JPH07119200B2 - Naphthylsulfonylalkylcarboxylic acid derivatives - Google Patents

Description

TECHNICAL FIELD The present invention relates to a naphthylsulfonylalkylcarboxylic acid derivative useful as a drug.

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 a cycloalkyl group having 3 to 6 carbon atoms, an acyloxy group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, and 3 carbon atoms. a 6 alkenyloxy group or an alkoxy group having 1 to 6 carbon atoms, R ³ is a hydrogen atom, an alkyl group or a benzyl group having 1 to 4 carbon atoms, m and n is 1
Or 3) is a naphthylsulfonylalkylcarboxylic 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 fire fighting 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 naphthylsulfonylalkylcarboxylic 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 The inventors of the present invention have conducted diligent research to find out a new compound having a CCK receptor antagonistic action, and as a result, a certain naphthylsulfonylalkylcarboxylic acid derivative has 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 naphthylsulfonylalkylcarboxylic 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 naphthylsulfonylalkylcarboxylic 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 or a benzyl group, and R ¹ , R ² , m and n have the same meanings as described above), and a naphthylthioalkylcarboxylic acid derivative represented by It can be produced by oxidizing with a different oxidizing agent and optionally hydrolyzing or hydrolyzing.

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 2-naphthalenethiol 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 (In the formula, R ¹ , R ² , m and n have the same meaning as described above)
The compound of the general formula (III) can be produced by reacting with an amine represented by

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 or a benzyl group. Then, this is hydrolyzed or hydrolyzed according to a conventional method to obtain a compound of the general formula (I) in which R ³ is a hydrogen atom.

The naphthylsulfonylalkylcarboxylic 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 acid, and irritable colitis, biliary dyskinesia,
It is useful as a prophylactic and therapeutic agent for diseases such as acute pancreatitis.

When the naphthylsulfonylalkylcarboxylic 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 2- (2-Methoxycarbonylethyl) -3- (2-naphthylthio) propionic acid 2-Naphthalenethiol 10.0 g and 2-methyleneglutaronitrile 6.8 ml were dissolved in ethanol 150 ml, and Triton B was added.
After adding 10 drops (40% methanol solution), the mixture was heated under reflux for 2 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 ethyl acetate-hexane to obtain 15.6 g of 2- (2-naphthylthiomethyl) glutaronitrile having a melting point of 52 to 55 ° C.

Elemental analysis value: (as C ₁₆ H ₁₄ N ₂ S) C% H% N% Calculated value 72.15 5.30 10.52 Measured value 71.98 5.24 10.41 IR (KBr): ν _CN 2245cm ⁻¹ NMR (DDCl ₃ ) δ: 1.95 to 2.3 (2H, m), 2.4 ~ 2.7 (2H, m), 2.8 ~ 2.95 (1
H, m), 3.13 (1H, dd, J = 7.1.13b7Hz), 3.30 (1H, dd, J =
6.6,13.7Hz), 7.4 ~ 7.6 (3H, m), 7.75 ~ 8.0 (4H, m) 2- (2-naphthylthiomethyl) glutaronitrile 15.5
g was dissolved in 70 ml of acetic acid, 70 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 17 hours. The reaction solution was concentrated under reduced pressure, diethyl ether was added, insoluble materials were removed by filtration, washed with water, and an aqueous sodium hydrogen carbonate solution was added, followed by shaking. 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 give a melting point of 140-142.
2- (2-naphthylthiomethyl) glutaric acid at 1 ℃ 15.9g
Got

Elemental analysis value: (as C ₁₆ H ₁₆ O ₄ S) C% H% Calculated value 63.14 5.30 Actual value 63.37 5.34 IR (KBr): ν _{C = O} 1720 cm ^-1 NMR (DMSO-d ₆ ) δ: 1.7 to 2.0 (2H, m), 2.15 ~ 2.4 (2H, m), 2.5 ~ 2.65 (1
H, m), 3.1 to 3.4 (2H, m), 7.35 to 7.6 (3H, m), 7.75 to 8.0
(4H, m), 12.32 (2H, s) 2- (2-naphthylthiomethyl) glutaric acid 28.8 g was dissolved in methanol 300 ml, and p-toluenesulfonic acid 0.9 g
Was added and reacted at 40 ° C. for 2.5 hours with stirring. The reaction mixture was concentrated under reduced pressure, water was added to the residue, the mixture was extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from isopropyl ether,
2- (2-methoxycarbonylethyl) with a melting point of 70-71 ° C
27.4 g of -3- (2-naphthylthio) propionic acid was obtained.

Elemental analysis value: (as C ₁₇ H ₁₈ O ₄ S) C% H% Calculated value 64.13 5.70 Measured value 64.11 5.50 IR (KBr): ν _{C = O} 1730,1700 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.95 to 2.2 (2H, m), 2.3 ~ 2.5 (2H, m), 2.65 ~ 2.8 (1
H, m), 3.10 (1H, dd, J = 6.6, 13.2Hz), 3.33 (1H, dd, J =
7.7, 13.2Hz), 3.62 (3H, s), 7.4 ~ 7.55 (3H, m), 7.7 ~
7.9 (4H, m) Reference Example 2 2- (2-benzyloxycarbonylethyl) -3-
(2-naphthylthio) propionic acid 2- (2-naphthylthiomethyl) glutaric acid 14.0 g was dissolved in acetonitrile 180 ml, and benzyl alcohol 57 ml
And 0.52 g of p-toluenesulfonic acid were added, and the mixture was heated under reflux for 23 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel flash column chromatography (elution solvent:
After purification with methylene chloride / methanol = 70/1), the crystals were recrystallized from ethyl acetate-hexane to give 2- (2-
11.0 g of benzyloxycarbonylethyl) -3- (2-naphthylthio) propionic acid was obtained.

Elemental analysis value: (as C ₂₃ H ₂₂ O ₄ S) C% H% Calculated value 70.03 5.62 Measured value 70.05 5.69 IR (KBr): ν _{C = O} 1730,1700 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.9 to 2.2 (2H, m), 2.3 to 2.55 (2H, m), 2.65 to 2.8 (1
H, m), 3.09 (1H, dd, J = 6.6, 13.2Hz), 3.26 (1H, dd, J =
7.7, 13.2Hz), 5.09 (2H, s), 7.2 ~ 7.5 (8H, m), 7.65 ~
7.85 (4H, m) Reference Example 3 Methyl 4- [N, N-bis (2-cyclohexylethyl) carbamoyl] -5- (2-naphthylthio) pentanoate 2- (2-Methoxycarbonylethyl) -3- (2 -Naphthylthio) propionic acid 0.64g dry methylene chloride 10m
It was dissolved in 1 l, thionyl chloride (0.3 ml) 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 dry methylene chloride (5 ml) was added dropwise to a solution of 0.48 g of bis (2-cyclohexylethyl) amine and 0.7 ml of triethylamine in 15 ml of dry methylene chloride under ice-cooling and then reacted at room temperature for 20 hours. The reaction solution was washed successively with diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel medium pressure liquid column chromatography (eluting solvent: ethyl acetate / hexane = 1 /
Purification in 2) gave 0.94 g of oily methyl 4- [N, N-bis (2-cyclohexylethyl) carbamoyl] -5- (2-naphthylthio) pentanoate.

IR (neat): ν _{C = O} 1735,1635 cm ^-1 NMR (CDCl ₃ ) δ: 0.3 to 1.75 (26H, m), 2.0 to 2.5 (4H, m), 2.85 to 3.4
(7H, m), 3.65 (3H, s), 7.35 ~ 7.55 (3H, m), 7.7 ~ 7.85
(4H, m) Reference Example 4 In the same manner as in Reference Example 3, the compound (oil) in the table 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 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.
After washing with 1 buffer, the 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 Methyl 4- [N, N-bis (2-cyclohexylethyl) carbamoyl] -5- (2-naphthylsulfonyl) pentanoate (Compound 1) 4- [N, N-bis (2-cyclohexylethyl) carbamoyl ] Methyl 5- (2-naphthylthio) pentanoate
0.50 g was dissolved in 20 ml of dry methylene chloride, 0.51 g of m-chloroperbenzoic acid (80%) was added little by little under stirring with water cooling, and the mixture was reacted at room temperature for 6 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. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel medium pressure liquid column chromatography (elution solution: ethyl acetate / hexane = 1 /
After purification in 2), it was recrystallized from ethyl acetate-hexane and methyl 4- [N, N-bis (2-cyclohexylethyl) carbamoyl] -5- (2-naphthylsulfonyl) pentanoate having a melting point of 115.5 to 118 ° C. 0.48 g was obtained.

Elemental analysis value: (as C ₃₃ H ₄₇ NO ₅ S) C% H% N% Calculated value 69.56 8.31 2.46 Measured value 69.51 8.22 2.33 NMR (CDCl ₃ ) δ: 0.75 to 2.1 (28H, m), 2.32 (2H, t, J = 7.1Hz), 2.95 to
3.45 (6H, m), 3.63 (3H, s), 3.84 (1H, dd, J = 7.7,13.7H
z), 7.55 to 7.75 (2H, m), 7.8 to 8.1 (4H, m), 8.48 (1H,
s) Example 2 The compounds in the table were prepared in the same manner as in Example 1.

Example 3 4- [N, N-bis (2-cyclohexylethyl) carbamoyl] -5- (2-naphthylsulfonyl) pentanoic acid (Compound 6) 4- [N, N-bis (2-cyclohexylethyl) carbamoyl] Methyl-5- (2-naphthylsulfonyl) pentanoate (150 mg) was dissolved in ethanol (3 ml), 1N aqueous sodium hydroxide solution (0.26 ml) was added, and the mixture was stirred at room temperature for 16 hr. The reaction solution was concentrated under reduced pressure, acidified with diluted hydrochloric acid, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethyl acetate-hexane to give 4- [N, N-melting point 138.5-139.5 ° C.
Bis (2-cyclohexylethyl) carbamoyl] -5
86 mg of-(2-naphthylsulfonyl) pentanoic acid was obtained.

Elemental analysis value: (as C ₃₂ H ₄₅ NO ₅ S) C% H% N% Calculated value 69.16 8.16 2.52 Measured value 69.22 8.28 2.48 _{NMR (CDCl 3) δ: 0.7~2.1} (28H, m), 2.37 (2H, t, J = 7.1Hz), 3.0~3.
5 (6H, m), 3.83 (1H, dd, J = 7.7,13.7Hz), 7.55 to 7.75
(2H, m), 7.8 to 8.05 (4H, m), 8.48 (1H, s) Example 4 4- [N, N-bis (ethoxycarbonylmethyl) carbamoyl] -5- (2-naphthylsulfonyl) pentanoic acid (Compound 7) 4- [N, N-bis (ethoxycarbonylmethyl) carbamoyl] -5- (2-naphthylsulfonyl) benzyl benzyl salt (0.52 g) is dissolved in ethanol (10 ml), and 10% palladium-carbon (50 mg) is added at room temperature under normal pressure. Hydrogenated at 4 days.
After removing the catalyst by filtration, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel flash column chromatography (elution solvent:
After purification with chloroform / methanol = 10/1), recrystallization from isopropyl ether-hexane, melting point 108-111 ° C
0.27 g of 4- [N, N-bis (ethoxycarbonylmethyl) carbamoyl] -5- (2-naphthylsulfonyl) pentanoic acid was obtained.

Elemental analysis value: (as C ₂₄ H ₂₉ NO ₉ S) C% H% N% Calculated value 56.79 5.76 2.76 Measured value 56.56 5.87 2.52 NMR (CDCl ₃ ) δ: 1.1 to 1.4 (6H, m), 1.9 to 2.55 (4H, m), 3.0 to 4.5 (11
H, m), 7.5 ~ 7.75 (2H, m), 7.85 ~ 8.1 (4H, m), 8.51 (1
H, s) Example 5 In the same manner as in Example 3 or 4, the compounds in the table (oil) were produced.

Effect of the Invention The naphthylsulfonylalkylcarboxylic acid derivative represented by the general formula (I) of the present invention exhibits a 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 a cycloalkyl group having 3 to 6 carbon atoms, an acyloxy group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, and 3 carbon atoms. a 6 alkenyloxy group or an alkoxy group having 1 to 6 carbon atoms, R ³ is a hydrogen atom, an alkyl group or a benzyl group having 1 to 4 carbon atoms, m and n is 1
Or 3) is a naphthylsulfonylalkylcarboxylic acid derivative.