JPH07119207B2 - Phenylthioalkylcarboxylic acid derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a general formula useful as an intermediate for the manufacture of pharmaceuticals. (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, and X is a carbon atom. Number 1
~ 3 is a group selected from an alkyl group, a nitro group, and an acetyl group, and n is 1 or 2), and a phenylthioalkylcarboxylic acid derivative.

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. (In the formula, Y is a sulfonyl group or a sulfinyl group, and R ¹ , R ² , X, m and n have the same meanings as described above.)
The present invention relates to a phenylthioalkylcarboxylic acid derivative represented by the general formula (I) which is useful as an intermediate for the production of phenylsulfonylalkylcarboxylic acid derivatives and phenylsulfinylalkylcarboxylic acid derivatives.

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 SCK in various diseases has been investigated.
The involvement of SK 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.

The object of the present invention is to have a CCK receptor antagonistic action, in the general formula (II) useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, acute pancreatitis and the like. It is an object of the present invention to provide a phenylthioalkylcarboxylic acid derivative represented by the general formula (I), which is useful as an intermediate for the production of the phenylsulfonylalkylcarboxylic acid derivative and the phenylsulfinylalkylcarboxylic acid derivative.

Means for Solving the Problems The phenylsulfonylalkylcarboxylic acid derivative and the phenylsulfinylalkylcarboxylic acid derivative represented by the general formula (II) have a strong CCK receptor antagonistic action, irritable colitis, biliary dyskinesia, It is useful as a prophylactic and therapeutic agent for diseases such as acute pancreatitis.

The phenylthioalkylcarboxylic acid derivative represented by the general formula (I) of the present invention can be very easily produced in good yield by oxidizing the compound with a suitable oxidizing agent and hydrolyzing it if necessary. It can lead to the compound of II).

The phenylthioalkylcarboxylic 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 X and n have the same meanings as described above), and a phenylthioalkylcarboxylic acid derivative or a reactive functional derivative thereof; (R ¹ and R ² in the formula have the same meaning as described above), and can be produced by reacting with an amine and optionally 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 general formula (Wherein X and n have the same meanings as described above), a thiophenol derivative represented by the general formula (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 (A, B, X and n in the formula have the same meanings as described above)
It can be obtained by producing a compound represented by and hydrolyzing and monoesterifying it by an appropriate method, if necessary.

The phenylthioalkylcarboxylic acid derivative represented by the general formula (I) of the present invention has an asymmetric carbon and has two kinds of optical isomers. Any mixture is included.

EFFECTS OF THE INVENTION The phenylthioalkylcarboxylic acid derivative represented by the general formula (I) of the present invention should be oxidized with a suitable oxidizing agent, for example, m-chloroperbenzoic acid, and hydrolyzed as necessary. With this, it is possible to very easily lead to a phenylsulfonylalkylcarboxylic acid derivative and a phenylsulfinylalkylcarboxylic acid derivative represented by the general formula (II) with high yield.

As described above, the compound represented by the general formula (II) produced from the compound of the general formula (I) of the present invention has a CCK receptor antagonistic action, and is susceptible to irritable colitis, biliary dyskinesia, acute pancreatitis, etc. It is useful as a therapeutic agent for the disease.

For example, in a binding assay for CCK receptor in rat isolated pancreas using CCK-8 labeled with ¹²⁵ I, 5- (3,4-dimethylphenylsulfonyl) -4 was obtained.
-(N, N-dipentylcarbamoyl) pentanoic acid and 5- (3,4-dimethylphenylsulfinyl) -4-
(N, N-dipentylcarbamoyl) pentanoic acid exhibits 50% binding inhibition (IC ₅₀ ) at 2.9 × 10 ⁻⁷ molar concentration and 1.4 × 10 ⁻⁷ molar concentration, respectively.

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- (3,4-Dimethylphenylthiomethyl) -4-methoxycarbonylbutyric acid 0.54 ml of 3,4-dimethylbenzenethiol and 0.48 ml of 2-methyleneglutaronitrile were dissolved in 10 ml of ethanol, and Triton B (40%) was added. After adding 5 drops of methanol solution, the mixture was heated under reflux for 5 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 purified by silica gel flash column chromatography (eluting solvent: benzene / ethyl acetate = 7/1) to give oily 2- (3,4-dimethylphenylthiomethyl) glutaro. 1.18 g of nitrile was obtained.

_{IR (neat): ν CN 2230cm} -1 NMR (CDC1 3) δ: 1.9~2.35 (8H, m), 2.45~2.7 (2H, m), 2.85~2.9
(1H, m), 2.98 (1H, dd, J = 7.7,13.7Hz), 3.18 (1H, dd, J
= 6.6,13.7Hz), 7.11 (1H, d, J = 7.7Hz), 7.19 (1H, dd, J
= 1.7,7.7Hz), 7.24 (1H, d, J = 1.7Hz) 2- (3,4-dimethylphenylthiomethyl) glutaronitrile 1.16g is dissolved in acetic acid 8ml, concentrated hydrochloric acid 8ml is added and refluxed for 19 hours. Let 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. The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether-hexane to give a melting point of 96.
Obtained 1.18 g of 2- (3,4-dimethylphenylthiomethyl) glutaric acid at -98 ° C.

Elemental analysis value: (as C ₁₄ H ₁₈ O ₄ S) C% H% Calculated value 59.55 6.43 Measured value 59.38 6.56 IR (KBr): ν _{C = O} 1705 cm ^-1 NMR (DMS0-d ₆ ) δ: 1.65 to 1.95 (2H, m), 2.1 ~ 2.55 (9H, m), 3.04 (2
H, d, J = 7.2Hz), 7.0-7.2 (3H, m), 12.28 (2H, s) 2- (3,4-dimethylphenylthiomethyl) glutaric acid
1.16 g was dissolved in 20 ml of methanol, 0.04 g of p-toluenesulfonic acid was added, and the mixture was reacted at 40 ° C. for 1.5 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 0.98 g of oily 2- (3,4-dimethylphenylthiomethyl) -4-methoxycarbonylbutyric acid.

_{IR (neat): ν C =} 0 1735,1705cm -1 NMR (CDC1 3) δ: 1.9~2.5 (10H, m), 2.55~2.7 (1H, m), 2.94 (1H,
dd, J = 6.6,13.7Hz), 3.19 (1H, dd, J = 7.7,13.7Hz), 3.6
5 (3H, s), 7.06 (1H, d, J = 7.7Hz), 7.1 to 7.2 (2H, m) Reference Example 2 The compounds in the table were produced in the same manner as in Reference Example 1.

Example 1 Methyl 5- (3,4-dimethylphenylthio) -4- (N, N-dipentylcarbamoyl) pentanoate 0.50 g of 2- (3,4-dimethylphenylthiomethyl) -4-methoxycarbonylbutyric acid was dried. Dissolve in 6 ml of benzene,
Thionyl chloride (0.2 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 (4 ml) was added to dipentylamine (0.3 ml).
2 ml of dry methylene chloride of 5 ml and triethylamine 0.3 ml
The solution was added dropwise to the solution with stirring under ice-cooling and then reacted at room temperature for 5 hours. The reaction solution was washed successively with diluted hydrochloric acid, water, 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 purified by silica gel flash column chromatography (eluting solvent: chloroform) to give oily 5- (3,4-dimethylphenylthio) -4- (N, N-dipentylcarbamoyl). ) 0.76 g of methyl pentanoate was obtained.

IR (neat): ν _{C = O} 1730,1635 cm ^-1 NMR (CDC1 ₃ ) δ: 0.84 (3H, t, J = 6.6Hz), 0.89 (3H, t, J = 6.6Hz),
0.95 ~ 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), 7.0 ~ 7.2 (3H,
m) Example 2 In the same manner as in Example 1, the compounds in the table (oil) were produced.

Example 3 5- (3,4-Dimethylphenylthio) -4- (N, N-dipentylcarbamoyl) pentanoic acid 5- (3,4-Dimethylphenylthio) -4- (N, N-dipentylcarbamoyl) pentane Dissolve 150 mg of methyl acid in 6 ml of ethanol, 0.35 m of 1N sodium hydroxide solution
l was added and reacted at room temperature for 4 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 distilling off the solvent under reduced pressure, the residue was subjected to silica gel flash column chromatography (eluting solvent: chloroform / ethanol = 20/1).
And oily 5- (3,4-dimethylphenylthio)
-4- (N, N-dipentylcarbamoyl) pentanoic acid 124
to obtain mg.

IR (neat): ν _{C = 0} 1725,1705,1635 cm ^-1 NMR (CDC1 ₃ ) δ: 0.83 (3H, t, J = 7.1Hz), 0.89 (3H, t, J = 7.1Hz),
0.95 ~ 1.6 (12H, m), 1.95 ~ 2.1 (2H, m), 2.22 (6H, s),
2.25 ~ 2.5 (2H, m), 2.8 ~ 3.35 (7H, m), 7.04 (1H, d, J =
8.2Hz), 7.11 (1H, dd, J = 1.7,8.2Hz), 7.15 (1H, d, J =
1.7 Hz) Example 4 The compounds in the table were produced in the same manner as in Example 3.

Reference Example 3 544 mg of methyl 5- (3,4-dimethylphenylthio) -4- (N, N-dipentylcarbamoyl) pentanoate was dissolved in 10 ml of dry methylene chloride, and m-chloroperbenzoic acid was stirred at -78 ° C. After adding 308 mg (70%) little by little, the mixture was reacted for 2 hours. After reacting for 1 hour at room temperature, sodium sulfite was added to the reaction solution, washed 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: benzene / ethyl acetate = 2/1) to give oily 5- (3,4-dimethylphenylsulfonyl) -4-. 65 mg of methyl (N, N-dipentylcarbamoyl) pentanoate was obtained.

NMR (CDC1 ₃ ) δ: 0.89 (3H, t, J = 7.1Hz), 0.94 (3H, t, J = 7.1Hz),
1.15 ~ 1.75 (12H, m), 1.85 ~ 2.1 (2H, m), 2.2 ~ 2.4 (8
H, m), 3.05 (1H, dd, J = 4.4,13.7Hz), 3.1 to 3.45 (5H,
m), 3.6 to 3.75 (4H, m), 7.29 (1H, d, J = 8.2Hz), 7.6 to
7.7 (2H, m) 5- (3,4-Dimethylphenylsulfonyl) -4- (N, N
-Methyl dipentylcarbamoyl) pentanoate 60 mg was dissolved in ethanol 3 ml, and 1N sodium hydroxide aqueous solution was added.
0.15 ml 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. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluting solvent: chloroform / ethanol = 10/1) and then recrystallized from chloroform-hexane to give 5- (5) having a melting point of 77-79 ° C. 44 mg of 3,4-dimethylphenylsulfonyl) -4- (N, N-dipentylcarbamoyl) pentanoic acid was obtained.

Elemental analysis value: (as C ₂₄ H ₃₉ NO ₅ S) C% H% N% Calculated value 63.54 8.66 3.09 Measured value 63.26 8.91 2.96 NMR (CDC1 ₃ ) δ: 0.89 (3H, t, J = 7.1Hz), 0.93 (3H, t, J = 7.1Hz),
1.1 to 2.4 (22H, m), 3.06 (1H, dd, J = 4.4,13.7Hz), 3.1
~ 3.5 (5H, m), 3.67 (1H, dd, J = 7.7,13.7Hz), 7.29 (1
H, d, J = 8.2 Hz), 7.55 to 7.7 (2H, m) Reference Example 4 5- (3,4-Dimethylphenylsulfinyl) -4-
Methyl (N, N-dipentylcarbamoyl) pentanoate and 5- (3,4-dimethylphenylsulfinyl) -4
-(N, N-dipentylcarbamoyl) pentanoic acid 5-
0.55 g of methyl (3,4-dimethylphenylthio) -4- (N, N-dipentylcarbamoyl) pentanoate was dissolved in 10 ml of dry methylene chloride, and m-chloroperbenzoic acid (70%) was stirred at -78 ° C. After adding 0.31 g little by little, the mixture was reacted for 3 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 the solvent was distilled off under reduced pressure, the residue was purified by silica gel flash column chromatography (eluting solvent: benzene / ethyl acetate = 2/1) and eluted first with 5- (3,4-dimethylphenylsulfinyl)- Four
0.12 g of methyl-(N, N-dipentylcarbamoyl) pentanoate (diastereomer A) and 0.36 g of diastereomer B, which was eluted later, were obtained.

[Diastereomer A]

Property: Oily IR (neat): ν _{C = O} 1730,1630 cm ⁻¹ ν _SO 1045 cm ⁻¹ NMR (CDC1 ₃ ) δ: 0.90 (3H, t, J = 6.6Hz), 0.93 (3H, t, J = 6.6) Hz),
1.1 to 2.45 (22H, m), 2.76 (1H, dd, J = 3.3,12.1Hz), 3.1
~3.5 (6H, m), 3.65 (3H, s), 7.2~7.45 (3H, m) [diastereomer B] Property: oil _{IR (neat): ν C =} O 1735,1635cm -1 ν SO 1045cm - _{^{1 NMR (CDC1 3) δ:}} 0.87 (3H, t, J = 7.1Hz), 0.93 (3H, t, J = 7.1Hz),
1.15 ~ 1.65 (12H, m), 2.1 ~ 2.5 (10H, m), 2.82 (1H, dd,
J = 9.3, 13.2Hz), 2.97 (1H, dd, J = 3.8, 13.2Hz), 3.1 ~
3.45 (5H, m), 3.68 (3H, s), 7.2 to 7.45 (3H, m) 5- (3,4-dimethylphenylsulfinyl) -4-
120 mg of methyl (N, N-dipentylcarbamoyl) pentanoate (diastereomer A) was dissolved in 3 ml of ethanol, 0.28 ml of 1N aqueous sodium hydroxide solution was added, and room temperature 16
Reacted for 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. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluting solvent: chloroform / ethanol = 10/1),
90 mg of 5- (3,4-dimethylphenylsulfinyl) -4- (N, N-dipentylcarbamoyl) pentanoic acid (diastereomer A) with a melting point of 50-54 ° C were obtained.

Elemental analysis value: (as C ₂₄ H ₃₉ NO ₄ S) C% H% N% Calculated value 65.87 8.98 3.20 Measured value 65.52 9.24 3.19 IR (KBr): ν _{C = O} 1720,1630cm ^-1 NMR (CDC1 ₃ ) δ : 0.90 (6H, t, J = 6.6Hz), 1.2 to 2.15 (14H, m), 2.25
~ 2.4 (8H, m), 2.90 (1H, dd, J = 3.3, 12.1Hz), 3.1 ~ 3.5
(6H, m), 7.2 ~ 7.45 (3H, m)

 ─────────────────────────────────────────────────── ─── 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 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, and X is a carbon atom. Number 1
To a alkyl group, a nitro group and an acetyl group, wherein n is 1 or 2).