JPH0495062A - Naphthylthioalkylcarboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A naphthylthioalkylcarboxylic acid derivative expressed by formula I (R<1> is H, carboxy, 2-7C alkoxycarbonyl, N-monosubstituted or N, N-disubstituted carbamoyl, 1-6C alkyl or 1-6C alkyl; R<2> is 1-10C alkyl; R<3> is 1-4C alkyl or benzyl; Y is 1-4C alkylene; n is 1 or 2). EXAMPLE:Methyl 4-(N, N-dibentylcarbamoyl)-5-(2-naphthylthio) pentanoate. USE:Useful as a synthetic intermediate of a naphthylsulfonylalkylcarboxylic acid derivative useful as a preventive or a remeby of disease such as hypersensitive colitis, biliary dyskinesia or acute pancreatitis, with exhibiting antagonism against cholecystokinin receptor. PREPARATION:A new compound expressed by formula II is reacted with amines expressed by formula III to afford the compound expressed by formula I. The compound expressed by formula II is synthesized from a compound expressed by formula IV and a compound expressed by formula V (A and B are cyano, etc.).

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention is directed to a chemical compound useful as an intermediate for the production of pharmaceuticals, a shipman (where R1 is a hydrogen atom, a carboxy group, and has 2 to 7 carbon atoms).
alkoxycarbonyl group, N-monosubstituted or N,N
- is a disubstituted carbamoyl group, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, 1112 is an alkyl group having 1 to 10 carbon atoms, and R3 is an alkyl group having 1 to 4 carbon atoms.
is an alkyl group or benzyl group, and Y has 1 to 1 carbon atoms.
4 alkylene group, and n is 1 or 2).

(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, alkyl group having 1 to 6 carbon atoms, or alkoxy group having 1 to 6 carbon atoms, R2 is an alkyl group having 1 to 10 carbon atoms, and R3 is an alkyl group having 1 to 4 carbon atoms or benzyl Y is an alkylene group having 1 to 4 carbon atoms, and n is 1 or 2).

More specifically, the present invention provides cholecystokinin (
cholecystokinin (hereinafter referred to as CCK) receptor antagonistic activity, and is useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis. -4 alkyl group or benzyl group, Rl, R2, Y and n have the same meanings as above), represented by the general formula (1) useful as an intermediate for the production of naphthylsulfonylalkylcarboxylic acid derivatives This invention relates to naphthylthioalkylcarboxylic acid derivatives.

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 exocrine pancreas, contraction of 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.

Problems to be Solved by the Invention The object of the present invention is to provide the above-mentioned Funenin (II) which has a CCK receptor antagonistic effect and is useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis. An object of the present invention is to provide a naphthylthioalkylcarboxylic acid derivative represented by the above-mentioned -Funenin (1), which is useful as an intermediate for the production of the represented naphthylsulfonylalkylcarboxylic acid derivative.

Means for Solving the Problems The naphthylsulfonylalkylcarboxylic acid derivative represented by Saijin (II) has a strong CCK receptor antagonistic effect and is effective against diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis. Useful as a prophylactic and therapeutic agent.

The naphthylthioalkylcarboxylic acid derivative represented by the above-mentioned shipman (I) of the present invention can be obtained very easily in yield by oxidizing it with an appropriate oxidizing agent and hydrolyzing or hydrogenolyzing it as necessary. This can easily lead to the compound of the above-mentioned shipman (II).

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

That is, it can be produced by reacting with amines represented by -funerin.

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

That is, 2-naphthalenethiol represented by the formula; a naphthylthioalkylcarboxylic acid derivative represented by -Funenin (R3 and n in the formula have the same meanings as above) or a reactive functional derivative thereof; - Boatman (R1, R2 and Y in the formula have the same meanings as above) (A and B in the formula are each a cyan group or an alkoxycarbonyl group having 2 to 5 carbon atoms, or A is a carbon number 2 group) ~5 alkoxycarbonyl group, B is a carboxyl group or an alkali metal salt thereof, and n has the same meaning as above) in the presence of a Lewis base or Lewis acid catalyst,
- It can be obtained by preparing a compound represented by Shipin (in the formula, ASB and n have the same meanings as above), and subjecting it to hydrolysis and monoesterification by an appropriate method as necessary. .

The naphthylthioalkylcarboxylic acid derivative represented by the general formula (1) of the present invention has an asymmetric carbon and exists in two types of optical isomers. Any mixture is included.

Effects of the Invention The naphthylthioalkylcarboxylic acid derivative represented by the general formula (I) of the present invention is oxidized using a suitable oxidizing agent, for example, m-chloroperbenzoic acid, and if necessary, hydrolyzed or hydrolyzed. By hydrogenolysis, the naphthylsulfonylalkylcarboxylic acid derivative represented by the general formula (II) can be easily led to a high yield at extremely low temperatures.

In this way, the compound represented by the general formula (I[) produced from the compound of the general formula (1) of the present invention has a CCK receptor antagonistic effect, and can be used to treat irritable colitis, biliary dyskinesia, etc.
It is useful as a therapeutic agent for diseases such as acute pancreatitis.

For example, (R)-4-(N-(3-methoxypropyl)
-N-petylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoic acid was detected at a molar concentration of 1.2 x 10-' in a binding assay for CCK receptors in isolated rat pancreas using CCK-8 labeled with 125. % binding inhibition (IC, .) in a gallbladder contraction inhibition test using CCK-8 in a guinea pig removed gallbladder.
．． It shows 50% inhibition (IC,.) at 8 x 10-6 molar concentration.

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 2-naphthalenethiol 4-methoxycarbonyl-2-(2-naphthylthiomethyl)butyrate 10. Og and 6.8 ml of 2-methylene geltalonitrile were dissolved in 150 mN of ethanol, 10 drops of Triton B (40% methanol solution) were added, and 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 distilling off the solvent under reduced pressure, the residue was recrystallized from acetate-chlorohexane to give 2.
-(2-naphthylthiomethyl)geltalonitrile 15.
6g was obtained.

Elemental analysis value' (as C16)11-N2S)0
% H% N% Calculated value 72.15 5.30 10.52 Actual value 71.98 5.24 10.411R
(KBr): I/CM 2245 cm-'N
MR (CDC13) δ: 1.95~2.3 (2fl, m), 2.4~
2.7 (2H, m).

2.8-2.95 (LH, m), 3.13 (1) 1.
dd, J=7.1. 13.7Hz), 3.3
0 (IH, dd, J=6.6°13.7Hz),
7.4-7.6 (3H, m), 7.75-80 (4H
, m) 2-(2-naphthylthiomethyl)geltalonitrile 15
．． Dissolve 5g in 70mN of acetic acid, add 70m of concentrated hydrochloric acid, and add 1
The mixture was heated under reflux for 7 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.
15.9 g of 2-(2-naphthylthiomethyl)glutaric acid having a melting point of 140-142°C was obtained.

Elemental analysis value: (C,6)1,504S)0
% H% Calculated value 63.14 5.30 Actual value 63.37 5.34 JR (KBr): C-Cl 1720 cm
-'NMR (DMSO-66) δ: 1.7~2.0 (2H, m), 2.15~
2.4 (2H, m) 2.5 to 2.65 (LH, m),
3.1-3.4 (2H, m).

7.35-7.6 (3H, m), 7.75-8.0
(4H, m).

12,32 (2H,5) 2-(2-naphthylthiomethyl)glutar was dissolved in 300 d of methanol and added with p-toluenesulfone. After concentrating the reaction solution under reduced pressure, water was added to the residue, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from isopropyl ether to give 4-methoxycarbonyl-2 having a melting point of 70-71°C.
27.4 g of -(2-naphthylthiomethyl)butyric acid was obtained.

Elemental analysis value' (as CI7811+04S) 0
% H% Calculated value 64.13 5.70 Actual value 64
．． 11 5.50IR (KBr): ν(
+Q 1730. 1700 cm-'NMR (
CDCl2) δ: 1.95-2.2 (2N, m), 2.
3-2.5 (28, m).

2,65 ~2.8<LH, m), 3.10(
11(, dd, J=6, 6. 13.2H
z), 3, 33 (IH, dd, J=7,713
, 2Hz), 3.62 (3H, s), 7.
4 ~ 7.55 (38m), 7.7 ~ 7.9 (4
H, m) Reference Example 2 10.00 g of (±)-4-methoxycarbonyl-2-(2-naphthylthiomethyl)butyric acid was added to 20 m7 of ethanol.
! Heat and dissolve in a mixture of 5rn1 of methanol and (+
)-1-phenylethylamine (3.80 g) was added, and the mixture was allowed to stand at room temperature, and the precipitated crystals were collected by filtration. The obtained crystals were further heated and dissolved in a mixture of 9 ml of ethanol and 3 ml of methanol, and after being left at room temperature, the precipitated crystals were collected by filtration to give (R)-
4-Methoxycarbonyl-2-(2-naphthylthiomethyl)butyric acid and (+)-1-phenylethylamine salt 2
, 88g was obtained. 10 m of 2N hydrochloric acid to 0.72 g of this salt
The mixture was 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 (
0.37 g of R)-4-methoxycarbonyl-2-(2-naphthylthiomethyl)butyric acid was obtained.

Specific optical rotation: [αL +46.8° (Cm1.50,
MeOH)IR (KBr): νc+o 1
740, 1725, 1690 Cm-'NMR (
CDCl2) Same as the racemate On the other hand, after concentrating the first solution of the salt with (+)-1-phenylethylamine, the residue was recrystallized three times from ethanol to obtain (S)-4-methoxycarbonyl. −
1.04 g of a salt of 2-(2-naphthylthiomethyl)butyric acid and (+)-1-phenylethylamine was obtained. This salt 0
．． 2N hydrochloric acid 15ff+7 for 90g! was added, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate.

After distilling off the solvent under reduced pressure, the residue was recrystallized from isopropyl ether to give (S)-4-methoxycarbonyl 2-(
0.46 g of 2-naphthylthiomethyl)butyric acid was obtained.

Specific optical rotation: [(X) D- 45.6° (Cm1.
07, MeOH) melting point, IR and NMR were consistent with the (R) form.

Reference example 3 2-(2-naphthylthiomethyl)glutaric acid 14.0g
was dissolved in 180 mj of acetonitrile, 57 mj of benzyl alcohol and 0.0 mj of p-)luenesulfonic acid.
52 g was added and 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: methylene chloride/methanol =
70/1) and recrystallized from ethyl acetate-hexane to give 4-benzyloxycarbonyl-2-(2-naphthylthiomethyl)butyric acid 11. Obtained Og.

Elemental analysis value: (as C23H2□04S) 0%
H% Calculated value 70.03 5.62 Actual value 70
．． 05 5.69IR (KBr): vc-
o 1730. 1700 cmNMR (CDCl
2) δ: 1. 'lJ~2.2 (2H, m), 2.3
~2.55 (28, m).

2.65-2.8 (IH, m), 3.09 (1) 1
．． dd, J6.6. 13.2)1z),
3.26 (1'H, dd, J=7.7°13.2)
1z), 5.09(2)1. s), 7.2
~7.5 (8fl.

m), 7.65-7.85 (4H, m) Reference example
4 0.38 g of 2-naphthalenethiol and 0.39 g of sodium 3-methoxycarbonyl-2-methylenepropionate
Dissolve g in methanol 20mN, Triton B (40
% methanol solution) were added thereto, and the mixture was heated under reflux for 12 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. 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 chloroporum/meth/-ol = 20/1), it was recrystallized from isopropyl ether to give 2.
0.38 g of -methoxycarbonylmethyl-3-(2-naphthylthio)propionic acid was obtained.

Elemental analysis value' (as C+gH1604S) 0%
H% 63.14 5.30 63.12 5.27 c+o 1735.1700 cm Calculated value Actual value IR (KBr): NMR (CDCl2) δ: 2.7-2.9 (2H, m), 3. 0 to 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) Example 4-Methoxycarbonyl-2-(2-naphthylthiomethyl)butyric acid 4. Dissolve Og in 80 mN of dry methylene chloride and add 4.0 mN of thionyl chloride. Oml 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 20 ml of dry methylene chloride was dissolved in 3.5 ml of dipentylamine and 5.4 ml of triethylamine.
The mixture was added dropwise to an 80 mA solution of dry methylene chloride under water cooling and stirring, and then reacted at room temperature for 16 hours. The reaction solution was washed successively with dilute hydrochloric acid, water, hydrogen carbonate aqueous solution, and water, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by medium pressure liquid column chromatography on silica gel (elution solvent: methylene chloride) to obtain an oily 4-(N,N dibentylrubamoyl)-5-(
5.1 g of methyl 2-naphthylthio)pentanoate was obtained.

IR(neat)' vc-o 1735.164
0 cm-'NMR (CDC13) δ: 0.66 (3) 1. 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), 3.63 (
3)1. s).

7.4-7.55 (3H, m), 7.7-7.85 (
4H, m) Example 2 The compounds shown in the table (oil) were produced in the same manner as in Example 1.

However, compounds whose specific rotation is not listed are racemic.

Reference Example 5 42.7 g of methyl (R)-4-[N-(3-methoxypropyl)-N-pentylcarbamoyl)-5-(2-naphthylthio)pentanoate was dissolved in 500 g of dry chloroform and stirred under water cooling. m-ri four mouth perbenzoic acid (80%)
After adding 50 g little by little, the mixture was reacted at room temperature for 2 hours. After adding sodium sulfite to the reaction solution, the mixture was washed successively with an aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an oily (R)-
42.0 g of methyl 4-[N-(3-methoxypropyl)-N-pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoate was obtained.

Specific optical rotation: [α) n” 9.4° (C=1.1
5. MeOH)IR(neaj)=I'c-o 1
730.1630 cm-'νso 1305.11
50 (m-1 HMR (CDCl2) δ: 0.86 and 0.92 (3H, t,
J=6.9Hz), 1 1~2.1(IOH,
m), 2.25-2.4 (2H, m), 3.0
~3.5 (IIH, m), 3.63 and
3.64(3)1. s) 3.84 and 3
．． 90(1)1. dd, J=7.9°13.9
Hz), 7.55-7.7 (2H, m), 7.
8-8, 05 (4H, m), 8.48 (IH, 5)
42.0 g of methyl (R)-4-[N-(3-methoxypropyl)-N-pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoate was added to 460 mg of methanol.
The mixture was dissolved in a mixed solution of 150 mi2 of water and 86 mN of a 1N aqueous sodium hydroxide solution was added dropwise thereto, followed by reaction at room temperature for 3 hours.

The reaction solution was adjusted to pH 4 by adding diluted hydrochloric acid, and then concentrated under reduced pressure. Water was added to the residue, 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-isopropyl ether to give (R)-4-[N-(3-methoxypropyl)-N-pentylcarbamoyl]- with a melting point of 68 to 70°C. 5-
29.4 g of (2-naphthylsulfonyl)pentanoic acid was obtained.

Elemental analysis value: (as C2SH3SNO6S) 0%
N% N% Calculated value 62.87 7.39 2.93 Actual value 62.64 7.17 2.90 Specific optical rotation: [αL-24.5° (C = 1.47° dioxane) IR (Kart: vc-o 1730.164
0 cm-'ν,. 1305.1150 cm-'N
MR (CDC13) δ: 0.86 and 0.90 (3H, t, J
=7.1Hz), 1.1~2, 15 (10ft,
m), 2.38 (2H, t, J=6.6Hz).

3.0-3.55 (11)1. m), 3.75
~3.95 (IH.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (R^1 in the formula is a hydrogen atom, a carboxy group, a carbon number of 2 to
7 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, R^2 is an alkyl group having 1 to 10 carbon atoms, and R^3 is an alkyl group having 1 to 10 carbon atoms.
4 alkyl group or benzyl group, Y has 1 carbon number
~4 alkylene group, n is 1 or 2).