JPH0436268A - Phenylsulfinylalkylcarboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R<1> and R<2> are 1-10C alkyl; R<3> is H or 1-4C alkyl; X is 1-3C alkyl or nitro; (n) is 1-or 2). EXAMPLE:Methyl 5-(3,4-dimethylphenylsulfinyl)-4-(N,N-dipentylcarbamoyl) pentanoate. USE:A drug having competitive cholecystokinin antagonism and useful as a preventive and therapeutic agent for diseases such as hypersensitivity colitis, biliary dyskinesia, acute pancreatitis, etc. PREPARATION:A compound shown by formula II is subjected to react with a compound shown by formula III (A and B are cyano, 2-5C alkoxycarbonyl, etc.) and then with an amine shown by formula IV to form a new compound shown by formula V (R<4> is 1-4C alkyl) as a starting raw material, which is oxidized with an oxidizing agent such as m-chloroperbenzoic acid in a solvent such as methylene chloride under cooling to give a compound shown by formula I where R<3> is 1-4C alkyl.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to phenylsulfide (in the formula, R1 and R2 may be the same or different, and each is an alkyl group having 1 to 10 carbon atoms), which is useful as a pharmaceutical. , R3 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and X is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
-3 alkyl groups and nitro groups, n is 1 or 2).

Conventional technology CCK contains gastrin, secretin (
It is a typical gastrointestinal hormone along with secretion (secret in), and is known to be particularly involved in stimulation of extramembranous secretion, contraction of the gallbladder, etc.

In recent years, research on CCK has progressed, and the involvement of CCK in various diseases has been elucidated.

As a result, specific, competitive, and reversible CCK receptor antagonists are expected to be used as preventive and therapeutic agents for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis, and are attracting attention.

Since it was reported that proglumide represented by the formula, which is used as a peptic ulcer treatment agent, exhibits CCK receptor antagonistic activity, research on progelmide derivatives has progressed, and several studies have been conducted so far. C
Compounds with CK receptor antagonism have been produced and reported (Japanese Patent Application Laid-Open Nos. 61-44855 and 62-1812).
46, 63-27468, 63-165352, 63-201156, εP-AI-0308885, B
P-A2-0272228, Wo 87103869,
88105774, 89102431>.

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

Problems to be Solved by the Invention An object of the present invention is to provide phenylsulfinyl alkylcarboxylic acid derivatives that have CCK receptor antagonistic activity and are useful as preventive and therapeutic agents 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 research to find new compounds with CCK receptor antagonism, the present inventors found that certain phenylsulfinyl alkyl carboxylic acid derivatives have strong CCK receptor antagonistic properties.
The present inventors have discovered that it has receptor antagonistic activity and is useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis, leading to the present invention.

The phenylsulfinyl alkylcarboxylic acid derivative represented by the general formula (1) of the present invention has CCK receptors.
It competitively antagonizes the binding of CK-8 and is useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis.

The phenylsulfinylalkylcarboxylic acid derivative represented by the general formula (1) of the present invention is a new compound, and can be produced as follows, by oxidizing the phenylthioalkylcarboxylic acid derivative represented by It can be produced by separating the mer and then hydrolyzing it if necessary.

The compound of general formula (1) used as a starting material in the method for producing a compound of general formula (I) of the present invention is a new compound, and can be produced as follows.

That is, a thiophenol transparent conductor represented by the general formula (in which χ and n have the same meanings as above), and a thiophenol transparent conductor represented by the general formula (in which R4 is an alkyl group having 1 to 4 carbon atoms, R1, R'' (X and n have the same meanings as above) (A and B in the formula are each a cyano group or an alkoxycarbonyl group having 2 to 5 carbon atoms, or A is an alkoxycarbonyl group having 2 to 5 carbon atoms) A conductor of the general formula and a compound represented by the general formula (AXB, X and n has the same meaning as above)
A compound represented by the formula (R4, X and n in the formula have the same meanings as above) is prepared by hydrolyzing and monoesterifying it by an appropriate method as necessary. A compound is obtained.

Then, a compound of general formula (I) can be produced by reacting this compound or an amine represented by its reactive functional derivative (in the formula, R1 and R2 have the same meanings as above). .

In order to suitably carry out the method for producing the compound of the general formula (1) of the present invention, the compound of the general formula (I) is dissolved in an inert organic solvent such as methylene chloride, and an equimolar to slightly excessive amount of the compound is dissolved under cooling. , preferably 1.2 times the molar amount of oxidizing agent, e.g. m-
Add chloroperbenzoic acid and let cool for 2 to 3 minutes at room temperature.
After the reaction is completed, the mixture is stirred for a period of time, and after completion of the reaction, the mixture is treated and purified according to a conventional method to obtain a compound of general formula (I) in which R3 is a lower alkyl group. Next, this is hydrolyzed according to a conventional method to obtain a compound of general formula (I) in which R3 is a hydrogen atom.

The phenylsulfinyl alkylcarboxylic acid derivative represented by the general formula (r) of the present invention has an asymmetric carbon and an asymmetric sulfur, and there are four types of optically active forms, but in the present invention, the H form, Any of the SS form, R5 form, SR form, or a mixture thereof can be used.

Furthermore, the carboxylic acids in which R3 is a hydrogen atom in the compound of general formula (I) of the present invention can be converted into pharmacologically acceptable salts according to conventional methods. Such as, for example, inorganic salts such as sodium salts, calcium salts, etc.
Organic salts such as morpholine salts, piperidine salts or salts with amino acids can be mentioned. 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.

When the phenylsulfinyl alkylcarboxylic acid derivative represented by the general formula (I) of the present invention is used as an actual therapeutic agent, it can be administered orally as a suitable pharmaceutical composition, such as a tablet, powder, granule, capsule, injection, etc. Administered locally or parenterally. These pharmaceutical compositions are prepared by conventional pharmaceutical techniques.

The dosage is determined appropriately depending on the gender, age, weight, type of disease, severity of symptoms, etc. of the target patient, but for oral administration it is approximately 1 to 1000 mg per day for adults, and for parenteral administration it is approximately 0 mg per day. It is administered within the range of .1 to 100 ■.

EXAMPLES The contents of the present invention will be explained in further 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.

Reference example 1 3.4-dimethylbenzenethiol 059m7! and 2-
0.48 ml of methylene geltalonitrile was dissolved in 10 mN of ethanol, 5 drops of Triton B (40% methanol solution) were added, and the mixture was heated under reflux for 5 hours. The reaction solution was concentrated under reduced pressure, extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (eluent: benzene/ethyl acetate = 7/1) to obtain oily 2-(3,4 dimethylphenylthiomethyl). 1.18 g of geltalonitrile was obtained.

IR(neat): νc-2230cm-'NM
R(CDCl2) δ: 1.9-2.35 (8H, m), 2.45-2
．． 7 (2H.

m), 2.85-2.9 (IH, m), 2.98 (
LH, dd.

J=7.7.13.7Hz), 3.18(1)1.
dd, J=6.6°13.7Hz), 7.11(L
H, d, J=7.7Hz), 7.19(LH, dd
, J=1.7.7.71(z), 7.24(If(
, d.

J4.7Hz) Dissolve 1.16 g of 2-(3,4-dimethylphenylthiomethyl)glutaroni)lyl in 8d2 of acetic acid, and add 8-d2 of concentrated hydrochloric acid.
was added and heated under reflux for 19 hours. The reaction solution was concentrated under reduced pressure, diethyl ether was added, insoluble matter was 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 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 obtain 1.18 g of 2-(3,4-dimethylphenylthiomethyl)glutaric acid having a melting point of 96 to 98°C.

Elemental analysis value' (as CI48IBO4S) 0%
H% Calculated value 59.55 6.43 Actual value 59.38 6.56 IR (KBr): ShiC-0 1705 cmNM
R(DMSO-66) δ: 1.65 to 1.95 (2) 1. m), 2.1
~2.55 (9H, m) 3.04 (2) 1. d, J
=7.2Hz>, 7.0~7.2<3Nm), 12
．． 28(2H,5) 1.16 g of 2-(3,4-dimethylphenylthiomethyl)glutaric acid was dissolved in 20 me of methanol, 0.04 g of p-)luenesulfonic acid was added, and the mixture was stirred at 40°C.
The reaction was allowed to proceed for 5 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by silica gel flash column chromatography (elution solvent: chloroform/ethanol = 10/1) to obtain oily 2-(3,4-dimethylphenylthiomethyl).
0.98 g of -4-methoxycarbonylbutyric acid was obtained.

rR(neat): shi c-0 1735. 170
5 Cm' NMR (CDCl2) δ: 1.9-2.5 (10 fl, m), 2.55
~2.7 (IH, m).

2.94(1)t, dd, J=6.6. 13.7
)1z), 3.19 (1N, cod, J=7.7.
13.7 Hz), 3.65 (3) 1 s).

7.06(1)1. d, J=7.7flz), 7
．． 1 to 7.2 (2) 1 mm) Reference Example 2 The compounds shown in the table (oil) were produced in the same manner as in Reference Example 1.

Reference Example 3 0.50 g of 2-(3,4-dimethylphenylthiomethyl)-4-methoxycarbonylbutyric acid was added to 6ff of dry benzene.
It was dissolved in Li2, 0.2 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. Dry this residue in methylene chloride 4rR1
The solution was added dropwise to a solution of 0.35 otl of dipentylamine and 0.3 liter of triethylamine in 2 d of dry methylene chloride while cooling with water and stirring, and the mixture was reacted at room temperature for 5 hours.

The reaction solution was washed successively with dilute hydrochloric acid, water, an aqueous solution of hydrogen carbonate, and water, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (elution solvent: chloroform) to obtain an oily 5-(3,4-dimethylphenylthio)-4-(N,N~dipentyl). 0.76 g) methyl hentanoate (rubamoyl) II).

IR(neat): v. 1730. 1635
cm-'NMR (CDC13) δ: 0.84 (3) 1. t, J=6.6)
1z), 0.89 (3N, t, J=6.6
)1z), 0.95 to 1.6 (12H, m), 1.
95-2.1 (2H, m), 2.15-2.5 (8
H, m), 2.8-3.4 (7H, m), 3.
65'(3H,s), ? , (1-7,2(3H.

m) Reference example 4 The compounds shown in the table (oil) were produced in the same manner as in Reference Example 3.

~1cH2) 4CH3 Reference Example 5 Pancreatic 11ccK receptor binding test Method of Chang et al. [Molecular Pharmacolo
A pancreatic tissue membrane specimen was prepared according to [Gy) Vol. 3Q, p. 212, 1986]. Wistar
The pancreas was removed from male rats of the ) strain, the adipose tissue was removed, and the pancreas was incubated with 50 times the wet weight of water-cooled 50 mM) squirrel (Tri).
s) After being shredded in HCI buffer (pH 7, 4, 37°C), it was homogenized using an ultradisperser. The homogenate was centrifuged at 50,000 x g for 10 minutes, and the pellet was suspended in Tris-HCI buffer and centrifuged again at 50,000 x g for 10 minutes. Analysis buffer (50mM) +) x HCL 5
mM MgCL, 5 mM dithiothreitol, 2 mg
The precipitate was resuspended in 0.14 mg/rnl bovine serum albumin, 0.14 mg/rnl bacitracin, and used as CCK binding test material.

Pancreatic tissue membrane suspension (usually 0.5 ■ original tissue weight/-), 3
0 pM [''I) CCK-8 and test drug or its solvent (for total binding), 10-'M CCK-8
(Add the non-specific binding agent to the analysis buffer and make the total volume lff.
+7! Closed.

After incubating for 30 minutes at 37°C, the sample was filtered by suction, and the filter was washed with ice-cold Tris-HCI buffer.
The radioactivity was measured using a counter (Packard 5650).

The amount of specific binding to the CCK receptor was determined from the difference between the total binding amount and the non-specific binding amount, and the IC5o value was calculated from the inhibition rate of the specific binding amount by the test drug.

1.6 0.13 Example 1 5 (3,4-dimethylphenylsulfinyl)-4(
N,N-dibentyl(rubamoyl)methidipentanoate=. 1045 crn-' 5-(3,4-dimethylphenylthio)-4-(N,
Methyl N-dipentyl(rubamoyl)pentanoate 0.
55g dry methylene chloride 10m7! Dissolve in -78
0.31 m-chloroperbenzoic acid (70%) under stirring at °C.
g was added little by little, and the mixture was allowed to react for 3 hours. After adding sodium sulfite to the reaction solution, it was washed with an aqueous sodium bicarbonate solution, washed with water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (elution solvent: benzene/ethyl acetate = 2/1), and the 5-(3,4-
0.12 g of methyl (dimethylphenylsulfinyl)4-(N,N-dipentylcarbamoyl)pentanoate (diastereomer A) and diastereomer B eluted later.
6 g of OJ was obtained.

[Diastereomer A]

Properties: Oil IR (neat): C-01730.1630c
m-'NMR (CDCl2) δ: 0.90 (311, t, J=6.6H2),
0.93(3)1. t, J=6, 6Hz)
, 1.1-2.45 (22H, m), 2.76
(1) 1°dd, J=3.3. 12.1Hz),
3.1-3.5 (6H, m>.

3.65 (3H, s), 7.2-7.45 (3H,
m) [Diastereomer B] Properties: Oil IR (neat): c-01735.1635 c
m−ν,. 1045 cm” NMR (CDCl2) δ: 0.87 (3H, t, J=7.1flz),
0.93 (3H, t, J7, IHz), 1.15~
1.65 (12) 1. m), 2.1 to 2.5 (IO
H, m), 2.82 (LH, dd, J=9.313
．． 2Hz), 2.97 (1B, dd, J=3.8
．． 13.2Hz).

3.1~3.45 (5ft, m), 3.68 (3H
, s), 7.2-7.45 (3H, m) Example 2 The compounds shown in the table (oil) were produced in the same manner as in Example 1.

Example 3 5 (3,4-dimethylphenylsulfinyl)-4(
Methyl N,N-dipentyl-rubamoyl)pentanoate (
Diastereomer A) 120 (1) was dissolved in ethanol 3-, 0.28 d of a 1N aqueous sodium hydroxide solution was added, and the mixture was reacted at room temperature for 16 hours. After concentrating the reaction solution under reduced pressure,
The mixture was made acidic by adding dilute 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 subjected to phosphoric gel flash column chromatography (elution solvent: chloroform/ethanol = lO/
5-(3,4-dimethylphenylsulfinyl)-4-(N,N-dipentylcarhamoyl)pentanoic acid (diastereomer A
) 90 ■ was obtained.

Elemental analysis value: (as C24H3, NO, S) 0%
8% N% Calculated value 65.87 8.98 3.20 Actual value 65.52 9.24 3.19IR
(KBr): νc+0 1720. 1630
cmN! , IR (CDCl2) δ: 0 90 (6H, t, J=6.6Hz),
1.2-2,15 (14HmL 2.25-2.
4 (8H, m), 2.90 (IHdd, J=3
．． 3. 12.1Hz), 3.1-3.5 (6H.

m), 7.2 -7.45 (3,H,m) Example 4 The compounds shown in the table were produced in the same manner as in Example 3.

''(CH214CH3 Effect of the Invention The phenylsulfinyl alkylcarboxylic acid derivative represented by the general formula (I) of the present invention exhibits competitive CCK receptor antagonism.

For example, binding T to the CCK receptor of isolated rat pancreas using CCK-8 labeled with 125I.
In Binding As5ay, 1
Approximately 50% at a molar concentration of X1fll-7 to 6X10-6
exerts a suppressive effect.

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

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (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, x is a group selected from an alkyl group having 1 to 3 carbon atoms and a nitro group, and n is 1 or 2). Phenylsulfinyl alkylcarboxylic acid derivatives.