JPH04210956A - Naphthylsulfonylalkyl carboxylic acid derivative - Google Patents

Abstract

PURPOSE:To provide a novel naphthylsulfonylalkyl carboxylic acid derivative and a pharmacologically acceptable salt thereof which exhibit a cholecystokinin receptor-antagonistic action and which are effective for preventing and treating diseases such as irritable colitis, biliary dyskinesia and acute pancreatitis. CONSTITUTION:A naphthylsulfonylalkyl carboxylic acid derivative of formula I (R<1> is H, carboxy, 2-7C alkoxycarbonyl, N-monosubstituted or N,N- disubstituted carbamoyl, 1-6C alkyl, 1-6C alkoxy; R<2> is 1-10C alkyl; R<3> is H, 1-4C alkyl, benzyl; Y is 1-4C alkylene; n is 1,2) and a pharmacologically acceptable salt thereof. e.g. 4-(N-tert-butoxycarbonylmethyl-N-pentylcarbamoyl)-5-(2- naphthylsulfonyl) pentanoic acid methyl ester. A novel compound of formula II (R<5> is 1-4C alkyl, etc.) is reacted with an oxidizing agent to produce the compound of formula I wherein R<3> is alkyl or benzyl.

Description

[Detailed description of the invention]

0001

TECHNICAL FIELD The present invention relates to naphthylsulfonylalkylcarboxylic acid derivatives useful as pharmaceuticals. (0002) More specifically, the present invention provides cholecystokinin (hereinafter referred to as C
CK) receptor antagonistic effect, and is useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis.

[8] (1) (R1 in the formula is a hydrogen atom, a carboxy group, and has 2 to 7 carbon atoms.
alkoxycarbonyl group, N-monosubstituted or N,
N-disubstituted carbamoyl group, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, R2 is an alkyl group having 1 to 10 carbon atoms, and R3 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkyl group or a benzyl group, Y is alkylene having 1 to 4 carbon atoms, and n is 1 or 2)
This invention relates to naphthylsulfonylalkylcarboxylic acid derivatives represented by the following formulas and their pharmacologically acceptable salts. [0004]

[Prior art] CCK is gastrin.
) and secretin, it is a typical gastrointestinal hormone, and is known to be particularly involved in stimulation of exocrine secretion, contraction of the gallbladder, etc. [0005] In recent years, research on CCK has progressed, and the involvement of CCK in various diseases has been elucidated. [0006] As a result, specific, competitive and reversible C
CK receptor antagonists can be used to treat irritable colitis, biliary dyskinesia,
It is attracting attention as it is expected to be a preventive and therapeutic agent for diseases such as acute pancreatitis. [0007] Used as a peptic ulcer treatment agent,
Progelamide represented by the formula [9]
Since it was reported that progelamide de) exhibits CCK receptor antagonism, research on progelamide derivatives has progressed, and so far several compounds having CCK receptor antagonism have been produced and reported (Unexamined Japanese Patent Publication No. Showa 61-4485
5, 62-181246, 63-27468, 6
3-165352, 63-201156, EP-Al
-0308885, EP-A2-0272228, WO
87103869, 88105774, 89102
431). [0008] All of these compounds are derivatives of amino acids such as glutamic acid or aspartic acid,
The compound of the present invention has a completely different structure from these compounds. [0009]

[Problems to be Solved by the Invention] The purpose of the present invention is to
The object of the present invention is to provide a naphthylsulfonylalkylcarboxylic acid derivative that has receptor antagonistic activity and is useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis. [00101

[Means for Solving the Problems] As a result of intensive research to find new compounds with CCK receptor antagonistic activity, the present inventors found that certain naphthylsulfonylalkylcarboxylic acid derivatives exhibit strong CCK receptor antagonistic activity. The present inventors have discovered that the present invention is useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis. [0011] The naphthylsulfonylalkylcarboxylic acid derivative represented by the general formula (I) of the present invention competitively antagonizes the binding of CCK-8 to the CCK receptor, and also inhibits gallbladder contraction induced by CCK-8. It has an inhibitory effect on amylase secretion and amylase secretion, and is useful as a preventive and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis. [0012] The naphthylsulfonylalkylcarboxylic acid derivative represented by the general formula (I) of the present invention is a novel compound, and can be produced as follows. [0013] That is, it is represented by the general formula [10] () (R5 in the formula is an alkyl group or benzyl group having 1 to 4 carbon atoms, and R1, R2, Y and n have the same meanings as above) It can be produced by oxidizing a naphthylthioalkylcarboxylic acid derivative using an appropriate oxidizing agent and, if necessary, hydrolyzing or hydrogenolyzing it. [0014] The above general formula (II) used as a starting material in the method for producing a compound of general formula (I) of the present invention
The compound is a new compound and can be produced as follows. [0015] That is, the formula

[11] () 2-naphthalenethiol represented by and the general formula

[Chem.12
] (IV) (A and B in the formula are each a cyano group or a carbon number of 2
~5 alkoxycarbonyl group, or A is an alkoxycarbonyl group having 2 to 5 carbon atoms, B is a carboxyl group or an alkali metal salt thereof, and n has the same meaning as above). Reacting in the presence of a Lewis base or Lewis acid catalyst, the general formula % formula %]

[13] A compound represented by () (in which A, B and n have the same meanings as above) is prepared, and if necessary, this is hydrolyzed and monoesterified by an appropriate method, General formula [001
7]

A compound represented by (VI) (R5 and n in the formula have the same meanings as above) is obtained. [0018] This compound or a reactive functional derivative thereof and the general formula

[15] () (R1, R2 and Y in the formula have the same meanings as above)
By reacting with amines represented by the general formula (
Compound II) can be produced. [0019] The compound of the general formula (I) of the present invention in which R1 is a carboxy group or an N-mono- or N,N-disubstituted carbamoyl group is a compound of the general formula (I) in which R1 is a carboxy group or an N-mono- or N,N-disubstituted carbamoyl group.
1 is a tert-butoxycarbonyl group, and R3 is t
It can also be produced by selectively removing only the tert-butyl group from a compound that is a lower alkyl group other than ert-butyl with trifluoroacetic acid, and if necessary, amidating this by a conventional method, and further hydrolyzing if necessary. be able to. [00201 Also, in the compound of general formula (I) of the present invention, R
A compound in which 1 is an alkoxycarbonyl group and R3 is a hydrogen atom can be produced by selectively eliminating the benzyl group by catalytic reduction of a compound in which R3 is a benzyl group. Furthermore, a compound in which R1 is an alkoxycarbonyl group having 3 or more carbon atoms and R3 is a hydrogen atom can be produced by selectively removing the methyl group from a compound in which R3 is a methyl group with lithium thiomethoxide. . [0021] To suitably carry out the method for producing the compound of general formula (I) of the present invention, the compound of general formula (II) is dissolved in an inert organic solvent, for example, methylene chloride, and under cooling,
Add an oxidizing agent, such as m-chloroperbenzoic acid, in a 2-fold molar to slightly excess amount, preferably 2.5-fold molar, and stir for 2 to 3 hours under cooling or at room temperature. After the reaction is complete, process and purify according to a conventional method. Then, a compound of general formula (I) in which R3 is a lower alkyl group or a benzyl group is obtained. Next, this is hydrolyzed or hydrolyzed according to a conventional method to obtain a compound of general formula (I) in which R3 is a hydrogen atom. [0022] The naphthylsulfonylalkylcarboxylic acid derivative represented by the general formula (I) of the present invention has an asymmetric carbon, and there are two types of optically active forms. Either the compound or a mixture thereof can be used. [0023] Furthermore, in the compound of general formula (I) of the present invention, R
Carboxylic acids in which 3 is a hydrogen atom can be converted into pharmacologically acceptable salts according to conventional methods. Examples of such salts include inorganic salts such as sodium salts and calcium salts, and organic salts such as morpholine salts, piperidine salts, and salts with amino acids. These pharmacologically acceptable salts also have CCK receptor antagonistic effects like free carboxylic acids, and are useful as prophylactic and therapeutic agents for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis. (00241 Among the naphthylsulfonylalkylcarboxylic acid derivatives represented by the general formula (I) of the present invention, 4-(N-(3-methoxypropyl)-
N-pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoic acid, their optically active forms, and their pharmacologically acceptable salts can be mentioned, but the most preferred compound is (R)-4- (N-(3-methoxypropyl)-N-pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoic acid and its L-arginine salt. [0025] When the naphthylsulfonylalkylcarboxylic acid derivative represented by general formula (I) of the present invention is used as an actual therapeutic agent, it can be used in suitable pharmaceutical compositions such as tablets, powders, granules, capsules, injections, etc. It is administered orally or parenterally. These pharmaceutical compositions are prepared by conventional pharmaceutical techniques. [0026] The dosage is appropriately determined depending on the sex, age, weight, type of disease, degree of symptoms, etc. of the target patient, but in the case of oral administration, it is generally 1 to 1000 per day for adults.
mg, approximately 0.0 mg per day when administered parenterally. 1-10
Administered within the range of 0 mg. [0027]

EXAMPLES The contents of the present invention will be explained in more detail with reference to the following reference examples and examples. Note that the melting points of the compounds in each Reference Example and Examples are all uncorrected. [0028] Reference Example 1 2-(2-methoxycarbonylethyl)-3-(2-naphthylthio)propionic acid [0029]2-naphthalenethiol 10. Add Og and 6.8 ml of 2 methylene geltalonitrile to 150 ml of ethanol.
Triton B (40% methanol solution) 1
After adding 0 drops, the mixture was heated under reflux for 2 hours. The reaction solution 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 give a melting point of 52~
15.6 g of 2-(2-naphthylthiomethyl)geltalonitrile at 55°C was obtained. [00301 Elemental analysis value: ((:1 (as NS)) 16142 Calculated value 0%72,15.H%5,30.H%1
0.52 Actual value C%? 1.98. H%5.24.
H%10.411 1R (KBr): ν (CN) 2245 c+n
NMR (coCI) δ: 1. 95-2. 3 (2H, m),
2. 4-2. 7 (2H, m), 2. 8-2
．． 95 (LH, m), 3. 13 (LH,
dd, J=7. 1. 13. 7Hz),
3. 30 (IH, dd, J=6.6.13
．． 7Hz), 7. 4-7. 6 (3H, m
), 7. 75-8. 0 (4H, m) [00
31] 2-(2-naphthylthiomethyl)geltalonitrile 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, and the mixture was washed with water. Then, an aqueous sodium hydrogen carbonate solution was added and the mixture was shaken. The aqueous layer was made acidic with hydrochloric acid, extracted with diethyl ether, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from diethyl ether-hexane to obtain 15.9 g of 2-(2-naphthylthiomethyl)glutaric acid having a melting point of 140 to 142°C. [0032] Elemental analysis value: (as CIO3) 16164 Calculated value 0%63.14. H%5430 Actual value 0%
63.37. H%5.341 1R(Kllr door ν(C=[I) 1720
cmN Dragon (DMSO-d) δ: 1. 7-2. 0 (2H, m), 2
．． 15-2. 4 (2H, m), 2. 5-2
．． 65 (LH, m), 3. 1-3. 4
(2H, m), 7. 35-7. 6 (3
H. m), 7. 75-8. 0 (4H, m),
12. 32 (2H,s) [0033] 28.8 g of 2-(2-naphthylthiomethyl)glutaric acid was dissolved in 300 ml of methanol, and p
-Toluenesulfonic acid (0.9 g) was added and the mixture was reacted at 40° C. with stirring for 2.5 hours. After concentrating the reaction solution under reduced pressure, water was added to the residue, 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 to obtain 27.4 g of 2(2-methoxycarbonylethyl)-3-(2-naphthylthio)propionic acid having a melting point of 70 to 71°C. [0034] Elemental analysis value: (as CIO3) 17184 Calculated value 0%64.13. H%5.70 Actual value 0%
64°11. H%5.501 1R (KBr): ν (C=0) 1730.170
0 cn+NIJR(ct+cl) δ: 1. 95-2. 2 (2H, m),
2. 3-2. 5 (2H, m), 2. 65～
2. 8 (LH, m), 3. 10 (IH
, dd, J=6. 6. 13. 2Hz),
3. 33 (LH, dd, J-7, 7, 13,
2Hz), 3. 62 (3H,s),
7. 4-7. 55 (3H, m), 7°7
~7. 9 (4H, m) [0035] Reference example 2 (+)-2-(2-methoxycarbonylethyl)-3(
2-naphthylthio)propionic acid and (-)-2(2
-methoxycarbonylethyl)-3-(2-naphthylthio)propionic acid [0036] (±)-2-(2-methoxycarbonylethyl)-3-(2-naphthylthio)propionic acid 1
0.00 g was heated and dissolved in a mixed solution of 20 ml of ethanol and 5 ml of methanol, 3.80 g of (+)-1-phenylethylamine was added, and after standing at room temperature, the precipitated crystals were collected by filtration. The obtained crystals were further mixed with 9 ml of ethanol and 3 ml of methanol.
ml of the mixed solution by heating, and after standing at room temperature, the precipitated crystals were collected by filtration, and (+)-2-(2-methoxycarbonylethyl)-3-(2-naphthylthio)propionic acid and (+)- Salt with 1-phenylethylamine2. ssg
I got it. To 0.72 g of this salt was added 10 ml of 2N hydrochloric acid, 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 to give (+)-2 with a melting point of 72-74°C.
0.37 g of (2-methoxycarbonylethyl)-3-(2-naphthylthio)propionic acid was obtained. [0037] Specific optical rotation: [: αF + 46.8″ (C=1.
50. Medal) 1 1R (KBr): ν([1=O) 1740.1
725.1690cn+NMR (CDCI) Consistent with racemate [0038] On the other hand, by concentrating the first solution of the salt with (+)-1-phenylethylamine and repeating recrystallization of the residue three times from ethanol, ( −
)-2-(2-methoxycarbonylethyl)-3-(2
1.04 g of a salt of -naphthylthio)propionic acid and (+)-1-phenylethylamine was obtained. This salt 0.90
15 ml of 2N hydrochloric acid was added to g, 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)-
0.46 g of 3-(2-naphthylthio)propionic acid was obtained. [0039] Specific optical rotation: [α]D45.6° (C=
1.07. (MeOH) Melting point, IR and NMR were consistent with the (+) form.

Reference Example 3 2-(2-benzyloxycarbonylethyl)-3-(
14.0 g of 2-naphthylthio)propionic acid (004112-(2-naphthylthiomethyl)glutaric acid) was dissolved in 180 ml of acetonitrile, 57 ml of benzyl alcohol and 0.52 g of p-toluenesulfonic acid were added, and the mixture was heated under reflux for 23 hours. was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (elution solvent: methylene chloride/methanol = 70/1) and then recrystallized from ethyl acetate-hexane to give 2-( 11.0 g of 2-benzyloxycarbonylethyl)-3-(2-naphthylthio)propionic acid was obtained. [0042] Elemental analysis value: (CHO3a) 23224 Calculated value C%?0.03. H%5,62 Actual value 0%
70.05. H%5,691 1R(KBr): y(C=O) 1730.17
00cmNMR(CD(:l) δ: 1.9-2.2 (2H,m), 2
．． 3-2. 55 (2H, m), 2. 65~
2. 8 (LH, m), 3. 09 (LH
, dd, J=6. 6. 13. 2Hz),
3. 26 (LH, dd, J=7. 7.
13. 2Hz), 5. 09 (2H,s)
, 7. 2-7. 5 (8H, m), 7
．． 65-7. 85 (4H, m) [0043] Reference Example 4 2-Methoxycarbonylmethyl-3-(2-naphthylthio)propionic acid [0044] 0.38 g of 2-naphthalenethiol and 3-
Dissolve 0.39 g of sodium methoxycarbonyl-2-methylenepropionate in 20 ml of methanol, add 10 drops of Triton B (40% methanol solution),
The mixture was heated to reflux for an hour. The reaction solution was concentrated under reduced pressure, acidified with dilute hydrochloric acid, extracted with ethyl acetate, washed with 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 solvent: After purification with chloroform/methanol (20/1), it was recrystallized from isopropyl ether with a melting point of 97-9.
0.38 g of 2-methoxycarbonylmethyl-3-(2-naphthylthio)propionic acid at 9°C was obtained. [0045] Elemental analysis value: (as CH[]S) 16164 Calculated value 0%63,14. H%5.30 Actual value 0%
63.12. H%5.271 1R(KBr): y([:=[I) 1735.1
700 cm NMR (CIICI) δ: 2. 7-2. 9 (2H, m), 3
．． 0-3. 25 (2H, m), 3. 47
(LH, dd, J=5.0.13, 2Hz)
, 3. 64 (3H,s), 7. 4～
7. 55 (3H, m), 7. 7-7. 9
(4H,m)[0046] Reference Example 5 4-(N,N-dipentyl Rubamoyl)-5-(2
-Methyl naphthylthio)pentanoate [0047] 4.0 g of 2-(2-methoxycarbonylethyl)-3-(2-naphthylthio)propionic acid was dissolved in 80 ml of dry methylene chloride, and 4.0 g of thionyl chloride was dissolved.
0 ml was added and 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 20 ml of dry methylene chloride was added to 3.5 ml of dipentylamine.
The mixture was added dropwise to a solution of 80 ml of dry methylene chloride containing 5.4 ml of triethylamine and 5.4 ml of triethylamine while cooling with water and reacting at room temperature for 16 hours. The reaction solution was washed successively with dilute hydrochloric acid, water, an aqueous sodium bicarbonate solution, and water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel medium pressure liquid column chromatography (elution solvent: methylene chloride) to obtain an oily 4-(N,N-
Dipentyl(rubamoyl)-5-(2-naphthylthio)
5.1 g of methyl pentanoate was obtained. [0048] IR(neat):v (C=O)1735.164
0cm' NMR (CDC13) δ: 0. 66 (3H, t, J=7.1Hz)
, 0. 8-1, 05 (7H, m),
1. 15-1. 6 (8H.m), 2. 0-2. 5 (4H, m),
2. 85-3. 4 (7H, m), 3. 6
3 (3H,s), 7. 4-7. 55 (3
H, m), 7. 7-7. 85 (4H, m)
[0049] Reference Example 6 The compounds shown in Tables 1 to 3 (oil) were produced in the same manner as in Reference Example 5. However, compounds whose specific rotation is not listed are racemic. [00501

[0054] Reference Example 7 Pancreatic CCK receptor binding test [0055] Method of Chang et al. [Molecular Pha
rmacology) Volume 30, Page 212, 1986
Pancreatic tissue membrane specimens were prepared according to [2013]. Wistar (
The pancreas was removed from a male Wistar rat, the adipose tissue was removed, and the pancreas was soaked in 50 m of water at a volume 50 times its wet weight.
M Tris HCl buffer (pH 7,4
, 37° C.) and homogenized using an ultradisperser. Homogenate at 50%. OO
Centrifuge for 10 minutes in OXg, and transfer the precipitate to Tris HC.
The suspension was suspended in I buffer and centrifuged again at 50,000×g for 10 minutes. Analysis buffer (50mM Tris-HCI, 5mM Mg
The precipitate was resuspended in Cl (2.5mM dithiothreitol, 2m 87ml bovine serum albumin, 0.14mg/ml bacitracin) to provide CCK binding test material. [0056] Pancreatic tissue membrane suspension (usually 0.5 mg original tissue weight/ml), 30 pM C'? ”I)CCK-
8 and test drug or its solvent (for total binding), 10
-6MCCK-8 (for non-specific binding) was added to the analysis buffer to make a total volume of 1 ml. After incubating at 37°C for 30 minutes, the sample was filtered by suction, and the filter was washed with ice-cold Tris H.
After washing with CI buffer, γ-counter (P a ck
The radioactivity was measured by A r d 5650). [0057] The amount of specific binding to the CCK receptor was determined from the difference between the total binding amount and the amount of non-specific binding, and the ICbo value was calculated from the inhibition rate of the amount of specific binding by the test drug. [0058]

[Table 4] Compound [”51:] CCK-8 binding inhibition control C5, (μM) 32.4 61.7 71.7 15 7.3 18 (134190,32 20(LO29 210,40 220,12 233 ,3 240,044 250,049 260,025 272,2 280,21 292,3 304, ■ 31 2.0 32 0.29 33 3.4 [0059] Reference example 8 CCK antagonism in removed gallbladder [0060] Gallbladder strips from Hartley male guinea pigs were prepared, and Krebs (Krebs)
It was suspended with an initial tension of 1 g in a Magnus bath filled with bS) solution. Biological gas (95
Isobenign contractions of the muscle strips were recorded via a strain transducer while aerating with 2.5% CO2). 10-8
The antagonistic effects of various concentrations of the test drug on MCCK-8-induced gallbladder contraction were investigated, and IC50 values were determined. [00611

[Table 5] Compound C5゜(
μM) 18 6.8 19 2.1 20 16 21 2.9 22 2.8 [0062] Reference Example 9 Effect on amylase secretion from the living pancreas [006
3] Wistar male rats were treated with urethane (1°5g/k
G, S, C,) were anesthetized. After a tracheal cannula was attached, the abdomen was opened, a polyethylene tube was inserted and fixed into the common bile duct, and bile and pancreatic juice were collected at the same time. The test drug was administered into the duodenum, and 30 minutes later, CCK-810 was administered.
Amylase secretion was stimulated by subcutaneous administration of μg/kg, and the amylase concentration in samples collected for 30 minutes was measured (Amylase B Test Wako). The ED50 value was determined from comparison with the control group. [0064]

[Table 6] Inhibition of compound C[:ni-8-induced amylase secretion
EDs,, (mg/kg) 18 15.7 19 33.3 20 9.6 25 8, O [0065] Example 1 4-(N-tert-butoxycarbonylmethyl-Npentylcarbamoyl) -5-(2 -Naphthylsulfonyl)methyl pentanoate (Compound 1) [0066]
4-(N-tert-butoxycarbonylmethyl-N
-pentylcarbamoyl)-5-(2-naphthylthio)
Dry 2.96 g of methyl pentanoate with 100 g of methylene chloride.
m-chloroperbenzoic acid (8
After adding 3.67 g of 0%) little by little, the mixture was allowed to react at room temperature for 4 hours. After adding sodium sulfite to the reaction solution,
It was washed successively with an aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel flash column chromatography (
Elution solvent: After purification with ethyl acetate/hexane-1/2),
Recrystallized from isopropyl ether-hexane, melting point 8
2.97 g of methyl 4-(N-tert-butoxycarbonylmethyl-N-pentylcarbamoyl)-5(2-naphthylsulfonyl)pentanoate at a temperature of 5 to 87°C was obtained. [0067] Elemental analysis value: (as CHNDs) 8397 Calculated value 6%63.02. N%7.37. N%2
．． 62 actual value 6%62.75. N%7.24. N
%2.371-1 1R (KBr): v (C=0) 1730.1
650 cm; v (So > 1310.
1170 cmNMR (CDCI > δ: 0.85 and 0.90 (3H, t, J=7.
1Hz), 1. 1-1. 7 (15H, m)
, 1. 85~2゜45 (4H, m),
3. 05-4. 0 (9H, m). 4.07 and 4.29 (LH, d, J=16.5
Hz), 7. 55-7. 75 (2H, m)
, 7. 8~8゜05 (4H, m), 8
．． 49 (IH,s) [0068] Example 2 The compounds shown in Tables 7 to 10 were produced in the same manner as in Example 1. However, compounds whose specific rotation is not listed are racemic. [0069]

[Chemical formula 17] [00701

[Table 7] [0071]

[Table 8] [0073]

[0074] Example 3 N-[:2- (2-methoxycarbonylethyl-3-
(2naphthylsulfonyl)propionyl]-N-pentylglycine (Compound 15) [0075] 4- (N-tert-butoxycarbonylmethyl-N-pentylcarbamoyl)-5-(2-
0.47 g of methyl naphthylsulfonylpentanoate was dissolved in 5 ml of trifluoroacetic acid under water cooling, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel flash column chromatography (elution solvent:
Purified with chloroform/methanol (15/1) to give amorphous N-[2-(2-methoxycarbonylethyl)3-(2-naphthylsulfonyl)propionyl]-N
0.34 g of pentylglycine was obtained. [0076] IR(KBr): v (C=O
)1725.1630cm';v (SO
2) 1305.110 cm NMR (CDCl2) δ: 0.86 and 0.92 (3H, t, J=7.1
Hz), 1. 1-2. 45 (10H, m)
, 3. 1-3°9 (9H, m), 4.
13and4. 42 (LH, d. J=16.5Hz), 7. 6-8. 1
(6H, m). 8,48 (LH,s) [0077] Example 4 4- [N-(N,N-dimethylcarbamoylmethyl-
N-pentylcarbamoyl: methyl -5-(2-naphthylsulfonyl)pentanoate (compound 16) [00
78] N-(2-(2-methoxycarbonylethyl)
-3-(2-naphthylsulfonyl)propionyl]N-
Pentylglycine 100mg, dimethylamine hydrochloride 21
mg and 70 μl of triethylamine under stirring under water cooling.
In addition to 1 ml of N,N-dimethylformamide, 42 μl of diethyl phosphate cyanide was added, and the mixture was allowed to react at room temperature for 16 hours. Dilute hydrochloric acid was added to the reaction mixture, extracted with ethyl acetate, washed with an aqueous sodium bicarbonate solution and 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 (elution solvent: chloroform/methanol = 15/1) to obtain an oily 4-(N-(N,N-dimethylcarbamoylmethyl)- 95 mg of methyl N-pentylcarbamoyl)-5-(2naphthylsulfonyl)pentanoate was obtained. [0079] IR(neat): v (C=O
) 1735.1650cm'; v
(SO2) 1310°150cm NMR (CDC13) δ:0.88and0.90 (3H, t, J=6.6
Hz), 1. 15-1. 7 (6H, m)
, 1. 95~2°5 (4H, m), 2.
90. 2. 91. 2. 97and3, 02
(6H,s), 3. 1-4. 15 (9
H. m), 4.23 and 4.42 (LH, d, J=15
゜9Hz), 7. 55-7. 75 (2H,
m), 7. 85-8. 05 (4H, m)
, 8. 50 (LH,s) [00801 Example 5 The following compound was produced in the same manner as in Example 4. 4- [N-(N,N-diisopropylcarbamoylmethyl)-N-pentylcarbamoyl]-5-(2-naphthylsulfonyl)methyl pentanoate (Compound 17)
[0081] Properties: Oily IR (neat): v (C=O) 1730
．． 1640cm'; v (SO2) 130
5.1150cmNMR (CDC13) δ: 0. 8-2. 5 (25H, m),
3. 1-4. 5 (12H, m), 7. 6～
8. 1 (6H, m), 8. 46 and 8
．． 50 (LH,s) [0082] Example 6 4-CN-(3-methoxypropyl)-N-pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoic acid (Compound 18) (0083) 4-(N -(3-methoxypropyl)-
2.50 g of methyl N-pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoate was added to 30 m of ethanol.
1 and 5.1 ml of 1N sodium hydroxide aqueous solution.
was added and reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, acidified with dilute hydrochloric acid, 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.
2.15 g of 4-CN-(3-methoxypropyl)-N-pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoic acid having a melting point of 79-82°C was obtained. [0084] Elemental analysis value: (CHN [as IS) 5356 Calculated value 6%62.87. H%? , 39. N%2.
93 Actual value 6%62.57. H%7.28. N%
2.951-1 1R(KBr): ν(C=O) 1720.162
5C[ll; ν(SO) 1300.114
0cmNMR (CDCI>δ:0.86and0.90 (3H, t, J=7.
1Hz), 1. 1-2. 15 (10H, m
), 2. 38 (2H, t, J=6.6
Hz), 3. 0-3. 55 (11H, m)
, 3. 75-3. 95 (LH, m),
7. 55-7. 75 (2H, m), 7
．． 8-8. 05 (4H. m), 8.48 (IH, s) [0085] Example 7 4-(N-Ethoxycarbonylmethyl-N-pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoic acid (Compound 19) [0086] 200 mg of benzyl 4-(N-ethoxycarbonylmethyl-Npentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoate was added to 1 part of ethanol.
0 ml, 20 mg of 10% palladium on carbon was added, and hydrogenation was carried out at normal pressure for 60 hours. After removing the catalyst by filtration, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (elution solvent: chloroform/methanol = 10/1), and then recrystallized from isopropyl ether-hexane. 4-(N-ethoxycarbonylmethyl-N-pentylcarbamoyl-5 at 80°C)
170 mg of (2-naphthylsulfonyl)pentanoic acid was obtained. [0087] Elemental analysis value: ([) as INO3) 25357 Calculated value 0%61.08. H%6.7? , N%2
．． 85 Actual value 6%60J2. H%6,71. N%
2.68l-1 JR (KBr): ν(C=0) 1735.169
0. L630 crn; ! /<So)
1140 cn+NMR ([:D[:1) δ:0.86and0.89 (3H, t, J=7.
1Hz), 1. 1-1. 7 (9H, m)
, 1. 85-2. 2 (2H, m), 2.
3-2. 55 (2H, m), 3. 1-4
．． 1 (6H, m), 4.15and4.18 (
2H, q, J=7.1Hz), 4.22and4.40
(IH, d, J=17.0Hz), 7.
55-7. 75 (2H, m), 7. 8-8.
05 (4H, m), 8. 49 (IH,s
) [0088] Example 8 Compounds in Tables 11 to 14 were produced in the same manner as in Example 6 or 7. However, compounds whose specific rotation is not listed are racemic. [0089]

[Chemical formula 18] [00901

[Table 11] [0091] [Table 12] [0092]

[Table 13]

[0093]

[0094] Example 9 4-(N-ethoxycarbonylmethyl-N-pentylcarbamoyl')-5-(2-naphthylsulfonyl)pentanoic acid [0095] 4-(N-ethoxycarbonylmethyl-N- 50 mg of methyl (pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoate was dissolved in 0.3 ml of dry hexamethyltriamide phosphoric acid in an argon atmosphere, and 5 mg of lithium thiomethoxide was added thereto under stirring for 30 minutes.
The reaction was allowed to proceed for minutes at room temperature. Dilute hydrochloric acid was added to the reaction mixture, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by medium-pressure liquid column chromatography on silica gel (eluent: chloroform/methanol = 9/1), then recrystallized from isopropyl ether-hexane to obtain 4-(N-ethoxycarbonyl). 23 mg of methyl-N-pentylcarbamoyl), -5-(2-naphthylsulfonyl)pentanoic acid was obtained. The physical properties of this product were the same as those of Compound 19 obtained in Example 7. [0096] Example 10 Sodium (R)-4-(N-(3-methoxypropyl)-N-pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoate (Compound 34) [0097
]-(-)-4-[:N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-
naphthylsulfonyl)pentanoic acid (compound 22)4. O
Og was dissolved in 40 ml of ethanol, and 8.39 ml of 1N aqueous sodium hydroxide solution was added dropwise to the solution under water-cooling and stirring, followed by concentration under reduced pressure at an external temperature of 35°C. Furthermore, the residue contains water/
40 ml of ethanol (1/1) was added, and the mixture was concentrated under reduced pressure at an external temperature of 35°C. Add 40m of isopropyl ether to the residue.
1 was added to crystallize the hygroscopic (R)-4-[N-(3
-methoxypropyl)-N-pentylcarbamoyl)-
3.90 g of sodium 5-(2-naphthylsulfonyl)pentanoate was obtained. [0098] Example 11 (R)-4-(N-(3-methoxypropyl)-N-pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoic acid L-arginine salt -hydrate (Compound 3
5) [0099] (-)-4-[:N-(3
-methoxypropyl)-N-pentylcarbamoyl]-
5-(2-naphthylsulfonyl)pentanoic acid (compound 2
2) Add 7.80 g and 2.84 g of L-arginine to a mixture of 19.5 ml of ethanol and 1.2 ml of water at an external temperature of 4.
It was heated to 0°C to melt it. Insoluble debris was removed by filtration, washed with a mixture of 7 ml of ethanol and 1.3 ml of water, and the filtrate and washing liquid were combined and allowed to stand at room temperature. The precipitated crystals were collected by filtration, and the melting point was 123.
9.80 g of (R)-4-[N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-naphthylsulfonyl)pentanoic acid L-arginine salt hydrate at ~126°C was obtained. .

Elemental analysis value: (as CHNDS) 315159 Calculated value 0%55.59. H%? ,67, N%1
0.46 Actual value 0%55,43. H%7.63.
N%10.45 Specific optical rotation: [αl] -3,86
([=l, O[), HO)2 [0101]

Effects of the Invention The naphthylsulfonylalkylcarboxylic acid derivative represented by the general formula (I) of the present invention has a competitive carbon
It shows CK receptor antagonistic action and suppresses gallbladder contraction and secretion caused by CCK. [0102] For example, CCK-8 labeled 125■
In a binding assay (Binding As5ay) for the CCK receptor in isolated rat pancreas using 2x10-8 to 7x10-6 molar concentration, it exerts an inhibitory effect of about 50%. In addition, in a gallbladder contraction inhibition test using CCK-8 in removed guinea pig gallbladders,
It exerts an inhibitory effect of about 50% at a concentration of about 10-6 molar,
In the amylase secretion inhibition test in rats, 8-33
Intraduodenal administration of about mg/kg exerts an inhibitory effect of about 50%. [0103] Thus, the compounds of general formula (I) of the present invention have competitive CCK receptor antagonism, e.g.
Since it suppresses gallbladder contraction and amylase secretion caused by CK, it is useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis.

Claims (7)

[Claims] Claim 1: General formula [1] (R1 in the formula is a hydrogen atom, a carboxy group, and has 2 to 7 carbon atoms.
an alkoxycarbonyl group, N-monosubstituted or N. N-disubstituted carbamoyl group, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, R2 is an alkyl group having 1 to 10 carbon atoms, and R3 is a hydrogen atom, and R3 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms; is an alkyl group or benzyl group, Y is alkylene having 1 to 4 carbon atoms, and n is 1 or 2), and pharmacologically acceptable salts thereof . [Claim 2] General formula [2] (in the formula, R4 is an alkyl group having 4 to 7 carbon atoms, and R1
, R3, Y and n have the same meanings as defined above) and their pharmacologically acceptable salts. 3. The naphthylsulfonylalkylcarboxylic acid derivative according to claim 2, represented by the general formula [3] (in which R1, R3, R4 and Y have the same meanings as above) and their pharmacological effects. Salt allowed in. [Claim 4] General formula [4] (R1, R3 and Y in the formula have the same meanings as above)
The naphthylsulfonylalkylcarboxylic acid derivative according to claim 3, which is represented by: and a pharmacologically acceptable salt thereof. 5. The naphthylsulfonylalkylcarboxylic acid derivative according to claim 4 represented by the general formula [5] (in which R1 and Y have the same meanings as above) and pharmacologically acceptable thereof. salt. 6. The naphthylsulfonylalkylcarboxylic acid derivative according to claim 5, represented by the formula [6], and a pharmacologically acceptable salt thereof. [Claim 7] Formula [7] (In the formula, the carbon atom with (R) has the configuration of (R), and the carbon atom with (S) has the configuration of (S). 7. The naphthylsulfonylalkyl carboxylic acid salt according to claim 6, which is represented by: