JPS62207270A - Azole compound substituted with 2-pyridylmethylthio group or 2-pyridylmethylsulfinyl group - Google Patents

Abstract

NEW MATERIAL:An azole compound substituted with 2-pyridylmethylthio(or sulfinyl) group and expressed by formula I [ring A is azole ring having 1-3C atoms, 1-4N atoms and and 0-1O atom; R is phenyl or lower alkyl; m is 0, 1 or 2; n is 0 or 1; 2-3 of R<1>-R<3> are lower alkyl, lower alkoxy or adjacent two groups together form group of formula IV (R<4> is H or lower alkyl) and the remaining 0-1 is H] or its salt. EXAMPLE:2-[[(3,5-Dimethyl-4-methoxy-2-pyridyl)methyl]thio]4,5-diphenyl oxazole. USE:An gastric acid secretion suppressing agent and antiulcer agent useful as a preventive and remedy for gastric diseases. PREPARATION:Reaction of the compound of formula II with the compound of formula III (X is halogen) gives the compound of formula Ia, which is treated with an oxidizing agent to obtain the compound of formula Ib.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention relates to pyridylmethylthio (or sulfinyl) expressed by the following general formula, which is useful as a preventive or therapeutic agent for gastric diseases.
The present invention relates to an azole compound substituted with a group or a pharmaceutically acceptable salt thereof.

(In the formula, A ring has 1 to 3 carbon atoms, 1 to 4 nitrogen atoms,
Azole ring R having 0 to 1 oxygen atom is phenyl group or lower alkyl group m is 0.1-1 or 2 n is O or 1 [1, 2 to 3 of R2 and R3 are lower alkyl group, lower An alkoxy group or a group formed by two adjacent groups together represented by the formula -CH,0CO- (in the formula, R4 is the same or different and means a hydrogen atom or a lower alkyl group), with the remaining 0 ~1 each means a hydrogen atom. (Prior Art) Heterocyclic compounds substituted with pyridylmethylthio (or sulfinyl) groups have been previously described in Japanese Patent Publication No. 59-24157 and Japanese Patent Publication No. 60-34956. The compound of the present invention is a novel compound having a different type of heterocycle from these known compounds.

(Means for Solving the Invention) The compound represented by the general formula (I) will be further explained as follows.

Ring A in general formula (I) is an azole ring (a nitrogen-containing 5-membered ring having two double bonds in a resonant state) as described above. The main azole rings of the present invention are as follows.

Virole ring, imidazole ring, pyrazole ring.

The compounds of the present invention have a triazole ring, a tetrazole ring, an oxazole ring, an isoxazole ring, and a 2-pyridylmethylthio group or a 2-
Substituted with pyridylmethylsulfini. Here, R
The "lower alkyl group" meant by 1, R'' and R3 is,
A linear or branched alkyl group having 1 to 5 carbon atoms such as a methyl group, ethyl group, propyl group, isopropyl group, butyl group, and "lower alkoxy group" refers to a methoxy group, ethoxy group, propoxy group. .

It includes impropoxy group, butoxy group, 5ee-butoxy group, etc. Also, a group represented by the formula -CH, -0-C-0- formed by combining two adjacent groups (in the formula, R4 means a hydrogen atom or a lower alkyl group).
Examples include groups represented by the formula -CH, OCH, O- and their mono- or di-lower alkyl H3, etc.). Also, when n is 0, 2-
It is a pyridylmethylthio group, and when n is 1, it is a 2-pyridylmethylsulfinyl group.

The azole ring may be substituted with a group represented by R in addition to the 2-pyridylmethylthio group (or sulfinyl group). The meaning of R is phenyl group or lower alkyl group.

Among them, the "lower alkyl group" refers to the above R1, R2 and H
This is the same as explained for g. When 1m is 2, two R's are substituted, and in this case, the two R's can be different substituents.

Next, as a salt of the compound of general formula (I).

It is a pharmaceutically acceptable salt with an inorganic or organic acid. Such acids include, for example.

Hydrohalic acids (hydrochloric acid, hydrobromic acid, etc.).

Inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, sulfonic acid and formic acid, acetic acid, propionic acid, lactic acid, tartaric acid.

Examples include organic acids such as citric acid, maleic acid, methanesulfonic acid, and toluenesulfonic acid.

(Manufacturing method) The compound of the present invention is manufactured by the method shown by the following reaction formula.

(In the formula, X means a halogen atom.) This method:
First, a thiol represented by formula (II) and 2-logenomethylpyridine represented by formula (m) are reacted to produce an azole compound substituted with a 2-pyridylmethylthio group (Ia
) is produced (first step), and then this compound (Ia) is treated with an oxidizing agent to produce the corresponding sulfinyl compound (Ib) (second step).

The first step is a method for producing the target compound (Ia) in which n in the compound of general formula (I) is O.

The second step is a method for producing the target compound (Ib) in which n is 1.

To carry out the reaction in the first step, corresponding amounts of thiol (II) or its salt and 2-logenomethylpyridine (III) or its salt are reacted in the presence of a base. Examples of the base used here include potassium hydroxide,
Examples include inorganic bases such as sodium hydroxide, sodium carbonate, and sodium hydrogen carbonate, and organic bases such as triethylamine. The amount of base added is 3 molar equivalents when both (n) and (l[I) are used as acid salts, and the free amount of (■)
When using the spacing and the salt of (m), 2 molar equivalents are appropriate. This reaction is usually carried out in a solvent at room temperature or at elevated temperatures.

Solvents include alcohols such as methanol and ethanol, water, and chloroform.

Dimethyl sulfoxide, benzene, ether, etc. are used.

The reaction product is obtained as a free base or as its acid addition salt, depending on the raw materials used and reaction conditions.

In the second step, the metal ring compound (Ia) or a salt thereof is treated with an oxidizing agent to obtain the corresponding sulfinyl compound. When using the salt of (Ia), it is first neutralized to form a free form of (Ia) and then treated with an oxidizing agent.

As the oxidizing agent, in addition to metachloroperbenzoic acid (MCPBA), peracetic acid, hydrogen peroxide, perester, etc. are used. The oxidation reaction is usually carried out in a solvent under cooling. As the solvent, dichloromethane, chloroform, alcohol, etc. are used.

Target compound (Ia) and (I) obtained by the above production method
When b) is a free base, it can be made into an acid addition salt by reacting it with a pharmaceutically acceptable acid in a conventional manner.

(Effect of the invention) Compound (I) and its salt provided by the present invention are:
It has gastric acid secretion suppressing action and antiulcer action, and is useful as a gastric acid secretion suppressing agent, gastric ulcer preventive and therapeutic agent, and other gastric disease preventive and therapeutic agents.

The gastric acid secretion suppressing effect and anti-ulcer effect of the compounds of the present invention are determined by the inhibitory activity (ICso = 50% inhibitory concentration) against H+, -adenosine triphosphatase (hereinafter referred to as H'', K''-ATPase) shown below. It has been confirmed that [Blochimica et Biophi
aica Acta).

728.3l-38 (1983)].

The compound (I) of the present invention and its salts may be used as such or in a known pharmaceutically acceptable carrier.

It is used as a pharmaceutical composition mixed with excipients. Administration is in tablets, capsules, powders, and granules.

Oral administration, injections, syrups, and emollients.

Parenteral administration such as suppositories may be used.

Although the dosage varies depending on the subject, administration route, and symptoms, it is usually 40 to 400 mg orally per day for an adult, and this is administered in divided doses 2 to 4 times a day.

(Example) EXAMPLES The present invention will be described in further detail with reference to Examples below.

However, the present invention is not limited to only those described in the examples.

Example 1 0.34 g of hydroxide under nitrogen stream was dissolved in 15 mL of methanol, and to this solution was added 1.01 g of 4,5-diphenyl-2-mercaptooxazole, and then 2-chloromethyl-3,5 Add 0.98 g of -dimethyl-4-methoxypyridine hydrochloride and stir at room temperature overnight. Thereafter, the solvent was distilled off under reduced pressure, and the insoluble materials were removed in hot ethyl acetate. After cooling, the precipitated crystals were collected and dried to obtain 0.86 g of 2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methylcothio]-4,5-diphenyloxazole.

Melting point: 145-147°C (ethyl acetate) Mass spectrum (m/z): 402 (M”) EI elemental analysis value (C
24N22 N20□S)C(@H(chi)
N(@S(chi) Calculated value 71,62 5.51 6.96 7.97
Measured value 71.67 5.29 6.89 7.93
Examples 2 to 7 The following compounds were obtained in the same manner as in Example 1.

Example 2 2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methylcothio]-4,5-diphenylimidazole dihydrochloride.

Melting point: 171-173°C (ethanol-ethyl acetate) Mass spectrum (m/z): 401 (M”) E
I elemental analysis value (as C, 4H,, N, O8・2HC1) C(@H(elb) N<@S(@C1(
@Calculated value 60.765.318.866.7614
．． 94 measurement value 60.855.118.716.73
15.11 Example 3 3.5-dimethyl-4-methoxy-6-[[(5-phenyl-1,2,4-triazol-3-yl)thiocomethylcopyridine Melting point: 135-136°C (ethyl acetate ) Mass spectrum (m/z): 326 (M”) Er elemental analysis value (C
I? As HI3N40S)C(@H(chi)N(
@s (Fishhook calculated value 62.55 5.56 17.16 9°82 measured value 62.72 5.58 17.06 1
0.05 Example 4 5-[[(4,5-diphenyl-2-imidazolyl)thio]methyl]-2,2-dimethyl-8-methyl-4H-
1,3-Dioxine[4,5-C]pyridine Melting point: 22
1.5-222°C Mass spectrum (m/z): 443 (M”) Elemental analysis value (as C2aH2sNsOzS) C(@H(
%) N (ch) S (%) Calculated value 70.40
5.68 9.47 7.23 Actual value 70.55
5.51 9.26 7.37 Example 5 5-[[(4,5-diphenyl-2-oxacylyl)
thio]methyl-2,2-dimethyl-8-methyl-4H
-1,3-dioxin[4,5-C]pyridine Melting point = 1
13-114℃ Mass spectrum (m/Z): 444 (M elemental analysis values (C, H, 4N, 0.S) C (chill K
(%l N(%)S(@calculated value 70.25 5.
44 6.30 7.21 Actual value 69.95 5.
18 6.09 7.12 Example 6 2-[[(4,5-diphenyl-1,2,4-)lyazol-3-yl)thio]methyl]-4-methoxy-3,
5-dimethylpyridine NMR (δ, CDC13): 2.20 (3H, s),
2.32 (3H, s).

3.76 (3H, s), 4.70 (2H, s), 7
10-7.50 (IOH, m).

8.10 (IH, s) Mass spectrum (m/z): 402 (M”) Example 7 and H3 5-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]thio]- 1-Methyl-tetrazole NMR (CDCl2.δ): 2.24 (3H, s),
2.32 (3H, +), 3.80 (3H, s), 3.
96 (3H, s), 4.76 (2H, s), 8.20 (
IH,s) Example 8 2-[[(
Dissolve 0.40 g of 3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-4,5-diphenyloxazole, and slowly add 0.20 g of m-chloroperbenzoic acid ( Add after 10 minutes.

Add 10 ml of a saturated aqueous bicarbonate solution to separate the layers, dry the organic layer over anhydrous magnesium sulfate, and then evaporate the solvent under reduced pressure. The resulting crude crystals were recrystallized from ether-hexane to give 2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methylcosulfinyl]-4,5
-Diphenyloxazole o, 2sg was obtained.

Melting point: 111-112°C (ether-hexane) mass spectrum (m/z) + 418 (M”) EI elemental analysis value (as C24H2,N, 0.S) C (plow H
(%) N (%) S (%) Calculated value 68.88
5.30 6.69 7.66 Measured value 69.08
5.19 6.66 7.74 Examples 9 to 12 In the same manner as in Example 8, the following compounds were obtained.

Example 9 2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-4,5-diphenylimidazole Melting point 169-170°C (methylene chloride-ether) Mass spectrum (m/z ): 417 (M”) EI elemental analysis value (as C,, H, 2N, 02S) c (eI4
H (%) N(@S(@calculated value 69.04
5.55 10.06 7.68 Measured value 69.0
1 5.53 9.86 7.63 Example 10 5-[[(4,5-diphenyl-2-oxacylyl)sulfinylcomethyl]-2,2-dimethyl-8-methyl-4H-1,3-dioxin [4,5-C Copyri
Gin melting point = 61-65℃ Mass spectrum (m/z): 460 (M”) Elemental analysis value (as C,, H, N, O, S -0,3H,0) (@5(es) Calculated value 67.02 5.32 6.01 6.88
Actual value 67.12 5.06 5.76 6.70
Example 11 6H8 5-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyrcosulfinyl]-1-methyltetrazole Melting point: 87.5-88°C Mass spectrum (m/z): 281 (M”) Elemental analysis value (as Co HI3N50□S) C (%)
H (%) N(@S(@calculated value 46.96
5.37 24.89 11.40 Actual value 47.
15 5.39 24.91 11.50 Example 12 2-[[(4,5-diphenyl-1,2,4-)riazol-3-yl)sulfinyl]methylco-4-methoxy-3,5-dimethylpyridine Melting point = 164-167℃

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, ring A is an azole ring having 1 to 3 carbon atoms, 1 to 4 nitrogen atoms, and 0 to 1 oxygen atom) R is a phenyl group or a lower alkyl group m is 0, 1 or 2 n is 0 or 1 2 to 3 of R^1, R^2 and R^3 are a lower alkyl group, a lower alkoxy group or two adjacent There are formulas ▲mathematical formulas, chemical formulas, tables, etc. that are formed when the groups are combined together. 0 to 1 each mean a hydrogen atom.) An azole compound substituted with a 2-pyridylmethylthio (or sulfinyl) group or a pharmaceutically acceptable salt thereof.