JPH08176113A - 2-sulfinyl nicotinamide derivative and its intermediate, and therapeutic agent for peptic ulcer containing the same as active ingredient - Google Patents

Abstract

(57) [Summary] [Structure] Chemical formula 1 [Chemical formula 1] [In the formula, R ¹ means phenyl optionally substituted with mono- or di-substituted amino at the 4-position; pyridyl optionally substituted with hydroxy (lower) alkyl, lower alkanoyloxy (lower) alkyl etc. R ² is hydrogen;
It means lower alkyl and the like, and R means a group represented by the following formula (A). Embedded image (In the formula, R ³ represents a hydrogen atom and the like, R ⁴ represents hydrogen; lower alkyl and the like, and R ⁵ represents unsubstituted or substituted aryl and the like.)], And an intermediate thereof. A therapeutic agent for peptic ulcer containing the body and the compound of Chemical formula 1 as an active ingredient. [Effect] The compound of the present invention has an excellent gastric acid secretion inhibitory action and can be used as a therapeutic agent for peptic ulcer.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention relates to H ⁺ , K ⁺ -ATPa.
A novel 2-sulfinylnicotinamide derivative having a gastric acid secretion inhibitory action based on se (proton pump) inhibitory action, a 2-mercaptonicotinamide derivative which is a novel intermediate thereof, and a digestion using the 2-sulfinylnicotinamide derivative as an active ingredient Ulcer treatment drug.

[0002]

[Prior Art] Tetrahedron Letters, 33 , 153-156 (19
92) includes 2- (benzyl) sulfinyl-N- (phenyl) nicotinamide and 2- (benzyl) sulfinyl-N- (4-methoxyphenyl) nicotinamide, 2-phenyl- and 2- (4-methoxy), respectively. The use as a synthetic intermediate of phenyl)-[5,4-b] -pyridoisothiazolone is disclosed, but no mention is made of its efficacy.

JP-A-5-32631 discloses a 2-mercaptonicotinic acid derivative represented by the following chemical formula 10 and describes that it is useful as an agent for controlling internal parasites.

[0004]

[Chemical 10]

(In the formula, R ¹ is optionally halogen, cyano, nitro, amino, alkylamino, aminoacyl, alkyl, aralkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, aryl. C ₁ optionally substituted with sulfonyl, halogenoalkylthio, halogenoalkylsulfinyl, halogenoalkylsulfonyl or carbonylaryl
-C ₈ - alkyl, aralkyl, aryl or heteroaryl group, X is O or -N (R ³⁾ - represents, R
² represents C ₁ -C ₅ -alkyl, aralkyl, alkenyl or alkynyl, R ³ represents H or alkyl,
Alternatively, R ¹ and R ³ together with adjacent N atoms may contain O or N as an additional heteroatom and are optionally 5- or 6-membered with C ₁ -C ₄ -alkyl. And R ⁴ represents hydrogen, halogen, optionally substituted alkyl, halogenoalkyl, cyano, nitro, amino, aminoacyl, phenyl, alkoxy, aryloxy, thioalkyl and arylthio. )

In JP-A-5-221994, a nicotinic acid anilide derivative represented by the following chemical formula 11 shows a bactericidal action against the fungus Botrytis bacterium (Botrytis) and is extremely effective in controlling it. Is described.

[0007]

[Chemical 11]

(In the formula, R ¹ represents halogen, methyl, trifluoromethyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl, and R ² represents alkyl, alkenyl, alkoxy, etc., which may be optionally substituted with halogen. )

[0009]

Recently, the number of patients with peptic ulcer such as gastric ulcer and duodenal ulcer has been increasing due to complication of social life, advent of aging society and the like. Excessive gastric secretion is considered to be the main cause of peptic ulcer, and its treatment is treated with histamine H ₂ receptor antagonists, anticholinergic agents, H ⁺ ,
Gastric acid secretion inhibitors such as K ⁺ -ATPase (hereinafter sometimes referred to as “proton pump”) inhibitors have been used. Currently marketed proton pump inhibitors are omeprazole [eg Merck Index, 11th Edition, 6800 (198
9) and lansoprazole [eg Drugs Fut., 1
4 , 625 (1989); see 16 , 665 (1991)]. All of these are taken up by the acidic site (secretory canaliculus) of gastric parietal cells, and then structurally changed into an active form by acid, and reacted with the cysteine residue of the proton pump which is an enzyme involved in the final stage of gastric acid secretion. It is said to deactivate the enzyme. It is considered that this mechanism of action leads to a strong gastric acid secretion inhibitory effect of these drugs, high tissue selectivity, and eventually fewer side effects.

However, existing proton pump inhibitors also have some drawbacks such as affecting drug metabolism and are not always satisfactory. Currently, several kinds of proton pump inhibitors are under development, but most of them have a benzimidazole or imidazole skeleton as a basic skeleton like existing proton pump inhibitors. Therefore, it has a completely different basic skeleton from existing and under development proton pump inhibitors, and has a mechanism of action similar to that of existing proton pump inhibitors, that is, it is activated by acid after being taken up at the acidic site of gastric parietal cells. A compound that changes its structure in the body and exerts a proton pump inhibitory action may possibly supplement the drawbacks of the existing and developing proton pump inhibitors.

[0011]

Means for Solving the Problems As a result of continuous studies, the present inventors have shown that a 2-sulfinylnicotinamide derivative represented by the following formula (I) exhibits a strong proton pump inhibitory action under acidic conditions, Moreover, they have found that they also have an excellent gastric acid secretion inhibitory effect in vivo, and completed the present invention.

According to the present invention, there is provided a 2-sulfinylnicotinamide derivative represented by the following formula (I) and a therapeutic agent for peptic ulcer containing the derivative as an active ingredient.

[0013]

[Chemical 12]

[Wherein R ¹ is a phenyl group which may be substituted at the 4-position with amino, mono- or di-substituted amino, amino (lower) alkyl or mono- or di-substituted amino (lower) alkyl; naphthyl group; halogen , Lower alkyl, lower alkoxy, hydroxy (lower) alkyl and lower alkanoyloxy (lower) alkyl, which may be substituted with 1 to 4 pyridyl groups; or quinolyl group, pyrimidinyl group, pyrazinyl group, thiazolyl group, It means a heteroaryl group selected from a 1,8-naphthyridinyl group and an acridinyl group, and the heteroaryl group may be substituted with 1 to 2 selected from halogen, lower alkyl and lower alkoxy, and R ² is Hydrogen atom; halogen atom; lower alkyl group; lower alkoxy group; or halogen if Or R means a phenyl group which may be substituted with lower alkyl, and R means a group represented by the following formula (A).

[0015]

[Chemical 13]

(Wherein R ³ represents a hydrogen atom or a lower alkyl group, R ⁴ represents a hydrogen atom; a lower alkyl group; or a phenyl group which may be substituted with halogen or lower alkyl, and R ⁵ Means an unsubstituted or substituted aryl group; or an unsubstituted or substituted heteroaryl group.)

However, (i) when both R ³ and R ⁴ are hydrogen atoms, R ⁵ is not an unsubstituted phenyl group, and (ii)
It is assumed that the pK _{R +} value of the carbonium ion R ⁺ derived from the group R, which is calculated by the following mathematical formula 2, satisfies the condition of larger than −16 and smaller than −7.

[0018]

## EQU2 ## pK _{R +} = 0.385 × (H _{R +} −H _ROH )
+78.0

[In the formula, H _{R +} and H _ROH are the heats of formation of the carbonium ion R ⁺ and the alcohol ROH, respectively (kcal
/ mol) is meant. ]]

The present invention also provides a compound of formula (II) which is useful as an intermediate of the compound of formula (I) (hereinafter sometimes referred to as "intermediate of the invention").

[0021]

Embedded image

(In the formula, R ¹ , R ² and R have the same meanings as described above.)

Since the compounds represented by the formulas (I) and (II) may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the present invention. To be done.

Since the compound of formula (I) has a sulfinyl group, at least two stereoisomers can exist. The compounds of formula (I) may optionally have one asymmetric carbon atom, in which case four stereoisomers may exist. These stereoisomers, their mixtures and racemates are included in the compounds of the present invention. In the case of the compound of formula (II) having one asymmetric carbon atom, two stereoisomers may exist, and therefore these stereoisomers, their mixtures and racemates are intermediates of the present invention. Included in.

It is considered that the compound of formula (I) is taken up by the secretory canaliculi of gastric parietal cells and converted into a compound represented by the following formula (III) to exhibit a proton pump inhibitory action. Depending on the type of compound, the compound of formula (I) may itself exhibit a proton pump inhibitory action, but even in this case, since the formation of the compound of formula (III) was confirmed after the acid treatment, It is considered that after being taken up by the secretory canaliculi, it is converted into the compound of formula (III) and exhibits a proton pump inhibitory action.

[0026]

[Chemical 15]

(In the formula, R ¹ and R ² have the same meanings as described above.)

The pK _{R +} value calculated according to Equation 2 above quantifies the stability of the carbonium ion R ⁺ expected to be produced when the compound of formula (I) is converted to the compound of formula (III). it is a parameter, which is the inverse logarithm -log K R ₊ the defined values of the alcohol ROH and the carbonium ion R ⁺ parameters for equilibrium K _{R +} represented by Formula 15. _R satisfying the condition -16 <pK _{R +} <-7
A compound of formula (I) having ## STR3 ## converts to a compound of formula (III) under acidic conditions while being stable as such. Formula 2 Formulation Method and Heats of Formation of R ⁺ and ROH H _{R +} and H
How to obtain _ROH will be described later.

[0029]

Embedded image

(In the formula, R means the same as above.)

R in the formula (I), that is, the group represented by the formula (A) can be mainly classified into the following 5 types according to the types of R ³ , R ⁴ and R ⁵ .

First group : R ³ and R ⁴ are both hydrogen atoms,
When R ⁵ is an aryl group or heteroaryl group having a substituent other than a basic substituent and R ⁵ contributes considerably to the pK _{R +} value,

Second class : R ³ and R ⁴ are both hydrogen atoms,
When R ⁵ is an aryl group or heteroaryl group having a basic substituent and R ⁵ contributes considerably to the pK _{R +} value,

Class 3 : R ³ is a hydrogen atom, R ⁴ is a lower alkyl group, R ⁵ is an unsubstituted or substituted aryl group or an unsubstituted or substituted heteroaryl group, and pK of R ⁵ is
If the contribution to the _{R +} value is small compared to the first and second classes,

Class 4 : R ³ and R ⁴ are lower alkyl groups, R ⁵ is an unsubstituted or substituted aryl group or an unsubstituted or substituted heteroaryl group, and R ⁵ contributes little to the pK _{R +} value. If

Class 5 : R ³ is a hydrogen atom, R ⁴ is a phenyl group which may be substituted with halogen or lower alkyl, R ⁵ is an unsubstituted or substituted aryl group, R ^5
4 and R ⁵ contribute approximately the same amount to the pK _{R +} value.

PK of a representative example of R belonging to the first to fifth classes
_{The R +} values are shown in Tables 1-9.

With reference to these tables, specific examples of the definitions of R ³ , R ⁴ and R ⁵ described in the section “Explanation of Terms in the Present Specification” below and their electronic equivalents are shown. Since those skilled in the art can easily derive specific examples of R belonging to each class not shown in the table from the combination of such groups, those groups are naturally included in R of the present invention.

It is preferable that _R has a pK _{R +} value larger than −14 and smaller than −8.

The following abbreviations may be used for simplification of description in Tables 1 to 9 of the present specification and the examples described later.

Me: methyl group, Et: ethyl group, Pr: n-propyl group, i-Pr: isopropyl group, i-Bu: isobutyl group, t-Bu: tert-butyl group, i-Pen: isopentyl group, Ph: Phenyl group, Py: Pyridyl group, Benzim: Benzimidazolyl group.

Therefore, for example, Ph-4-OMe is a 4-methoxyphenyl group, Ph-2,4,6-Me ₃ is a 2,4,6-trimethylphenyl group, 3-Py-2,4- (OMe) ₂ is 2,4-dimethoxy-
3-pyridyl group, CH (Me) Ph is 1-phenylethyl group, P
h- (2-OCH ₂ O-3-) represents a 2,3-methylenedioxyphenyl group.

[0043]

[Table 1] pK _{R +} value of a representative example of R belonging to the first class ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ No. R ⁴ R ⁵ R ³ pK _{R +} ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 1 H Ph-4-OMe H -15.24 2 H Ph-4 -OEt H -14.59 3 H Ph-4-OPr H -14.61 4 H Ph-2,4- (OMe) ₂ H -11.49 5 H Ph-2,4- (OEt) ₂ H -11.43 6 H Ph-2 , 6- (OMe) ₂ H -12.35 7 H Ph-2-OMe-4-OEt H -11.91 8 H Ph-4-OMe-2-OEt H -11.89 9 H Ph-2-OMe-4-OCH ₂ FH -12.64 10 H Ph-4-OMe-2-OCH ₂ FH -12.73 11 H Ph-2,4,6- (OMe) ₃ H-9.57 12 H Ph-2,4,5- (OMe) ₃ H -10.87 13 H Ph-3,4,5- (OMe) ₃ H -15.65 14 H Ph-2,3,4,6- (OMe) ₄ H-9.50 15 H Ph-2,3,4,5- (OMe) ₄ H -11.50 16 H Ph-2,3,5,6- (OMe) ₄ H -13.18 17 H Ph-2,3,4,5,6- (OMe) ₅ H -11.58 18 H Ph -2,4- (OMe) ₂ -3-Me H -13.99 19 H Ph-2,4- (OMe) ₂ -6-Me H -11.39 20 H Ph-2,4- (OMe) ₂ -6- OCF ₃ H -12.66 21 H Ph-2,4,6- (OMe) ₃ -3,5-F ₂ H -13.51 22 H Ph-2,4- (OMe) ₂ -5-Br H -12.84 ━━ ━━━━━━━━━━━━━━━━━ ━━━━━━━━━

[0044]

[Table 2] Continuation of Table 1 : pK _{R +} value of a representative example of R belonging to the first class ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━ No. R ⁴ R ⁵ R ³ pK _{R +} ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 23 H Ph-2,4- (OMe ) ₂ -6-OH H-9.86 24 H Ph-2,6-Me ₂ -4-OH H -14.23 25 H Ph-2,3-Me ₂ -4-OMe H -13.87 26 H Ph-2,4 , 6-Me ₃ H -14.14 27 H Ph-4-NHCOMe H -15.08 28 H 3-Py-2,4- (OMe) ₂ H -13.53 29 H 3-Py-4,6- (OMe) ₂ H -13.71 30 H 3-Py-2,4,6- (OMe) ₃ H -10.48 31 H 2-Benzim-5-OMe H -14.72 32 H 2-Benzim-5,6- (OMe) ₂ H -11.85 33 H 2-Benzim- (5-OCH ₂ O-6-) H -14.21 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

[0045]

[Table 3] pK _{R +} value of a representative example of R belonging to the second class ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ No. R ⁴ R ⁵ R ³ pK _{R +} ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 34 H Ph-2-NH ₂ H -13.11 35 H Ph- 2-NHMe H -12.35 36 H Ph-2-NHPr H -11.67 37 H Ph-2-NH-i-Bu H -11.05 38 H Ph-2-NMe ₂ H -10.87 39 H Ph-2-N (Me ) Et H -10.32 40 H Ph-2-N (Me) Pr H -10.39 41 H Ph-2-N (Me) -i-Bu H -10.95 42 H Ph-2- (1-prolysinyl) H -10.22 43 H Ph-2-NMe ₂ -4-OMe H-8.93 44 H Ph-2-NMe ₂ -5-OMe H -10.54 45 H Ph-2-NMe ₂ -4-Cl H -11.72 46 H Ph-2 -NMe ₂ -3,5-Br ₂ H -14.85 47 H Ph-2-NMe ₂ -4,5-F ₂ H -13.47 48 H Ph-2-NMe ₂ -5-Me H -10.44 49 H Ph- 4-NMe ₂ -2,5-F ₂ H -12.53 50 H Ph-4-NH ₂ H -11.13 51 H Ph-4-NHMe H -10.43 52 H Ph-4-NMe ₂ H-9.79 53 H 3- _{py-2-NMe 2 H -11.69} 54 H 2-NMe 2 -3- Piraji sulfonyl _{H -15.01 55 H 4-NMe 2} -3- pyrazole Lil _{H -10.68 56 H 4-NMe 2} -5- Isochiaso Bu Lil H - 9.80 ━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━

[0046]

[Table 4] pK _{R +} value of a representative example of R belonging to the third class ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ No. R ⁴ R ⁵ R ³ pK _{R +} ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 57 Me Ph H -14.50 58 Me Ph-2-OMe H- 11.59 59 Et Ph-2-OMe H -11.08 60 Pr Ph-2-OMe H -11.62 61 Me Ph-3-OMe H -14.85 62 Me Ph-4-OMe H -11.02 63 Et Ph-4-OMe H- 10.66 64 i-Pr Ph-4-OMe H -10.53 65 Me Ph-2,4- (OMe) ₂ H-7.69 66 Me Ph-3,4- (OMe) ₂ H -11.17 67 Me Ph-3,4 , 5- (OMe) ₃ H -11.25 68 Me Ph- (2-OCH ₂ O-3-) H -12.86 69 Et Ph- (2-OCH ₂ O-3-) H -12.38 70 i-Pr Ph- (2-OCH ₂ O-3-) H -12.02 71 Me Ph- (3-OCH ₂ O-4-) H -12.58 72 Me Ph-4-Me H -13.05 73 Me Ph-4-t-Bu H -12.84 74 Me Ph-4-CH = CH ₂ H -12.52 75 Me Ph-4-Cl H -15.14 76 Me Ph-4-FH -15.00 77 Me Ph-4-NH ₂ H-7.30 78 Me Ph-4 -OH H -12.06 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

[0047]

[Table 5] Continuation of Table 4 : pK _{R +} value of a representative example of R belonging to the third class ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━ No. R ⁴ R ⁵ R ³ pK _{R +} ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 79 Me Ph-4-Ph H -12.15 80 Me 7-Benzisothiazolyl H -14.08 81 Me 5-Benzisothiazolyl H -14.60 82 Et 5-Benzisothiazolyl H -14.17 83 Pr 5-Benzisothiazolyl H -14.00 84 Me 4-Benzisothyl Asolyl H -15.74 85 Me 6-Benz Isothiazolyl H -15.98 86 Me 3-Benzofuranil H -10.89 87 Me 7-Benzofuranil H -11.56 88 Me 2-Benzofuranil H -11.80 89 Me 4-Benzofuranil H -11.81 90 Me 5-Benzofuranil H -12.13 91 Me 6-Benzofuranil H -12.17 92 Me 5-Benzoseuranyl H -10.46 93 Me 4-Benzoseuran Ril H -10.78 94 Me 6-Benz thiazolyl H--11.23 95 Me 7-Benz thiazolyl H -12.23 96 Me 2-Benz thiazolyl H -15.27 97 Me 2-Zenthienyl H -11.14 98 Me 3-Zenthienyl H -11.54 99 Me 4- Benzothienyl H -11.86 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

[0048]

[Table 6] Continuation of Table 4 : pK _{R +} value of a representative example of R belonging to the third class ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━ No. R ⁴ R ⁵ R ³ pK _{R +} ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 100 Me 6-benzenenyl H -12.27 101 Me 7-Benzothienyl H -12.31 102 Me 5-Benzothienyl H -12.50 103 Et 5-Benzothienyl H -12.09 104 i-Pr 5-Benzothienyl H -11.98 105 Me 7-Dibenzologenofuranil H-9.63 106 Me 5-Dictyl benzofuranyl H-9.96 107 Me 6-Dictyl benzofuranyl H -13.21 108 Me 4-Dictyl benzofuranyl H -14.03 109 Me 2-furyl H -13.46 110 Me 3-furyl H -14.12 111 Me 4 -Imidazolyl H -11.05 112 Me 5-Imidazolyl H -12.42 113 Me 2-Imidazolyl H -14.20 114 Me 3-Interzoryl H -10.67 115 Me 5-Interaryl H -10.78 116 Me 4-Interaryl H -12.51 117 Me 7-Interaryl H -13.08 118 Me 6-Interaryl H -13.39 119 Me 4-Indolyl H -8.20 120 Me 5-Indolyl H -8.29 ━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━

[0049]

[Table 7] Continuation of Table 4 : pK _{R +} value of a representative example of R belonging to the third class ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━ No. R ⁴ R ⁵ R ³ pK _{R +} ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 121 Et 5-Indoryl H-7.92 122 Pr 5-indryl H-7.71 123 Me 6-indryl H-9.07 124 Me 7-indryl H-9.76 125 Me 2-indryl H -10.10 126 Me 4-indolinyl H -12.80 127 Me 4-isothiazolyl H -15.68 128 Me 3- Py-2-OMe H -10.45 129 Et 3-Py-2-OMe H -11.01 130 Pr 3-Py-2-OMe H -10.89 131 Me 2-Py-3-OMe H -14.12 132 Me 3-Py- 4-OMe H -11.41 133 Me 2-Py-5-OMe H -14.64 134 Me 3-Py-5-OMe H -15.70 135 Me 3-Py-6-OMe H -11.43 136 Me 4-Polasolyl H -10.75 137 Me 3-Pholazolyl H -13.35 138 Me 3-Poloryl H -8.25 139 Me 2-Poloryl H -10.26 140 Me 5-Thiasolyl H -14.76 141 Me 2-Thienyl H -13.49 142 Me 3-Thienyl H -14.68 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

[0050]

[Table 8] pK _{R +} value of a representative example of R belonging to the fourth class ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ No. R ⁴ R ⁵ R ³ pK _{R +} ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 143 Me Ph-4-COMe Me -12.25 144 Me Ph-4 -CONH ₂ Me -12.67 145 Me Ph-4-CN Me -13.86 146 Me Ph-4-COOH Me -13.91 147 Me Ph-4-COOMe Me -13.42 148 Me Ph-4-CF ₃ Me -14.98 149 Me 2 -Py Me -11.79 150 Me 3-Py Me -12.23 151 Me 4-Py Me -15.43 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

[0051]

[Table 9] pK _{R +} value of a representative example of R belonging to the 5th class ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ No. R ⁴ R ⁵ R ³ pK _{R +} ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 152 Ph Ph H -10.77 153 Ph-4-Cl Ph-4 -Cl H -11.63 154 Ph Ph-4-Cl H -12.32 155 Ph-4-F Ph-4-FH -12.12 156 Ph-4-Me Ph-4-Me H-8.94 157 Ph Ph-4-Me H -9.79 158 Ph Ph-4-OMe H-8.31 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

The terms used in this specification will be further described. “Lower” means 1 to 6 carbon atoms unless otherwise specified. The lower alkyl moiety, lower alkyl group and lower alkoxy group may be linear or branched.

The "halogen atom" means fluorine, chlorine, bromine and iodine, and fluorine, chlorine and bromine are preferable.
Specific examples of "lower alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, te.
Examples include rt-butyl, pentyl, isopentyl, and hexyl. Specific examples of the "lower alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy and hexyloxy, and those having 1 to 3 carbon atoms are preferable.
The "halogeno (lower) alkoxy group" means a lower alkoxy group substituted with 1 to 3 halogen atoms,
Specific examples include chloromethoxy, bromomethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy, 2-bromoethoxy, 2
-Fluoroethoxy. Specific examples of "hydroxy (lower) alkoxy" include 2-hydroxyethoxy and 3-hydroxypropoxy. Specific examples of "lower alkoxy (lower) alkoxy" include:
Methoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 3-propoxypropoxy may be mentioned.
Specific examples of "lower alkoxy (lower) alkoxy (lower) alkoxy" include (2-methoxyethoxy) methoxy, 2-methoxymethoxyethoxy, 2- (2-methoxyethoxy) ethoxy, 2- (2-ethoxyethoxy). Ethoxy, 2- (3-methoxypropoxy) ethoxy, 3- (methoxymethoxy) propoxy, 3- (2-
Methoxyethoxy) propoxy. The “cycloalkyl group” means one having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclopentyl and cyclohexyl. Specific examples of the “hydroxy (lower) alkyl group” include hydroxymethyl and 2-hydroxyethyl. Specific examples of the "lower alkanoyloxy (lower) alkyl group" include acetoxymethyl, propionyloxymethyl, butyryloxymethyl, 2-acetoxyethyl.

The "mono- or di-substituted amino group" and the mono- or di-substituted amino moiety mean a group or moiety represented by the following chemical formula 17.

[0055]

Embedded image —N (R ²³ ) (R ²⁴ ).

[In the formula, R ²³ represents a hydrogen atom or a lower alkyl group, and R ²⁴ represents amino or mono- or di (lower)
It means a lower alkyl group or a cycloalkyl group which may be substituted with alkylamino, or R ²³ and R ²⁴
May form a 5- to 7-membered heterocycle with an adjacent nitrogen atom, and the heterocycle further has a group —N (O) nR ²⁵ [n represents 0 or 1; R ²⁵ represents a hydrogen atom or lower alkyl; Basis,
It means a hydroxy (lower) alkyl group or a phenyl (lower) alkyl group, and when R ²⁵ is a hydrogen atom, n is 0.
Is. ] Or may contain an oxygen atom. ]

Specific examples of the group represented by the above chemical formula 17 include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino,
2- (dimethylamino) ethylamino, dimethylamino, ethylmethylamino, isopropylmethylamino,
Isobutylmethylamino, diethylamino, cyclohexylamino, 1-pyrrolidinyl, piperidino, 1-piperazinyl, 4-methyl-1-piperazinyl, 4- (2-
Hydroxyethyl) -1-piperazinyl, 4-benzyl-1-piperazinyl, 4-methyl-4-oxide-1-
Examples include piperazinyl and morpholino.

Specific examples of "amino (lower) alkyl group" include aminomethyl, 2-aminoethyl and 3-aminopropyl.

The "mono- or di-substituted amino (lower) alkyl group" means a lower alkyl group substituted with the group represented by the above chemical formula 16, and specific examples thereof include 2-methylaminoethyl, 2 -Dimethylaminoethyl, 2- (isopropylmethylamino) ethyl, 2-cyclohexylaminoethyl, 2- (1-pyrrolidinyl) ethyl, 2-
Piperidinoethyl, 2- (1-piperazinyl) ethyl,
3- (4-methyl-1-piperazinyl) propyl, 2-
(4-Methyl-4-oxide-1-piperazinyl) ethyl, 2-morpholinoethyl may be mentioned.

Specific examples of "aryl group" include phenyl and naphthyl. The “heteroaryl group” is a monocyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom, and optionally further containing one or more nitrogen atoms,
Bicyclic or tricyclic, for example pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thienyl, furyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, 1,
Examples include 8-naphthyridinyl, indolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl and acridinyl.

Examples of the “substituted aryl group” include the above-mentioned halogen, lower alkyl, lower alkoxy, halogeno (lower) alkoxy and hydroxy (lower).
Alkoxy, lower alkoxy (lower) alkoxy, lower alkoxy (lower) alkoxy (lower) alkoxy, hydroxy, hydroxy (lower) alkyl, lower alkanoyloxy (lower) alkyl, amino, mono- or di-substituted amino, amino (lower) alkyl and The above-mentioned aryl group substituted with 1 to 5 selected from mono- or di-substituted amino (lower) alkyl, or C ₂ -C ₄ alkenyl, cyano, trifluoromethyl, phenyl, carboxyl, lower alkoxycarbonyl, lower alkanoyl , Carbamoyl, lower alkanoylamino, oxy lower alkylene, lower alkylenedioxy, imino (lower) alkylene and lower alkylimino (lower) alkylene, which is substituted with one of the above-mentioned aryl groups. Physically, 2- or 4-methoxyphenyl, 2,4- or 2,6-dimethoxyphenyl, 2,4,6-, 2,3,4-, 2,4,5- or 3,4 5-trimethoxyphenyl, 2,3
4,5-, 2,3,4,6-or 2,4,5,6-
Tetramethoxyphenyl, 2,3,4,5,6-pentamethoxyphenyl, 2,4-diethoxyphenyl, 2,
4,6-triethoxyphenyl, 2-ethoxy-4-methoxyphenyl, 4-ethoxy-2-methoxyphenyl, 2-fluoromethoxy-4-methoxyphenyl, 4
-Fluoromethoxy-2-methoxyphenyl, 4-methoxy-2-methoxymethoxyphenyl, 4-methoxy-
2- (2-methoxyethoxy) phenyl, 2- (2-ethoxyethoxy) -4-methoxyphenyl, 4-methoxy-2- (3-methoxypropoxy) phenyl, 2-
(3-ethoxypropoxy) -4-methoxyphenyl,
4-methoxy-2- (3-propoxypropoxy) phenyl, 4-methoxy-2- [2- (methoxymethoxy)
Ethoxy] phenyl, 4-methoxy-2-[(2-methoxyethoxy) methoxy] phenyl, 4-methoxy-2
-[2- (2-Methoxyethoxy) ethoxy] phenyl, 2- [2- (2-ethoxyethoxy) ethoxy]-
4-methoxyphenyl, 4-methoxy-2- [3- (methoxymethoxy) propoxy] phenyl, 4-methoxy-2- [3- (2-methoxyethoxy) propoxy] phenyl, 2- (2-fluoroethoxy)- 4-methoxyphenyl, 2,4-dipropoxyphenyl, 2,4,6
-Tripropoxyphenyl, 2,4-dimethoxy-3-
Methylphenyl, 2,4-dimethoxy-6-methylphenyl, 5-bromo-2,4-dimethoxyphenyl, 3,
5-difluoro-2,4,6-trimethoxyphenyl,
2,4-dimethoxy-6-trifluoromethylphenyl, 2,6-dimethoxy-4-trifluoromethylphenyl, 2- or 4-methylphenyl, 2,4-dimethylphenyl, 4-hydroxy-2,6-dimethyl Phenyl, 4-methoxy-2,3-dimethylphenyl, 2,
4,6-trimethylphenyl, 4-chlorophenyl, 4
-Bromophenyl, 4-fluorophenyl, 2-aminophenyl, 2-methylaminophenyl, 2-dimethylaminophenyl, 3-dimethylamino-2-naphthyl, 4
-Chloro-2-dimethylaminophenyl, 5-chloro-
2-dimethylaminophenyl, 2-dimethylamino-3
-Methoxyphenyl, 2-dimethylamino-3-methylphenyl, 2-dimethylamino-5-methylphenyl,
2-dimethylamino-4,5-difluorophenyl,
3,5-dibromo-2-dimethylaminophenyl, 2-
(Isopropylmethylamino) phenyl, 2-cyclohexylaminophenyl, 2- (1-pyrrolidinyl) phenyl, 2-piperidinophenyl, 2- (4-methyl-1)
-Piperazinyl) phenyl, 2-morpholinophenyl,
4-dimethylaminophenyl, 4-dimethylamino-
2,5-difluorophenyl, 2,5-difluoro-4
-(1-Pyrrolidinyl) phenyl, 2,5-difluoro-4-piperidinophenyl, 2,5-difluoro-4-
Morpholinophenyl, 2,5-difluoro-4- (4-
Methylpiperazinyl) phenyl, 2,5-difluoro-
[4- (4-methyl-4-oxide-1-piperazinyl) phenyl], 4-dimethylamino-2,3,5-trifluorophenyl, 4-dimethylamino-2,5,6
-Trifluorophenyl, 4-allylphenyl, 4-hydroxyphenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-biphenyl, 4-carboxyphenyl, 4-methoxycarbonylphenyl, 4-acetylphenyl, 4-carbamoyl Phenyl, 4-acetylaminophenyl, 2,3-methylenedioxyphenyl, 4-, 5- or 6-dihydrobenzofuranyl,
4-indolinyl, 1-ethyl-1,2,3,4-tetrahydroquinolin-8-yl and the like can be mentioned.

The "substituted heteroaryl group" is, for example, the above-mentioned hetero substituted with 1 to 2 each selected from the above-mentioned halogen, lower alkyl, lower alkoxy, lower alkylenedioxy and mono- or di-substituted amino. And an aryl group, more specifically, 2-,
4- or 6-methoxy-3-pyridyl, 2,4,6
-Trimethoxy-3-pyridyl, 2-dimethylamino-
3-pyridyl, 2-dimethylamino-6-methyl-3-
Pyridyl, 2- (4-methyl-1-piperazinyl) -3
-Pyridyl, 2-dimethylamino-3-pyrazinyl, 3
-Dimethylamino-4-pyrazolyl, 4-dimethylamino-5-isothiazolyl, 5,6-dimethoxy-2-benzimidazolyl and the like can be mentioned.

Preferred among the compounds of the present invention are R ¹ in formula (I), a phenyl group which may be substituted at the 4-position of the phenyl group with amino or a mono- or di-substituted amino, or a lower alkyl, A 4-pyridyl group optionally substituted by 1 to 2 selected from hydroxy (lower) alkyl and lower alkanoyloxy (lower) alkyl, wherein R ² is a hydrogen atom, a halogen atom at the 5th or 6th position, 6 2-sulfinyl nicotinamide derivative, which is a lower alkyl group at the 5-position, a lower alkoxy group at the 5- or 6-position or a phenyl group at the 6-position, and R is the same as the above.

Further preferred compounds are those in which R ¹ and R ² are as described above in formula (I), and R is represented by the following formula (a), (b), (c) or (d). 2-sulfinyl nicotinamide derivatives which are groups and satisfy the condition -16 <pK _{R +} <-7.

[0065]

Embedded image

[Wherein (a) R ^6a is a hydrogen atom, C ₁ -C
₃ alkoxy group, halogeno (C ₁ -C ₃ ) alkoxy group, hydroxy (C ₁ -C ₃ ) alkoxy group, C ₁ -C
₃ alkoxy (C ₁ -C ₃ ) alkoxy group or C ₁ -C
₃ alkoxy (C ₁ -C ₃₎ alkoxy (C ₁ -C ₃₎
R ^7a means an alkoxy group, R ^7a means a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group or a C ₁ -C ₃ alkoxy group, and one of R ^8a and R ^10a is a hydrogen atom, a halogen atom, C ₁ To C ₃ alkyl group or C _{1 to} C ₃ alkoxy group, the other is hydrogen atom, C _{1 to} C ₃ alkyl group or C ₁ to
C ₃ alkoxy group, R ^9a is hydrogen atom, C ₁ -C
₃ Alkyl group or C ₁ -C ₃ alkoxy group is meant.
However, at least one of R ^6a , R ^8a and R ^10a is C
₁ -C is a ₃ alkoxy groups. (B) R ^6b means an amino group or a mono- or di-substituted amino group, Q means C—R ^7b or a nitrogen atom, and one of R ^7b and R ^9b is a hydrogen atom, a halogen atom, C ₁ -C. ₃ alkyl group or C ₁ -C ₃ alkoxy group, the other means hydrogen atom, halogen atom or C ₁ -C ₃ alkyl group,
R ^8b means a hydrogen atom, R ^10b means a hydrogen atom, a halogen atom or a C ₁ -C ₃ alkyl group, or R
^{When 8b} is attached to the 4-position, it may be taken together with R ^9b together with the carbon atom to which they are attached to form a benzene ring. However, when Q is a nitrogen atom, R ^8b is a hydrogen atom or a C ₁ -C ₃ alkyl group bonded to the 4-position, and R ^9b and R ^10b are both hydrogen atoms. (C) R ^6c and R ^7c represent a halogen atom, R ^8c represents an amino group or a mono- or di-substituted amino group, and R ^9c
Means a hydrogen atom or a halogen atom. (D) R ⁴ 'means a C ₁ -C ₃ alkyl group or a phenyl group which may be substituted with halogen or C ₁ -C ₃ alkyl, and _{one of} R ^6d and R ^7d is a hydrogen atom or C _1-
A C ₃ alkoxy group, the other means a hydrogen atom, and R ^8d represents a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group or C ₁
To C ₃ alkoxy groups are meant. ]

In the group represented by the formula (a) in the above chemical formula 18, when _one C ₁ -C ₃ alkoxy group is present, it is at the 4-position, when it is present, it is at the 2,4-position or 2,6-position. −
When there are three positions, they are preferably bonded to the 2,4,6-position.

Further preferred further compounds are the compounds of formula (I)
R ¹ and R ² are as described above, and R is No. 9, 20, 21, 23, 25, 28 in Tables 1 to 9 above.
~ 30, 32, 43, 50 ~ 52, 55, 56, 67 ~
71, 73, 74, 78, 79, 86-95, 97-1
07,109,111,112,114-120,12
3-126, 128-130, 132, 135-13
The 2-sulfinyl nicotinamide derivative which is 9,141,143-147,149 or 150 is mentioned.

Among the compounds of the present invention, a more preferable compound is a 2-sulfinylnicotinamide derivative represented by the following chemical formula 19.

[0070]

[Chemical 19] [In the formula, R ¹ 'means a group represented by the following Chemical formula 20,

[0071]

Embedded image

[Wherein R ¹¹ is a hydrogen atom, a methyl group, a hydroxymethyl group or (C ₂ -C ₄ alkanoyloxy))
It means a methyl group, R ¹² means a hydrogen atom or a methyl group, R ¹³ means a C ₁ -C ₃ alkyl group, and n means 0 or 1. R ² 'means a hydrogen atom or a lower alkyl group, and R ⁶ ' is C
₁ -C ₃ alkoxy, fluoro (C _{1 ~C 3)} alkoxy, hydroxy (C ₂ ~C ₃₎ alkoxy, methoxy (C _{1 ~C 3)} alkoxy group or a methoxy (C ₁ ~
C ₂ ) alkoxy (C ₂ -C ₃ ) alkoxy group, R ⁷ ′ means hydrogen atom, halogen atom or C ₁ -C ₃ alkyl group, and R ⁸ ′ means C ₁ -C ₃ alkoxy group. Means R ⁹ ′ means a hydrogen atom, R ¹⁰ ′ means a hydrogen atom, C ₁
To C ₃ alkyl group or C _{1 to} C ₃ alkoxy group. ]

Another more preferable compound among the compounds of the present invention is a 2-sulfinylnicotinamide derivative represented by the following chemical formula 21.

[0074]

[Chemical 21]

(Wherein R ¹ 'and R ² ' have the same meanings as described above, R ¹⁴ represents a hydrogen atom or a lower alkyl group,
R ¹⁵ represents a lower alkyl group, or R ¹⁴ and R
¹⁵ may form a pyrrolidine ring, a piperidine ring or a piperazine ring in which the 4-position is substituted with C ₁ -C ₃ alkyl together with an adjacent nitrogen atom, and R ¹⁶ is a hydrogen atom, a halogen atom, or a C ₁ -C ₃ alkyl. A group or C _{1 at the} 3 or 5 position
To C ₃ alkoxy groups, and R ¹⁷ represents a hydrogen atom or a halogen atom. However, R ¹⁶ and R ¹⁷ are each 4
When attached at positions 6 and 6, they are not halogen atoms. )

Another more preferable compound among the compounds of the present invention is a 2-sulfinylnicotinamide derivative represented by the following chemical formula 22.

[0077]

[Chemical formula 22]

(Wherein R ¹ 'and R ² ' have the same meanings as described above, R ¹⁸ and R ¹⁹ both represent a fluorine atom, and R ²⁰
Represents a hydrogen atom or a lower alkyl group, R ²¹ represents a lower alkyl group, or R ²⁰ and R ²¹ are a pyrrolidine ring, a piperidine ring or a C ₁ -C ₃ alkyl group at the 4-position together with an adjacent nitrogen atom. It may form a substituted piperazine ring, and R ²² represents a hydrogen atom or a fluorine atom. )

Another more preferable compound among the compounds of the present invention is a 2-sulfinylnicotinamide derivative represented by the following chemical formula 23.

[0080]

[Chemical formula 23]

(In the formula, R ¹ 'and R ² ' have the same meanings as described above, R ⁴ '' means a C ₁ -C ₃ alkyl group,
One of R ⁶ ″ and R ⁸ ″ is a hydrogen atom, and the other is C _{1 to} C _3.
It means an alkoxy group. )

Particularly preferable compounds include the above-mentioned compounds
In Chemical formula 21, Chemical formula 22 and Chemical formula 23, R ¹ 'is 4-pyridyl group, 2-hydroxymethyl-4-pyridyl group, 2-acetoxymethyl-4-pyridyl group or 4- (4-methyl-
A 2-sulfinylnicotinamide derivative in which R ² ′ is a hydrogen atom is a 1-piperazinyl) phenyl group.

Specific examples of particularly suitable compounds include the following compounds.

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

N- (4-pyridyl) -2-[(2,4,
6-trimethoxybenzyl) sulfinyl] nicotinamide,

2-[(2-dimethylaminobenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide,

2-[[1- (4-methoxyphenyl) ethyl] sulfinyl] -N- (4-pyridyl) nicotinamide or its diastereomer,

2-[[1- (2-methoxyphenyl) ethyl] sulfinyl] -N- (4-pyridyl) nicotinamide or its diastereomer,

N- (2-acetoxymethyl-4-pyridyl) -2-[(2,4-dimethoxybenzyl) sulfinyl] nicotinamide,

2-[(2,4-dimethoxybenzyl) sulfinyl] -N- (2-hydroxymethyl-4-pyridyl)] nicotinamide,

2-[[2- (2-fluoroethoxy)-
4-methoxybenzyl] sulfinyl] -N- (4-pyridyl) nicotinamide,

2-[(4-chloro-2-dimethylaminobenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide,

2-[(2,5-difluoro-4-dimethylaminobenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide and

2-[(2,4-dimethoxybenzyl) sulfinyl] -N- [4- (4-methyl-1-piperazinyl) phenyl] nicotinamide.

Specific examples of the compounds included in the present invention include:
In addition to the compounds of Examples described below, the following compounds may be mentioned.

2-[(2-Dimethylaminobenzyl) sulfinyl] -N- (2-methyl-4-pyridyl) nicotinamide, 2-[(2-Dimethylaminobenzyl) sulfinyl] -N- [4- (4 -Methyl-1-piperazinyl) phenyl] nicotinamide, 2-[(2-dimethylaminobenzyl) sulfinyl] -N- [4- (4-
Ethyl-1-piperazinyl) phenyl] nicotinamide, 2-[(2-dimethylaminobenzyl) sulfinyl] -N- [4- [4- (2-hydroxyethyl) -1.
-Piperazinyl] phenyl] nicotinamide, 4- [
[4- [2- (2-Dimethylaminobenzyl) sulfinyl] nicotinoylamino] phenyl] -1-methylpiperazine 1-oxide,

2-[(2-dimethylamino-3-methylbenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide, 2-[(2-dimethylamino-5-methylbenzyl) sulfinyl] -N- ( 4-pyridyl) nicotinamide, 2-[(2-dimethylamino-3-methoxybenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide, 2-[(4,5-difluoro-2-dimethylaminobenzyl) Sulfinyl] -N- (4-pyridyl) nicotinamide, 2-[(5-chloro-2-dimethylaminobenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide, 2-[(3-dimethylamino-
2-naphthylmethyl) sulfinyl] -N- (4-pyridyl) nicotinamide,

2-[(2,4-Dimethoxybenzyl) sulfinyl] -N- (2-methyl-4-pyridyl) nicotinamide, 2-[(2,4-dimethoxybenzyl) sulfinyl] -N- [4- (4-Ethyl-1-piperazinyl) phenyl] nicotinamide,

2-[[1- (4-methoxyphenyl) ethyl] sulfinyl] -N- (2-methyl-4-pyridyl) nicotinamide or its diastereomer, N-
(2-Hydroxymethyl-4-pyridyl) -2- [[1
-(4-Methoxyphenyl) ethyl] sulfinyl] nicotinamide or its diastereomer, 2-[[1-
(4-Methoxyphenyl) ethyl] sulfinyl] -N
-[4- (4-Methyl-1-piperazinyl) phenyl]
Nicotinamide or its diastereomer, N- [4-
(4-Ethyl-1-piperazinyl) phenyl] -2-
[[1- (4-Methoxyphenyl) ethyl] sulfinyl] nicotinamide or its diastereomer, 2-
[[1- (4-Methoxyphenyl) ethyl] sulfinyl] -N- [4- [4- (2-hydroxyethyl) -1]
-Piperazinyl] phenyl] nicotinamide or its diastereomer, 4-[[4- [2- [1- (4-methoxyphenyl) ethyl] sulfinyl] nicotinoylamino] phenyl] -1-methylpiperazine 1-oxide or Its diastereomer,

2-[[1- (2-methoxyphenyl) ethyl] sulfinyl] -N- (2-methyl-4-pyridyl) nicotinamide or its diastereomer, N-
(2-Hydroxymethyl-4-pyridyl) -2- [[1
-(2-Methoxyphenyl) ethyl] sulfinyl] nicotinamide or its diastereomer, 2-[[1-
(2-Methoxyphenyl) ethyl] sulfinyl] -N
-[4- (4-Methyl-1-piperazinyl) phenyl]
Nicotinamide or its diastereomer, N- [4-
(4-Ethyl-1-piperazinyl) phenyl] -2-
[[1- (2-Methoxyphenyl) ethyl] sulfinyl] nicotinamide or its diastereomers, N-
[4- [4- (2-Hydroxyethyl) -1-piperazinyl] phenyl] -2-[[1- (2-methoxyphenyl) ethyl] sulfinyl] nicotinamide or its diastereomer, 4-[[4- [2- [1- (2-Methoxyphenyl) ethyl] sulfinyl] nicotinoylamino] phenyl] -1-methylpiperazine 1-oxide or a diastereomer thereof,

N- (2-methyl-4-pyridyl) -2-
[(2,4,6-Trimethoxybenzyl) sulfinyl] Nicotinamide, N- (2-hydroxymethyl-4)
-Pyridyl) -2-[(2,4,6-trimethoxybenzyl) sulfinyl] nicotinamide, N- [4- (4
-Methyl-1-piperazinyl) phenyl] -2-
[(2,4,6-Trimethoxybenzyl) sulfinyl]
Nicotinamide, 4-[[4- [2- (2,4,6-trimethoxybenzyl) sulfinyl] nicotinoylamino] phenyl] -1-methylpiperazine 1-oxide,

2-[(2,4-dipropoxybenzyl)
Sulfinyl] -N- (4-pyridyl) nicotinamide, N- (4-pyridyl) -2-[(2,4,6-triethoxybenzyl) sulfinyl] nicotinamide, 2
-[(4-Ethoxy-2-methoxybenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide,

2-[(2-dimethylaminobenzyl) sulfinyl] -6-isopropyl-N- (4-pyridyl) nicotinamide,

2-[(2,4-Dimethoxybenzyl) sulfinyl] -6-isopentyl-N- (2-methyl-
4-pyridyl) nicotinamide, 2-[(2,4-dimethoxybenzyl) sulfinyl] -N- (2-hydroxymethyl-4-pyridyl) -6-isopentylnicotinamide, 2-[(2,4-dimethoxy Benzyl) sulfinyl] -6-isopentyl-N- [4- (4-methyl-1-piperazinyl) phenyl] nicotinamide, 4-
[[4- [2- (2,4-dimethoxybenzyl) sulfinyl-6-isopentyl] nicotinoylamino] phenyl] -1-methylpiperazine 1-oxide,

6-Isopentyl-N- (4-pyridyl)
-2-[(2,4,6-trimethoxybenzyl) sulfinyl] nicotinamide, 6-isopentyl-N- (2
-Methyl-4-pyridyl) -2-[(2,4,6-trimethoxybenzyl) sulfinyl] nicotinamide, N
-(2-Hydroxymethyl-4-pyridyl) -6-isopentyl-2-[(2,4,6-trimethoxybenzyl) sulfinyl] nicotinamide, 6-isopentyl-N- [4- (4-methyl-1) -Piperazinyl) phenyl] -2-[(2,4,6-trimethoxybenzyl) sulfinyl] nicotinamide, 4-[[4- [6-isopentyl-2- (2,4,6-trimethoxybenzyl)]
Sulfinyl] Nicotinoylamino] phenyl] -1-
Methylpiperazine 1-oxide,

2-[(2-Dimethylaminobenzyl) sulfinyl] -6-isopentyl-N- (4-pyridyl) nicotinamide, 2-[(2-dimethylaminobenzyl) sulfinyl] -6-isopentyl-N- ( 2-
Methyl-4-pyridyl) nicotinamide, 2-[(2-
Dimethylaminobenzyl) sulfinyl] -N- (2-
Hydroxymethyl-4-pyridyl) -6-isopentylnicotinamide, 2-[(2-dimethylaminobenzyl) sulfinyl] -6-isopentyl-N- [4-
(4-Methyl-1-piperazinyl) phenyl] nicotinamide, 4-[[4- [2- (2-Dimethylaminobenzyl) sulfinyl-6-isopentyl] nicotinoylamino] phenyl] -1-methylpiperazine 1-oxide ,

2-[(2,4-Dimethoxybenzyl) sulfinyl] -6-methyl-N- (2-methyl-4-pyridyl) nicotinamide, 2-[(2,4-dimethoxybenzyl) sulfinyl] -N -(2-Hydroxymethyl-4-pyridyl) -6-methylnicotinamide, 2-
[(2,4-dimethoxybenzyl) sulfinyl] -6
-Methyl-N- [4- (4-methyl-1-piperazinyl) phenyl] nicotinamide, 4-[[4- [2-
(2,4-dimethoxybenzyl) sulfinyl-6-methyl] nicotinoylamino] phenyl] -1-methylpiperazine 1-oxide,

6-methyl-N- (4-pyridyl) -2-
[(2,4,6-Trimethoxybenzyl) sulfinyl] nicotinamide, 6-methyl-N- (2-methyl-
4-Pyridyl) -2-[(2,4,6-trimethoxybenzyl) sulfinyl] nicotinamide, N- (2-hydroxymethyl-4-pyridyl) -6-methyl-2-
[(2,4,6-Trimethoxybenzyl) sulfinyl]
Nicotinamide, 6-methyl-N- [4- (4-methyl-1-piperazinyl) phenyl] -2-[(2,4,
6-trimethoxybenzyl) sulfinyl] nicotinamide, 4-[[4- [6-methyl-2- (2,4,6-
Trimethoxybenzyl) sulfinyl] nicotinoylamino] phenyl] -1-methylpiperazine 1-oxide,

2-[(2-Dimethylaminobenzyl) sulfinyl] -6-methyl-N- (4-pyridyl) nicotinamide, 2-[(2-Dimethylaminobenzyl) sulfinyl] -6-methyl-N- ( 2-Methyl-4-pyridyl) nicotinamide, 2-[(2-dimethylaminobenzyl) sulfinyl] -N- (2-hydroxymethyl-4-pyridyl) -6-methylnicotinamide, 2-
[(2-Dimethylaminobenzyl) sulfinyl] -6
-Methyl-N- [4- (4-methyl-1-piperazinyl) phenyl] nicotinamide, 4-[[4- [2-
(2-Dimethylaminobenzyl) sulfinyl-6-methyl] nicotinoylamino] phenyl] -1-methylpiperazine 1-oxide,

2-[[(2-Dimethylamino-3-pyridyl) methyl] sulfinyl] -N-phenylnicotinamide, 2-[[2- (4-Methyl-1-piperazinyl) -3-pyridyl] methyl] Sulfinyl] -N-phenylnicotinamide,

2-[(2-Dimethylaminobenzyl) sulfinyl] -N- [4- (1-pyrrolidinyl) phenyl] nicotinamide, 2-[(2-Dimethylaminobenzyl) sulfinyl] -N- (4-py Peridinophenyl) nicotinamide, 2-[(2-dimethylaminobenzyl) sulfinyl] -N- (4-morpholinophenyl) nicotinamide, 2-[(2-dimethylaminobenzyl) sulfinyl] -N- [4- ( 2-Dimethylaminoethyl) phenyl] nicotinamide, N- [4- (1
-Benzyl-4-piperidinylamino) phenyl] -2
-[(2-Dimethylaminobenzyl) sulfinyl] nicotinamide, N- [4- (4-benzyl-1-piperazinyl) phenyl] -2-[(2-dimethylaminobenzyl) sulfinyl] nicotinamide, 2-[( 2-Dimethylaminobenzyl) sulfinyl] -N- (2,6
-Dimethyl-4-pyridyl) nicotinamide, N- (2
-Bromo-4-pyridyl) -2-[(2-dimethylaminobenzyl) sulfinyl] nicotinamide,

2-[(2,4-Dimethoxybenzyl) sulfinyl] -N- [4- (2-dimethylaminoethyl) phenyl] nicotinamide, N- [4- (1-benzyl-4-piperidinylamino) ) Phenyl] -2-
[(2,4-Dimethoxybenzyl) sulfinyl] nicotinamide, N- [4- (4-benzyl-1-piperazinyl) phenyl] -2-[(2,4-dimethoxybenzyl) sulfinyl] nicotinamide, 2- [ (2,4-
Dimethoxybenzyl) sulfinyl] -N- (2,6-
Dimethyl-4-pyridyl) nicotinamide, N- (2-
Bromo-4-pyridyl) -2-[(2,4-dimethoxybenzyl) sulfinyl] nicotinamide,

5-chloro-2-[(2-dimethylaminobenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide, 5-chloro-2-[(2,4-dimethoxybenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide, 2-[[[1-ethyl-8- (1,2,
3,4-Tetrahydroquinolyl)] methyl] sulfinyl] -N- (4-pyridyl) nicotinamide and N-
(4-pyridyl) -2-[[2- (1-pyrrolidinyl)
Benzyl] sulfinyl] nicotinamide.

N- (2-acetoxymethyl-4-pyridyl) -2-[(2,4,6-trimethoxybenzyl) sulfinyl] nicotinamide, N- (2-acetoxymethyl-4-pyridyl) -2- [[2- (2-Fluoroethoxy) -4-methoxybenzyl] sulfinyl] nicotinamide, N- (2-acetoxymethyl-4-pyridyl) -2-[(4-dimethylamino-2,5-difluorobenzyl) Sulfinyl] Nicotinamide, N- (2
-Acetoxymethyl-4-pyridyl) -2-[(5-chloro-2-dimethylaminobenzyl) sulfinyl] nicotinamide, N- (2-acetoxymethyl-4-pyridyl) -2-[[2- (3- Hydroxypropyl) -4
-Methoxybenzyl] sulfinyl] nicotinamide,
N- (2-acetoxymethyl-4-pyridyl) -2-
[[4-methoxy-2-[(2-methoxymethoxy) ethoxy] benzyl] sulfinyl] nicotinamide,

N- (2-hydroxymethyl-4-pyridyl) -2-[(2,4,6-trimethoxybenzyl) sulfinyl] nicotinamide, 2-[[2- (2-fluoroethoxy) -4-] Methoxybenzyl] sulfinyl] -N- (2-hydroxymethyl-4-pyridyl) nicotinamide, N- (2-hydroxymethyl-4-pyridyl) -2-[[2- (3-hydroxypropyl) -4
-Methoxybenzyl] sulfinyl] nicotinamide,
2-[(4-Dimethylamino-2,5-difluorobenzyl) sulfinyl] -N- (2-hydroxymethyl-
4-pyridyl) nicotinamide,

2-[[4-methoxy-2- (2-methoxyethoxy) benzyl] sulfinyl] -N- (4-pyridyl) nicotinamide, 2-[[2- (2-ethoxyethoxy) -4-methoxy] Benzyl] sulfinyl]-
N- (4-pyridyl) nicotinamide, 2-[[4-methoxy-2- (3-methoxypropoxy) benzyl] sulfinyl] -N- (4-pyridyl) nicotinamide,
2-[[2- (3-ethoxypropoxy) -4-methoxybenzyl] sulfinyl] -N- (4-pyridyl) nicotinamide, 2-[[4-methoxy-2- (3-propoxypropoxy) benzyl] sulfinyl ] -N-
(4-pyridyl) nicotinamide,

2-[[4-methoxy-2- [2- (2-
Methoxyethoxy) ethoxy] benzyl] sulfinyl] -N- (4-pyridyl) nicotinamide, 2-
[[2- [2- (2-ethoxyethoxy) ethoxy]-
4-Methoxybenzyl] sulfinyl] -N- (4-pyridyl) nicotinamide, 2-[[4-methoxy-2-
[3- (methoxymethoxy) propoxy] benzyl] sulfinyl] -N- (4-pyridyl) nicotinamide,
2-[[4-methoxy-2- [3- (2-methoxyethoxy) propoxy] benzyl] sulfinyl] -N-
(4-pyridyl) nicotinamide,

2-[(2,4-dimethoxybenzyl) sulfinyl] -N- (2-propionyloxymethyl-
4-pyridyl) nicotinamide, 2-[(2-dimethylaminobenzyl) sulfinyl] -N- (2-propionyloxymethyl-4-pyridyl) nicotinamide, 2
-[[1- (4-Methoxyphenyl) ethyl] sulfinyl] -N- (2-propionyloxymethyl-4-pyridyl) nicotinamide or its diastereomer, N
-(2-propionyloxymethyl-4-pyridyl)-
2-[(2,4,6-trimethoxybenzyl) sulfinyl] nicotinamide, 2-[[2- (2-fluoroethoxy) -4-methoxybenzyl] sulfinyl] -N
-(2-propionyloxymethyl-4-pyridyl) nicotinamide, 2-[(4-dimethylamino-2,5-
Difluorobenzyl) sulfinyl] -N- (2-propionyloxymethyl-4-pyridyl) nicotinamide, 2-[(5-chloro-2-dimethylaminobenzyl) sulfinyl] -N- (2-propionyloxymethyl-4- Pyridyl) nicotinamide, 2-[[2-
(3-Hydroxypropyl) -4-methoxybenzyl]
Sulfinyl] -N- (2-propionyloxymethyl-4-pyridyl) nicotinamide and 2-[[4-methoxy-2-[(2-methoxymethoxy) ethoxy] benzyl] sulfinyl] -N- (2-propionyloxy Methyl-4-pyridyl) nicotinamide.

The production method of the compound of the present invention is described below.

The compound of the formula (I) can be prepared, for example, by the above formula (I
It can be produced by oxidizing the compound of I). This reaction is carried out by reacting the compound of 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, and examples thereof include 3-chloroperbenzoic acid, perbenzoic acid, monoperphthalic acid, peracetic acid, trifluoroperacetic acid, and peroxidation. hydrogen,
Examples thereof include sodium periodate, iodosobenzene, and 3-methyliodosobenzene. The amount of the oxidizing agent used varies depending on the kind of the compound of the formula (II), the kind of the desired compound of the formula (I) and the like, but it is usually about 0.9 to about 2 equivalents relative to the compound (II). 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, aromatic hydrocarbons such as benzene and toluene, Water. These solvents may be used alone or in admixture of two or more. The reaction temperature is usually about −50 ° C. to about 10
C, preferably about -20 to about 5 ° C.

In the formula (II), the substituent R ¹ and / or R has a relatively strong basic group (for example, 4-methyl-1-).
When a compound having a piperazinyl group) is used,
It is preferable to carry out the main oxidation reaction while suppressing the basicity of these groups. Specific methods for suppressing the basicity include, for example, a method in which the main oxidation reaction is carried out in the presence of hydrochloric acid, and a method after the borane-tetrahydrofuran complex is allowed to act to form a complex with borane. . The decomposition of the borane complex after completion of the reaction is preferably carried out by heating under reflux in an alcohol such as methanol using sodium carbonate.

Compounds in which R in the formula (II) has an asymmetric carbon atom, that is, R ³ , R ⁴ and R in the above formula (A)
^When a compound in which the carbon atom to which ⁵ is attached is asymmetric is oxidized, the compound of formula (I) is obtained as a mixture of two diastereomers. Separation into each diastereomer can be performed by a conventional method such as chromatography.

The compound of formula (II) which is an intermediate of the present invention can be produced, for example, by the following production method (a) or production method (b).

[0124]

[Chemical formula 24]

(In the formula, R ¹ , R ² and R have the same meanings as described above, and X means a halogen atom.)

Each manufacturing method will be described below.

Process (a ): The compound of formula (II) can be produced by reacting the compound of formula (IV) or its reactive derivative with the compound of formula (V).

Examples of the reactive derivative of the compound of the formula (IV) include active ester, acid anhydride and acid halide (particularly acid chloride). Specific examples of the active ester include p-nitrophenyl ester, N-hydroxysuccinimide ester, and N-hydroxyphthalimide ester. As the acid anhydride, a symmetrical acid anhydride or a mixed acid anhydride is used, and specific examples of the mixed acid anhydride include ethyl chlorocarbonate, a mixed acid anhydride with a chlorocarbonic acid alkyl ester such as isobutyl chlorocarbonate, Examples include mixed acid anhydrides with alkanoic acids such as isovaleric acid and pivalic acid. When the compound of formula (IV) itself is used, dicyclohexylcarbodiimide, 1-
The reaction is preferably carried out in the presence of a condensing agent such as ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or N, N'-carbonyldiimidazole.

This reaction is usually carried out in a suitable solvent.
The solvent to be used should be appropriately selected according to the type of raw material compound, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, methylene chloride, Examples thereof include halogenated hydrocarbons such as chloroform, ethyl acetate, acetonitrile, pyridine, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, ethylene glycol, and water. These solvents may be used alone or in combination of two or more. Used. This reaction is carried out in the presence of a base, if necessary, and specific examples of the base include alkali hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali carbonate such as sodium carbonate and potassium carbonate, or triethylamine and diisopropyl. Examples thereof include organic bases such as ethylamine and N-methylmorpholine. The reaction temperature will differ depending on the types of starting compounds used, etc., but is usually about -30 ° C to about
The temperature is 100 ° C, preferably about -10 ° C to about 80 ° C.

When the group involved in the reaction is present in the compound of the formula (IV) and / or the compound of the formula (V), it can be easily converted into those groups by a conventional method. Alternatively, it is preferable to convert the group in the product to a desired group after reacting in a protected form. For example, in the case of obtaining a compound in which an amino group is present in R ¹ and / or R in the formula (II), it is preferable to obtain the corresponding nitro compound by this reaction and then reduce it according to a conventional method. Further, in the case of obtaining a compound in which a carboxyl group or a phenolic hydroxy group is present in R in the formula (II) or a compound in which a mono-substituted amino group is present in R ¹ and / or R in the formula (II), After carrying out this reaction using a compound of the formula (IV) and / or a compound of the formula (V) in which these groups are protected, the protecting group in the product is eliminated by a conventional method. Is preferred.

4-in the formula (II), R ¹ has hydroxymethyl or lower alkanoyloxymethyl at the 2-position.
The compound which is a pyridyl group is a compound (IV) or its reactive derivative and 4-aminopyridine-having methyl at the 2-position.
It can also be produced by reacting with N-oxides according to this method, and then subjecting the product to a rearrangement reaction with an acid anhydride (eg, trifluoroacetic acid, acetic anhydride).

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 books and literatures. 1) E. Klingsberg (ed.), "Pyridine and Its Derivati
ves Part Three ", JohnWiley & Sons, Inc., New York,
p.3-177 (1962); 2) PA Abramovitch (ed.), "Pyridine and Its Deriv
atives Supplement PartThree ", John Wiley & Sons, I
nc., New York, p.41-255 (1974); 3) J. Am. Chem. Soc., 73 , 3100 (1951).

The starting compound represented by the formula (IV) can be produced, for example, by the method shown in the following Chemical formula 25.

[0134]

[Chemical 25]

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

The reaction between the compound of formula (VIII) and the compound of formula (IX) can be carried out in the same manner as in the production method (b) described later. The reaction temperature varies depending on the type of raw material compound,
It is usually about 30 ° C to about 150 ° C, preferably about 80 ° C to about 120 ° C.

In the formula (IV), R is 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl,
2,4-dimethoxy-3-methylbenzyl, 1- (4-
When a compound having a strong electron donating group such as methoxyphenyl) ethyl is obtained, a compound in which Y is a mercapto group in formula (VIII) and a compound in which Z is a hydroxy group in formula (IX) are used. It is also preferably carried out by reacting with concentrated hydrochloric acid as a catalyst in a suitable solvent such as tetrahydrofuran, acetone, acetonitrile, methanol or ethanol. The reaction temperature is usually about 0 ° C to about 30 ° C.

In the formula (IV), R is 4-methoxy-2-
(2-Methoxyethoxy) benzyl group, 4-methoxy-
When a compound which is a lower alkoxy (lower) alkoxy or a group containing a lower alkoxy (lower) alkoxy (lower) alkoxy such as a 2-[(2-methoxymethoxy) ethoxy] benzyl group is obtained, the compound of the formula (IV) is Corresponding hydroxy (lower) such as compounds where R is a 2- (2-hydroxyethoxy) -4-methoxybenzyl group.
It is also preferably carried out by reacting an alkoxy compound with a halogeno (lower) alkyl or a halogeno (lower) alkyl (lower) alkyl ether in the presence of a base in a suitable solvent. Specific examples of the solvent include tetrahydrofuran, methylene chloride, chloroform, toluene, dimethylformamide, and N-methylpyrrolidone, and specific examples of the base include triethylamine, diisopropylethylamine, sodium hydride, and potassium carbonate. The reaction temperature is usually about 0 ° C to about 30 ° C. Formula (VIII)
The raw material compound in which Y is a mercapto group is commercially available or Eur. J. Med. Chem.- Chim. The
It can be produced according to the method described in r., 20 , 61 (1985). Starting compounds in which Y is a halogen atom in formula (VIII) are commercially available, or Chem. Pharm. B
ull., 30 , 4314 (1982), a method of halogenating a corresponding hydroxy compound according to a conventional method, or a method described in Reference Examples 33 (1) to (3) described below. Compounds of formula (VIII) in which Y is a hydroxy group are commercially available or available from Synth.
Commun., 19 , 553 (1989) or the following Reference Examples 33 (1) and (2).

The starting compound in which Z is a halogen atom in formula (IX) is commercially available or J. Am. Che.
m. Soc., 50 , 1808 (1928); JP 58-77841 A;
It can be produced according to the method described in JP-A-62-145069; JP-A-64-3157. The starting compound in which Z is a hydroxy group in formula (IX) is commercially available, or; J. Chem. Soc. (B), 1967, 535; J. Ch.
em. Soc. Perkin I, 2498 (1975); J. Org. Chem., 57 ,
3013 (1992); JP-A-58-77841; JP-A-64-3157.
No. 4,772,619 or Reference Example 34 described later,
It can be manufactured according to the method described in 47, 56, 65 and 69. The starting compound in which Z is a mercapto group in formula (IX) can be produced according to the method described in Chem. Ind., 546 (1968) or Reference Example 42 described later.

Production method (b) : Formula (VI) in the above chemical formula 24
The reaction of the compound of formula (III) with the compound of formula (VII) is usually carried out in the presence of a base in a suitable solvent. Specific examples of the base include alkali carbonates such as sodium carbonate and potassium carbonate, quaternary ammonium hydroxides such as tetrabutylammonium hydroxide and benzyltriethylammonium hydroxide, alkalis such as sodium methoxide and sodium ethoxide. Examples thereof include metal alkoxides, alkali metal hydrides such as sodium hydride and potassium hydride. The solvent to be used should be appropriately selected according to the raw material compound, the type of base, etc., but for example, methylene chloride, acetone, acetonitrile, methanol, ethanol, isopropyl alcohol, diglyme, dimethylformamide, N-methylpyrrolidone and mixtures thereof. Is mentioned. The reaction temperature will differ depending on the types of starting compounds used but it is usually from about 30 ° C to about 150 ° C.
C., preferably about 80.degree. C. to about 120.degree.

When a compound having a phenolic hydroxy group in R in the formula (II) is obtained, after carrying out this reaction using the compound of the formula (VII) in which the group is protected, It is preferable to remove the protecting group in the product according to a conventional method.

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 the above chemical formula 25, and its manufacturing method has been already described. The raw material compound represented by the formula (VI) is produced by reacting the compound of the formula (VIII) in formula 25 in which Y is a halogen atom with the compound of the formula (V) in the same manner as in the production method (a). can do.

The compound produced by each of the above production methods is isolated by a conventional method such as chromatography, recrystallization, reprecipitation, and the like.
Refined.

Below, the method of preparing the above-mentioned formula 2 and the heat of formation H _{R + of the} carbonium ion R ⁺ and the alcohol ROH are described.
And how to obtain H _ROH will be described. As described above, the pK _{R +} value is a parameter K relating to the equilibrium between the alcohol ROH and the carbonium ion R ⁺ shown in the following Chemical formula 26.
_R is an inverse logarithm -log K R ₊ the defined values of _+, but literature known only Only limited. Therefore,
The estimation method of pK _{R +} value was examined.

[0145]

[Chemical formula 26]

(In the formulae, R means the same as above.)

It is known that the equilibrium represented by the above Chemical formula 26 is a reaction in which solvation has a very small influence in the ionization process and is enthalpy-controlled. Based on this fact, AC
Using the method ^* of Hopkinson et al., The above-mentioned formula 2 capable of estimating the pK _{R +} value by the semi-empirical molecular orbital method (AM1) ^** was prepared as follows.

^* : ACHopkinson, K.Yates, G.Csizmad
ia, Tetrahedron, 26 , 1845-1857 (1970). ^** : (1) MOPAC (version 5.00), Quantum Chemistry Pr
ogram Exchange, No. 455 (1989); (2) MJSDewar,
EGZoebisch, EFHealy, JJPStewart, J.Am.Chem.
Soc., 107 , 3902-3909 (1985); (3) JJPStewart, JC
omp.Chem., 10 , 209-220 (1989).

The alcohol ROH corresponding to the substituent R of the compound of the present invention was converted to software SYBYL5.5 [Sybyl M
olecular Modeling System (version 5.5), TRIPOS As
s., St.Louis, USA]
Tripos force field
[J. Computer-Aided Molecular Design, 1 , 31-51 (198
7)], the semi-empirical molecular orbital method (AM
The structure was further optimized in 1). In this way, the heat of formation of alcohol ROH [H _ROH (kcal / mol)] was determined. Next, remove the OH alcohol ROH, a carbonium ion R ^+, perform structural optimization by semiempirical molecular orbital method (AM1), R ⁺ heat of formation of [H _{R +} (kcal / mol)]
I asked.

Next, the difference between H _{R +} and H _ROH was obtained, and this value and the measured values of 25 pK _{R +} known in the literature [JFW Mc
Omie (ed.), "Protective Group in Organic Chemistr
y ", Plenum Press, London & New York, p.251-253 (19
73)] was used to create the linear multiple regression model of Equation 2 above. The standard deviation of this formula is 2.54, and the correlation coefficient is 0.8.
At 83 and p <0.0001, a reliable mathematical model was obtained.

The test results of the representative compounds of the present invention, known proton pump inhibitors and compounds (III) which are ring-closure compounds are shown below, and the characteristics of the action of the compounds of the present invention are explained.

The following compounds were used as control compounds.
Compound A: omeprazole, Compound B: 3-oxo-2
-(4-Pyridyl) isothiazolo [5,4-b] pyridine [Ring closure: a compound of formula (III) in which R ¹ is a 4-pyridyl group and R ² is a hydrogen atom]

Test Example 1 --H ⁺ , K ⁺ -ATPas
e Inhibitory effect ( in vitro ) —The H ⁺ , K ⁺ -ATPase inhibitory activity of the test compound was measured both under the condition without acid treatment and after the acid treatment.

The method of Nagaya et al. [J. Pharmacol. Exp. The
r., 248 , 799-805 (1989)], microsome fractions were prepared from porcine fundic glands and used as enzyme preparations in this test. H ⁺ , K ⁺ -ATPase activity was measured by 50 mM Tris-hydrochloric acid (pH 7.4), 4 mM magnesium chloride, 5 μg /
ml gramicidin, 2 mM ATP (adenosine triphosphate)
It was carried out in a 1.0 ml reaction solution containing or not containing 2 sodium, a test compound and 20 mM potassium chloride.

First, the enzyme preparation (10-20 μg protein) was allowed to react with the test compound at 37 ° C. for 30 minutes, and then the substrate ATP.
Disodium was added and reacted for 20 minutes. Then 16%
The reaction was stopped by adding 1 ml of trichloroacetic acid solution, and after centrifugation (3,000 rpm, 10 minutes), the inorganic phosphorus concentration in the supernatant was determined by the method of Sanui [Anal. Biochem., 60 , 489-504 (197
4)].

The H ⁺ , K ⁺ -ATPase activity value was determined from the difference in activity 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.

Acid treatment was carried out by subjecting the test compound to 37% in 0.1 N hydrochloric acid.
The reaction was carried out at 30 ° C for 30 minutes. After the acid treatment, the same amount of 100 mM tris-hydrochloric acid buffer solution (pH 7.5) was added to the solution containing the test compound, and H ⁺ , K ⁺ -AT was added in the same manner as above.
The Pase inhibitory activity was measured.

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

H ⁺ , K ⁺ -ATPase inhibitory activity (IC) of the test compound under both conditions (untreated and acid-treated)
₅₀ ) are shown in Tables 10 and 11. For reference, the pK _{R +} value of the substituent R of the test compound calculated according to Formula 2 is also shown.

[0160]

[Table 10] ^*) Means the compound of Example 1 (the same applies hereinafter).

[0161]

[Table 11]

As is clear from Table 10, Compound B (closed ring compound) exhibited a strong proton pump inhibitory activity under the untreated condition, and this inhibitory activity was not changed by the acid treatment. On the other hand, as is clear from Tables 10 and 11, the tested compounds of the present invention were found to exhibit or enhance the proton pump inhibitory activity after acid treatment as compared with the untreated condition, and the IC _{50 of} most of the compounds was The value was almost the same as that of compound B. Further, as is clear from Tables 10 and 11, the pK _{R +} value of the substituent R of the compound of the present invention tested was larger than −16 and smaller than −8. This fact is due to the condition (-16 <pK _{R +} <set in the definition of equation (I).
It supports the validity of -7).

The fact that the compound [Compound (I)] of the present invention was converted to the ring-closed compound [Compound (III)] after acid treatment means that the compound (I) under the same acid treatment conditions as in Test Example 1 was used. Was subjected to high performance liquid chromatography, and it was confirmed by the appearance of a new peak at the elution position of the standard of compound (III).

Test Example 2 -Inhibition activity of acid formation in isolated parietal cells ( in vitro ) -Method of Fryklund et al. [Biochem. Pharmacol., 33 , 273-280]
(1984)] and parietal cells isolated from rabbit fundic glands were used in this test. The acid-forming ability of parietal cells is determined by the method of Nagaya et al. [J. Pharmacol. Exp. Ther., 248 , 1289-1295 (198
9)] according to the amount of [ ¹⁴ C] -aminopyrine uptake into cells.

2-4 × 10 ⁶ cells / ml parietal cells, 0.1 μCi
Earle's containing / ml of [ ¹⁴ C] -aminopyrine, 1 mM dibutyryl cyclic AMP, 0.2% bovine serum albumin, 25 mM HEPES-sodium hydroxide.
15 μl of the test compound dissolved in dimethyl sulfoxide was added to 1.5 ml of a balanced salt solution (pH 7.4), and the mixture was reacted at 37 ° C. for 30 minutes in a mixed gas of 95% oxygen and 5% carbon dioxide. After the reaction was completed, the reaction solution was centrifuged (14,000 rpm, 1 minute) to obtain a cell precipitate. The cell precipitate was lysed with a solubilizing agent for liquid scintillation counting [NCS (registered trademark), Amersham Co., Ltd.], and radioactivity was measured with a liquid scintillation spectrometer.

The inhibition rate was determined from the amount of [ ¹⁴ C] -aminopyrine uptake into cells in the control and the amount of uptake at each concentration of the test compound.
_C50 ) was calculated. The results are shown in Tables 12 and 13.

[0167]

[Table 12]

^*) Means the compound of Example 1 (the same applies hereinafter).

[0169]

[Table 13]

As is clear from Tables 12 and 13, about half of the tested compounds of the present invention exhibited the same acid formation inhibitory activity as that of omeprazole (Compound A) in isolated parietal cells. The remaining compounds also showed a clear acid formation inhibitory activity, albeit weaker than omeprazole.

Test Example 3 —Inhibition of gastric acid secretion in pylorus-ligated rats ( in vivo ) —This test was carried out by the method of Satoh et al. [J. Pharmacol. Exp. Ther.
248 , 806-815 (1989)].

One group of 5 male Std: Wistar rats weighing about 200 g was used. After fasting the rats for 17 hours, the abdomen was opened under urethane (1 g / kg, intraperitoneal administration) anesthesia to ligate the pylorus, and then the test compound was administered into the duodenum or intravenously. 5 minutes after intravenous administration and 30 minutes after intraduodenal administration, histamine dihydrochloride (30 mg /
(kg) was subcutaneously administered, and 3 hours later, the stomach was excised and gastric juice was collected, and the liquid volume and acid concentration were measured. Acid concentration is neutralized (pH
Calculated from the amount of sodium hydroxide required for 7.0), the gastric acid excretion amount was expressed as the product of the liquid amount and the acid concentration. The test compound was dissolved or suspended in a 0.5% tragacanth suspension in the case of intraduodenal administration, and dissolved in glycerol formal in the case of intravenous administration.

The inhibition rate (%) was determined from the gastric acid excretion in the control group and the gastric acid excretion in each test compound dose-administered group. The results are shown in Tables 14 and 15.

[0174]

[Table 14]

^*) Means the compound of Example 1 (the same applies hereinafter). ^**) Administration route: Only the compound of Example 58 was intravenously administered, and the rest of the compounds were intraduodenally administered.

[0176]

[Table 15]

As is clear from Tables 14 and 15, all the tested compounds of the present invention showed a significant gastric acid secretion inhibitory effect at a dose of 100 mg / kg. In particular, Examples 1 and 2
The compounds of 0 and 59 showed a gastric acid secretion inhibitory action almost equivalent to that of omeprazole, and the compounds of Examples 3, 10, 11, 19, 2
2, 23, 72, 75, 77, 85, 172 and 173
The compound was slightly weaker than omeprazole in suppressing gastric acid secretion.

Test Example 4 — Cytochrome P ₄₅₀ Monooxygenase Reaction Inhibitory Action ( In Vitro ) — Drug metabolism is mainly carried out by hepatic cytochrome P ₄₅₀ , and monooxygenase (monoatomic oxygenase) reaction is the main. It has a metabolic format. Omeprazole (Compound A) is said to delay the blood half-life of several drugs by directly inhibiting this monooxygenase reaction [see, for example, Gastroenterology, 89 , 1235-1241 (1985)]. Therefore, the effect of liver cytochrome P _{450 on} the monooxygenase reaction was investigated.

The monooxygenase reaction inhibition test was conducted by Rein.
ers et al. [Anal. Biochem., 188 , 317-324 (199
[0]], the microsome fraction purified from rat liver was used as a cytochrome P ₄₅₀ (enzyme) sample, and 7-ethoxycoumarin was used as a model substrate to examine the inhibitory effect of the test compound on its O-deethylation activity. went.

This activity was measured by measuring 10 mM-Tris-hydrochloric acid (pH
7.8), 1 mM NADP (β-nicotinamide adenosine dinucleotide phosphate), 5 mM magnesium sulfate, 6 mM glucose-6-phosphate, 0.2 mg / ml bovine serum albumin, 2 units / ml glucose-6-phosphate Dehydrogenase, 0.
It was carried out in a 1.0 ml reaction solution containing 1 mM 7-ethoxycoumarin.

First, the enzyme preparation (about 80 μg protein) and the test compound were allowed to stand at 37 ° C. for 10 minutes, and then the substrate 7-ethoxycoumarin 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 the precipitated protein was removed by centrifugation (3,000 rpm, 10 minutes), 1.8 ml of 1.6 M glycine solution (pH 10.3) was added to 0.9 ml of the supernatant, and fluorescence was detected (excitation wavelength).
7-hydroxycoumarin was quantified at 365 nm and a fluorescence wavelength of 455 nm).

The 7-ethoxycoumarin-O-deethylation activity value was determined from the amount of 7-hydroxycoumarin produced by the reaction. The inhibition rate was calculated from the control activity value and the activity value at each concentration of the test compound, and the 50% inhibition concentration (I
_C50 ) was calculated. The test compound used in this test was dissolved in dimethylformamide before use, and the final concentration of dimethylformamide in the reaction solution was 0.1%. The results are shown in Table 16.

[0183]

[Table 16] ^*) Means the compound of Example 58 (the same applies hereinafter).

As is apparent from Table 16, the inhibitory effects of the tested compounds of Examples 58, 59 and 85 on 7-ethoxycoumarin-O-deethylation activity in rat liver microsomes were weaker than that of omeprazole. This result suggests that these compounds have weaker drug interactions than omeprazole due to inhibition of monooxygenase reaction.

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 proton pump inhibitory action and has low toxicity.
As a therapeutic agent for peptic ulcer, it can be used for treating and preventing peptic ulcer such as gastric ulcer, duodenal ulcer, reflux esophagitis, Zollinger-Ellison syndrome, anastomotic gastric ulcer, gastritis and related diseases and symptoms.

The route of administration of the compound of the present invention may be oral administration, parenteral administration or rectal administration.
The dose of the compound of the present invention depends on the type of compound, the administration method,
Usually 0.01 to 20 mg /, depending on the patient's symptoms and age
kg / day, preferably 0.1-5 mg / kg / day.

The compound of the present invention is usually administered in the form of preparation prepared by mixing with a carrier for preparation. As the carrier for formulation, a substance which is commonly used in the field of formulation and which does not react with the compound of the present invention is used. Specifically, for example, lactose, glucose, mannitol, dextran, starch, partially pregelatinized starch, sucrose, magnesium aluminometasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl starch, carboxymethyl cellulose calcium, ion Exchange resin, methylcellulose, gelatin, gum arabic, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone,
Polyvinyl alcohol, alginic acid, sodium alginate, light anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol , Vegetable oil, wax, propylene glycol, water and the like.

Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, injections and the like. These preparations are prepared according to a conventional method. The liquid preparation may be dissolved or suspended in water or another suitable medium before use. The tablets and granules may be coated by a known method.

These formulations contain 0.5% of the compound of the invention.
Above, it can be contained in a ratio of preferably 10 to 70%. These formulations may also contain other therapeutically effective ingredients such as defense factor enhancers such as teprenone, sulpiride.

The therapeutic agent for peptic ulcer containing the compound of the present invention as an active ingredient can be used in combination with the above-mentioned protective factor enhancer.

[0191]

EXAMPLES The present invention will be described in more detail with reference to the following Reference Examples and Examples, but the present invention is not limited to these Examples. In addition, the identification of the compound is the elemental analysis value,
It was performed by mass spectrum, IR spectrum, NMR spectrum, high performance liquid chromatography (HPLC) and the like. The composition ratio in the mixture of diastereomers was determined by the ratio of the peak areas of specific signals in the NMR spectrum.

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

[Recrystallization Solvent] A: Ethanol, E: Diethyl ether, M: Methanol, T: Toluene, AC: Acetonitrile, AT: Acetone, CF: Chloroform, IP: Diisopropyl ether.

[NMR] s: singlet, d: doublet, dd: doublet, m: multiplet, J: coupling constant.

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

6.4 g of 2-[(2,4-dimethoxybenzyl) thio] -N- (4-pyridyl) nicotinamide was added to 200 ml of methylene chloride, and 4.1 g of 3-chloroperbenzoic acid was added with stirring at 0 ° C. After adding 50 ml of the methylene chloride solution prepared in step 1 above, the mixture is stirred at the same temperature for 3 minutes. 100 ml of 10% aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted twice with 100 ml of chloroform. 20 m of the extract was saturated aqueous sodium hydrogen carbonate solution
Wash twice with l, dry over magnesium sulfate and concentrate under reduced pressure. The residue is subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (30: 1), and recrystallized from acetonitrile to obtain 4.2 g of the desired product. Melting point 190-192 ° C

Examples 2 to 9—2- in Example 1
[(2,4-dimethoxybenzyl) thio] -N- (4-
Using the corresponding starting material compound instead of pyridyl) nicotinamide, reacting and treating in the same manner as in Example 1 and recrystallizing from acetonitrile to obtain the compound of Table 17 represented by the following chemical formula 27.

[0198]

[Chemical 27]

[0199]

[Table 17] Example R ⁵ hydrate Melting point (° C) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 2 Ph-2,6- (OMe) ₂ 243-246 3 Ph-2,4, 6- (OMe) ₃ 182-185 4 Ph-2,3,4- (OMe) ₃ 1 / 4H ₂ O 164-166 5 Ph-2,4,5- (OMe) ₃ 1 / 2H ₂ O 103- 106 6 Ph-3,4,5- (OMe) ₃ 207-210 7 Ph-2,4- (OMe) ₂ -3-Me 1 / 4H ₂ O 105-108 8 Ph-2,4- (OMe) ₂ -6-Me 1 / 4H ₂ O 195-198 9 Ph-4-OMe 210-212 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━━

Example 10- Preparation of 2-[(2-dimethylaminobenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide:-

5.7 g of 2-[(2-dimethylaminobenzyl) thio] -N- (4-pyridyl) nicotinamide was added to 200 ml of methylene chloride, and 5.7 g of 3-chloroperbenzoic acid was added thereto while stirring with ice cooling. After adding 50 ml of methylene chloride solution, the mixture is stirred at the same temperature for 3 minutes. 100 ml of saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted twice with 100 ml of chloroform. The extract was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (10: 1) and purified to give an oil. This will crystallize over time, so recrystallize from acetonitrile to obtain 2.5 g of the desired product. Melting point 1
74-176 ° C

Examples 11 to 16 --2 -[(2-Dimethylaminobenzyl) thio] -N- in Example 10
Using the corresponding starting material compound instead of (4-pyridyl) nicotinamide, the reaction and treatment were carried out in the same manner as in Example 10 to obtain the compounds of Table 18 represented by the following chemical formula 28.

[0203]

[Chemical 28]

[0204]

[Table 18] Melting point recrystallization Example R ¹⁴ R ¹⁵ Hydrate ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ (℃) Solvent ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 11 H Me 3 / 4H ₂ O 136-140 M 12 H Pr 1 / 2H ₂ O 178-181 A-CF 13 H i-Bu 1 / 4H ₂ O 194-198 CF-M 14 Me Et 178-180 AC 15 Me Pr 1 / 4H ₂ O 155-158 AC 16 Me i-Bu 145-147 AC ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

Example 17 —Preparation of 2-[(2-aminobenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide 1/4 hydrate:

Instead of 2-[(2-dimethylaminobenzyl) thio] -N- (4-pyridyl) nicotinamide in Example 10, 2-[(2-aminobenzyl) thio] -N- (4-pyridyl) ) Using 1.2 g of nicotinamide, the reaction is carried out as in Example 10. After the reaction is complete, add 30 ml of saturated aqueous sodium hydrogen carbonate solution to the reaction mixture, add 30 ml of chloroform, stir, and let stand for 10 minutes. The crystals precipitated in the aqueous phase are collected by filtration and recrystallized from acetonitrile to obtain 0.45 g of the desired product. Melting point 208-210 ° C

Example 18 --2-[[1- (4-Methoxyphenyl) ethyl] sulfinyl] -N- (4-pyridyl) nicotinamide 1/4 hydrate [diastereomers A and B (1 : 3) mixture]:

2-[[1- (4-Methoxyphenyl) ethyl] thio] -instead of 2-[(2,4-dimethoxybenzyl) thio] -N- (4-pyridyl) nicotinamide in Example 1 Using 1.5 g of N- (4-pyridyl) nicotinamide, reaction and treatment were carried out in the same manner as in Example 1 to obtain an oily substance, which was crystallized from toluene to obtain 0.5 g of the desired product. Melting point 190-194 ℃

Example 19 Preparation of 2-[[1- (4-methoxyphenyl) ethyl] sulfinyl] -N- (4-pyridyl) nicotinamide 1/4 hydrate (diastereomer A): -

2-[[1- (4-methoxyphenyl) ethyl] thio] -instead of 2-[(2,4-dimethoxybenzyl) thio] -N- (4-pyridyl) nicotinamide in Example 1 Using 4.0 g of N- (4-pyridyl) nicotinamide, the reaction and treatment are carried out in the same manner as in Example 1 to obtain an oily substance containing diastereomers A and B. This was subjected to silica gel column chromatography, eluted with a mixture of chloroform-methanol (25: 1), the eluate was concentrated under reduced pressure, and the residue was recrystallized from acetonitrile to give the desired product.
Get 0.68 g. Melting point 232-237 ° C

Example 20 Preparation of 2-[[1- (4-methoxyphenyl) ethyl] sulfinyl] -N- (4-pyridyl) nicotinamide (diastereomer B):
-

After the diastereomer A was eluted by the chromatography of Example 19, the mixture was eluted with a mixed solution of chloroform-methanol (10: 1), the eluate was concentrated under reduced pressure, and the residue was recrystallized from diethyl ether. And 0.72 g of the desired product is obtained. Melting point 240-243 ℃

Example 21 --2-[[1- (2-Methoxyphenyl) ethyl] sulfinyl] -N- (4-pyridyl) nicotinamide [diastereomers C and D]
Preparation of (1: 8) mixture]:

2-[[1- (2-methoxyphenyl) ethyl] thio] -instead of 2-[(2,4-dimethoxybenzyl) thio] -N- (4-pyridyl) nicotinamide in Example 1 2.5 g of N- (4-pyridyl) nicotinamide was reacted and treated in the same manner as in Example 1, and the product was recrystallized from acetonitrile to obtain 0.78 g of the desired product. Melting point 242-246 ℃

Example 22 Preparation of 2-[[1- (2-methoxyphenyl) ethyl] sulfinyl] -N- (4-pyridyl) nicotinamide (diastereomer C):
-

Instead of 2-[(2,4-dimethoxybenzyl) thio] -N- (4-pyridyl) nicotinamide in Example 1, 2-[[1- (2-methoxyphenyl) ethyl] thio]- Using 1.24 g of N- (4-pyridyl) nicotinamide, the same reaction and treatment as in Example 1 are carried out to obtain an oil containing diastereomers C and D. This was subjected to silica gel column chromatography, eluted with a mixture of chloroform-methanol (100: 1), the eluate was concentrated under reduced pressure, and the residue was recrystallized from acetonitrile to give the desired product.
Get 0.13 g. Melting point 241-242 ° C

Example 23 Preparation of 2-[[1- (2-methoxyphenyl) ethyl] sulfinyl] -N- (4-pyridyl) nicotinamide (diastereomer D):
-

After diastereomer C was eluted by the chromatography of Example 22, eluting with a mixture of chloroform-methanol (50: 1), the eluate was concentrated under reduced pressure, and the residue was recrystallized from acetonitrile. Obtain 0.14 g of the desired product. Melting point 239-241 ° C

Example 24 Preparation of 2-[[1- (3-methoxyphenyl) ethyl] sulfinyl] -N- (4-pyridyl) nicotinamide (diastereomer E):
-

2-[[1- (3-Methoxyphenyl) ethyl] thio] -instead of 2-[(2,4-dimethoxybenzyl) thio] -N- (4-pyridyl) nicotinamide in Example 1 Using 3.0 g of N- (4-pyridyl) nicotinamide, the reaction and treatment are carried out in the same manner as in Example 1 to obtain an oily substance containing diastereomers E and F. This was subjected to silica gel column chromatography, eluted with a mixed solution of chloroform-methanol (30: 1), the eluate was concentrated under reduced pressure, and the residue was recrystallized from toluene to obtain 0.73 g of the desired product.
Get. Melting point 222-225 ° C

Example 25 Preparation of 2-[[1- (3-methoxyphenyl) ethyl] sulfinyl] -N- (4-9lysyl) nicotinamide (diastereomer F):
-

The diastereomer E was eluted by the chromatography of Example 24 and then eluted with a mixed solution of chloroform-methanol (10: 1). The eluate was concentrated under reduced pressure and the residue was recrystallized from toluene. Obtain 0.79 g of the desired product. Melting point
233-236 ° C

Example 26 --2-[[1- (3,4-dimethoxyphenyl) ethyl] sulfinyl] -N- (4
-Pyridyl) nicotinamide [mixture of two diastereomers (1: 1)]:

2-[[1- (3,4-dimethoxyphenyl) ethyl] thio was used instead of 2-[(2,4-dimethoxybenzyl) thio] -N- (4-pyridyl) nicotinamide in Example 1. ] -N- (4-pyridyl) nicotinamide is reacted and treated in the same manner as in Example 1, and the product is recrystallized from acetone to obtain the desired product. Melting point 211-
215 ℃

Example 27 —Preparation of 2-[(1-phenylethyl) sulfinyl] -N- (4-pyridyl) nicotinamide [mixture of two diastereomers (5: 2)]:

2-[(1-phenylethyl) thio] in place of 2-[(2,4-dimethoxybenzyl) thio] -N- (4-pyridyl) nicotinamide in Example 1
Using -N- (4-pyridyl) nicotinamide, the reaction and treatment were carried out in the same manner as in Example 1, and the product was recrystallized from acetonitrile to obtain the desired product. Melting point 178-180 [deg.] C. In this mixed crystal, the content of highly polar diastereomers is higher.

Example 28 --2-[(4-Methoxybenzhydryl) sulfinyl] -N- (4-pyridyl) nicotinamide 1/4 hydrate [2 diastereomers (3: 1)] Mixture of]

1.1 g of 2-[(4-methoxybenzhydryl) thio] -N- (4-pyridyl) nicotinamide was added to 50 ml of methylene chloride, and 0.7 g of 3-chloroperbenzoic acid was added thereto while stirring with ice cooling. After adding 10 ml of the methylene chloride solution in step (3), the mixture is stirred at the same temperature for 3 minutes. 20 ml of a saturated aqueous solution of sodium hydrogencarbonate is added to the reaction mixture, and the mixture is extracted twice with 30 ml of chloroform. The extract was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (10: 1) for purification to give an oil. This crystallizes soon, so recrystallize from diethyl ether to obtain 0.3 g of the desired product. Melting point 192-1
95 ° C. In this mixed crystal, the content of the low polar diastereomer is higher.

Examples 29 to 33 --2 -[(4-methoxybenzhydryl) thio] -N- in Example 28
Using the corresponding starting material compound instead of (4-pyridyl) nicotinamide, reaction and treatment were carried out in the same manner as in Example 28 to obtain the compounds of Table 19 represented by the following chemical formula 29.

[0230]

[Chemical 29]

[0231]

Table 19 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Melting point Recrystallization Example R ¹¹ R hydrate (℃) Solvent ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━ 29 H CHPh ₂ 1 / 4H ₂ O 175- 178 M 30 H CH (Ph-4-Me) ₂ 159-163 AC 31 H CH (Ph-4-F) ₂ 159-162 AC 32 Me CHPh ₂ 1 / 10H ₂ O 180-182 AC 33 Me CH (Ph -4-Me) ₂ 175-177 AC ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

Example 34 —Preparation of 2-[(2-dimethylaminobenzyl) sulfinyl] -N- (2-hydroxymethyl-4-pyridyl) nicotinamide:

Instead of 2-[(2-dimethylaminobenzyl) thio] -N- (4-pyridyl) nicotinamide in Example 10, 2-[(2-dimethylaminobenzyl) thio] -N- (2- Hydroxymethyl-4-pyridyl) nicotinamide (0.42 g) was used and the reaction was carried out in the same manner as in Example 10. After completion of the reaction, triethylamine 0.
After adding 32 g and stirring at 0 ° C for 5 minutes, the mixture is concentrated under reduced pressure at 30 ° C.
The residue is subjected to silica gel column chromatography, eluted with chloroform-methanol (10: 1 to 8: 1) and purified to obtain an oily substance, which is crystallized from acetonitrile to obtain 0.31 g of the desired product. Melting point 173-175 ° C

Example 35 —Preparation of N- (2-acetoxymethyl-4-pyridyl) -2-[(2-dimethylaminobenzyl) sulfinyl] nicotinamide: —

N- (2-acetoxymethyl-4-) was used in place of 2-[(2-dimethylaminobenzyl) thio] -N- (4-pyridyl) nicotinamide in Example 10.
Pyridyl) -2-[(2-dimethylaminobenzyl) thio] nicotinamide was used and reacted in the same manner as in Example 10.
After treatment, the product is recrystallized from acetonitrile to obtain the desired product. Melting point 171-173 ℃

Examples 36 to 42 --2 -[(4-methoxybenzhydryl) thio] -N- in Example 28
Using the corresponding starting material compound instead of (4-pyridyl) nicotinamide, reaction and treatment were carried out in the same manner as in Example 28 to obtain the compound of Table 20 represented by the following Chemical formula 30.

[0237]

Embedded image

[0238]

[Table 20] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Melting point Recrystallization Example R ² R ¹ (° C ) Solvent ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 36 H 4-Py-2-Me-6-CH ₂ OH 174-176 E 37 Me 4-Py 183-184 M-CF 38 i-Pen 4-Py 158-161 M-CF 39 H 2-Py 160-163 AC 40 H 3-Py 165-166 M 41 H 3-Py-6-OMe 177-183 M 42 H Ph 179-183 CF ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━

Example 43 —Preparation of 2-[(2-dimethylaminobenzyl) sulfinyl] -N-phenylnicotinamide 1/4 hydrate:

2-[(2-Dimethylaminobenzyl) thio] -N-phenylnicotine instead of 2-[(4-methoxybenzhydryl) thio] -N- (4-pyridyl) nicotinamide in Example 28. Reaction and treatment are carried out in the same manner as in Example 28 using an amide, and the product is recrystallized from acetonitrile to obtain the desired product. Melting point 158-161 ° C

Example 44 —Preparation of N- (4-aminophenyl) -2-[(benzhydryl) sulfinyl] nicotinamide 3/5 acetonitrile solvate:

N- (4-aminophenyl) -2-[(benzhydryl) thio] nicotinamide (0.69 g) and 2N hydrochloric acid (0.8 ml) were added to a mixture of methylene chloride (20 ml) and methanol (20 ml) with stirring under ice cooling. 3-chloroperbenzoic acid
After adding 10 g of 0.4 g of methylene chloride solution, the mixture is stirred at the same temperature for 3 minutes. Saturated aqueous sodium hydrogen carbonate solution in the reaction mixture
Add 30 ml and extract twice with 100 ml chloroform. The extract is dried over magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (20: 1), and recrystallized from acetonitrile to obtain 0.37 g of the desired product. Melting point 104-10
6 ° C

Example 45 --2- [(Benzhydryl)
Sulfinyl] -N- (4-dimethylaminophenyl)
Manufacture of nicotinamide:-

N- (4-Aminophenyl) -2-[(benzhydryl) thio] in Example 44 In place of nicotinamide, 2-[(benzhydryl) thio] -N- was used.
Using (4-dimethylaminophenyl) nicotinamide, the reaction and treatment are carried out in the same manner as in Example 44, and the product is recrystallized from acetonitrile to obtain the desired product. Melting point 155-157
℃

Example 46 --4-[[4- [2- (Benzhydryl) sulfinyl] nicotinoylamino] phenyl] -1-methylpiperazine 1-oxide. 1/4
Hydrate production:-

2-[(Benzhydryl) thio] -N-
[4- (4-Methyl-1-piperazinyl) phenyl] nicotinamide (2.4 g) and 2N hydrochloric acid (15.6 ml) were added to a mixture of methylene chloride (70 ml) and methanol (70 ml), and 3-chloroperbenzoic acid was added while stirring under ice cooling. After adding 50 ml of 1.07 g methylene chloride solution, the mixture is stirred at the same temperature for 3 minutes. 100 ml of a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction solution, and the mixture was extracted twice with 200 ml of chloroform. The extract was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was used as Diaion CHP-20P.
(Trademark) [High-porous polystyrene resin (75-150 μ
m), Mitsubishi Kasei], and eluted and purified with 20% acetonitrile, and recrystallized from acetonitrile to obtain 0.20 g of the desired product. Melting point
139-141 ℃

Example 47 --2- [(Benzhydryl)
Preparation of sulfinyl] -N- [4- (4-methyl-1-piperazinyl) phenyl] nicotinamide:-

After eluting the compound of Example 46 by CHP-20P medium-pressure column chromatography of Example 46, 4-[[4- [2- (benzhydryl) thio] nicotinoylamino] phenyl]-was eluted with 30% acetonitrile. 1-Methylpiperazine 1-oxide (compound of Example 100) was eluted, followed by elution and purification with 40% acetonitrile to obtain an oily substance. This was recrystallized from acetonitrile to give the desired product.
Get 13 g. Melting point 165-168 ℃

Example 48 --2- [(Benzhydryl)
Preparation of sulfinyl] -N- [4- (2-dimethylaminoethyl) phenyl] nicotinamide 1/4 hydrate:
-

N- (4-Aminophenyl) -2-[(benzhydryl) thio] in Example 44 Instead of nicotinamide, 2-[(benzhydryl) thio] -N- was used.
[4- (2-Dimethylaminoethyl) phenyl] Nicotinamide was used, treated and treated in the same manner as in Example 44, and the product was recrystallized from diethyl ether to obtain the desired product.
Melting point 119-121 ° C

Examples 49 to 57 : Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 28, and the compounds shown below were used.
The compounds of Table 21 represented by are obtained.

[0252]

[Chemical 31]

[0253]

[Table 21] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Implementation Melting point (° C) Example R ¹ R hydrate (Recrystallization solvent) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 49 1-Naphthyl CHPh ₂ 152-154 (M ) 50 6-quinolyl CHPh ₂ 165-168 (A) 51 5-quinolyl CH (Ph-4-Me) ₂ 157-159 (AC) 52 2-Me-8-quinolyl CHPh ₂ 145-150 (T) 53 2 , 4-Me ₂ -1,8-Naphthyridin-7-yl CHPh ₂ 1 / 2H ₂ O 141-145 (AC) 54 9-Acridinyl CHPh ₂ 1 / 4H ₂ O 245-248 (AC) 55 2-Primimidinyl CHPh ₂ 153-156 (AC) 56 2-Plasagenyl CHPh ₂ 1 / 4H ₂ O 164-165 (CF-M) 57 2-Thiazolyl CHPh ₂ 172-175 (AC) ━━━━━━━━━━━━━ ━━━━━━━━━━━━━━━━━━━━━━━

Example 58 —Preparation of 2-[(2,4-dimethoxybenzyl) sulfinyl] -N- (2-hydroxymethyl-4-pyridyl) nicotinamide 1/4 hydrate:

2-[(2,4-Dimethoxybenzyl) thio] -N- (2-hydroxymethyl-4-pyridyl) nicotinamide (1.9 g) was added to 100 ml of methylene chloride, and the mixture was cooled to 0 ° C.
30 ml of a methylene chloride solution containing 1.3 g of 3-chloroperbenzoic acid was added dropwise while stirring at 3, and then the mixture was stirred at the same temperature for 3 minutes.
To the reaction solution, add 50 ml of 10% sodium hydrogen carbonate aqueous solution,
Extract twice with 50 ml of chloroform. The extract is dried over magnesium sulfate, concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (10: 1), and recrystallized from methanol to obtain 0.5 g of the desired product. . Melting point 201-203 ℃

Example 59 —Preparation of N- (2-acetoxymethyl-4-pyridyl) -2-[(2,4-dimethoxybenzyl) sulfinyl] nicotinamide:

3.8 g of N- (2-acetoxymethyl-4-pyridyl) -2-[(2,4-dimethoxybenzyl) thio] nicotinamide was added to 200 ml of methylene chloride, and -78 was added.
50 ml of a methylene chloride solution containing 1.7 g of 3-chloroperbenzoic acid was added dropwise with stirring at ℃, and the mixture was stirred at the same temperature for 3 minutes. 50 ml of 10% sodium hydrogencarbonate aqueous solution is added to the reaction mixture, and the mixture is extracted twice with 100 ml of chloroform. The extract is dried over magnesium sulfate, concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (50: 1), and recrystallized from acetone to obtain 2.0 g of the desired product. . Melting point 180-182 ° C

Examples 60-66 --2 -[( 2,4 -dimethoxybenzyl) thio] -N- in Example 58
Using the corresponding starting material compound instead of (2-hydroxymethyl-4-pyridyl) nicotinamide, reaction and treatment were carried out in the same manner as in Example 58 to obtain the compounds of Table 22 represented by the following Chemical Formula 32.

[0259]

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[0260]

[Table 22] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Example R ² hydrate / solvate Melting point (° C ) Recrystallization solvent ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 60 Me 197-200 AC 61 i-Pr 201-203 AC 62 i-Bu 205-207 CF-M 63 i-Pen 183-186 AC 64 Ph 1 / 4CH ₃ CN 209-212 AC 65 Cl 1 / 2H ₂ O 185-189 M 66 OMe 1 / 2EtOH 162-164 A- IP ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

Example 67- Preparation of 2-[(2,4-diethoxybenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide:-

3.5 g of 2-[(2,4-diethoxybenzyl) thio] -N- (4-pyridyl) nicotinamide was added to 100 ml of methylene chloride, and 3-chloroperbenzoic acid 2.1 with stirring at 0 ° C. After adding 30 ml of methylene chloride solution (g), the mixture is stirred at the same temperature for 3 minutes. To the reaction mixture was added 10% aqueous sodium hydrogen carbonate solution (50 ml), and chloroform (50 ml) added to the reaction mixture.
Extract twice. The extract was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (30: 1), and recrystallized from acetonitrile to give 1.5 g of the desired product.
Get. Melting point 165-166 ° C

Examples 68-74 --2 -[( 2,4 -diethoxybenzyl) thio] -N- in Example 67
Using the corresponding starting material compound instead of (4-pyridyl) nicotinamide, reaction and treatment were carried out in the same manner as in Example 67 to obtain the compound of Table 23 represented by the following chemical formula 33.

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[Chemical 33]

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[Table 23] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Example R ⁵ hydrate Melting point (° C) Re Crystal solvent ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 68 Ph-4-OEt 183-185 AC 69 Ph-2 , 4- (OMe) ₂ -5-Br 209-211 AC 70 Ph-2-OEt-4-OMe 200-202 AC 71 Ph-2-OCH ₂ OMe-4-OMe 189-191 AC 72 Ph-2- OCH ₂ CH ₂ F-4-OMe 163-164 AC 73 Ph-2-OCH ₂ CH ₂ OH-4-OMe 1 / 4H ₂ O 182-184 AT 74 Ph-2-OCH ₂ CH ₂ OCH ₂ OMe-4 -OMe 200-202 M ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

Example 75 --2-[(4-chloro-2-
Dimethylaminobenzyl) sulfinyl] -N- (4-
Production of pyridyl) nicotinamide:-

5.0 g of 2-[(4-chloro-2-dimethylaminobenzyl) thio] -N- (4-pyridyl) nicotinamide was added to 200 ml of methylene chloride, and this was cooled with ice.
50 ml of a methylene chloride solution containing 3.7 g of 3-chloroperbenzoic acid was added dropwise with stirring, and then the mixture was stirred at the same temperature for 3 minutes. 100 ml of saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted twice with 100 ml of chloroform. The extract was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (10: 1) and purified to give an oil. This crystallizes soon, so recrystallize from acetonitrile to obtain 1.3 g of the desired product. Melting point 187-190 ° C

Example 76 --2-[(3,5-Dibromo-2-dimethylaminobenzyl) sulfinyl] -N-
Production of (4-pyridyl) nicotinamide:

2-[(4-chloro-in Example 75
2-[(3,5-Dibromo-2-dimethylaminobenzyl) thio] -N- (4 instead of 2-dimethylaminobenzyl) thio] -N- (4-pyridyl) nicotinamide
-Pyridyl) nicotinamide was reacted and treated in the same manner as in Example 75, and the product was recrystallized from chloroform-methanol to obtain the desired product. Melting point 250-251 ℃

Example 77 --2-[(4-Dimethylamino-2,5-difluorobenzyl) sulfinyl] -N
-Production of (4-pyridyl) nicotinamide 1/2 dihydrate:-

2-[(4-Dimethylamino-2,5-difluorobenzyl) thio] -N- (4-pyridyl) nicotinamide (4.2 g) was added to 200 ml of methylene chloride, and this was stirred under ice cooling while stirring. After adding 50 ml of a methylene chloride solution containing 3.2 g of 3-chloroperbenzoic acid, the mixture is stirred at the same temperature for 3 minutes. 100 ml of a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction solution, and the mixture was extracted twice with 200 ml of chloroform. The extract was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (10: 1) and purified to give an oil.
This crystallizes soon, so recrystallize from acetone to obtain 0.8 g of the desired product. Melting point 176-178 ℃

Example 78 Preparation of 2-[(4-dimethylamino-2,3,5-trifluorobenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide:-
―

2-[(4-Dimethylamino-2,5-difluorobenzyl) thio] -N- in Example 77
Instead of (4-pyridyl) nicotinamide, 2-[(4
-Dimethylamino-2,3,5-trifluorobenzyl) thio] -N- (4-pyridyl) nicotinamide was reacted and treated in the same manner as in Example 77, and the product was recrystallized from acetonitrile to give the desired product. Get things. Melting point 183-185
℃

Example 79 Preparation of 2-[(4-dimethylamino-2,5,6-trifluorobenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide:-
―

2-[(4-Dimethylamino-2,5-difluorobenzyl) thio] -N-in Example 77
Instead of (4-pyridyl) nicotinamide, 2-[(4
-Dimethylamino-2,5,6-trifluorobenzyl) thio] -N- (4-pyridyl) nicotinamide was reacted and treated in the same manner as in Example 77, and the product was recrystallized from chloroform-methanol. To get the target. Melting point
221-224 ° C

Example 80 --4- [2,5-difluoro-4-[[[3- (4-pyridylcarbamoyl) -2-
Preparation of Pyridyl] sulfinylmethyl] phenyl] -1-methylpiperazine-1-oxide 3/4 tetrahydrate:-
―

2- [[2,5-difluoro-4- (4-
Methyl-1-piperazinyl) benzyl] thio] -N-
(4-Pyridyl) nicotinamide (4.0 g) in methanol (20 g)
To this, 50 ml of an aqueous solution of 2.0 g of sodium periodate was added with stirring under ice cooling, and the mixture was stirred at 70 ° C for 1 hour. The reaction mixture is concentrated under reduced pressure, and the residue is subjected to CHP-20P medium pressure column chromatography, eluted with 15% acetonitrile and purified to give an oil. This is crystallized from isopropyl ether to obtain 1.0 g of the desired product. Melting point 160-16
5 ° C

Examples 81 to 84 --2 -[( 2,4 -dimethoxybenzyl) thio] -N- in Example 58
Using the corresponding starting material compound instead of (2-hydroxymethyl-4-pyridyl) nicotinamide, reaction and treatment were carried out in the same manner as in Example 58 to obtain the following compound.

Example 81 N- (4-diethylaminophenyl) -2-[(2,4-dimethoxybenzyl) sulfinyl] nicotinamide 1/4 hydrate: melting point 153-156 ° C. (recrystallization Solvent: acetonitrile)

Example 82-2 -([2,4-dimethoxybenzyl) sulfinyl] -N- (4-morpholinophenyl) nicotinamide 3/4 hydrate: mp 208
-210 ℃ (Recrystallization solvent: acetonitrile)

Example 83-2 -[(2,4-dimethoxybenzyl) sulfinyl] -N- [4- (1-pyrrolidinyl) phenyl] nicotinamide 1/4 hydrate: melting point 203-206 ℃ (recrystallization solvent: methanol)

( Example 84 ) -2-[(2,4-dimethoxybenzyl) sulfinyl] -N- (4-piperidinophenyl) nicotinamide: melting point 195-197 ° C (recrystallization solvent: acetonitrile)

Example 85 —Preparation of 2-[(2,4-dimethoxybenzyl) sulfinyl] -N- [4- (4-methyl-1-piperazinyl) phenyl] nicotinamide:

2-[(2,4-Dimethoxybenzyl) thio] -N- [4- (4-methyl-1-piperazinyl) phenyl] nicotinamide (11.4 g) was added to 400 ml of methylene chloride, and the reaction mixture was ice-cooled. Under stirring, 48 ml of 1M borane-tetrahydrofuran complex was added with stirring, and the mixture was stirred at the same temperature for 1 hour. 100 ml of a methylene chloride solution containing 8.8 g of 3-chloroperbenzoic acid was added dropwise to the reaction solution, and the mixture was stirred at the same temperature for 30 minutes.
Add 100 ml of saturated aqueous sodium hydrogen carbonate solution to the reaction mixture,
Extract twice with 300 ml of chloroform. The extract is dried over magnesium sulfate and then concentrated under reduced pressure, and 300 ml of methanol is added to the residue. To this, 13 g of sodium carbonate is added, and the mixture is heated under reflux for 3 hours. After concentrating the reaction mixture under reduced pressure, 100 ml of water
Is added and extracted twice with 300 ml of chloroform. The extract was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (5: 1) and purified to give an oil. This crystallizes soon, so recrystallize from methanol to obtain 2.0 g of the desired product. Melting point 197-200 ℃

Example 86 --2-[(2,4-dimethoxybenzyl) sulfinyl] -N- [4- [4- (2-
Hydroxyethyl) -1-piperazinyl] phenyl] Nicotinamide Preparation:

2-[(2,4-dimethoxybenzyl) thio] -N- [4- (4-methyl-1) in Example 85
-Piperazinyl) phenyl] nicotinamide instead of 2-[(2,4-dimethoxybenzyl) thio] -N-
[4- [4- (2-Hydroxyethyl) -1-piperazinyl] phenyl] nicotinamide was reacted and treated in the same manner as in Example 85, and the product was recrystallized from methanol to obtain the desired product. Melting point 214-218 ℃

Example 87 --4- [4- [2-[(2,
4-Dimethoxybenzyl) sulfinyl] nicotinoylamino] phenyl] -1-methylpiperazine 1,4-
Preparation of dioxide 5/2 hydrate:-

2-[(2,4-dimethoxybenzyl) thio] -N- [4-[(4-methyl-1-piperazinyl)
Phenyl] 5.0 g of nicotinamide 200 ml of methylene chloride
In addition to this, 50 ml of a methylene chloride solution of 5.7 g of 3-chloroperbenzoic acid is added dropwise thereto with stirring under ice cooling, and the mixture is stirred at the same temperature for 3 minutes. The reaction solution is extracted twice with 200 ml of water. After the reaction solution is concentrated under reduced pressure, the residue is subjected to CHP-20P medium pressure column chromatography and eluted with 10% acetonitrile for purification to obtain a solid. This is recrystallized from diethyl ether to obtain 1.0 g of the desired product. Melting point 161-165 ℃

Example 88 --4- [4- [2-[(2,
Production of 4-dimethoxybenzyl) sulfinyl] nicotinoylamino] phenyl] -1-methylpiperazine 1-oxide:

CHP-20P medium pressure column chromatography of Example 87 showed 4- [4- [2-[(2,4-dimethoxybenzyl) sulfinyl] nicotinoylamino] phenyl] -1-methylpiperazine 1,4-. After elution of the dioxide (compound of Example 87), elution and purification with 20% acetonitrile gave a solid. This is recrystallized from acetonitrile to obtain 1.1 g of the desired product. Melting point 223-226 ℃

Example 89 --2-[[[3- (2-Dimethylamino) pyridyl] methyl] sulfinyl] -N-
Production of (4-pyridyl) nicotinamide:

Instead of 2-[(2,4-dimethoxybenzyl) thio] -N- (2-hydroxymethyl-4-pyridyl) nicotinamide in Example 58, 2-[[
[3- (2-Dimethylamino) pyridyl] methyl] thio]
Using -N- (4-pyridyl) nicotinamide, the reaction and treatment were carried out in the same manner as in Example 58, and the product was recrystallized from acetonitrile to obtain the desired product. Melting point 174-176 ° C

Example 90 —Preparation of 2-[(2,4-dimethoxybenzyl) thio] -N- (4-pyridyl) nicotinamide:

2-[(2,4-dimethoxybenzyl) thio] nicotinic acid (26 g), 4-aminopyridine (9.7 g) and tetrahydrofuran (700 ml) were added to a mixed solution of 1-ethyl-
20 g of 3- (3-dimethylaminopropyl) carbodiimide hydrochloride is added, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure and extracted twice with 300 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. The residue is subjected to silica gel column chromatography, eluted with chloroform-methanol (30: 1) and purified to obtain 6.4 g of the desired product as an oil.

¹ H-NMR (DMSO-d ₆ ) δ; 3.72 (s, 3H), 3.77
(s, 3H), 4.32 (s, 2H), 6.46 (dd, J = 8.4Hz, J = 2.6Hz, 1H),
6.54 (d, J = 2.6Hz, 1H), 7.25 (d, J = 8.4Hz, 1H), 7.28 (dd, J =
7.7Hz, J = 4.9Hz, 1H), 7.66 (m, 2H), 7.96 (dd, J = 7.7Hz, J =
1.9Hz, 1H), 8.47 (m, 2H), 8.64 (dd, J = 4.9Hz, J = 1.9Hz, 1
H), 10.81 (s, 1H)

Examples 91 to 98 —2-[( 2,4 -dimethoxybenzyl) thio] in Example 90 The corresponding starting material compound was used instead of nicotinic acid, and the reaction and treatment were carried out in the same manner as in Example 90, The compounds of Table 24 represented by Chemical formula 34 are obtained. The compounds of Examples 91, 93, 96 and 97 are oily substances, and the other compounds are crystals.

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[0298]

[Table 24] ━━━━━━━━━━━━━━━━━━━━━ Example R ⁵ ━━━━━━━━━━━━━━━━━━━━━ ━ 91 Ph -2,6- (OMe) ₂ 92 Ph-2,4,6- (OMe) ₃ 93 Ph-2,3,4- (OMe) ₃ 94 Ph-2,4,5- (OMe) ₃ 95 Ph -3,4,5- (OMe) ₃ 96 Ph-2,4- (OMe) ₂ -3-Me 97 Ph-2,4- (OMe) ₂ -6-Me 98 Ph-4-OMe ━━━ ━━━━━━━━━━━━━━━━━━

Example 99 --Preparation of 2-[(2-dimethylaminobenzyl) thio] -N- (4-pyridyl) nicotinamide:-

2-[(2-Dimethylaminobenzyl) thio] nicotinic acid 6.0 g, 4-aminopyridine 2.35 g, 1
A mixture of 4.77 g of ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 300 ml of methylene chloride is stirred for 3 hours at room temperature. The reaction solution is washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, chloroform-
Elution and purification with methanol (50: 1) gives 7.5 g of the desired product as an oil.

¹ H-NMR (DMSO-d ₆ ) δ; 2.67 (s, 6H), 4.42
(s, 2H), 7.31 (dd, J = 7.5Hz, J = 4.5Hz, 1H), 7.69 (m, 2H), 8.
01 (dd, J = 7.5Hz, J = 2.0Hz, 1H), 8.49 (m, 2H), 8.66 (dd, J =
4.5, J = 2.0, H), 10.86 (s, 1H)

Examples 100 to 105 —2 -[(2-Dimethylaminobenzyl) thio] in Example 99 The corresponding starting compound was used in place of nicotinic acid, and Example 9 was used.
By reacting and treating in the same manner as in Example 9, the compound of Table 25 represented by Chemical formula 35 is obtained as an oil.

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[Table 25] ━━━━━━━━━━━━━━━━━ Example R ¹⁴ R ¹⁵ ━━━━━━━━━━━━━━━━━ 100 H Me 101 H Pr 102 H i-Bu 103 Me Et 104 Me Pr 105 Me i-Bu ━━━━━━━━━━━━━━━━━

Example 106 Preparation of 2-[(2-aminobenzyl) thio] -N- (4-pyridyl) nicotinamide:

(1) 2-[(2, 4 in Example 90
-Dimethoxybenzyl) thio] 2 instead of nicotinic acid
-[(2-Nitrobenzyl) thio] nicotinic acid (7.2 g) was used and reacted and treated in the same manner as in Example 90 to give 2-[(2-
5.8 g of nitrobenzyl) thio] -N- (4-pyridyl) nicotinamide are obtained.

(2) Ethanol was added to 4.5 g of the above amide compound.
Dissolve in a mixture of 300 ml of ethyl acetate and 100 ml of ethyl acetate, add 0.50 g of 5% palladium carbon, and carry out catalytic reduction at room temperature and atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is subjected to silica gel column chromatography, eluted with chloroform-methanol (20: 1) and purified to obtain 1.2 g of the desired product as crystals.

Examples 107 to 111 —2 -[(2,4-dimethoxybenzyl) thio] in Example 90 Using the corresponding starting compound instead of nicotinic acid, Example 9
By reacting and treating in the same manner as in 0, the compound of Table 26 represented by Chemical formula 36 is obtained as an oil.

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[0310]

[Table 26] ━━━━━━━━━━━━━━━━━━ Example R ⁴ R ⁵ ━━━━━━━━━━━━━━━━━━━ 107 Me Ph- 4-OMe 108 Me Ph-2-OMe 109 Me Ph-3-OMe 110 Me Ph-3,4- (OMe) ₂ 111 Ph Ph-4-OMe ━━━━━━━━━━━━━━━ ━━━━

Example 112 --Preparation of 2-[(benzhydryl) thio] -N- (4-pyridyl) nicotinamide:-

2-[(Benzhydryl) thio] nicotinic acid (10 g) is added to dioxane (400 ml), oxalyl chloride (25 ml) is added dropwise with stirring under ice-cooling, and the mixture is stirred at 80 ° C. for 30 minutes. After distilling off the solvent under reduced pressure, tetrahydrofuran 30
0 ml and 4-aminopyridine (3.2 g) were added, and triethylamine (4.8 g) was added dropwise with stirring under ice-cooling, followed by stirring at room temperature for 30 minutes. 200 ml of water was added to the reaction mixture, and 300 ml of ethyl acetate was added.
Extract twice with ml. The extract is dried over magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, chloroform-methanol (50: 1).
Elute and purify with and recrystallize from acetonitrile to obtain the desired product
Get 12 g. Melting point 200-201 ℃

Examples 113 to 117 : Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 112, and
The compounds of Table 27 represented by 7 are obtained. In addition, Example 11
The compounds of 3,114 and 117 are oily substances, and the other compounds are crystals.

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[0315]

[Table 27] ━━━━━━━━━━━━━━━━━━━━━ Example R ¹¹ R ━━━━━━━━━━━━━━━━━━━━━ ━ 113 H CH (Me) Ph 114 H CH (Ph-4-Me) ₂ 115 H CH (Ph-4-F) ₂ 116 Me CHPh ₂ 117 Me CH (Ph-4-Me) ₂ ━━━━━ ━━━━━━━━━━━━━━━━

Example 118 --2-[(2-Dimethylaminobenzyl) thio] -N- (2-hydroxymethyl-
Production of 4-pyridyl) nicotinamide:-

(1) Rec. Trav. Chim., 70 , 591 (1951)
And 4-amino-2-methylpyridine 1-oxide 1.6 g, 2-[(2-dimethylaminobenzyl) synthesized according to the method described in J. Org. Chem., 26 , 2740 (1961).
Thio] nicotinic acid 3.0 g and tetrahydrofuran 100 ml
2.4 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride is added to the mixed solution consisting of and the mixture is stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and then ethyl acetate
Extract twice with 50 ml. The extract is washed twice with 10 ml of saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-methanol (1
Elution and purification with 5: 1) gave an oil, which was recrystallized from acetonitrile to give 4- [2-[(2-dimethylaminobenzyl) thio] nicotinoylamino] -2-methyl-pyridine 1-oxide 1.2. get g

(2) 1.0 g of the above amide compound is suspended in 50 ml of methylene chloride, 3.5 ml of trifluoroacetic anhydride is added, and the mixture is stirred at room temperature for 6 hours. The reaction mixture is concentrated under reduced pressure, water is added to the residue, and the mixture is concentrated again under reduced pressure. The residue is subjected to CHP-20P medium pressure column chromatography, and eluted and purified with 50% acetonitrile to obtain 0.42 g of the desired product as an oil.

Example 119 Preparation of 2-[(benzhydryl) thio] -N- (2-hydroxymethyl-6-methyl-4-pyridyl) nicotinamide:

4-Amino-2-methyl-pyridine 1-oxide and 2-[(2-dimethylaminobenzyl) thio] in Example 118 4-amino-2,6-dimethylpyridine 1-oxide instead of nicotinic acid And 2
-[(Benzhydryl) thio] Nicotinic acid is used and reacted and treated in the same manner as in Example 118 to obtain the desired product as crystals. The starting compound 4-amino-2,6-dimethylpyridine 1-oxide was prepared according to Rec. Trav. Chim., 70 , 591.
(1951) and J. Org. Chem., 26 , 2740 (1961).

Example 120 --Preparation of N- (2-acetoxymethyl-4-pyridyl) -2-[(2-dimethylaminobenzyl) thio] nicotinamide:-

4- [2- obtained in Example 118 (1)
[(2-Dimethylaminobenzyl) thio] nicotinoylamino] -2-methyl-pyridine 1-oxide 1.0 g
Is added to 35 ml of acetic anhydride, the mixture is stirred at 90 ° C. for 1 hour, and concentrated under reduced pressure. Water is added to the reaction solution and the mixture is concentrated again under reduced pressure, and the residual solution is extracted twice with 30 ml of chloroform. The extract is washed twice with 10 ml of saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography, eluted with chloroform-methanol (50: 1) and purified to obtain 0.80 g of the desired product as an oil.

Example 121 --Preparation of 2-[(benzhydryl) thio] -6-methyl-N- (4-pyridyl) nicotinamide:

(1) 28 g of 2-hydroxy-6-methylnicotinic acid is added to 200 ml of phosphorus oxychloride and heated under reflux for 3 hours with stirring. After concentrating the reaction mixture under reduced pressure,
Toluene (500 ml) is added, 4-aminopyridine (18.9 g) and triethylamine (28.0 g) are added with stirring under ice-cooling, and the mixture is stirred at room temperature for 12 hours. 200 ml of water is added to the reaction mixture, and the mixture is extracted twice with 200 ml of ethyl acetate. The extract is dried over magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (20: 1) and purified to give 2-chloro-6.
-Methyl-N- (4-pyridyl) nicotinamide 9.8 g
Get.

(2) 8.6 g of the above amide compound, Chem.In
A mixture of 9.2 g of diphenylmethanethiol, 19.2 g of potassium carbonate and 200 ml of dimethylformamide, synthesized according to the method described in d., 546 (1968), was added at 100 ° C for 3 hours.
Stir for hours. The reaction mixture is concentrated under reduced pressure, 100 ml of water is added, and the mixture is extracted twice with 300 ml of chloroform. The extract was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (20: 1), and recrystallized from acetonitrile to obtain 12 g of the desired product. obtain. Melting point 182-184 ℃

Example 122 --2-[(Benzhydryl) thio] -6-isopentyl-N- (4-pyridyl)
Manufacture of nicotinamide:-

2-Hydroxy-6 in Example 121
Using 2-hydroxy-6-isopentylnicotinic acid instead of methylnicotinic acid and reacting and treating in the same manner as in Example 121, the target product is obtained as an oil.

Example 123 --Preparation of 2-[(benzhydryl) thio] -N- (2-pyridyl) nicotinamide:-

Using 2-aminopyridine instead of 4-aminopyridine in Example 112, the reaction and treatment were conducted in the same manner as in Example 112 to obtain the desired product as crystals.

Example 124 --- Preparation of 2-[(benzhydryl) thio] -N- (3-pyridyl) nicotinamide:-

Using 3-aminopyridine in place of 4-aminopyridine in Example 112 and reacting and treating in the same manner as in Example 112, the desired product is obtained as an oil.

Example 125 --Preparation of 2-[(benzhydryl) thio] -N- (6-methoxy-3-pyridyl) nicotinamide:-

Using 3-amino-6-methoxypyridine instead of 4-aminopyridine in Example 112,
Reaction and treatment are conducted in the same manner as in Example 112 to obtain the desired product as an oil.

Example 126 --Preparation of 2-[(benzhydryl) thio] -N-phenylnicotinamide:

As in Example 99, 2-[(2-dimethylaminobenzyl) thio] nicotinic acid and 4-aminopyridine in Example 99 were replaced with 2-[(benzhydryl) thio] nicotinic acid and aniline, respectively. Then, the product is recrystallized from methanol to obtain the desired product. Melting point 156-159 ℃

Example 127 Preparation of 2-[(2-dimethylaminobenzyl) thio] -N-phenylnicotinamide:

By using aniline in place of 4-aminopyridine in Example 99 and reacting and treating in the same manner as in Example 99, the desired product is obtained as an oily substance.

Example 128 --Preparation of 2-[(benzhydryl) thio] -N- (4-aminophenyl) nicotinamide:-

(1) Using 4-nitroaniline (5.0 g) instead of 4-aminopyridine in Example 112, the reaction and treatment were carried out in the same manner as in Example 112, and 2-[(benzhydryl) thio] -N- (4 3.7 g of -nitrophenyl) nicotinamide are obtained.

(2) 1.0 g of the above amide compound was dissolved in 100 ml of ethyl acetate, and 0.10 g of 10% palladium carbon was added,
Catalytic reduction is performed at 40 ° C under normal pressure. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is subjected to silica gel column chromatography, eluted with chloroform-methanol (20: 1) and purified to obtain 0.69 g of the desired product as an oil.

Example 129 Preparation of 2-[(benzhydryl) thio] -N- (4-dimethylaminophenyl) nicotinamide:

Using 4-dimethylaminoaniline in place of 4-aminopyridine in Example 112, the reaction and treatment were conducted in the same manner as in Example 112 to obtain the desired product as an oil.

Example 130 —Preparation of 2-[(benzhydryl) thio] -N- [4- (4-methyl-1-piperazinyl) phenyl] nicotinamide:

Using 4- (4-methyl-1-piperazinyl) aniline in place of 4-aminopyridine in Example 112, the reaction and treatment were conducted in the same manner as in Example 112 to obtain the desired product as an oil.

Example 131 --2-[(Benzhydryl) thio] -N- [4- (2-dimethylaminoethyl)]
Phenyl] Production of nicotinamide:

Using 4- (2-dimethylaminoethyl) aniline instead of 4-aminopyridine in Example 112, the reaction and treatment were conducted in the same manner as in Example 112 to obtain the desired product as crystals.

Example 132 --4-[[4- [2- (Benzhydryl) thio] nicotinoylamino] phenyl]
Production of -1-methylpiperazine 1-oxide:

CHP-20P of Example 46 By medium pressure column chromatography, the compound of Example 46 was eluted with 20% acetonitrile and then eluted and purified with 30% acetonitrile to obtain the desired product as crystals.

Example 133 Preparation of 2-[(benzhydryl) thio] -N- (1-naphthyl) nicotinamide:

2-[(2-Dimethylaminobenzyl) thio] nicotinic acid and 4-aminopyridine in Example 99 were replaced by 2-[(benzhydryl) thio] nicotinic acid and 1-aminonaphthalene. Reaction and treatment are performed in the same manner as in (1) to obtain the desired product as crystals.

Examples 134 to 139 --Reaction and treatment were carried out in the same manner as in Example 112 using the corresponding starting compounds, and
The compounds of Table 28 represented by 8 are obtained. In addition, Example 13
The compounds of 4 and 135 are oily substances, and the other compounds are crystals.

[0352]

[Chemical 38]

[0353]

[Table 28] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Example R ¹ R ━━━━━━━━━━━━━ ━━━━━━━━━━━━━━━━━━━ 134 6-quinolyl CHPh ₂ 135 5-quinolyl CH (Ph-4-Me) ₂ 136 2-Me-8-quinolyl CHPh ₂ 137 2 , 4-Me ₂ -1,8-naphthyridin-7-yl CHPh ₂ 138 9-acridinyl CHPh ₂ 139 2-thiazolyl CHPh ₂ ━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━━

Example 140 Preparation of 2-[(benzhydryl) thio] -N- (2-pyrimidinyl) nicotinamide:

2-[(Benzhydryl) thio] nicotinic acid (5.0 g) was added to dioxane (200 ml), and oxalyl chloride (10 g) was added dropwise with stirring at 0 ° C, followed by stirring at 80 ° C for 30 minutes. After distilling off the solvent under reduced pressure, 200 ml of pyridine and 1.5 g of 2-aminopyrimidine are added, and the mixture is stirred at 60 ° C for 2 hours.
The reaction mixture is concentrated under reduced pressure, 100 ml of water is added, and the mixture is extracted twice with 300 ml of chloroform. The extract is dried over magnesium sulfate and then concentrated under reduced pressure. The residue is subjected to silica gel column chromatography, eluted with chloroform-methanol (50: 1) and purified to give 3.5 g of the desired product as crystals.

Example 141 Preparation of 2-[(benzhydryl) thio] -N- (2-pyrazinyl) nicotinamide: Using 2-aminopyrazine instead of 2-aminopyrimidine in Example 140. Reaction and treatment are carried out in the same manner as in Example 140 to obtain the desired product as an oil.

Example 142 --Preparation of N- (2-acetoxymethyl-4-pyridyl) -2-[(2,4-dimethoxybenzyl) thio] nicotinamide:-

(1) Rec.Trar.Chim., 70 , 591 (1951)
And 4-amino-2-methylpyridine-N-oxide 8.2 g, 2-[(2,4-dimethoxybenzyl) thio synthesized according to the method described in J. Org. Chem., 26 , 2740 (1961). ] To a mixed solution of 10 g of nicotinic acid and 400 ml of pyridine, 6.9 g of 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride is added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and chloroform 200 ml
Extract twice with. Extract the 1N aqueous solution of sodium hydroxide
The crystals are washed twice with 50 ml and twice with 50 ml of saturated saline, dried over magnesium sulfate and then concentrated under reduced pressure to obtain crude crystals. This was recrystallized from methanol and 4-
[2-[(2,4-Dimethoxybenzyl) thio] nicotinoylamino] -2-methylpyridine-N-oxide 6.
Get 9 g.

(2) The above pyridine-N-oxide compound (6.9 g) was added to acetic anhydride (300 ml), and the mixture was stirred at 90 ° C. for 2 hours, concentrated under reduced pressure, water was added, and the mixture was concentrated again under reduced pressure. The residue is extracted twice with 200 ml of chloroform, the extract is washed twice with 30 ml of a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, chloroform-
Elute and purify with methanol (30: 1) to obtain 4.3 g of the desired product as crystals.

¹ H-NMR (DMSO-d ₆ ) δ: 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, 1H), 6.54 (d, J = 2.4Hz, 1H), 7.25 (d, J =
8.2Hz, 1H), 7.28 (dd, J = 7.9Hz, J = 3.8Hz, 1H), 7.62 (dd, J =
7.8Hz, J = 2.0Hz, 1H), 7.64 (d, J = 2.0Hz, 1H), 7.96 (dd, J =
7.9Hz, J = 1.4Hz, 1H), 8.43 (d, J = 7.8Hz, 1H), 8.64 (dd, J =
3.8Hz, J = 1.4Hz, 1H), 10.84 (s, 1H)

Example 143 --2-[(2,4-dimethoxybenzyl) thio] -N- (2-hydroxymethyl-
Production of 4-pyridyl) nicotinamide:-

2.7 g of N- (2-acetoxymethyl-4-pyridyl) -2-[(2,4-dimethoxybenzyl) thio] nicotinamide was added to 150 ml of methanol and added thereto.
Add 100 ml of 0.1N potassium carbonate aqueous solution and stir at room temperature for 30 minutes. The reaction solution is concentrated to 100 ml under reduced pressure, and 1N hydrochloric acid is added to the solution under ice cooling to neutralize it. 2 with 100 ml of chloroform
Extract twice, wash the extract twice with 30 ml of saturated saline, dry over magnesium sulfate, and then concentrate under reduced pressure to obtain the desired product 1.
1 g is obtained as an oil.

¹ H-NMR (DMSO-d ₆ ) δ; 3.73 (s, 3H), 3.78 (s,
3H), 4.33 (s, 2H), 4.63 (s, 2H), 5.75 (broad, 1H), 6.44 (d
d, J = 8.1Hz, J = 2.4Hz, 1H), 6.54 (d, J = 2.4Hz, 1H), 7.26 (d,
J = 8.1Hz, 1H), 7.29 (dd, J = 7.8Hz, J = 4.8Hz, 1H), 7.72 (dd,
J = 4.2Hz, J = 2.2Hz, 1H), 8.03 (dd, J = 7.8Hz, J = 1.8Hz, 1H),
8.45 (d, J = 4.2Hz, 1H), 8.66 (dd, J = 4.8Hz, J = 1.8Hz, 1H), 1
1.19 (s, 1H)

Example 144 Preparation of 2-[(2,4-dimethoxybenzyl) thio] -6-methyl-N- (4-pyridyl) nicotinamide:

2-[(2,4-Dimethoxybenzyl) thio] -6-methylnicotinic acid 5.5 g, 4-aminopyridine 1.94 g, 1-ethyl-3-[(3-dimethylamino)
A mixture of 4.0 g of propyl] carbodiimide hydrochloride and 200 ml of methylene chloride is stirred at room temperature for 3 hours. The reaction solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (20: 1), and recrystallized from methanol to give the desired compound 2.0. get g Melting point 150-151 ℃

Example 145 --2-[(2,4-dimethoxybenzyl) thio] -6-isopentyl-N- (4-
Preparation of Pyridyl) Nicotinamide 1/4 hydrate:-

(1) 13 g of 2-hydroxy-6-isopentylnicotinic acid is added to 50 ml of phosphorus oxychloride, and the mixture is heated under reflux for 3 hours with stirring. The reaction mixture is concentrated under reduced pressure, 200 ml of tetrahydrofuran is added, 18 g of 4-aminopyridine and 19 g of triethylamine are added with stirring under ice cooling, and the mixture is stirred at room temperature for 3 hours. Add 200 ml of water to the reaction mixture,
Extract twice with 400 ml of ethyl acetate. The extract was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (50: 1) to give 2-chloro-6-isopentyl-N- (4 -Pyridyl) nicotinamide 9.8 g
As an oil.

(2) 2-chloro-6-isopentyl-
N- (4-pyridyl) nicotinamide 10 g, 2,4-dimethoxyphenylmethanethiol 7.3 g and potassium carbonate
A mixture of 9.1 g and 300 ml of dimethylformamide was added to 10
Stir at 0 ° C. for 1 hour. After concentrating the reaction mixture under reduced pressure, water 100
Add 2 ml and extract twice with 400 ml of chloroform. The extract is dried over magnesium sulfate, concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography, and eluted and purified with chloroform-methanol (70: 1). This is recrystallized from acetonitrile to obtain 10 g of the desired product. Melting point 104
-106 ° C

Example 146 --2-[(2,4-dimethoxybenzyl) thio] -6-isopropyl-N- (4-
Production of pyridyl) nicotinamide:-

EXAMPLE 14 2-hydroxy-6-isopropylnicotinic acid was used in place of 2-hydroxy-6-isopentylnicotinic acid in Example 145 (1).
Reaction and treatment are performed in the same manner as in 5 to obtain the desired product as crystals.

Example 147 Preparation of 2-[(2,4-dimethoxybenzyl) thio] -6-isobutyl-N- (4-pyridyl) nicotinamide:

Using 2-hydroxy-6-isobutylnicotinic acid instead of 2-hydroxy-6-isopentylnicotinic acid in Example 145 (1), Example 145
Reaction and treatment are performed in the same manner as in (1) to obtain the desired product as crystals.

Example 148 Preparation of 2-[(2,4-dimethoxybenzyl) thio] -6-phenyl-N- (4-pyridyl) nicotinamide:

2-[(2,4-dimethoxybenzyl) thio] -6-phenylnicotinic acid (4.9 g) was added to dioxane (200 m).
In addition to l, 7.6 ml of oxalyl chloride is added dropwise with stirring, and the mixture is stirred at 80 ° C for 30 minutes. After the solvent was distilled off under reduced pressure, tetrahydrofuran (200 ml) and 4-aminopyridine (1.5 g) were added, and triethylamine (2.6 ml) was added with stirring under ice cooling.
And then stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, extracted twice with 100 ml of chloroform, and saturated saline solution was added.
Wash twice with 20 ml, dry over magnesium sulfate and concentrate under reduced pressure. The residue is subjected to silica gel column chromatography, eluted with chloroform-methanol (40: 1) and purified to obtain 3.2 g of the desired product as an oil.

Example 149 --6-chloro-2-
[(2,4-dimethoxybenzyl) thio] -N- (4-
Preparation of Pyridyl) nicotinamide 1/4 hydrate:

2,6-dichloro-N- (4-pyridyl)
A mixture of 2 g of nicotinamide, 1.5 g of 2,4-dimethoxyphenylmethanethiol, 9.1 g of potassium carbonate and 50 ml of ethyl methyl ketone is heated to reflux with stirring for 1 hour. The reaction mixture is concentrated under reduced pressure, 50 ml of water is added, and the mixture is extracted twice with 100 ml of chloroform. The extract is dried over magnesium sulfate and then concentrated under reduced pressure. The residue is subjected to silica gel column chromatography and eluted with chloroform-methanol (10: 1) for purification. This is recrystallized from acetonitrile to obtain 1.8 g of the desired product. Melting point 153-155 ℃

Example 150 Preparation of 2-[(2,4-dimethoxybenzyl) thio] -6-methoxy-N- (4-pyridyl) nicotinamide:

2-[(2,4-Dimethoxybenzyl) thio] -instead of 2-[(2,4-dimethoxybenzyl) thio] -6-methylnicotinic acid in Example 144.
Using 6-methoxynicotinic acid, the reaction and treatment are carried out in the same manner as in Example 144 to obtain the desired product as crystals.

Example 151 Preparation of 2-[(2,4-diethoxybenzyl) thio] -N- (4-pyridyl) nicotinamide:

2-[(2,4-Diethoxybenzyl) thio] nicotinic acid (14 g), 4-aminopyridine (4.7 g) and tetrahydrofuran (400 ml) were added to a mixed solution of 1-ethyl-
Add 9.7 g of 3- [3- (dimethylamino) propyl] carbodiimide hydrochloride and stir at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure and then extracted twice with 300 ml of ethyl acetate. The extract is washed twice with 50 ml of saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue is subjected to silica gel column chromatography and eluted with chloroform-methanol (50: 1) for purification to obtain 4.0 g of the desired product as an oil.

Examples 152 to 156 --Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 144 or Example 148 to obtain the compounds of Table 29 represented by Chemical formula 39.
The compounds of Examples 152 and 153 are crystals, and the other compounds are oily substances.

[0382]

[Chemical Formula 39]

[0383]

[Table 29] ━━━━━━━━━━━━━━━━━━━━━━━━━
━ Example R ⁵ manufacturing method ━━━━━━━━━━━━━━━━━━━━━━━━━
-152 Ph-4-OEt Example 144 ^* 153 Ph-2,4- (OMe) ₂ -5-Br Example 144 154 Ph-2-OEt-4-OMe Example 148 155 Ph-2-OCH ₂ OMe -4-OMe Example 144 156 Ph-2-OCH ₂ CH ₂ F-4-OMe Example 148 ━━━━━━━━━━━━━━━━━━━━━━━━━━
━━ ^* : means manufactured by the same method as in Example 144 (the same applies hereinafter).

Example 157 --2-[[2- (2-hydroxyethoxy) -4-methoxybenzyl] thio] -N
-Production of (4-pyridyl) nicotinamide:-

2-[[2- (2-acetoxyethoxy)
0.8 g of -4-methoxybenzyl] thio] -N- (4-pyridyl) nicotinamide was added to 30 ml of methanol,
To this, add 30 ml of 0.1 N potassium carbonate aqueous solution, and at room temperature
Stir for 30 minutes. The reaction solution is concentrated to 100 ml under reduced pressure, and 1N hydrochloric acid is added to the solution under ice cooling to neutralize it. Chloroform 30 m
The mixture was extracted twice with l, the extract was washed twice with 10 ml of saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 0.6 g of the desired product as an oil.

Example 158 --2-[[4-methoxy-
2- [2- (methoxymethoxy) ethoxy] benzyl]
Production of Thio] -N- (4-pyridyl) nicotinamide:
-

Instead of 2-[(2,4-dimethoxybenzyl) thio] -6-phenylnicotinic acid in Example 148, 2-[[4-methoxy-2- [2- (methoxymethoxy) ethoxy] benzyl] ] Thio] Using nicotinic acid, the reaction and treatment are carried out in the same manner as in Example 148 to obtain the desired product as an oil.

Example 159 --2-[(4-chloro-2
-Dimethylaminobenzyl) thio] -N- (4-pyridyl) nicotinamide:

2-[(4-chloro-2-dimethylaminobenzyl) thio] nicotinic acid 7.0 g, 4-aminopyridine 2.2 g, 1-ethyl-3-[(3-dimethylamino)
Propyl] carbodiimide hydrochloride (4.57 g) and methylene chloride (300 ml) are stirred at room temperature for 3 hours. The reaction solution is washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue is subjected to silica gel column chromatography, eluted with chloroform-methanol (50: 1) and purified to give the desired product (5.5 g) as an oil. ¹ H-NMR (DMSO-
d ₆ ) δ: 2.66 (s, 6H), 4.46 (s, 2H), 7.02 (dd, J = 1.5Hz, J =
4.0Hz, 1H), 7.13 (d, J = 1.5Hz), 7.32 (dd, J = 3.0Hz, J = 4.0H
z, 1H), 7.38 (d, J = 4.0Hz, 1H), 7.66 (m, 2H), 8.02 (dd, J =
4.0Hz, J = 1.5Hz, 1H), 8.48 (m, 2H), 8.64 (dd, J = 3.0Hz, J =
1.5Hz, 1H), 10.84 (s, 1H)

Example 160 --2-[(3,5-dibromo-2-dimethylaminobenzyl) thio] -N- (4-
Production of pyridyl) nicotinamide:-

2-[(3,5-Dibromo-2-dimethylaminobenzyl) thio] nicotinic acid was used in place of 2-[(4-chloro-2-dimethylaminobenzyl) thio] nicotinic acid in Example 159. The reaction and treatment are conducted in the same manner as in Example 159 to obtain the desired product as an oil.

Example 161 --2-[(4-Dimethylamino-2,5-difluorobenzyl) thio] -N- (4
-Pyridyl) Nicotinamide production:-

2-[(4-dimethylamino-2,5-difluorobenzyl) thio] nicotinic acid 15 g, 4-aminopyridine 4.9 g, 1-ethyl-3-[(3-dimethylamino) propyl] carbodiimide hydrochloride A mixture consisting of 9.9 g and 400 ml of tetrahydrofuran is stirred at room temperature for 3 hours. 200 ml of water was added to the reaction mixture, and the mixture was mixed with 400 ml of ethyl acetate to 2
Extract twice, dry over magnesium sulfate, and concentrate under reduced pressure. The residue is subjected to silica gel column chromatography, eluted with chloroform-methanol (20: 1) and purified to obtain 8.3 g of the desired product as an oil.

¹ H-NMR (DMSO-d ₆ ) δ: 2.77 (s, 6H), 4.35 (s,
2H), 6.60 (dd, J = 4.0Hz, J = 6.0Hz, 1H), 7.21 (dd, J = 4.0Hz, J
= 7.0Hz, 1H), 7.32 (dd, J = 4.0Hz, J = 2.5Hz, 1H), 7.78 (m, 2
H), 8.01 (dd, J = 1.0Hz, J = 4.0Hz, 1H), 8.50 (m, 2H), 8.66
(dd, J = 1.0, J = 2.5, H), 10.83 (s, 1H)

Example 162 2-2-[(4-dimethylamino-2,3,5-trifluorobenzyl) thio] -N
-Production of (4-pyridyl) nicotinamide:-

2-[(4-Dimethylamino-2,5-difluorobenzyl) thio] in Example 161 Instead of nicotinic acid, 2-[(4-dimethylamino-2,3,3) was used.
5-trifluorobenzyl) thio] nicotinic acid,
Reaction and treatment are carried out in the same manner as in Example 161, to obtain the desired product as an oil.

Example 163 --2-[(2-Dimethylamino-2,5,6-trifluorobenzyl) thio] -N
-Production of (4-pyridyl) nicotinamide:-

2-[(4-Dimethylamino-2,5-difluorobenzyl) thio] in Example 161 In place of nicotinic acid, 2-[(4-dimethylamino-2,5,5) was used.
6-trifluorobenzyl) thio] nicotinic acid,
The desired product is obtained as crystals by reacting and treating in the same manner as in Example 161.

Example 164 --N- (4-diethylaminophenyl) -2-[(2,4-dimethoxybenzyl)
Thio] Production of nicotinamide: ――

In place of 2-[(2,4-dimethoxybenzyl) thio] -6-phenylnicotinic acid and 4-aminopyridine in Example 148, 2-
[(2,4-Dimethoxybenzyl) thio] Nicotinic acid and 4-diethylaminoaniline were used and reacted and treated in the same manner as in Example 148 to obtain the desired product as crystals.

Examples 165 to 167 --2 -[( 2,4 -dimethoxybenzyl) thio] -in Example 144
Instead of 6-methylnicotinic acid and 4-aminopyridine, the corresponding nicotinic acids and anilines are used, respectively, and they are reacted and treated in the same manner as in Example 144 to obtain the following compound as crystals.

Example 165--2 -[(2,4-dimethoxybenzyl) thio] -N- (4-morpholinophenyl) nicotinamide

Example 166—2-[(2,4-dimethoxybenzyl) thio] -N- [4- (1-pyrrolidinyl) phenyl] nicotinamide

Example 167—2 -[(2,4-dimethoxybenzyl) thio] -N- (4-piperidinophenyl) nicotinamide

Example 168 --2-[(2,4-dimethoxybenzyl) thio] -N- [4-[(4-methyl-1
-Piperazinyl) phenyl] Nicotinamide Production:-
―

2-[(2,4-dimethoxybenzyl) thio] nicotinic acid 10 g, J. Am. Chem. Soc., 73 , 3100 (19
4- (4-methyl-) synthesized according to the method described in 51).
1-piperazinyl) aniline 6.6 g, 1-ethyl-3-
A mixture consisting of 7.5 g of [(3-dimethylamino) propyl] carbodiimide hydrochloride and 400 ml of tetrahydrofuran is stirred for 3 hours at room temperature. 100 ml of water is added to the reaction solution, which is extracted twice with 300 ml of ethyl acetate, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-methanol (2
Elution and purification with 0: 1) gives an oil. This will crystallize over time, so recrystallize from acetonitrile to obtain 11 g of the desired product.
Get. Melting point 176-180 ℃

Example 169 Preparation of 2-[(2,4-dimethoxybenzyl) thio] -N- [4- [4- (2-hydroxyethyl) -1-piperazinyl] phenyl] nicotinamide:

Instead of 2-[(2,4-dimethoxybenzyl) thio] -6-methylnicotinic acid and 4-aminopyridine in Example 144, 2-[(2,
4-dimethoxybenzyl) thio] nicotinic acid and 4-
[4- (2-hydroxyethyl) -1-piperazinyl]
Using aniline, the reaction and treatment are performed in the same manner as in Example 144 to obtain the desired product as crystals.

Example 170 Preparation of 2-[[(2-dimethylamino-3-pyridyl) methyl] thio] -N- (4-pyridyl) nicotinamide:

Instead of 2-[(2,4-dimethoxybenzyl) thio] -6-methylnicotinic acid in Example 144, 2-[[(2-dimethylamino-3-pyridyl) methyl] thio] nicotinic acid was used. Is reacted and treated in the same manner as in Example 144 to obtain the desired product as an oil.

Reference Example 1 --2-[(2,4-Dimethoxybenzyl) thio] Production of Nicotinic Acid:-

2-Mercaptonicotinic acid 42 g, 2,4-
To a mixture of 50 g of dimethoxybenzyl alcohol and 300 ml of tetrahydrofuran was added 40 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature.
Stir for 30 minutes. After the reaction is complete, add 400 ml of saturated aqueous sodium hydrogen carbonate solution to neutralize, and then concentrate under reduced pressure to 400 ml. After cooling the mixed solution containing the precipitate, the precipitate is collected by filtration and washed with water to obtain 69 g of the desired product.

Reference Examples 2 to 15 -2 in Reference Example 1,
Using the corresponding starting material compound instead of 4-dimethoxybenzyl alcohol, the reaction and treatment were carried out in the same manner as in Reference Example 1 to obtain the following compound.

Reference Example 2 --2-[(2,6-dimethoxybenzyl) thio] nicotinic acid; The starting compound 2,6-dimethoxybenzyl alcohol was prepared according to J. Chem. Soc.
(B), 535 (1967).

Reference Example 3 --2-[(2,4,6-trimethoxybenzyl) thio] nicotinic acid; The starting compound 2,4,6-trimethoxybenzyl alcohol is described in J.
It is synthesized according to the method described in Org. Chem., 57 , 3013 (1992).

Reference Example 4-2-([2,3,4-trimethoxybenzyl) thio] nicotinic acid

Reference Example 5 : 2-[(2,4,5-trimethoxybenzyl) thio] nicotinic acid; The starting compound 2,4,5-trimethoxybenzyl alcohol is described in J.
It is synthesized according to the method described in Chem. Soc. Perkin I, 2498 (1975).

Reference Example 6-2-[(2,4-dimethoxy-3-methylbenzyl) thio] nicotinic acid

Reference Example 7-2-[(2,4-dimethoxy-6-methylbenzyl) thio] nicotinic acid

Reference Example 8 : 2-[[1- (4-Methoxyphenyl) ethyl] thio] nicotinic acid; the starting compound 1- (4-methoxyphenyl) ethyl alcohol was disclosed in JP-A-58-77841. It is synthesized according to the method described in the publication.

Reference Example 9 : 2-[[1- (2-methoxyphenyl) ethyl] thio] nicotinic acid; the starting compound 1- (2-methoxyphenyl) ethyl alcohol was disclosed in JP-A-58-77841. It is synthesized according to the method described in the publication.

Reference Example 10 : 2-[(4-ethoxybenzyl) thio] nicotinic acid

Reference Example 11-2-[(5-bromo-
2,4-Dimethoxybenzyl) thio] nicotinic acid

Reference Example 12-2-[(2-Ethoxy-4-methoxybenzyl) thio] nicotinic acid

Reference Example 13-2 -[(4-methoxy-2-methoxymethoxybenzyl) thio] nicotinic acid

Reference Example 14-2-[[2- (2-Fluoroethoxy) -4-methoxybenzyl] thio] nicotinic acid

Reference Example 15-2-[[2- (2-hydroxyethoxy) -4-methoxybenzyl] thio] nicotinic acid

Reference Example 16 --Production of 2-[(2-dimethylaminobenzyl) thio] nicotinic acid:-

2-mercaptonicotinic acid (6.2 g) and 2-mercaptonicotinic acid synthesized according to the method described in JP-A-62-145069
Dimethylaminobenzyl chloride hydrochloride (9.0 g) is added to dimethylformamide (300 ml), triethylamine (16.1 g) is added dropwise with stirring under ice-cooling, and the mixture is further stirred at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, 100 ml of water is added, and the mixture is extracted twice with 300 ml of chloroform. The extract is dried over magnesium sulfate and then concentrated under reduced pressure. Acetonitrile 30 on residue
0 ml is added and the insoluble matter is collected by filtration. This is acetonitrile
Wash with 100 ml to obtain 7.8 g of the desired product.

Reference Examples 17 to 22 —In place of 2-dimethylaminobenzyl chloride hydrochloride in Reference Example 16, corresponding raw material compounds synthesized according to the method described in JP-A-64-3157 were used. The following compounds are obtained by reacting and treating in the same manner as in Example 16.

Reference Example 17-2-[(2-Methylaminobenzyl) thio] nicotinic acid

Reference Example 18 --2-[(2-Propylaminobenzyl) thio] nicotinic acid

Reference Example 19 : 2-[(2-isobutylaminobenzyl) thio] nicotinic acid

Reference Example 20 --2-[[2- (ethylmethylamino) benzyl] thio] nicotinic acid

Reference Example 21 : 2-[[2- (methylpropylamino) benzyl] thio] nicotinic acid

Reference Example 22 : 2-[[2- (isobutylmethylamino) benzyl] thio] nicotinic acid

Reference Example 23 --Preparation of 2-[(4-methoxybenzyl) thio] nicotinic acid:-

26 g of 2-mercaptonicotinic acid and 25 ml of 4-methoxybenzyl chloride were added to 30 g of dimethylformamide.
Add to 0 ml and add triethylamine 3 with stirring under ice cooling.
Add 7.4 g dropwise and stir for another 2 hours at the same temperature. The reaction mixture is concentrated under reduced pressure, 200 ml of water is added, and the insoluble matter is collected by filtration. This is washed with 100 ml of acetonitrile to obtain 37.5 g of the desired product.

Reference Examples 24 to 31 : Using the corresponding starting material compound in place of 4-methoxybenzyl chloride in Reference Example 23, the reaction and treatment were conducted in the same manner as in Reference Example 23 to obtain the following compounds.

( Reference Example 24 )-2-[(3,4,5,5-
Trimethoxybenzyl) thio] nicotinic acid

Reference Example 25 --2-[[1- (3-Methoxyphenyl) ethyl] thio] nicotinic acid; The starting compound 1- (3-methoxyphenyl) ethyl chloride is described in JP-A-58-77841. It is synthesized according to the method described in the publication.

Reference Example 26 --2- [[1- (3, 4
-Dimethoxyphenyl) ethyl] thio] nicotinic acid; the starting compound 1- (3,4-dimethoxyphenyl) ethyl chloride is synthesized according to the method described in JP-A-58-77841.

Reference Example 27 : 2-[(1-phenylethyl) thio] nicotinic acid

Reference Example 28 : 2-[(2-nitrobenzyl) thio] nicotinic acid

Reference Example 29 --2-[(4,4'-Difluorobenzhydryl) thio] nicotinic acid

Reference Example 30 --2-[(4,4'-Dimethylbenzhydryl) thio] nicotinic acid; The starting compound 4,4'-dimethylbenzhydryl chloride is described in J.
It is synthesized according to the method described in Am. Chem. Soc., 50 , 1808 (1928).

Reference Example 31 --2-[(4-Methoxybenzhydryl) thio] nicotinic acid; The starting compound 4-methoxybenzhydryl chloride is J. Am. Chem. So.
c., 50 , 1808 (1928).

Reference Example 32 --2- [(Benzhydryl)
Thio] Production of nicotinic acid:

2-Mercaptonicotinic acid (1.0 g) and benzhydryl bromide (1.72 g) were added to dimethylformamide (300 ml).
And triethylamine 789 mg with stirring under ice cooling
Is added dropwise, and the mixture is stirred at the same temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, 200 ml of water is added, and the insoluble matter is collected by filtration. This is washed with 100 ml of acetonitrile to obtain 750 mg of the desired product.

Reference Example 33 --2- [(Benzhydryl)
Thio] -6-isopentylnicotinic acid production:

(1) 26 g of sodium methoxide was added to 500 ml of diethyl ether, and a mixture of isoamyl methyl ketone and ethyl formate was added dropwise while stirring under ice cooling. Fifteen
After ice cooling, stir for another 90 minutes at room temperature. After concentrating the reaction mixture under reduced pressure, 400 ml aqueous solution of 36.8 g of cyanoacetic acid amide was added to the residue, 8 ml of 20 ml aqueous solution of acetic acid and 8 ml of piperidine were added, and the mixture was heated under reflux for 3 hours with stirring. After cooling, the reaction mixture is acidified with acetic acid and the precipitated crystals are collected by filtration. This was recrystallized from toluene-hexane to obtain 60 g of 3-cyano-2-hydroxy-6-isopentylpyridine.

(2) 60 g of the above pyridine compound is added to a mixed solution of 250 ml of 10N sodium hydroxide aqueous solution and 250 ml of ethanol, and the mixture is heated under reflux for 24 hours. The reaction mixture was concentrated under reduced pressure, 400 ml of water was added, acidified with concentrated hydrochloric acid, and chloroform.
Extract twice with 500 ml. The extract was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was recrystallized from chloroform-hexane to obtain 40 g of 2-hydroxy-6-isopentylnicotinic acid.

(3) 25 g of the above-mentioned 2-hydroxynicotinic acid compound was added to 200 ml of phosphorus oxychloride, and the mixture was stirred at 3
Heat to reflux for hours. After concentrating the reaction mixture under reduced pressure, ice water 30
Add 0 ml and extract twice with 400 ml of chloroform. The extract was dried over magnesium sulfate and concentrated under reduced pressure to give 2-chloro-6-isopentylnicotinic acid (14 g).

(4) The above 2-chloronicotinic acid compound 4.
5 g, diphenylmethanethiol 5.2 g, potassium carbonate
A mixture consisting of 3.56 g and 100 ml of dimethylformamide is stirred at 100 ° C. for 3 hours. After concentrating the reaction mixture under reduced pressure, water 1
Add 00 ml and extract twice with 300 ml of chloroform. The extract is dried over magnesium sulfate and concentrated under reduced pressure to give 2.0 g of the desired product.

Reference Example 34 --2,4-dimethoxy-6-
Manufacture of methylbenzyl alcohol:

(1) Ethyl 2,4-dihydroxy-6-methylbenzoate (25.0 g) and methyl iodide (31.7 ml) were added to dimethylformamide (400 ml), and potassium carbonate (3) was added.
After adding 8.6 g, the mixture is stirred at 70 ° C. for 2 hours. The reaction solution is concentrated under reduced pressure and then extracted with diethyl ether. The extract was washed with 20 ml of saturated saline and dried over magnesium sulfate.
Concentration under reduced pressure gives 28.0 g of crude ethyl 2,4-dimethoxy-6-methylbenzoate.

(2) The above-mentioned compound (28.0 g) is dissolved in tetrahydrofuran (500 ml), lithium aluminum hydride (6.98 g) is added under ice cooling, and the mixture is stirred at room temperature for 2 hours. Under ice cooling, 40 ml of methanol and 5 ml of water are added, the reaction mixture is concentrated under reduced pressure, and then extracted twice with 200 ml of ethyl acetate. The extract was washed twice with 20 ml of saturated saline solution and dried over magnesium sulfate.
Concentrate under reduced pressure to obtain 23.0 g of the desired product.

Reference Example 35 —Production of 3-oxo-2- (4-pyridyl) isothiazolo [5,4-b] pyridine (Compound B in Test Example 1):

2-[(benzhydryl) sulfinyl]
15 g of -N- (4-pyridyl) nicotinamide is added to 400 ml of methanol, 25 ml of concentrated hydrochloric acid is added dropwise with stirring under ice cooling, and the mixture is stirred at room temperature for 4 hours. Add 200 ml of saturated aqueous sodium hydrogen carbonate solution and extract twice with 400 ml of chloroform. The extract is dried over magnesium sulfate, concentrated under reduced pressure, and the residue is recrystallized from chloroform-methanol to obtain 4 g of the desired product. Melting point 238-240 ℃

Reference Example 36 --Production of 2-hydroxy-6-isopentylnicotinic acid:-

60 g of 3-cyano-2-hydroxy-6-isopentylpyridine was added to 250 N of 10N sodium hydroxide solution.
Add 250 ml of ethanol and 250 ml of ethanol and heat to reflux for 24 hours. The reaction mixture is concentrated under reduced pressure, 200 ml of water is added, acidified with concentrated hydrochloric acid, and then extracted twice with 500 ml of chloroform. The extract is dried over magnesium sulfate, concentrated under reduced pressure, and the residue is recrystallized from chloroform-hexane to obtain 40 g of the desired product. Melting point 193-194 ℃

Reference Examples 37 and 38 : Using the corresponding pyridines instead of 3-cyano-2-hydroxy-6-isopentylpyridine in Reference Example 36, reacting and treating in the same manner as in Reference Example 36, the following compounds were obtained. To get

( Reference Example 37 )-2-Hydroxy-6-
Isopropyl nicotinic acid

( Reference Example 38) --2-Hydroxy-6-
Isobutyl nicotinic acid

Reference Example 39 --Preparation of 3-cyano-2-hydroxy-6-isopentylpyridine:-

26 g of sodium methoxide was added to 500 ml of diethyl ether, and a mixture of isoamyl methyl ketone and ethyl formate was added dropwise while stirring under ice cooling. Another 15
Cool on ice for 1 minute, then stir for 90 minutes at room temperature. After concentrating the reaction solution under reduced pressure, 400 ml aqueous solution of 36.8 g of cyanoacetic acid amide was added to the residue, 8 ml of 20 ml aqueous solution of acetic acid and 8 ml of piperidine were added, and the mixture was heated under reflux for 3 hours with stirring. After cooling, the reaction solution is acidified with acetic acid, and the precipitated crystals are collected by filtration. This is recrystallized from toluene-hexane to obtain 60 g of the desired product. Melting point 120-122 ℃

Reference Examples 40 and 41 : Using the corresponding starting compounds, the same reaction and treatment as in Reference Example 39 were carried out to give the following compounds.

( Reference Example 40 ) -3-Cyano-2-hydroxy-6-isopropylpyridine

Reference Example 41 : 3-Cyano-2-hydroxy-6-isobutylpyridine

Reference Example 42 ——Production of 2,4-dimethoxyphenylmethanethiol: —

2,4-dimethoxybenzyl alcohol 19
A mixture of g, 25 g of Lawesson's reagent and 300 ml of toluene is heated to reflux. The reaction mixture is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography and eluted with chloroform-hexane (1: 1) for purification to obtain 6.2 g of the desired product as an oil.

Reference Example 43 --Production of 2-chloro-6-phenylnicotinic acid:-

2-Chloro-3-cyano-6 synthesized according to the method described in Chem. Pharm. Bull., 30 , 4314 (1982).
-Add 8.9 g of phenylpyridine to 50 ml of concentrated sulfuric acid and add 120
Stir for 2 hours at ° C. After cooling, sodium nitrite 11.5 g
20 ml aqueous solution of is added dropwise under ice cooling and stirred at 80 ° C for 30 minutes. After cooling the reaction solution, it is poured into 500 ml of ice water, the precipitate is collected by filtration, and dried under reduced pressure at 110 ° C to obtain 9.7 g of the desired product.

Reference Example 44 --2,6-dichloro-N-
Production of (4-pyridyl) nicotinamide:

10 g of 2,6-dichloronicotinic acid was added to 200 ml of dioxane, 20 ml of oxalyl chloride was added dropwise with stirring under ice cooling, and the mixture was stirred at 80 ° C. for 30 minutes. After the solvent is distilled off under reduced pressure, tetrahydrofuran (300 ml) and 4-aminopyridine (4.9 g) are added, and triethylamine (7.1 g) is added dropwise with stirring under ice-cooling, followed by stirring at room temperature for 30 minutes.
200 ml of water is added to the reaction solution, and the mixture is extracted twice with 300 ml of ethyl acetate. The extract is dried over magnesium sulfate and then concentrated under reduced pressure to obtain 12 g of the desired product.

Reference Example 45 : Preparation of 2-[[2,4-dimethoxybenzyl) thio] -6-methoxynicotinic acid:
-

(1) To a mixture of 1.0 g of 2,4-dimethoxyphenylmethanethiol and 20 ml of tetrahydrofuran was gradually added 60% sodium hydride with stirring at room temperature, and then 2-chloro-6-methoxynicotinic acid was added. Methyl
0.91 g is added dropwise. After heating under reflux with stirring for 3 hours, concentrate under reduced pressure, add 50 ml of water to the residue, and add chloroform.
Extract twice with 100 ml. The extract is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, chloroform-hexane.
Elute and purify with (1: 2) and methyl 2-[(2,4-dimethoxybenzyl) thio] -6-methoxynicotinate 1.4 g
As an oil.

(2) 1.4 g of methyl 2-[(2,4-dimethoxybenzyl) thio] -6-methoxynicotinate was dissolved in 30 ml of methanol, and 15 ml of 1N aqueous sodium hydroxide solution was added to the solution at 50-60 ° C. After heating and stirring for 2 hours, the mixture is concentrated under reduced pressure and neutralized with dilute hydrochloric acid, and the precipitated crystals are collected by filtration to obtain 1.2 g of the desired product.

Reference Example 46 --2-[(2,4-diethoxybenzyl) thio] Production of nicotinic acid:-

2,4-diethoxybenzyl alcohol 20
After adding g to 400 ml of toluene and adding 60 ml of concentrated hydrochloric acid,
Stir for 30 minutes at room temperature. The reaction mixture is extracted twice with 100 ml of toluene, washed twice with 30 ml of saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. Methylene chloride 50 in the residue
0 ml and 13.8 g of 2-mercaptonicotinic acid are added, 13.5 g of triethylamine is added under ice cooling, and the mixture is stirred at room temperature for 6 hours. After extracting the reaction solution twice with 100 ml of chloroform,
Wash twice with 30 ml of saturated saline. The extract is dried over magnesium sulfate and concentrated under reduced pressure to give the desired product (28 g).

Reference Example 47 --Production of 2- (2-hydroxyethoxy) -4-methoxybenzyl alcohol:-

32 g of 2- (2-acetoxyethoxy) -4-methoxybenzaldehyde is dissolved in 500 ml of methanol, 4.5 g of sodium borohydride is gradually added under ice cooling, and the mixture is stirred at room temperature for 30 minutes. Acetone (20 ml) is gradually added to the reaction mixture, which is then concentrated under reduced pressure and extracted twice with 200 ml of chloroform. The extract was washed twice with 40 ml of saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain the desired product.
Get 25 g.

Reference Examples 48 to 51 : Using the corresponding starting materials, the following compounds were obtained by reacting and treating in the same manner as in Reference Example 47.

( Reference Example 48 )-5-bromo-2,4
-Dimethoxybenzyl alcohol

( Reference Example 49 )-2-Ethoxy-4-
Methoxybenzyl alcohol

( Reference Example 50 ): 4-methoxy-2-
Methoxy methoxybenzyl alcohol

( Reference Example 51 )-2,4-diethoxybenzyl alcohol

Reference Example 52 --Preparation of 2- (2-acetoxyethoxy) -4-methoxybenzaldehyde:-

20 g of 2-hydroxy-4-methoxybenzaldehyde and 16.7 ml of acetic acid 2-chloroethyl ester
Was added to 200 ml of dimethylformamide, and potassium carbonate 2
After adding 7.2 g, the mixture was stirred at 150 ° C. for 3 days. The reaction mixture was concentrated under reduced pressure and extracted twice with 200 ml of diethyl ether.
The extract is washed twice with 40 ml of saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure to give 32 g of the desired product.

Reference Example 53 --Production of 2-ethoxy-4-methoxybenzaldehyde:-

Using ethyl bromide instead of acetic acid 2-chloroethyl ester of Reference Example 52, the reaction and treatment were conducted in the same manner as in Reference Example 52 to obtain the desired product.

Reference Example 54 --Production of 2,4-diethoxybenzaldehyde:-

Instead of 2-hydroxy-4-methoxybenzaldehyde and acetic acid 2-chloroethyl ester of Reference Example 52, 4-ethoxy-2-hydroxybenzaldehyde and ethyl bromide were used, respectively. Process to obtain the desired product.

Reference Example 55 --Production of 4-methoxy-2-methoxymethoxybenzaldehyde:-

25 g of 2-hydroxy-4-methoxybenzaldehyde, 25 ml of chlorodimethyl ether and 90 ml of diisopropylethylamine were dissolved in 500 ml of tetrahydrofuran.
Add to ml and stir at room temperature for 24 hours. The reaction mixture is concentrated under reduced pressure and then extracted twice with 200 ml of diethyl ether. The extract is washed twice with 40 ml of saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 33 g of the desired product.

Reference Example 56 --Preparation of 2- (2-fluoroethoxy) -4-methoxybenzyl alcohol:-

(1) Instead of 2-hydroxy-4-methoxybenzaldehyde and acetic acid 2-chloroethyl ester in Reference Example 52, 2-hydroxy-
Using 10 g of methyl 4-methoxybenzoate and 4.7 ml of 2-fluoroethyl chloride, the same reaction and treatment as in Reference Example 52 is performed to obtain 12 g of methyl 2- (2-fluoroethoxy) -4-methoxybenzoate.

(2) The 2-fluoroethoxy compound
To a mixture of 12 g and 150 ml of diethyl ether, under cooling with ice, add 1.9 g of lithium aluminum hydride and stir at the same temperature for 30 minutes. Methanol 10 ml and water under ice cooling
After adding 5 ml and concentrating the reaction solution under reduced pressure, chloroform 100
Extract twice with ml. The extract is washed twice with 20 ml of saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 16 g of the desired product.

Reference Example 57 --2-[[4-methoxy-2
-[2- (Methoxymethoxy) ethoxy] benzyl] thio] Production of nicotinic acid:-

2-[[2- (2-hydroxyethoxy)
After adding 7.0 g of -4-methoxybenzyl] thio] nicotinic acid, 4.8 ml of chloromethyl methyl ether and 18 ml of diisopropylethylamine to 200 ml of methylene chloride, the mixture is stirred at room temperature for 16 hours. The reaction solution is concentrated under reduced pressure and then extracted twice with 200 ml of ethyl acetate. The extract is washed twice with 30 ml of saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. To the residue are added 400 ml of methanol and 60 ml of 1N aqueous sodium hydroxide solution, and the mixture is heated under reflux with stirring for 1 hour. After cooling, the mixture is neutralized with 1N hydrochloric acid and then concentrated under reduced pressure.
The residue is extracted twice with 200 ml of chloroform, the extract is washed twice with 40 ml of saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 7.4 g of the desired product.

Reference Example 58 --2-[(4-chloro-2-
Dimethylaminobenzyl) thio] Production of nicotinic acid: ―
―

4.3 g of 4-chloro-2-dimethylaminobenzyl alcohol was added to 100 ml of toluene, and 4.1 g of thionyl chloride was added dropwise thereto while stirring with ice cooling, and the mixture was stirred at the same temperature for 30 minutes and concentrated under reduced pressure. 2-Mercaptonicotinic acid in the residue
3.6 g and 200 ml of dimethylformamide were added, and 7.0 g of trimethylamine was added dropwise with stirring with ice cooling, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction mixture under reduced pressure, 100 ml of water
Add 200 ml of chloroform and extract twice. The extract is dried over magnesium sulfate and then concentrated under reduced pressure. 300 ml of acetonitrile is added to the residue, the insoluble matter is filtered off, and washed with 100 ml of acetonitrile to obtain 6.0 g of the desired product.

Reference Examples 59 to 64 : Using the corresponding starting materials, the following compounds were obtained by reacting and treating in the same manner as in Reference Example 58.

Reference Example 59 -2--2-[(3,5-dibromo-2-dimethylaminobenzyl) thio] nicotinic acid

( Reference Example 60 ) -2-[[4-Dimethylamino-2,5-difluorobenzyl) thio] nicotinic acid

Reference Example 61-2 -[(4-Dimethylamino-2,3,5-trifluorobenzyl) thio] nicotinic acid

Reference Example 62 —2-[(4-Dimethylamino-2,5,6-trifluorobenzyl) thio] nicotinic acid

( Reference Example 63 ) -2-[[2,5-difluoro-4- (1-methyl-4-piperazinyl) benzyl] thio] nicotinic acid

( Reference Example 64 ) -2-[[(2-Dimethylamino-3-pyridyl) methyl] thio] nicotinic acid;
The starting compound 2-dimethylamino-3-hydroxymethylpyridine is synthesized according to the method described in US Pat. No. 4,772,619.

Reference Example 65 --Preparation of 4-chloro-2-dimethylaminobenzyl alcohol:-

A mixture of 1.9 g of lithium aluminum hydride and tetrahydrofuran was added to a mixture of 4-chlorobenzene with stirring under ice cooling.
A tetrahydrofuran solution of 8 g of methyl chloro-2-dimethylaminobenzoate is added dropwise, and the mixture is heated under reflux for 30 minutes while stirring. After cooling, a saturated aqueous solution of sodium sulfate is added to the reaction solution, and the insoluble matter is filtered. The filtrate is ethyl acetate 30
Extract twice with 0 ml, dry over magnesium sulfate, and concentrate under reduced pressure to obtain 4.5 g of the desired product.

Reference Example 66 --Production of 3,5-dibromo-2-dimethylaminobenzyl alcohol:-

[0513] Instead of methyl 4-chloro-2-dimethylaminobenzoate in Reference Example 65, methyl 3,5-dibromo-2-dimethylaminobenzoate was used, and Reference Example 6 was used.
Reaction and treatment are carried out in the same manner as in 5 to obtain the desired product.

Reference Example 67 --Preparation of methyl 4-chloro-2-dimethylaminobenzoate:-

(1) To a mixed solution of 50 g of 4-chloroanthranilic acid and 600 ml of methanol was added 20 ml of concentrated sulfuric acid, and the mixture was heated under reflux for 12 hours while stirring. After cooling, 100 ml of water and 50 g of potassium carbonate are added to the reaction solution for neutralization, and the mixture is extracted twice with 500 ml of chloroform. The extract was dried over magnesium sulfate and concentrated under reduced pressure to give methyl 4-chloroanthranilate (17 g).

(2) 17 g of the above methyl ester compound was added to 12 g of dimethylsulfate, and the mixture was heated with stirring at 100 ° C. for 1 hour. After cooling, add 50 g of an aqueous solution of 5 g of sodium hydroxide and extract twice with 300 ml of ethyl acetate. The extract is dried over magnesium sulfate, concentrated under reduced pressure, 12 g of dimethyl sulfate is added to the residue again, and the mixture is stirred at 100 ° C for 1 hr. After cooling, add 50 ml of an aqueous solution of 5 g of sodium hydroxide and extract twice with 400 ml of diethyl ether. The extract is dried over magnesium sulfate and then concentrated under reduced pressure to obtain 8.5 g of the desired product.

Reference Example 68 --Preparation of methyl 3,5-dibromo-2-dimethylaminobenzoate:-

Using 3,5-dibromoanthranilic acid instead of 4-chloroanthranilic acid in Reference Example 67 (1), the reaction and treatment were conducted in the same manner as in Reference Example 67 to obtain the desired product.

Reference Example 69 --4-Dimethylamino-2,
Production of 5-difluorobenzyl alcohol:

(1) Oxalyl chloride (100 ml) was added dropwise to a mixed solution of 2,4,5-trifluorobenzoic acid (100 g) and dioxane (600 ml), and the mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. To the residue was added 100 ml of tetrahydrofuran, 100 ml of methanol was added dropwise with stirring under ice cooling, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture under reduced pressure, water 20
Add 0 ml and extract twice with 500 ml of diethyl ether each time. The extract was dried over magnesium sulfate and concentrated under reduced pressure to give methyl 2,4,5-trifluorobenzoate (77 g).

(2) 2.0 g of the above methyl ester compound
, 50% dimethylamine aqueous solution 50 ml and ethanol 50
The ml mixture is heated to reflux with stirring for 3 hours. The reaction mixture is concentrated under reduced pressure and then extracted twice with 100 ml of ethyl acetate each time. The extract was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with chloroform-hexane (4: 1) and purified to 4
-Methyl dimethylamino-2,5-difluorobenzoate
1.8 g are obtained as an oil.

(3) 20 g of the above-mentioned dimethylamino compound was added to 300 ml of toluene, and 70 g of this was stirred under ice-cooling with stirring.
% Toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride (53g)
Stir for a minute. 20 g of Celite and 100 ml of water are added to the reaction mixture and the mixture is filtered. The filtrate is extracted twice with 400 ml of ethyl acetate, the extract is dried over magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (10: 1) and purified to obtain the desired product.
14 g are obtained as an oil.

Reference Examples 70 to 72 : Using the corresponding starting compounds, the following compounds were obtained by reacting and treating in the same manner as in Reference Example 69.

( Reference Example 70 ) -4-Dimethylamino-
2,3,5-trifluorobenzyl alcohol

( Reference Example 71 ): 4-Dimethylamino-
2,5,6-trifluorobenzyl alcohol

( Reference Example 72 ) -2,5-difluoro-
4- (4-methyl-1-piperazinyl) benzyl alcohol

Example 171 —Preparation of N- (2-acetoxymethyl-4-pyridyl) -2-[[1- (4-methoxyphenyl) ethyl] thio] nicotinamide:

Instead of 2-[(2,4-dimethoxybenzyl) thio] nicotinic acid and 4-aminopyridine in Example 90, 2-[[1- (4-methoxyphenyl) ethyl] thio] nicotinic acid was obtained. And 2-acetoxymethyl-4-aminopyridine are reacted and treated in the same manner as in Example 90 to obtain the desired product as an oil.

Example 172 —Preparation of N- (2-acetoxymethyl-4-pyridyl) -2-[[1- (4-methoxyphenyl) ethyl] sulfinyl] nicotinamide (diastereomer G): —

Instead of 2-[(2,4-dimethoxybenzyl) thio] -N- (4-pyridyl) nicotinamide in Example 1, N- (2-acetoxymethyl-4-pyridyl) -2-[[ 1- (4-Methoxyphenyl) ethyl] thio] nicotinamide is reacted and treated in the same manner as in Example 1 to obtain an oily substance containing diastereomers G and H. This is subjected to silica gel column chromatography, eluted with a mixed solution of chloroform-methanol (50: 1), the eluate is concentrated under reduced pressure, and the residue is recrystallized from toluene to obtain the desired product. Melting point 120-122 ° C

Example 173 --Preparation of N- (2-acetoxymethyl-4-pyridyl) -2-[[1- (4-methoxyphenyl) ethyl] sulfinyl] nicotinamide (diastereomer H):-

After diastereomer G was eluted by the chromatography of Example 172, it was eluted with a mixture of chloroform-methanol (30: 1), and the eluate was concentrated under reduced pressure.
The residue is recrystallized from acetonitrile to obtain the desired product. Melting point 159-161 ° C

Example 174 --Preparation of tablets:-

N- (2-acetoxymethyl-4-pyridyl) -2-[(2,4-dimethoxybenzyl) sulfinyl] nicotinamide (20 g), corn starch (28 g), lactose (65 g), crystalline cellulose (30
g), hydroxypropyl cellulose (5 g), light anhydrous silicic acid (1 g), and magnesium stearate (1
g).

According to a conventional method, the above components are mixed, granulated and compression-molded to prepare 1000 tablets of 150 mg each as a tablet core. Then, using methacrylic acid / ethyl acrylate copolymer, polyethylene glycol 6000, Tween 80 and talc, a coating is applied according to a conventional method to give an enteric film-coated tablet.

Example 175 --Preparation of powder:-

N- (2-acetoxymethyl-4-pyridyl) -2-[(2,4-dimethoxybenzyl) sulfinyl] nicotinamide (100 g), corn starch (200 g), lactose (660 g), hydroxypropyl cellulose ( 30 g), and light anhydrous silicic acid (10
g).

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

[0539]

INDUSTRIAL APPLICABILITY As described above, the compound of the present invention represented by the formula (I) has an excellent gastric acid secretion inhibitory action based on the proton pump inhibitory action and has low toxicity.
As a therapeutic agent for peptic ulcer, it can be used for prevention and treatment of gastric ulcer, duodenal ulcer, reflux esophagitis, Zollinger-Ellison syndrome, anastomotic ulcer, gastritis and the like. In addition, the intermediate of the present invention represented by the formula (II) is useful as a synthetic intermediate for the compound of the formula (I).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area C07D 401/12 235 241 405/12 213 409/12 213 417/12 213 471/04 114 A 491 / 056 7019-4C (72) Masanobu Komiya, Masanobu Komiya 14 3 from Babai Ryoda, Nagaokakyo City, Kyoto Prefecture (72) Inventor Keiji Nakamura 7-11-5 Mamigaoka, Kashiba City, Nara Prefecture (72) Inventor Yukio Tominaga Osaka Prefecture 2-3-5 Hotaruike Minamicho, Toyonaka City

Claims (10)

[Claims] 1. A 2-sulfinylnicotinamide derivative represented by the following chemical formula 1. Embedded image [In the formula, R ¹ is a phenyl group which may be substituted at the 4-position with amino, mono- or di-substituted amino, amino (lower) alkyl or mono- or di-substituted amino (lower) alkyl; naphthyl group; halogen, lower alkyl , A lower alkoxy, a hydroxy (lower) alkyl and a lower alkanoyloxy (lower) alkyl, which may be substituted with 1 to 4 pyridyl groups; or a quinolyl group, a pyrimidinyl group, a pyrazinyl group, a thiazolyl group, 1,8 -Means a heteroaryl group selected from a naphthyridinyl group and an acridinyl group, wherein the heteroaryl group is 1 to 5 selected from halogen, lower alkyl and lower alkoxy.
R ² represents a hydrogen atom; a halogen atom; a lower alkyl group; a lower alkoxy group; or a phenyl group which may be substituted with a halogen or a lower alkyl. It means a group represented by A). Embedded image (In the formula, R ³ represents a hydrogen atom or a lower alkyl group,
R ⁴ represents a hydrogen atom; a lower alkyl group; or a phenyl group which may be substituted with halogen or lower alkyl, and R ⁵ represents an unsubstituted or substituted aryl group; or an unsubstituted or substituted heteroaryl group. ) However,
(I) When R ³ and R ⁴ are both hydrogen atoms, R ⁵ is not an unsubstituted phenyl group, and (ii) the pK _{R + of the} carbonium ion R ⁺ derived from the group R, which is calculated by the following formula 1.
The value satisfies the condition of being larger than −16 and smaller than −7. ## EQU1 ## pK _{R +} = 0.385 × (H _{R +} −H _ROH )
+ 78.0 [In the formula, H _{R +} and H _ROH mean the heats of formation (kcal / mol) of the carbonium ion R ⁺ and the alcohol ROH, respectively. ]] 2. R ¹ is selected from a phenyl group which may be substituted with amino or a mono- or di-substituted amino at the 4-position of the phenyl group, or a lower alkyl, hydroxy (lower) alkyl and lower alkanoyloxy (lower) alkyl. A 4-pyridyl group which may be substituted with 1 to 2 and R ² is a hydrogen atom, a halogen atom at the 5th or 6th position, a lower alkyl group at the 6th position, a lower alkoxy group at the 5th or 6th position or The 2-sulfinylnicotinamide derivative according to claim 1, which is a phenyl group at the 6-position, and R is a group represented by the following formula (a), (b), (c) or (d). Embedded image [In the formula, (a) R ^6a represents a hydrogen atom, a C ₁ -C ₃ alkoxy group, a halogeno (C ₁ -C ₃ ) alkoxy group, a hydroxy (C ₁ -C ₃ ) alkoxy group, a C ₁ -C ₃ alkoxy ( C ₁ -C ₃ ) alkoxy group or C ₁ -C ₃ alkoxy (C ₁ -C ₃ ) alkoxy (C ₁ -C ₃ ) alkoxy group is meant, and R ^7a is hydrogen atom, halogen atom, C ₁ -C ₃
An alkyl group or a C ₁ -C ₃ alkoxy group, R ^8a
And one of R ^10a is a hydrogen atom, a halogen atom, C _{1 to} C
₃ alkyl group or C ₁ -C ₃ alkoxy group, the other means hydrogen atom, C ₁ -C ₃ alkyl group or C ₁ -C ₃ alkoxy group, R ^9a is hydrogen atom, C ₁ -C ₃ alkyl group or means C ₁ -C ₃ alkoxy group. However, R ^6a , R
At least one of ^8a and R ^10a is C ₁ -C ₃ alkoxy group. (B) R ^6b means an amino group or a mono- or di-substituted amino group, Q means C—R ^7b or a nitrogen atom, and one of R ^7b and R ^9b is a hydrogen atom, a halogen atom, C ₁ -C. ₃ alkyl group or C ₁ -C ₃ alkoxy group, the other means hydrogen atom, halogen atom or C ₁ -C ₃ alkyl group,
R ^8b means a hydrogen atom, R ^10b means a hydrogen atom, a halogen atom or a C ₁ -C ₃ alkyl group, or R
^{When 8b} is attached to the 4-position, it may be taken together with R ^9b together with the carbon atom to which they are attached to form a benzene ring. However, when Q is a nitrogen atom, R ^8b is a hydrogen atom or a C ₁ -C ₃ alkyl group bonded to the 4-position, and R ^9b and R ^10b are both hydrogen atoms. (C) R ^6c and R ^7c represent a halogen atom, R ^8c represents an amino group or a mono- or di-substituted amino group, and R ^9c
Means a hydrogen atom or a halogen atom. (D) R ⁴ 'means a C ₁ -C ₃ alkyl group or a phenyl group which may be substituted with halogen or C ₁ -C ₃ alkyl, and _{one of} R ^6d and R ^7d is a hydrogen atom or C _1-
A C ₃ alkoxy group, the other means a hydrogen atom, and R ^8d represents a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group or C ₁
To C ₃ alkoxy groups are meant. ] 3. A 2-sulfinylnicotinamide derivative represented by the following chemical formula 4. [Chemical 4] [In the formula, R ¹ 'means a group represented by the following formula 5, [In the formula, R ¹¹ represents a hydrogen atom, a methyl group, a hydroxymethyl group or a (C ₂ -C ₄ alkanoyloxy) methyl group, R ¹² represents a hydrogen atom or a methyl group, and R ¹³ represents C
Means ₁ -C ₃ alkyl group, n means 0 or 1. R ² 'means a hydrogen atom or a lower alkyl group, and R ⁶ ' is C
₁ -C ₃ alkoxy, fluoro (C _{1 ~C 3)} alkoxy, hydroxy (C ₂ ~C ₃₎ alkoxy, methoxy (C _{1 ~C 3)} alkoxy group or a methoxy (C ₁ ~
C ₂ ) alkoxy (C ₂ -C ₃ ) alkoxy group, R ⁷ ′ means hydrogen atom, halogen atom or C ₁ -C ₃ alkyl group, and R ⁸ ′ means C ₁ -C ₃ alkoxy group. Means R ⁹ ′ means a hydrogen atom, R ¹⁰ ′ means a hydrogen atom, C ₁
To C ₃ alkyl group or C _{1 to} C ₃ alkoxy group. ] 4. A 2-sulfinylnicotinamide derivative represented by the following chemical formula 6. [Chemical 6] (In the formula, R ¹ ′ and R ² ′ are as defined in claim 3, R ¹⁴ represents a hydrogen atom or a lower alkyl group, and R ¹⁵
Represents a lower alkyl group, or R ¹⁴ and R ¹⁵ together with an adjacent nitrogen atom may form a pyrrolidine ring, a piperidine ring or a piperazine ring in which the 4-position is substituted with C ₁ -C ₃ alkyl. ¹⁶ is a hydrogen atom, a halogen atom, C
₁ -C ₃ alkyl group or a 3- or 5-position C ₁ -C ₃
It means an alkoxy group, and R ¹⁷ means a hydrogen atom or a halogen atom. However, when R ¹⁶ and R ¹⁷ are bonded to the 4th and 6th positions, respectively, they are not halogen atoms. ) 5. A 2-sulfinylnicotinamide derivative represented by the following chemical formula 7. [Chemical 7] (Wherein R ¹ ′ and R ² ′ are as defined in claim 3, R ¹⁸ and R ¹⁹ both represent a fluorine atom, R ²⁰ represents a hydrogen atom or a lower alkyl group, and R ²¹ Means a lower alkyl group, or R ²⁰ and R ²¹ together with the adjacent nitrogen atom are a pyrrolidine ring, a piperidine ring or C _{1 at the} 4-position.
It may form a piperazine ring substituted with ˜C ₃ alkyl, and R ²² represents a hydrogen atom or a fluorine atom. ) 6. A 2-sulfinylnicotinamide derivative represented by the following chemical formula 8. Embedded image (Wherein R ¹ ′ and R ² ′ are as defined in claim 3, R ⁴ ″ means a C ₁ -C ₃ alkyl group, and one of R ⁶ ″ and R ⁸ ″ is hydrogen atom and the other means a C ₁ -C ₃ alkoxy group.) 7. R ¹ 'is 4-pyridyl group, 2-hydroxymethyl-4-pyridyl group, 2-acetoxymethyl-4-
Pyridyl group or 4- (4-methyl-1-piperazinyl)
A phenyl group and R ² 'is a hydrogen atom.
The 2-sulfinyl nicotinamide derivative according to any one of 1. 8. 2-[(2,4-dimethoxybenzyl)
Sulfinyl] -N- (4-pyridyl) nicotinamide, 2-[(2-dimethylaminobenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide, 2-
[[1- (4-Methoxyphenyl) ethyl] sulfinyl] -N- (4-pyridyl) nicotinamide or its diastereomer, N- (4-pyridyl) -2-[(2,
4,6-Trimethoxybenzyl) sulfinyl] nicotinamide, 2-[[1- (2-methoxyphenyl) ethyl] sulfinyl] -N- (4-pyridyl) nicotinamide or its diastereomer N- (2- Acetoxymethyl-4-pyridyl) -2-[(2,4-dimethoxybenzyl) sulfinyl] nicotinamide, 2-
[(2,4-Dimethoxybenzyl) sulfinyl] -N
-(2-Hydroxymethyl-4-pyridyl)] nicotinamide, 2-[[2- (2-fluoroethoxy) -4-
Methoxybenzyl] sulfinyl] -N- (4-pyridyl) nicotinamide, 2-[(4-chloro-2-dimethylaminobenzyl) sulfinyl] -N- (4-pyridyl) nicotinamide, 2-[(2,5 -Difluoro-4
-Dimethylaminobenzyl) sulfinyl] -N- (4
A 2-sulfinylnicotinamide derivative selected from -pyridyl) nicotinamide and 2-[(2,4-dimethoxybenzyl) sulfinyl] -N- [4- (4-methyl-1-piperazinyl) phenyl] nicotinamide. 9. A 2-mercaptonicotinamide derivative represented by the following chemical formula 9. [Chemical 9] (In the formula, R ¹ , R ² and R are as defined in claim 1.) 10. A therapeutic agent for peptic ulcer containing the 2-sulfinylnicotinamide derivative according to any one of claims 1 to 8 as an active ingredient.