml of ethyl acetate. After washing with water, the extract is dried over magnesium sulfate and then contracted, and the residue is crystallized from acetonitrile. As a result, 6.0 g of the target product is obtained.

 Using the corresponding starting compounds, react and treat in the same manner as above to obtain the following compounds

6-Chloro-2-([2,4-dimethoxybenzyl) thio] nicotinic acid

Preparation of 4-amino-2-dimethylamino-1-methylpyridine:

 Using 2-bromo-13-methylpyridine synthesized according to the method described in J. Am. Chem. Soc, 68, 2574 (1946) as the starting compound, and described in Rec. Trav. Chim., 20, 591 (1951) Reaction and treatment according to the method described above to obtain the desired product.

 Using the corresponding starting compounds, react and treat in the same manner to obtain the following compounds.

 (1) 4-amino-1-2-dimethylamino-6-methylpyridine

 (2) 4-amino-1 2-dimethylamino-5-methylpyridine

 (3) 4 _amino-2- (4-oxopiperidino) pyridine

 (4) 4-amino-2- (4-methyl-1-piperazinyl) pyridine

Reference example 5

 Production of 2-[[2- (2-acetoxethoxy) -1-4-methoxybenzyl] thio] nicotinic acid:

Add 4.5 g of 2-[[[2- (2-hydroxylethoxy) -14-methoxybenzyl] thio] nicotinic acid to 40 ml of pyridine, add acetic anhydride dropwise with stirring, and heat for 1 hour with stirring Reflux. After cooling, the reaction mixture was concentrated under reduced pressure, extracted twice with 100 ml of chloroform, washed twice with 20 ml of saturated saline, dried over magnesium sulfate, and concentrated to give the desired product. To obtain 5. O g. 每 Example 6

 Production of N- (2-bromo-1-4-pyridyl) 1-2-[(2,4-dimethoxybenzyl) thio] nicotinamide:

 The same procedure as in Example 147 was carried out using N- (2-bromo-14-pyridyl) -12-cloniconicotinamide to obtain the desired product.

 The corresponding compounds are reacted and treated in the same manner to obtain the following compounds.

 (1) 2-[(2,4-Dimethoxybenzyl) thio] 1 N— (2 -Dimethylamino 1-4 -pyridyl) 1 -5-Fluoronicotinamide

 (2) 6-chloro-2-([2,4-dimethoxybenzyl) thio] — N— (4-pyridyl) nicotinamide · 1/4 tetrahydrate: mp 153-155 ° C

 (3) 6-chloro-2-([2,4-dimethoxybenzyl) thio] -1-5-N- (4-pyridyl) nicotinamide

 (4) 2 — [(2,4-Dimethoxybenzyl) thio] -1-6- (4-Methyl-1-piperazinyl) -1-N— (4-Pyridyl) nicotinamide

Reference Example 7

 Production of N- (2-bromo-4-1-pyridyl) -12-clonicotinamide: Synthesized as a starting compound according to the method described in Rec. Trav. Chim., 591 (1951)

The reaction is carried out in the same manner as in Example 88 using 4-amino-2-bromopyridine to obtain the desired product.

 Using the corresponding starting compounds, the reaction is similarly performed to obtain the following compounds.

 (1) 2,6-Dichloro-N- (2-dimethylamino-4-pyridyl) -1-fluoro-nicotinamide:

 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.

(2) N- (2-Dimethylamino 4-pyridyl) 1,2,6-difluoronicotine (3) 2-N- [2- (4-Methyl-1-1-piperazinyl) -14-pyridyl] nicotinamide

 (4) 2 — [(2,4-Dimethoxybenzyl) thio] -1-6-N- [4- (4-methyl-1-piperazinyl) phenyl] nicotinamide

 (5) 2,6-Dichloro-N- (4-pyridyl) nicotinamide

 Glue 8

 Production of 2,6-dichloro-5-fluoro-N- (4-pyridyl) nicotinamide:

 3.5 g of 2,6-dichloro-1,5-fluoronicotinic acid synthesized in accordance with the method described in JP-A-61-72753, 1.9 g of 4-aminopyridine, and 200 m of methylene chloride 3.9 g of 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride is added to the mixture consisting of 1 and stirred at room temperature for 1 hour. The reaction solution is extracted twice with 300 ml of black-mouthed form, and the extract is washed twice with 100 mL of a saturated diet. After drying over magnesium sulfate, the mixture was concentrated, the residue was subjected to silica gel column chromatography, eluted with chloroform (20: 1), purified, and recrystallized from acetonitrile, 2.7 g. Get.

Melting point 1 68— 1 70:

Participant example 9

 Production of 2,4-difluoronicotinic acid:

Dissolve 20 g of 2,4-difluoroviridine in 200 ml of tetrahydrofuran, and add 130 ml of 1.56 M n-butyllithium hexane solution dropwise while stirring at 178 under nitrogen replacement. Stir at warm for 30 minutes. Then slowly add dry ice and when the temperature stops rising, add 10 ml of methanol. Add the reaction mixture to 10 Om1 in ice, wash with 7 Om1 of getyl ether, and add Extract twice with 550 ml of getyl ether, wash twice with 150 ml of saturated saline, dry over magnesium sulfate, and concentrate to obtain 26.2 g of the desired product. Glue 1 Q

 Preparation of 2-Methoxy methoxymethyl 4- 4-nitropyridine:

 3.0 g of 60% sodium hydride was washed with getyl ether, 100 ml of tetrahydrofuran was added, and the mixture was stirred at 0 and stirred according to the method described in J. Antibiotics 44, 1172 (1991). 9.5 g of hydroxymethyl-1-nitropyridine are added dropwise. After 30 minutes, a mixture of 6.0 g of chloromethyl methyl ether and 100 ml of tetrahydrofuran is added. After heating under reflux with stirring for 2 hours, add 100 ml of ice water, neutralize with diluted hydrochloric acid, and extract twice with 300 ml of ethyl acetate. After washing with water, the extract was dried over magnesium sulfate, and then difficult. The residue was subjected to silica gel column chromatography, and eluted with chloroform to purify to obtain 9.0 g of the desired product as an oil.

Reference example 1 1

 Preparation of N— (2-chloromethyl-4-pyridyl) _2 — [(2,4-dimethoxybenzyl) thio] nicotinamide:

 2-[(2,4-Dimethylbenzyl) thio] —N- (2-Hydroxymethyl-41-pyridyl) nicotinamide (10 g) was added to methylene chloride (200 ml), and the mixture was stirred. 5 ml is added dropwise, and the mixture is stirred at room temperature for 1 hour. Under ice cooling, 20 ml of water is added dropwise to the reaction mixture, and a saturated aqueous solution of sodium hydrogen carbonate is added until the solution becomes neutral. The reaction solution is extracted twice with 100 ml of chloroform, washed twice with 50 ml of saturated saline, dried over magnesium sulfate, and then dried. The residue was subjected to silica gel column chromatography, and eluted with chloroform-methanol (40: 1). Purification yielded 5.4 g of the desired product.

 ■ 1 2

2 — [(2,4-Dimethoxybenzyl) thio] -1-N— (2-phthalimidomethyl-4 —Pyridyl) nicotinamide production:

 N- (2-chloromethyl_4-pyridyl) 1-2-[(2,4 dimethylbenzyl) thio] nicotinamide 3.0 g and phthalimid potassium 1.555 g dimethylformamide 200 m1 And stirred at 90 for 1 hour. The reaction mixture is concentrated under reduced pressure, extracted twice with 100 ml of chloroform, washed twice with 20 ml of saturated saline, dried over magnesium sulfate, and dried. The residue was subjected to silica gel column chromatography, and eluted and purified with chloroform-methanol (50: 1) to give 2.65 g of the desired product.

Reference Example 1 3

 Preparation of 2-ethyl-1-fluoro-4- (4-methyl-1-piperazinyl) nicotine ethyl ester:

 Chem. Pharm. Bull. 35, 2280 (1987), synthesized according to the method described in 2,6-Dichloro-1-ethyl 5-fluoronicotinate 31 g, 1-methylbiperazine 19 g, acetonitrile 150 The mixture is heated to reflux for 30 minutes with stirring. After concentration under reduced pressure, add 20% aqueous solution of 10% sodium carbonate, and extract twice with 50 mL of outlet. The extract is dried over magnesium sulfate and then condensed to obtain 39 g of the desired product.

Participant example 1 4

 Production of 2-—chloro-5-fluoro-6— (4-methyl-1-piperazinyl) nicotinic acid:

2-N-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) To a mixture consisting of 2.9 g of ethyl nicotinate and 3 Om1 of ethanol was added 28 ml of a 1N aqueous sodium hydroxide solution and 80 ml And stir for 10 minutes. After neutralization with dilute hydrochloric acid, the crystals are collected to give 2 g of the desired product. Glue 1 5

 Preparation of 2-[(2,4-dimethoxybenzyl) thio] nicotinic acid:

 4 Oml of concentrated hydrochloric acid is added to a mixture of 42 g of 2-mercaptonicotinic acid, 50 g of 2,4-dimethoxybenzyl alcohol and 30 Om1 of tetrahydrofuran, and the mixture is stirred at room temperature for 30 minutes. After the completion of the reaction, neutralize by adding 400 ml of a saturated aqueous solution of sodium hydrogen carbonate, and concentrate under reduced pressure to 400 ml. After cooling the mixture containing the precipitate, the precipitate is collected by filtration and washed with water to obtain 69 g of the desired product.

 Using the corresponding starting compound instead of 2,4-dimethoxybenzyl alcohol in the above, the reaction and treatment are carried out in the same manner as above to obtain the following compound.

(1) 2— [(2,4,6-trimethoxybenzyl) thiodinicotinic acid;

 The starting compound 2,4,6-trimethoxybenzyl alcohol is synthesized according to the method described in J. Org. Chem., 513013 (1992).

 (2) 2 — [(2,4-dimethoxy-13-methylbenzyl) thio] nicotinic acid

 (3) 2-[(2,4-Dimethoxy-1-6-methylbenzyl) thio] nicotinic acid

(4) 2 — [[1- (4-Methoxyphenyl) ethyl] thio] nicotinic acid;

 The starting compound 11- (4-methoxyphenyl) ethyl alcohol is synthesized according to the method described in JP-A-58-77841.

 (5) 2 — [(2-ethoxy-1-4-methoxybenzyl) thio] nicotinic acid

 (6) 2-[(4-Methoxy-1- 2-methoxymethoxybenzyl) thio] nicotinic acid

(7) 2 — [[2- (2-Fluoroethoxy) 1-4-methoxybenzyl] thio] nicotinic acid

 (8) 2 — [[2- (2-hydroxyethoxy) 1-4-methoxybenzyl) thio] nicotinic acid

 1

Preparation of 2,4-Dimethoxy 6-methylbenzyl alcohol: (1) 25.Og of 2,4-dihydroxy-6-methylethylbenzoate and 31.7m1 of methyl iodide were added to 40Om1 of dimethylformamide, and 38.6g of carbon dioxide rim was added. After the addition, stir at 70 for 2 hours. The reaction mixture is concentrated under reduced pressure and extracted with getyl ether. The extract is washed with saturated saline (2 Om1), dried over magnesium sulfate, and concentrated under reduced pressure to obtain 28.0 g of crude ethyl 2,4-dimethoxy-6-methylbenzoate.

 (2) Dissolve 28 g of the above compound in 500 ml of tetrahydrofuran, add 6.98 g of lithium aluminum hydride under ice cooling, and stir the mixture at room temperature for 2 hours. Under ice-cooling, 4 Om 1 of methanol and 5 ml of water are added, and the reaction mixture is concentrated under reduced pressure, and extracted twice with 200 ml of ethyl acetate. The extract is washed twice with 2 Om 1 of saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 23.O g of the desired product.

Participant example 1 7

 Preparation of 2-[(2,4-Jetoxybenzyl) thio] nicotinic acid:

 Add 2 Og of 2,4-diethoxybenzyl alcohol to 400 ml of toluene, add 6 Om1 of concentrated hydrochloric acid, and stir at room temperature for 30 minutes. The reaction solution is extracted twice with 100 ml of toluene, washed twice with 3 Om 1 of saturated saline, dried over magnesium sulfate, and then compressed under reduced pressure. Methylene chloride 50 Om 1 and 1-3.8 g of 2-mercaptonicotinic acid are added to the residue, and triethylamine 13.5 g is added under ice-cooling, followed by stirring at room temperature for 6 hours. After the reaction solution is extracted twice with 10 ml of form, then washed twice with 3 ml of saturated saline. The extract is dried over magnesium sulfate and reduced under reduced pressure to obtain the desired product 28.

Participant example 1 S

Production of 2- (2-hydroxyethoxy) -1-methoxybenzyl alcohol: Dissolve 32 g of 2- (2-acetoxethoxy) -14-methoxybenzaldehyde in 50 Om 1 of methanol, 4.5 g of sodium borohydride slowly under ice-cooling Stir at room temperature for 30 minutes. After slowly adding acetone 2 Om 1 to the reaction mixture, the mixture is concentrated under reduced pressure, and extracted twice with 20 mL of form. Extract the saturated saline 4

Wash twice with Oml, dry over magnesium sulfate, and compress under reduced pressure to obtain 25 g of the desired product.

 Using the corresponding starting compounds, react and treat in the same manner as above to obtain the following compounds

 (1) 2 ethoxy-1-4-methoxybenzyl alcohol

 (2) 4-Methoxy 2-Methoxy methoxybenzyl alcohol

 (3) 2,4-Jetoxybenzyl alcohol

 Example 1 9

 Preparation of 2- (2-acetoxetoxy) -1-4-methoxybenzaldehyde: 20 g of 2-hydroxyl 4-benzaldehyde and 26.7 g of acetic acid 2-chloroethyl ester 16.7 ml In addition to dimethylformamide 20 Om1, 27.2 g of potassium carbonate was added, and the mixture was stirred at 150 "C for 3 days. The reaction mixture was concentrated under reduced pressure, Extract twice with Om1, wash the extract twice with 40 ml of saturated aqueous sodium hydrogen carbonate solution, dry over magnesium sulfate, and concentrate under reduced pressure to obtain 32 g of the desired product.

Participant example 2 0

 2—Ethoxy 4-Methoxyethoxybenzaldehyde Production:

 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.

Reference Example 2 1

 Production of 2,4-diethoxybenzaldehyde:

Instead of 2-hydroxy-4-methylbenzaldehyde and acetic acid 2-cloethyl ester in Reference Example 19, 4-ethoxy-2-hydroxy was used respectively. The desired product is obtained by reaction and treatment in the same manner as in Reference Example 19 using schibenzaldehyde and bromo bromide.

Reference Example 22

 Manufacture of 4-Methoxy 2-benzaldehyde:

 Add 25 g of 2-hydroxyl 4-hydroxybenzaldehyde, 25 ml of dimethyl ether and 9 Om 1 of disopropyrethylamine to 500 ml of tetrahydrofuran and stir at room temperature for 24 hours. . After concentrating the reaction mixture under reduced pressure, extract twice with 200 ml of ethyl ether. The extract is washed twice with 40 ml of saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 33 g of the desired product.

Reference Example 23

 Preparation of 2- (2-fluoroethoxy) -1-4-methoxybenzyl alcohol:

(1) Instead of 2-hydroxy-14-methoxybenzaldehyde and acetic acid 2-chloroethyl ester in Reference Example 24, 10 g of methyl 2-hydroxy-14-methylbenzoate and 2-fluoroethyl chloride were used, respectively. 4. Using 7 ml, the reaction was carried out in the same manner as in Reference Example 24 to obtain 12 g of methyl 2- (2-fluoroethoxy) -14-methoxybenzoate.

 (2) To a mixture of 12 g of the 2-fluoroethoxy compound and 150 ml of getyl ether, 1.9 g of lithium aluminum hydride was added under ice-cooling, followed by stirring at room temperature for 30 minutes. Under ice-cooling, add 10 ml of methanol and 5 ml of water, compress the reaction solution under reduced pressure, and extract twice with 100 ml of chloroform. The extract is washed twice with 20 ml of a saturated saline solution, dried over magnesium sulfate, and reduced under reduced pressure to obtain 16 g of the desired product as a crude product.

Reference Example 24

2-[[4-Methoxy-1-2- [2- (Methoxymethoxy) ethoxy] benzyl] thio] Production of nicotinic acid: 2 — [[2- (2-Hydroxychetoxy) -14-methoxybenzyl] thio] nicotinic acid (7.0 g), chlorodimethyl ether (4.8 ml) and diisopropylethylamine (18 ml) were added to methylene chloride (200 ml). Then, stir at room temperature for 16 hours. After concentrating the reaction mixture under reduced pressure, extract twice with 200 ml of ethyl acetate. 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.

Participant example 2 Ώ

 Production of 2,4-dimethoxyphenylmethanethiol:

 A mixture of 19 g of 2,4-dimethoxybenzyl alcohol, 25 g of Lawesson's reagent and 30 Om1 of toluene is heated to reflux. After the reaction mixture was reduced under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with chloroform-hexane (1: 1). Purification was performed to obtain 6.2 g of the desired product as an oil.

Reference Example 26

 Preparation of 3-oxo-1- (4-pyridyl) isothiazolo [5,4-b] pyridine (compound B in Test Example 1):

2-[(Benzhydryl) sulfinyl] 1 N- (4-pyridyl) nicotinamide 15 g was added to methanol 40 Om1, 25 ml of concentrated hydrochloric acid was added dropwise with stirring under ice-cooling, and the mixture was allowed to stand at room temperature for 4 hours Stir. Add 200 ml of a saturated aqueous solution of sodium bicarbonate and extract twice with 400 ml of form. After the extract is dried over magnesium sulfate, the extract is compressed under reduced pressure, and the residue is recrystallized from chloroform-methanol to obtain 4 g of the desired product. 238-240

 Reference Example 2 7 to 32

 The corresponding nicotinamides were used in place of 2-([benzhydryl) sulfinyl] -N- (4-pyridyl) nicotinamide in Reference Example 26, and the reaction and treatment were performed in the same manner as in Reference Example 26 to obtain the following. Obtain the compound.

 (Reference Example 27)

 2- (2,6-Dimethyl-1-4-pyridyl) -1,3-oxoisothiazolo [5,4-1b] Pyridine (Compound C in Test Example 1): Melting point 164-167 V (from acetate nitrile) Crystal)

 (Reference Example 28)

 2- (2-Methyl-1-pyridyl) -13-oxoisothiazolo [5,4-b] pyridine · pentahydrate (Compound D in Test Example 1): Melting point 160-161 (acetonitrile Recrystallized from)

 (Participant example 2 9)

 2- (2-dimethylamino-4-pyridyl) -1,3-oxoisothiazolo [5,

41-b] Pyridine · 14 ethanol (Compound E in Test Example 1): melting point 182-184 (recrystallized from ethanol)

 (Reference Example 30)

 2- (2,5-dimethyl-14-pyridyl) -1,3-oxoisothiazolo [5,4-1b] pyridine: melting point 142-144 (recrystallized from acetone)

 (Reference Example 3 1)

 2- (2-Methylamino-1-4-pyridyl) 1,3-oxoisothiazolo [5,4-b] pyridine · 1/20 hydrate: melting point 180-185 (reconstituted from methanol

B \

Saying /

(Example 32) 2- (2-amino-1-4-pyridyl) -1,3-oxoisothiazolo [5,4-b] pyridine: melting point 224–226 (recrystallized from methanol)

Reference Examples 33 to 34

 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.

 (m a a)

 N— (2-Chloromethyl-1-pyridyl) -2 -— [(2,4-Dimethoxybenzyl) sulfinyl] nicotinamide: crystal

 (#Example 34)

 2-[(2,4-Dimethoxybenzyl) sulfinyl] 1 N (2-phthalimidmethyl-1 4-pyridyl) nicotinamide: oil

 Shelf 1

 Preparation of tablets:

 '2— [(2,4-Dimethoxybenzyl) sulfinyl] — N (2,6-dimethyl' 4-pyridyl) nicotinamide 20 g

 • 2 8 g corn starch

 • Shioshi f 65 g

 • 30 g crystalline cellulose

 '' Hydroxypropylcellulose 5 g

 -1 g of light caffeic anhydride

 '' 1 g magnesium stearate

According to a conventional method, 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.

Formulation Example 2

 Preparation of powder:

 • 2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— (2-Dimethylamino-1-pyridyl) nicotinamide 100 g

• 200 g of corn starch

 -Lactose 660 g

 '' Hydroxypropylcellulose 30 g

 -Light caylic anhydride 10 g

 According to a conventional method, the above components are mixed and granulated to prepare a 10% powder.

 Uto-no Hell llfflW #

 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).

Claims

The scope of the claims 1. A 2-sulfinylnicotinamide derivative represented by the following formula (I) or a pharmaceutically acceptable acid addition salt thereof.

In the formula, R 1 represents a group represented by the following formula (A), (B) or (C),

 [A] [B] [C] Here, R 11 is a hydrogen atom, a Ci-C ₃ alkyl group, a hydroxy (Ci C ^ alkyl group, a C ₂ -C ₅ alkanoyloxy (C i- (: ₃ ) alkyl group, a methoxy (Ci C means alkoxymethyl, aminomethyl, mono- or di-substituted aminomethyl, amino or mono- or di-substituted amino, R 1 ² is a hydrogen atom or a C i~C ₃ alkyl group, R 1 ³ is a hydrogen atom or a C! Means ~ C ₃ alkyl group, R 14 and R 15 each represent a hydrogen atom, and the other represents a C] to C ₃ alkoxy group or a mono- or di-substituted amino group; R 16 represents a ci-C ゥ alkyl group, R 2 is a hydrogen atom,. Means an alkyl group, an amino group or a mono- or di-substituted amino group,  R 3 represents a hydrogen atom or a halogen atom, R represents a hydrogen atom or a C i -C ₃ alkyl group, and (i) when R 4 is a hydrogen atom,  R 5 is Ci Cs alkoxy group, halogeno (C i C alkoxy group, hydroxy (C ₂ ~C ₃₎ alkoxy groups, C i Cs alkoxy (C i~ (: ₃₎ alkoxy group or means C i Cs alkoxy (Ci~C ₂₎ alkoxy (C ₂ ~C ₃₎ alkoxy , R ⁶ represents a hydrogen atom or a C i -C ₃ alkyl group, R 7 represents a C i Cg alkoxy group, R 8 represents a hydrogen atom, R ⁹ represents a hydrogen atom, a C i C ^ alkyl group or a C i Cg alkoxy group, and (ii) when R 4 is C i-(: 3 alkyl group, R5, R6, R8 and R9 represent a hydrogen atom, R 7 represents a C Cs alkoxy group. ] 2. The compound according to claim 1, wherein Ri is of the formula [A] or [B].  3. The compound according to claim 1, wherein R 4 is a hydrogen atom. 4. In the formula [A], Ri 1 is a C ₃ -C ₃ alkyl group, a hydroxymethyl group, a C _2- (: ₅ alkanoyloxymethyl group or a di (di-) alkylamino group, A hydrogen atom or a C i -C ₃ alkyl group, a R 13 hydrogen atom, In the formula [B], R 14 is a C i Cg alkoxy group, and R 15? Is a hydrogen atom 4. The compound according to claim 2, wherein R 14 is a hydrogen atom, and R 15 is a di (C i -C ₃ ) alkylamino group.  5. R 5 and R 7 are the same or different and each is a methoxy group or an ethoxy group; 5. The compound according to claim 4, wherein R ⁶ , R ⁸ and R ⁹ are all hydrogen atoms.  6. A 2-sulfinylnicotinamide derivative represented by the following formula (Γ).

In the formula, R i ′ represents a group represented by the following formula [A,] or [Β ′],

Here, 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, 'The eyes butoxy group, R 1 5' R 14 or is a hydrogen atom, or R 1 ⁴ 'is hydrogen atom, R i 5, means Jimechiruamino group. ]  7. 2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— (2-Methyl-1-pyridyl) nicotinamide, 2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— (2,5-dimethyl Chill-1 41-pyridyl) nicotinamide,  2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— (3-Methyl-2-dimethylamino-4-pyridyl) nicotinamide,  N— (2-acetoxymethyl-4-pyridyl) -1-2 _ [(2,4-dimethoxybenzyl) sulfinyl] nicotinamide,  N- (2-Acetoxymethyl-13-methyl-4-pyridyl) 1-2-[(2,4 Dimethoxybenzyl) sulfinyl] nicotinamide,  N— (6-acetoxymethyl-2-methyl-1-pyridyl) — 2 — [(2,4—dimethoxybenzyl) sulfinyl] nicotinamide,  2 — [(2,4-Dimethoxybenzyl) sulfinyl] 1 N— (2-propionyloxymethyl-4-pyridyl) nicotinamide,  N— (2-Ptyryloxymethyl-4-pyridyl) 1-2 — [(2,4-Dimethoxybenzyl) sulfinyl] nicotinamide,  2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— (2-valeryloxymethyl-4-pyridyl) nicotinamide,  2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— (2-Methyl-6-propionyloxymethyl-14-pyridyl) nicotinamide,  2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— (2-hydroxymethyl-4-pyridyl) nicotinamide,  2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— (2-Hydroxymethyl-3-methyl-4-pyridyl) nicotinamide,  2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— (6—Hydroxymethyl1-2-methyl-1-4-pyridyl) nicotinamide, 2-[(2,4-Dimethoxybenzyl) sulfinyl] — N— (4-Methoxy-3-pyridyl) nicotinamide, and 2-[(2,4-Dimethoxybenzyl) sulfinyl] — A 2-sulfinylnicotinamide derivative selected from N- (6-dimethylamino 3-pyridyl) nicotinamide.  8. 2 — [(2,4-Dimethoxybenzyl) sulfinyl] 1 N— (2,6-Dimethyl-4-pyridyl) nicotinamide.  9. 2 — [(2,4-Dimethoxybenzyl) sulfinyl] —N— (2-Dimethylamino-1-4-pyridyl) nicotinamide.  10. Equation (II)

 (Wherein, R i represents a group represented by the following formula (A), (B) or (C),

 [A] [B] [C] Here, R 11 is a hydrogen atom, a C i-(: ₃ alkyl group, a hydroxy (C i-(: ₃ ) alkyl group, a C ₂ -C ₅ alkanoyloxy ((:!-じ ^ alkyl group) , Methoxy ((:-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 1 ² is a hydrogen atom or a C ~ C ₃ alkyl group, R i ³ represents a hydrogen atom or a C ₃ alkyl group, R 14 and R is one 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-C 3 alkyl group, R 2 represents a hydrogen atom, a Ci-C ₃ alkyl group, an amino group or a 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-C ₃ alkyl group,  (i) When R 4 is a hydrogen atom,  R5 is CiCg alkoxy group, halogeno (CiC alkoxy group, hydroxy (C _2- (: ₃ ) alkoxy group, Ci-C ₃ alkoxy (Ci C alkoxy group or Ci-C ₂ alkoxy (Ci-C ₂ ) alkoxy (C ₂ -C ₃ ) alkoxy group, R ⁶ is a hydrogen atom or C! Means -C ₃ alkyl group, 1¾ 7 means (1 ₍₃ Arukokishi group, R 8 represents a hydrogen atom, R 9 represents a hydrogen atom, a C i -C ₃ alkyl group or a C 1-(: ₃ alkoxy group, and (ii) when R 4 is a C i Cs alkyl group,  R5, R6, R8 and R9 represent a hydrogen atom, 1 to 7 is ₁ to ₃ ( ₃ means alkoxy group.) Wherein the compound represented by the following formula (I) is oxidized, and if necessary, the product is converted into a pharmaceutically acceptable acid addition salt.

 (In the formula, R1, R2, R3, R4, R5, R6, R7, R8 and R9 mean the same as described above.) Or a pharmaceutically acceptable acid addition salt thereof.  1 1. Equation (1-1)

 [Wherein, X represents a halogen atom, n means 0 or 1,  R2 represents a hydrogen atom, a C i Cg alkyl group, an amino group or a mono- or di-substituted amino group,  R 3 represents a hydrogen atom or a halogen atom, R is a hydrogen atom or a C ~ C ₃ alkyl group,  (i) When R 4 is a hydrogen atom, R 5 is a C i -C ₃ alkoxy group, a halogeno (C 1-(: ₃ ) alkoxy group, a hydroxy (C ₂ ~C ₃₎ alkoxy groups, C i~C ₃ alkoxy (C i~ (: ₃₎ alkoxy group or the C ~ (: ₂ alkoxy (Ci~ (: ₂₎ alkoxy (C ₂ ~C ₃₎ Means an alkoxy group, R 6 represents a hydrogen atom or a C i -C ₃ alkyl group, R 7 represents a C i-C ₃ alkoxy group,  R 8 represents a hydrogen atom, R 9 represents a hydrogen atom, a C i-C ₃ alkyl group or a C: L-C ₃ alkoxy group, and (ii) when R 4 is a C i-C ₃ alkyl group,  R5, R6, R8 and R9 represent a hydrogen atom, R 7 is C. 3 means an alkoxy group, R 1 ² is a hydrogen atom or a C i~C ₃ alkyl group, R 1 ³ represents a hydrogen atom or a C Interview -C ₃ alkyl group. The compound represented by the following formula (X)  R 19-H (X) (In the formula, R ¹⁹ represents a phthalimid group or a mono- or di-substituted amino group.) Characterized by a hydrolysis reaction or a hydrazine decomposition reaction as required.

 (Wherein R i 9, represents an amino group or a mono- or di-substituted amino group, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13 and _n have the same meanings given above. ) A method for producing a compound represented by the formula:  12. A 2-mercaptonicotinamide derivative represented by the following formula (II).

 Wherein Ri represents a group represented by the following formula (A), (B) or (C),

 [A] [B] [C] In the formula, R 11 is a hydrogen atom, Ci〜 (: ₃ alkyl group, hydroxy (Ci C ₃ ) Alkyl group, C ₂ -C ₅ alkanoyloxy Noi Ruo carboxymethyl (C i~C ₃₎ alkyl group, main butoxy (Ci~ (: ₃₎ alkoxymethyl group, aminomethyl group, a mono- or di-substituted aminomethyl group, an amino group or Means a mono- or di-substituted amino group, R 12 represents a hydrogen atom or a C i-C ₃ alkyl group, R 1 ³ is a hydrogen atom or a C Cg alkyl group,  R 14 and R 15 each represent a hydrogen atom, the other represents a C i C ^ alkoxy group or a mono- or di-substituted amino group, R 16 represents a CC ₃ alkyl group, R ² represents a hydrogen atom, an alkyl group, a no group or a mono- or di-substituted no group, R ³ represents a hydrogen atom or a halogen atom, R ⁴ represents a hydrogen atom or a C i-C 3 alkyl group,  (i) When R 4 is a hydrogen atom, R5 is Ci C ^ alkoxy group, a halogeno-alkoxy group, hydroxy (C ₂ - (: ₃₎ alkoxy group, Ci～C ₃ alkoxy ₃₎ alkoxy group or an alkoxy (Ci~C ₂₎ alkoxy (C ₂ -C ₃ ) means an alkoxy group, R ⁶ represents a hydrogen atom or a C to (: ₃ alkyl group; R 7 represents a C 1-(: ₃ alkoxy group; R 8 represents a hydrogen atom, R ⁹ is a hydrogen atom, a C ₃ -C ₃ alkyl group or C! Means ~C ₃ alkoxy group, (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. ]  13. A 3-oxoisothiazolo [5,4-b] pyridine derivative represented by the following formula (III).

 Wherein Ri represents a group represented by the following formula (A), (B) or (C),

Here, Ri] is hydrogen atom, Ci Cg alkyl group, human Dorokishi (C! Cs) alkyl group, C 2 to C ₅ alkanoyloxy Noi Ruo carboxylate (CC alkyl group, main butoxy (Ci-C 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 1 ² is a hydrogen atom or a C i~C ₃ alkyl group, R 1 ³ is a hydrogen atom or a C ₃ alkyl group, One of R 14 and R 15 represents a hydrogen atom, the other represents a C-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, a Ci Cg alkyl group, an amino group or a mono- or di-substituted amino group, R ³ represents a hydrogen atom or a halogen atom. ] 14. A pharmaceutical composition comprising the 2-sulfinylnicotinamide derivative according to claim 1 or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.  15. A pharmaceutical composition comprising the 2-sulfinylnicotinamide derivative according to claim 6 as an active ingredient.  16. A remedy for peptic ulcer, comprising as an active ingredient a 2-sulfinylnicotinamide derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 1.  17. A remedy for peptic ulcer, comprising the 2-sulfinylnicotinamide derivative according to claim 6 as an active ingredient.  18. A method for treating peptic ulcer, which comprises administering an effective amount of the 2-sulfinylnicotinamide derivative or the pharmaceutically acceptable acid addition salt thereof according to claim 1 to a patient having symptoms of peptic ulcer. .  19. A method for treating peptic ulcer, which comprises administering an effective amount of the 2-sulfinylnicotinamide derivative according to claim 6 to a patient having symptoms of anaplastic ulcer.  20. Use of the 2-sulfinylnicotinamide derivative or the pharmaceutically acceptable acid addition salt thereof according to claim 1 for the treatment of peptic slippage.  21. Use of the 2-sulfinylnicotinamide derivative according to claim 6 for the treatment of peptic ulcer.