JPH07119204B2 - Phenylsulfinylalkylcarboxylic acid derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a phenylsulfinylalkylcarboxylic acid derivative useful as a medicine.

More specifically, the present invention shows a cholecystokinin (hereinafter referred to as CCK) receptor antagonistic action, and is useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis. (R ¹ and R ² in the formula may be the same or different and each is an alkyl group having 1 to 10 carbon atoms, R ³ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and X is a carbon atom. Number 1
To 3 and a nitro group, wherein n is 1 or 2), and a phenylsulfinylalkylcarboxylic acid derivative.

Conventional technology CCK is gastrin, secretin
It is a typical gastrointestinal hormone along with, especially pancreatic exocrine stimulation,
It is known to be a hormone involved in gallbladder contraction and the like.

In recent years, research on CCK has been advanced, and C
The involvement of CK has been elucidated.

As a result, specific, competitive and reversible CCK receptor antagonists have come to be expected as preventive and therapeutic agents for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis,
It is getting attention.

Formula used as a therapeutic agent for peptic ulcer Since it was reported that proglumide represented by the formula CCK receptor antagonist action, research on proglumide derivatives has been advanced, and several CCs have been studied so far.
Compounds having K receptor antagonistic activity have been produced and reported (Japanese Patent Laid-Open Nos. 61-44855, 62-181246, and 63-2746).
8, 63-165352, 63-201156, EP-A1-0308885, EP
-A2-0272228, WO 87/03869, 88/05774, 89/0243
1).

All of these compounds are derivatives of amino acids such as glutamic acid and aspartic acid, and the compounds of the present invention have completely different structures from these compounds.

The object of the present invention is to provide a phenylsulfinylalkylcarboxylic acid derivative having a CCK receptor antagonistic action and useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis. It is to be.

Means for Solving the Problems As a result of intensive studies to find out a new compound having a CCK receptor antagonism, the present inventors have found that a certain phenylsulfinylalkylcarboxylic acid derivative has a strong CCK receptor antagonism. , Irritable colitis, biliary dyskinesia,
The present invention was found to be useful as a preventive and therapeutic agent for diseases such as acute pancreatitis.

The phenylsulfinylalkylcarboxylic acid derivative represented by the above general formula (I) of the present invention is a CCK-receptor for CCK-
It competitively antagonizes the binding of 8 and is useful as a preventive and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis.

The phenylsulfinylalkylcarboxylic acid derivative represented by the general formula (I) of the present invention is a novel compound and can be produced as follows.

That is, the general formula (In the formula, R ⁴ is an alkyl group having 1 to ⁴ carbon atoms, R ¹ ,
R ² , X and n have the same meanings as described above), and the compound can be produced by oxidizing a phenylsulfinylalkylcarboxylic acid derivative represented by the above formula, separating the diastereomers, and optionally hydrolyzing them.

The compound of the general formula (III) used as a starting material in the method for producing the compound of the general formula (I) of the present invention is a novel compound and can be produced as follows.

That is, the general formula (Wherein X and n have the same meaning as described above) and a thiophenol derivative represented by the general formula (A and B in the formula are each a cyano group or a carbon number of 2 to
5 is an alkoxycarbonyl group, or A is an alkoxycarbonyl group having 2 to 5 carbon atoms and B is a carboxy group or an alkali metal salt thereof) in the presence of a Lewis base or a Lewis acid catalyst. Reacting,
General formula (A, B, X and n in the formula have the same meanings as described above)
The compound represented by the formula is prepared, and if necessary, it is hydrolyzed and monoesterified by an appropriate method to give a compound of the general formula (Wherein R ⁴ , X and n have the same meaning as described above).

Then this compound or its reactive functional derivative,
General formula The compound of the general formula (III) can be produced by reacting with an amine represented by the formula (R ¹ and R ² in the formula have the same meanings as described above).

In order to suitably carry out the method for producing the compound of the general formula (I) of the present invention, the compound of the general formula (III) is dissolved in an inert organic solvent such as methylene chloride and, under cooling, in an equimolar or slightly excess amount. , Preferably 1.2 times the molar amount of oxidizing agent, eg m-
Add chloroperbenzoic acid and cool to room temperature for 2-3
After stirring for a period of time, after completion of the reaction, the compound is treated and purified by a conventional method to obtain a compound of the general formula (I) in which R ³ is a lower alkyl group. Then, this is hydrolyzed according to a conventional method to obtain a compound of the general formula (I) in which R ³ is a hydrogen atom.

The phenylsulfinylalkylcarboxylic acid derivative represented by the general formula (I) of the present invention has an asymmetric carbon and an asymmetric sulfur, and there are four types of optically active isomers. Any of SS body, RS body, SR body or a mixture thereof can be used.

Further, the carboxylic acids of the compound of the general formula (I) of the present invention in which R ³ is a hydrogen atom can be converted into a pharmacologically acceptable salt according to a conventional method. As such, for example, inorganic salts such as sodium salt, calcium salt,
Examples thereof include organic salts such as morpholine salt, piperidine salt and salts with amino acids. These pharmacologically acceptable salts also have a CCK receptor antagonistic action like free carboxylic acid, and irritable colitis, biliary dyskinesia,
It is useful as a prophylactic and therapeutic agent for diseases such as acute pancreatitis.

When the phenylsulfinylalkylcarboxylic acid derivative represented by the general formula (I) of the present invention is used as an actual therapeutic agent, it is orally used as a suitable pharmaceutical composition such as tablets, powders, granules, capsules and injections. Alternatively, it is administered parenterally. These pharmaceutical compositions are prepared by conventional pharmaceutical techniques.

The dose is appropriately determined according to the sex, age, body weight, type of disease, degree of symptoms, etc. of the target patient. Oral administration is generally 1 to 1000 mg per adult per day, and parenteral administration is generally 0.1 per day. It is administered within the range of 100 mg.

EXAMPLES The contents of the present invention will be described in more detail with reference to the following reference examples and examples. The melting points of the compounds in Reference Examples and Examples are all uncorrected.

Reference Example 1 2- (3,4-Dimethylphenylthiomethyl) -4-methoxycarbonylbutyric acid 0.59 ml of 3,4-dimethylbenzenethiol and 0.48 ml of 2-methyleneglutaronitrile were dissolved in 10 ml of ethanol, and Triton B (40%) was added. After adding 5 drops of methanol solution, the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (eluting solvent: benzene / ethyl acetate = 7/1) to give oily 2- (3,4-dimethylphenylthiomethyl) glutaro. 1.18 g of nitrile was obtained.

IR (neat): ν _CN 2230cm ^-1 NMR (CDCl ₃ ) δ: 1.9 to 2.35 (8H, m), 2.45 to 2.7 (2H, m), 2.85 to 2.9
(1H, m), 2.98 (1H, dd, J = 7.7,13.7Hz), 3.18 (1H, dd, J
= 6.6,13.7Hz), 7.11 (1H, d, J = 7.7Hz), 7.19 (1H, dd, J
= 1.7,7.7Hz), 7.24 (1H, d, J = 1.7Hz) 2- (3,4-dimethylphenylthiomethyl) glutaronitrile 1.16g is dissolved in acetic acid 8ml, concentrated hydrochloric acid 8ml is added and refluxed for 19 hours. Let The reaction mixture was concentrated under reduced pressure, diethyl ether was added, the insoluble material was filtered off, the mixture was washed with water, then an aqueous sodium hydrogen carbonate solution was added, and the mixture was shaken. The aqueous layer was acidified with hydrochloric acid, extracted with diethyl ether, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether-hexane to give a melting point of 96-
1.18 g of 2- (3,4-dimethylphenylthiomethyl) glutaric acid at 98 ° C was obtained.

Elemental analysis value: (as C ₁₄ H ₁₈ O ₄ S) C% H% Calculated value 59.55 6.43 Measured value 59.38 6.56 IR (KBr): ν _{C = 0} 1705 cm ⁻¹ NMR (DMSO-d ₆ ) δ: 1.65 to 1.95 (2H, m), 2.1 ~ 2.55 (9H, m), 3.04 (2H,
d, J = 7.2Hz), 7.0 to 7.2 (3H, m), 12.28 (2H, s) 2- (3,4-dimethylphenylthiomethyl) glutaric acid
1.16 g was dissolved in 20 ml of methanol, 0.04 g of p-toluenesulfonic acid was added, and the mixture was reacted at 40 ° C. for 1.5 hours with stirring. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel flash column chromatography (elution solvent: chloroform /
Purified with ethanol = 10/1), oily 2- (3,4-dimethylphenylthiomethyl) -4-methoxycarnylbutyric acid
Obtained 0.98 g.

IR (neat): ν _{C = 0} 1735, 1705 cm ^-1 NMR (CDCl ₃ ) δ: 1.9 to 2.5 (10H, m), 2.55 to 2.7 (1H, m), 2.94 (1H, d)
d, J = 6.6,13.7Hz), 3.19 (1H, dd, J = 7.7,13.7Hz), 3.65
(3H, s), 7.06 (1H, d, J = 7.7Hz), 7.1 to 7.2 (2H, m) Reference Example 2 In the same manner as in Reference Example 1, the compound (oil) in the table was produced.

Reference Example 3 Methyl 5- (3,4-dimethylphenylthio) -4- (N, N-dipentylcarbamoyl) pentanoate 2-((3,4-Dimethylphenylthiomethyl) -4-methoxycarbonylbutyric acid 0.50 g This was dissolved in 6 ml of dry benzene, 0.2 ml of thionyl chloride was added, and the mixture was heated under reflux for 2 hours, and the reaction solution was concentrated to dryness under reduced pressure to give an oily residue.
A solution of this residue in dry methylene chloride (4 ml) was added dropwise to a solution of dipentylamine (0.35 ml) and triethylamine (0.3 ml) in dry methylene chloride (2 ml) under ice-cooling, and the mixture was stirred at room temperature for 5 minutes.
Reacted for hours. The reaction solution was washed successively with diluted hydrochloric acid, water, an aqueous solution of sodium hydrogen carbonate and water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel flash column chromatography (eluting solvent:
After purification with chloroform), 0.76 g of oily methyl 5- (3,4-dimethylphenylthio) -4- (N, N-dipentylcarbamoyl) pentanoate was obtained.

IR (neat): ν _{C = 0} 1730, 1635 cm ^-1 NMR (CDCl ₃ ) δ: 0.84 (3H, t, J = 6.6Hz), 0.89 (3H, t, J = 6.6Hz), 0.9
5 ~ 1.6 (12H, m), 1.95 ~ 2.1 (2H, m), 2.15 ~ 2.5 (8H,
m), 2.8 to 3.4 (7H, m), 3.65 (3H, s), 7.0 to 7.2 (3H, m) Reference Example 4 In the same manner as in Reference Example 3, the compound in the table (oil) was produced.

Reference Example 5 Pancreatic CCK Receptor Binding Assay Method by Chang et al. [Molecular Pharmacology, Vol. 30, p. 212, 198]
6 years] and a pancreatic tissue membrane sample was prepared. Pancreas was removed from male Wistar rats, adipose tissue was removed, and 50 times the wet weight of ice-cold 50 mM Tris HC.
After being shredded in a buffer solution (pH 7.4, 37 ° C.), it was homogenized using an ultra disperser. The homogenate was centrifuged at 50,000 xg for 10 minutes and the precipitate was washed with Tris HC.
The cells were suspended in a buffer solution and again centrifuged at 50,000 × g for 10 minutes. Assay buffer (50 mM Tris HCl, 5 mM MgCl ₂ , 5 mM dithiothreitol, 2 mg / ml bovine serum albumin, 0.14 mg / m
The precipitate was resuspended in 1 bacitracin) to provide a CCK binding test material.

Pancreatic tissue membrane suspension (usually 0.5 mg original tissue weight / ml), 30 pM [
¹²⁵ I] CCK-8 and the test drug or its solvent (for total binding) and 10 ⁻⁶ CCK-8 (for nonspecific binding) were added to the assay buffer to make the total volume 1 ml. After incubating at 37 ℃ for 30 minutes, the sample is suction filtered and the filter is cooled with ice-cold Tris-HCl.
After washing with buffer, its radioactivity was measured by a γ-counter (Packard 5650).

The specific binding amount to the CCK receptor was determined from the difference between the total binding amount and the non-specific binding amount, and the IC ₅₀ value was calculated from the inhibition rate of the specific binding amount by the test drug.

Example 1 5- (3,4-dimethylphenylsulfinyl) -4-
Methyl (N, N-dipentylcarbamoyl) pentanoate
(Diastereomer A: Compound 1, Diastereomer B: Compound 2) 0.55 g of methyl 5- (3,4-dimethylphenylthio) -4- (N, N-dipentylcarbamoyl) pentanoate in 10 ml of dry methylene chloride. After being dissolved, 0.31 g of m-chloroperbenzoic acid (70%) was added little by little with stirring at -78 ° C, and then the mixture was reacted for 3 hours. Sodium sulfite was added to the reaction solution, washed with an aqueous solution of sodium hydrogen carbonate, washed with water, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel flash column chromatography (eluting solvent: benzene / ethyl acetate = 2/1) and eluted first with 5- (3,4-dimethylphenylsulfinyl)-
There were obtained 0.12 g of methyl 4- (N, N-dipentylcarbamoyl) pentanoate (diastereomer A) and 0.36 g of diastereomer B which was eluted later.

[Diastereomer A]

Properties: Oily IR (neat): ν _{C = 0} 1730, 1630cm ⁻¹ ν _SO 1045cm ⁻¹ NMR (CDCl ₃ ) δ: 0.90 (3H, t, J = 6.6Hz), 0.93 (3H, t, J = 6.6) Hz), 1.1
~ 2.45 (22H, m), 2.76 (1H, dd, J = 3.3,12.1Hz), 3.1 ~
3.5 (6H, m), 3.65 (3H, s), 7.2 to 7.45 (3H, m) [Diastereomer B] Property: Oily IR (neat): ν _{C = 0} 1735, 1635cm ^-1 ν _SO 1045cm ^-1 NMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 7.1Hz), 0.93 (3H, t, J = 7.1Hz), 1.1
5 to 1.65 (12H, m), 2.1 to 2.5 (10H, m), 2.82 (1H, dd, J =
9.3,13.2Hz), 2.97 (1H, dd, J = 3.8, 13.2Hz), 3.1 to 3.45
(5H, m), 3.68 (3H, s), 7.2 to 7.45 (3H, m) Example 2 In the same manner as in Example 1, the compound in the table (oil) was produced.

Example 3 5- (3,4-Dimethylphenylsulfinyl) -4-
(N, N-dipentylcarbamoyl) pentanoic acid (Compound 7) 5- (3,4-dimethylphenylsulfinyl) -4-
120 mg of methyl (N, N-dipentylcarbamoyl) pentanoate (diastereomer A) was dissolved in 3 ml of ethanol, and 0.28 ml of 1N aqueous sodium hydroxide solution was added at room temperature.
The reaction was carried out for 16 hours. The reaction solution was concentrated under reduced pressure, acidified with diluted hydrochloric acid, extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluting solvent: chloroform / ethanol = 10/1), 5- (3,4-dimethylphenylsulfinyl) having a melting point of 50 to 54 ° C. 90 mg of -4- (N, N-dipentylcarbamoyl) pentanoic acid (diastereomer A) was obtained.

Elemental analysis value: (as C ₂₄ H ₃₉ NO ₄ S) C% H% N% Measured value 65.87 8.98 3.20 Measured value 65.52 9.24 3.19 IR (KBr): ν _{C = 0} 1720, 1630cm ⁻¹ NMR (CDCl ₃ ) δ : 0.90 (6H, t, J = 6.6Hz), 1.2 to 2.15 (14H, m), 2.25 to
2.4 (8H, m), 2.90 (1H, dd, J = 3.3, 12.1Hz), 3.1 ~ 3.5
(6H, m), 7.2 to 7.45 (3H, m) Example 4 In the same manner as in Example 3, the compounds in the table were produced.

Effect of the Invention The phenylsulfinylalkylcarboxylic acid derivative represented by the general formula (I) of the present invention exhibits competitive CCK receptor antagonistic action.

For example, the binding assay for CCK receptor of rat isolated pancreas using CCK-8 labeled with ¹²⁵ I (Bin
ding Assay), about 50% of the inhibitory effect is exhibited at a molar concentration of about 1 × 10 ^{−7 to} 6 × 10 ⁻⁶ .

Thus, the compounds of general formula (I) of the present invention are competitive
It has a CCK receptor antagonistic action and is useful as a preventive and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Masaaki Saka, Masaaki Saka 1-2-34 Nomizo Woodwork, Matsumoto-shi, Nagano Kissei Yakuhin Dairyo Dormitory (72) Inventor Toyohiro Kobayashi 3158 Nakagawate, Meishina-cho, Higashichikuma-gun, Nagano Prefecture Address Examiner Zenichi Wakimura

Claims (1)

[Claims] 1. A general formula (R ¹ and R ² in the formula may be the same or different and each is an alkyl group having 1 to 10 carbon atoms, R ³ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and X is a carbon atom. Number 1
A phenylsulfinylalkylcarboxylic acid derivative represented by the formula (3), wherein n is 1 or 2.