JPH07119198B2 - Phenylsulfonylalkylcarboxylic acid derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a phenylsulfonylalkylcarboxylic 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 in the formula is an alkyl group having 1 to 10 carbon atoms or 7 carbon atoms
~ 12 aralkyl groups, R ² is an aralkyl group having 7 to 12 carbon atoms, and R ³ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) It is a thing.

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 (C) has a CCK receptor antagonism, research on the proglumide derivative has been advanced and some CCK
Compounds having a receptor antagonism have been produced and reported (Japanese Patent Laid-Open Nos. 61-44855, 62-181246, 63-27468, and 61-44855).
63-165352, 63-201156, EP-A1-0308885, EP-A
2-0272228, 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 phenylsulfonylalkylcarboxylic 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 diligent research to find out a new compound having a CCK receptor antagonistic action, the present inventors have found that certain phenylsulfonylalkylcarboxylic acid derivatives have a strong CCK receptor antagonistic action. The present invention has been found to be useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis, and has completed the present invention.

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

The phenylsulfonylalkylcarboxylic 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 (Wherein R ⁴ is an alkyl group having 1 to ⁴ carbon atoms and R ¹ and R ² have the same meanings as described above), the phenylthioalkylcarboxylic acid derivative is oxidized with a suitable oxidizing agent. Then, the compound of the general formula (III) is temporarily hydrolyzed by hydrolyzing the compound of the general formula (III). (R ¹ , R ² and R ⁴ in the formula have the same meanings as described above), and then further oxidized to a sulfonyl compound, and then hydrolyzed if necessary. You can

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 formula A thiophenol derivative represented by (A and B in the formula are each a cyano group or a carbon number of 2
A compound represented by the formula (1) to (5) 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. In response to the general formula (Wherein A and B have the same meaning as described above), and if necessary, this is subjected to hydrolysis and monoesterification by a suitable method to give a compound of the general formula A compound represented by the formula (R ⁴ in the formula has the same meaning as described above) is obtained.

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, a 2-fold molar to a slight excess. Amount, preferably 2.5 times the molar amount of oxidizing agent, eg m
-Add chloroperbenzoic acid and add 2 to
After stirring for 3 hours and after the 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 phenylsulfonylalkylcarboxylic acid derivative represented by the general formula (I) of the present invention has an asymmetric carbon, and there are two kinds of optically active compounds.
Either the 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 acids, and are useful as prophylactic and therapeutic agents for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis.

When the phenylsulfonylalkylcarboxylic acid derivative represented by the general formula (I) of the present invention is used as an actual therapeutic agent, suitable pharmaceutical compositions such as tablets, powders, granules,
It is orally or parenterally administered as a capsule or injection. 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 3- (3,4-dichlorophenylthio) -2- (2-methoxycarbonylethyl) propionic acid 3,4-dichlorobenzenethiol 3.00 ml and 2-methyleneglutaronitrile 2.57 ml were dissolved in 25 ml of ethanol, and Triton was added. After adding 10 drops of B (40% methanol solution), the mixture was heated under reflux for 4 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 recrystallized from diethyl ether-hexane to give 2- (3,4) having a melting point of 53 to 55 ° C.
-Dichlorophenylthiomethyl) glutaronitrile 6.14 g
Got

Elemental analysis value: (as C ₁₂ H ₁₀ Cl ₂ N ₂ S) C% H% N% Calculated value 50.54 3.53 9.82 Measured value 50.35 3.39 9.87 IR (KBr): ν _CN 2240cm ⁻¹ NMR (CDCl ₃ ) δ: 1.95 ~ 2.25 (2H, m), 2.45 ~ 2.75 (2H, m), 2.85 ~ 2.9
5 (1H, m), 3.10 (1H, dd, J = 6.6,14.3Hz), 3.22 (1H, dd,
J = 7.1, 14.3Hz), 7.28 (1H, dd, J = 1.7, 8.2Hz), 7.43 (1
H, d, J = 8.2Hz), 7.54 (1H, d, J = 1.7Hz) 2- (3,4-dichlorophenylthiomethyl) glutaronitrile 5.40 g was dissolved in 36 ml of acetic acid and 36 ml of concentrated hydrochloric acid was added.
Heated to reflux for hours. The reaction solution was concentrated under reduced pressure, diethyl ether was added, the insoluble material was filtered off, 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. After evaporating the solvent under reduced pressure, the residue was recrystallized from diethyl ether-hexane to obtain 4.44 g of 2- (3,4-dichlorophenylthiomethyl) glutaric acid having a melting point of 112 to 114 ° C.

Elemental analysis value: (as C ₁₂ H ₁₂ Cl ₂ N ₄ S) C% H% Calculated value 44.60 3.74 Measured value 44.35 3.66 IR (KBr): ν _{C = 0} 1710 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.9 to 2.1 (2H, m), 2.25 ~ 2.5 (2H, m), 2.55 ~ 2.7 (1
H, m), 3.01 (1H, dd, J = 6.0, 13.2Hz), 3.23 (1H, dd, J =
7.7,13.2Hz), 7.20 (1H, dd, J = 2.2,8.2Hz), 7.35 (1H,
d, J = 8.2Hz), 7.44 (1H, d, J = 2.2Hz) 2- (3,4-dichlorophenylthiomethyl) glutaric acid
3.00 g was dissolved in 30 ml of methanol, 0.09 g of p-toluenesulfonic acid was added, and the mixture was reacted at 40 ° C. for 2.5 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 /
Purification with ethanol = 10/1) gave 2.92 g of oily 3- (3,4-dichlorophenylthio) -2- (2-methoxycarbonylethyl) propionic acid.

IR (neat): ν _{C = 0} 1740,1710 cm ^-1 NMR (CDCl ₃ ) δ: 1.95 to 2.1 (2H, m), 2.3 to 2.5 (2H, m), 2.6 to 2.75 (1
H, m), 3.01 (1H, dd, J = 6.0, 13.2Hz), 3.23 (1H, dd, J =
7.7,13.2Hz), 3.67 (3H, s), 7.19 (1H, dd, J = 2.2,8.2H
z), 7.36 (1H, d, J = 8.2Hz), 7.45 (1H, d, J = 2.2Hz) Reference Example 2 5- (3,4-dichlorophenylthio) -4- (N-pentyl-N-phenethyl) Methyl carbamoyl) pentanoate 190 mg of 3- (3,4-dichlorophenylthio) -2- (2-methoxycarbonylethyl) propionic acid was dissolved in 3 ml of dry benzene, 0.1 ml of thionyl chloride was added, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain an oily residue. A solution of this residue in 3 ml of dry methylene chloride was added to
-A solution of 110 mg of pentiphenethylamine and 0.1 ml of triethylamine in 3 ml of dry methylene chloride was added dropwise under stirring with ice cooling, and then reacted at room temperature for 4 hours. Dilute hydrochloric acid,
The extract was washed successively with water, an aqueous solution of sodium hydrogen carbonate and 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: methylene chloride / diethyl ether / hexane = 1/1/4) to give oily 5- (3,4-dichlorophenylthio). ) -4- (N-Pentyl-N-phenethylcarbamoylpentanoic acid methyl ester 280 mg was obtained.

IR (neat): ν _{C = 0} 1730,1635cm ^-1 NMR (CDCl ₃ ) δ: 0.84and0.89 (3H, t, J = 6.6Hz), 1.0 to 1.6 (6H, m),
1.85 ~ 2.1 (2H, m), 2.2 ~ 2.45 (2H, m), 2.65 ~ 3.7 (12
H, m), 6.97 (1H, d, J = 6.6Hz), 7.1 to 7.4 (7H, m) Reference Example 3 In the same manner as in Reference Example 2, the compound (oil) in the table was produced.

Reference Example 4 5- (3,4-dichlorophenylsulfinyl) -4-
Methyl (N-pentyl-N-phenethylcarbamoyl) pentanoate Methyl 5- (3,4-dichlorophenylthio) -4- (N-pentyl-N-phenethylcarbamoyl) pentanoate
280 mg was dissolved in 10 ml of dry chloroform, 140 mg of m-chloroperbenzoic acid (70%) was added little by little with stirring at -78 ° C, and the reaction was carried out for 2 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 evaporating the solvent under reduced pressure, the residue was subjected to silica gel flash column chromatography (eluting solvent: methylene chloride / diethyl ether /
Purify with hexane = 1/1/2) and elute first with 5- (3,4-
There were obtained 100 mg of methyl dichlorophenylsulfinyl) -4- (N-pentyl-N-phenethylcarbamoyl) pentanoate (diastereomer A) and 110 mg of diastereomer B which was eluted later.

[Diastereomer A]

Property: Oily IR (neat): ν _{C = 0} 1735,1630cm ^-1 ν _S-0 1050cm ^-1 NMR (CDCl ₃ ) δ: 0.90and0.92 (3H, t, J = 7.1Hz), 1.2〜 2.05 (8H, m),
2.28 (2H, t, J = 7.1Hz), 2.7 to 3.05 (3H, m), 3.15 to 3.85
(9H, m), 7.15 to 7.4 (5H, m), 7.46 (1H, dd, J = 1.7,8.2H
z), 7.60 (1H, d , J = 8.2Hz), 7.77 (1H, d, J = 1.7Hz) [diastereomer B] Typical Properties: Oily _{IR (neat): ν C =} 0 1740,1630cm - ¹ ν _S-0 1045 cm ^-1 NMR (CDCl ₃ ) δ: 0.87and0.92 (3H, t, J = 7.1Hz), 1.15 to 1.65 (8H,
m), 2.05 to 2.45 (4H, m), 2.7 to 3.0 (3H, m), 3.1 to 3.6
(4H, m), 3.66and3.69 (3H, s), 7.1 ~ 7.45 (6H, m) 7.57
and7.59 (1H, d, J = 8.2Hz), 7.73 (1H, d, J = 1.6Hz) Reference Example 5 In the same manner as in Reference Example 4, the compound (oil) in the table was produced.

Reference Example 6 Pancreatic CCK Respter Binding Test Method of 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 trised.
The cells were suspended in HCl buffer and again centrifuged at 50,000 × g for 10 minutes. Analytical buffer (50 mM Tris HCl, 5 mM MgCl ₂ , 5 mM
Dithiothreitol, 2 mg / ml bovine serum albumin, 0.14 mg
/ ml bacitracin) to resuspend the precipitate as the 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 M 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 ice-cold Tris HC.
l Wash with buffer and gamma counter (Packard 5650)
The radioactivity was measured by.

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 4- (N-benzyl-N-methylcarbamoyl) -5-
Methyl (3,4-dichlorophenylsulfonyl) pentanoate 4- (N-benzyl-N-methylcarbamoyl) -5-
(3,4-Dimethylrophenylthio) methyl pentanoate 110mg
Was dissolved in 4 ml of dry chloroform, and 160 mg of m-chloroperbenzoic acid (80%) was added little by little under stirring with ice cooling.
The reaction was carried out at room temperature for 4 hours. Sodium sulfite was added to the reaction solution, which was then washed successively with an aqueous solution of sodium hydrogen carbonate and water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel preparative thin layer chromatography (developing solvent: methylene chloride / diethyl ether = 2/1).
The product was purified with a solvent to give 100 mg of oily methyl 4- (N-benzyl-N-methylcarbamoyl) -5- (3,4-dichlorophenylsulfonyl) pentanoate.

NMR (CDCl ₃ ) δ: 1.75 to 2.4 (4H, m), 2.9 to 3.15 (4H, m), 3.45 to 3.7
(4H, m), 3.84and3.94 (1H, dd, J = 9.3,13.7Hz), 4.3〜
4.75 (2H, m), 7.2 ~ 7.45 (5H, m), 7.55 ~ 7.75 (2H, m),
7.92and8.00 (1H, d, J = 2.2Hz) Example 2 5- (3,4-dichlorophenylsulfonyl) -4- [N, N
Methyl bis (3-phenylpropyl) carbamoyl] pentanoate 5- (3,4-dichlorophenylsulfinyl) -4-
[N, N-bis (3-phenylpropyl) carbamoyl]
220 mg of methyl pentanoate was dissolved in 20 ml of dry methylene chloride, and 120 mg of m-chloroperbenzoic acid (80%) was stirred under ice cooling.
Was added little by little and reacted at room temperature for 4 hours. After adding sodium sulfite to the reaction solution, it was washed successively with an aqueous solution of sodium hydrogen carbonate and 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: chloroform / ethanol = 50/1) to give oily 5- (3,4-dichlorophenylsulfonyl) -4- [N, N- 200 mg of methyl bis (3-phenylpropyl) carbamoyl] pentanoate was obtained.

NMR (CDCl ₃ ) δ: 1.7 to 2.35 (8H, m), 2.5 to 2.75 (4H, m), 3.0 to 3.45
(6H, m), 3.63 (3H, s), 3.84 (1H, dd, J = 9.3,14.3Hz),
7.05 ~ 7.35 (10H, m), 7.59 (1H, d, J = 8.2Hz), 7.70 (1
H, dd, J = 2.2,8.2Hz), 7.96 (1H, d, J = 2.2Hz) Example 3 In the same manner as in Example 1 or 2, the compounds in the table (oil) were produced.

Example 4 5- (3,4-dichlorophenylsulfonyl) -4- (N
-Pentyl-N-phenethylcarbamoyl) pentanoic acid 5- (3,4-dichlorophenylsulfonyl) -4- (N
57 mg of methyl-pentyl-N-phenethylcarbamoyl) pentanoate was dissolved in 1 ml of ethanol, 0.12 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was reacted at room temperature 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. After evaporating the solvent under reduced pressure, the residue was purified by silica gel preparative thin layer chromatography (developing solvent: chloroform / ethanol = 10/1) to give an oily 5- (3,4-dichlorophenylsulfonyl)- 45 mg of 4- (N-pentyl-N-phenethylcarbamoyl) pentanoic acid was obtained.

NMR (CDCl ₃ ) δ: 0.89 and 0.92 (3H, t, J = 7,1Hz), 1.15 to 2.1 (8H, m),
2.31and2.34 (2H, t, J = 6.6Hz), 2.7 to 3.85 (9H, m), 7.1
5 to 7.4 (5H, m), 7.63and7.64 (1H, d, J = 8.2Hz), 7.73
(1H, dd, J = 2.2,8.2Hz), 7.98and7.99 (1H, d, J = 2.2H
z) Example 5 The compounds in the table were prepared in the same manner as in Example 4.

Effect of the Invention The phenylsulfonylalkylcarboxylic 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 in the formula is an alkyl group having 1 to 10 carbon atoms or 7 carbon atoms
A 12 aralkyl group, R ² is an aralkyl group having 7 to 12 carbon atoms, R ³ is phenylsulfonyl alkyl carboxylic acid derivative represented by hydrogen or an alkyl group having 1 to 4 carbon atoms).