JPH0124145B2 - - Google Patents

Description

[Detailed description of the invention]

This invention provides a novel α-
This invention relates to aryl-α-pyridyl fatty acid derivatives. More specifically, the invention relates to the general formula (In the formula, R ² is hydrogen or halogen, R ³ is hydrogen or a lower alkyl group, one of R ⁴ and R ⁵ is hydrogen and the other is a lower alkyl group, R ⁶ is a lower alkyl group, R ⁷ is a lower The present invention relates to α-aryl-α-pyridyl fatty acid derivatives represented by the following formulas, salts thereof, and methods for producing them. Examples of the halogen represented by R ² in the above general formula [] include chlorine, bromine, iodine,
Examples include fluorine. Examples of the lower alkyl group represented by R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary
Examples include butyl, pentyl, hexyl, etc. Salts of the target compound [] include salts with inorganic acids such as hydrochloride, hydrobromide, and sulfate, and salts with organic acids such as acetate, citrate, tartrate, and methanesulfonate. can be mentioned. The object compound of this invention [] and its salt are:
Manufactured by the following method. (In the formula, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meanings as before.) The target compound [] and its salt can be used to hydrolyze the compound [] or its salt. It is obtained by This reaction is usually carried out in the presence of an acid or a base. Examples of acids include sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, etc.; examples of bases include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, pyridine, 1,8-diazabicyclo [5.4.0]
Examples include -7-undecene. This reaction is usually carried out in water or a water-containing solvent, and examples of the water-containing solvent include water-containing methanol,
Examples include aqueous ethanol, aqueous dioxane, aqueous tetrahydrofuran, and aqueous dimethylformamide. Furthermore, when the acid or base used is a liquid, it can also be used as a solvent. Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature or under heating. The target compound [] has isomers based on asymmetric carbon atoms in the molecule. These can be isolated and purified by conventional means such as column chromatography and optical resolution. The target compound [ ] obtained in this way is
If desired, salts such as those mentioned above may be introduced. The starting compound [ ] and its salt are produced by the following method. (In the formula, R ⁸ is a lower alkyl group, Y is a leaving group, R ² ,
(R ³ , R ⁶ and R ⁷ have the same meanings as before) In the above reaction formula, examples of the lower alkyl group represented by R ⁸ include those similar to the lower alkyl groups exemplified in the target compound [ ]. Yes, Y
Examples of the leaving group represented by include the above-mentioned halogen, tosyloxy group, mesyloxy group, and the like. Next, the method for producing the raw material compound [] will be specifically explained. Production method A The target compounds [a] and [b] and their salts are obtained by reacting the compound [] or a salt thereof with the compound [] or a salt thereof in the presence of a base. Examples of the salts of the compounds [] and [] include the salts exemplified as the salts of the target compound []. Examples of the base used in this reaction include metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tertiary butoxide; metal amides such as sodium amide and lithium diisopropylamide; metal hydrides such as sodium hydride and calcium hydride; Examples include organic metal compounds such as n-butyllithium, methyllithium, and phenyl sodium, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. This reaction is usually carried out in a solvent, such as alcohols such as methanol, ethanol and tertiary butyl alcohol, aromatic hydrocarbons such as benzene and xylene, aliphatic hydrocarbons such as hexane and heptane, diethyl Examples include ether, ether such as tetrahydrofuran, dimethylformamide, and water. These solvents are
It is appropriately selected depending on the type of raw material compound and base used. Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature or under heating. Note that depending on the type of base used, it may be preferable to carry out this reaction under an inert atmosphere such as under a nitrogen gas stream. In this reaction, compound [] passes through ethyleneimmonium ion as a reaction intermediate, so
Compounds [a] and [b] are obtained as reaction products. In addition, compounds [a] and [
b] has isomers based on asymmetric carbon atoms in the molecule. These isomers can be isolated and purified by conventional means such as column chromatography, recrystallization, distillation, and optical resolution. The object compound [] and starting material compound [] of this invention also include isomers based on asymmetric carbon atoms in the molecule and mixtures thereof. The object compound of the present invention [ ] exhibits antiulcer activity as is clear from the test results described below. Peptic ulcers occur due to various causes, but
It is thought to occur mainly due to a loss of balance between attacking factors such as gastric juice and protective factors such as the protective power of the gastrointestinal mucosa. Conventionally, drugs with antacid, anticholinergic, or antigastrogenic effects have been used to attenuate attack factors, and drugs with effects such as mucosal tissue repair and mucosal tissue activation have been used to enhance protective factors. has been used. In the treatment of peptic ulcers, it is desirable to have a drug that simultaneously acts on the two major factors of attack and defense, but the object compound of the present invention [] has the effect of attenuating the attack factor and enhancing the defense factor with a single drug. and is useful as a new anti-ulcer agent. The object compound of this invention [] and its salt are:
It is administered in dosage forms such as capsules, tablets, granules, suppositories, suspensions or emulsions, and injections. These various preparations are manufactured by conventional methods. The dosage of the active ingredient is determined appropriately depending on the patient's age, weight, symptoms, etc., but it is usually administered in a daily dose range of 1 mg to about 1000 mg. Next, test data regarding the gastric acid secretion suppressing effect and anti-ulcer effect of a representative example of the target compound [] will be shown. Test method (1) Test A Gastric acid secretion suppression test in Heidenhain dogs Beagle dogs weighing 8 to 13 kg were used. The so-called Heidenhain dog was created by creating a denervated gastric pouch in an animal and undergoing surgery to remove the tube.
More than one month after the surgery, tetragastrin (10 μg/Kg/hr) was continuously injected intravenously to stimulate gastric acid secretion. Gastric juice is collected every 15 minutes, and after the gastric juice volume reaches a certain level, a predetermined amount of the test drug is administered.
0.2% solution suspended in 0.1% methyl cellulose solution
It was administered intravenously at a dose of ml/Kg. After administration, the amount of gastric juice and its acidity were measured. Acidity was measured using an automatic titration measuring device (manufactured by Hiranuma, model RAT-11).
Measurement was performed by titrating to PH7.0 with 0.1N sodium hydroxide. The total acid amount was calculated by multiplying the gastric juice amount by the acidity, and the inhibition rate was determined by comparing it with the value before administration of the test drug. (2) Test B Stress ulcer suppression test Group of 5 animals S/D (Sprague-Doury,
Sprague-Dawley male rats (7 weeks old,
(Weighing approximately 200 g) were fasted for 24 hours before use. A predetermined amount of the test drug was suspended in 0.1% methylcellulose solution and orally administered at a dose of 5 ml/Kg. Immediately after administration, the animals were placed in wire mesh stress cages to immobilize them for 22 hours.
The animals were immersed in a water tank at ℃ to the depth of the xiphoid bone, and stress was applied. After 7 hours, the rat was killed, the whole stomach was removed, 2% formalin was injected into the stomach, and the stomach was immersed in 2% formalin for fixation. After immobilization, the stomach was opened along the greater curvature and the area of the resulting ulcer was measured in mm ² . A 0.1% methylcellulose solution was administered to the control group, and the ulcer area was compared with that of the test drug administration group to calculate the inhibition rate of the test drug. (3) Test C Ethanol-induced ulcer inhibition test A group of 5 S/D male rats (7 weeks old, weight approximately 200 g) were used after fasting for 24 hours. A predetermined amount of the test drug was suspended in 0.1% methylcellulose solution and orally administered at a dose of 5 ml/Kg. 30 minutes after drug administration, 5 ml/Kg of absolute ethanol was administered. One hour after ethanol administration, the rats were sacrificed, the whole stomach was removed and opened along the greater curvature, and the inside of the stomach was washed with water. The area of the ulcer formed in the gastric corpus was measured in mm ² . A 0.1% methylcellulose solution was administered to the control group, and the ulcer area was compared with the test drug administration group.
The inhibition rate of the test drug was calculated. Test results

[Table] (4) Test D Acute toxicity test 10 male rats and 10 female rats (JCL
−SD series) were included in the group. Test compounds were adjusted to various concentrations by the following method and administered to rats intravenously, intraperitoneally, subcutaneously, or orally, and then observed for 14 days. LD ₅₀ values were calculated by the Probit method. (Preparation of test compound) The test compound was dissolved in hydrochloric acid, adjusted to pH 6 to 7 with sodium bicarbonate, and then diluted with physiological saline to various concentrations before use. Test results Test compound 4-(N,N-dimethylamino)-2-phenyl-2-(2-pyridyl)valeramide (compound of Example 1)

【table】

[Table] Next, the method for producing the object compound [] of the present invention will be explained with reference to Reference Examples, Production Examples, and Examples. Reference example (1) α-phenyl-α-(2-pyridyl)acetonitrile (10.2 g) was dissolved in a mixed solvent of t-butyl alcohol (100 ml) and xylene (5 ml), and potassium-t-butoxide (6.18 g) was dissolved in a mixed solvent of t-butyl alcohol (100 ml) and xylene (5 ml).
g) is added at room temperature in a nitrogen atmosphere. After stirring for 50 minutes, 1-(2-chloropropyl)-4 was added to this.
- A solution of methylpiperazine (10.2 g) in t-butyl alcohol (30 ml) was added dropwise at room temperature while stirring. After the dropwise addition, the mixture was refluxed for 2.5 hours, and then the solvent was distilled off under reduced pressure. Pour the residue into water and extract three times with ethyl acetate (50 ml). The extracts are combined, washed with saturated brine (50 ml), dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (320 g) and eluted with a mixed solvent of chloroform-methanol (95:5) to obtain an oily substance and a crystalline substance. The oil is dissolved in diethyl ether and treated with ethanolic hydrogen chloride to give crude crystals.
When this is recrystallized from ethanol, 3-methyl-4-(4-ethyl-1-piperazinyl)-2
-Phenyl-2-(2-pyridyl)butyronitrile dihydrochloride (6.4 g) is obtained. mp203~205
℃. IR (nujiyor): 3350, 2300, 1590, 1460cm
^-1 NMR (DMSO-d ₆ , δ): 1.2-1.3 (3H, m),
2.73 (3H, s), 2.9~4.16 (11H, m), 7.2~
7.9 (8H, m), 8.5-8.8 (1H, m) Elemental analysis: ( _{C21H26N4 ・}2HCl) Calculated value: C61.92, H6.93, N13.75 Actual value: C61.68 _, H7 .22, N13.35 (2) Also, when the above crystalline substance is recrystallized from diisopropyl ether, 4-(4-methyl-
1-piperazinyl)-2-phenyl-2-(2-
pyridyl)valeronitrile (1.25 g) is obtained.
mp89~90℃. IR (nujiyor): 2230, 1585, 1570, 1495cm
^-1 NMR (CDCl ₃ , δ): 0.95 (3H, d, J = 6
Hz), 2.20 (3H, s), 2.0~3.35 (11H, m),
7.0~7.7 (8H _, m), 8.4~8.7 ( _1H , m) Elemental analysis: (C21H26N4) Calculated value: C75.41, H7.84, N16.75 Actual value: C75.69 _, H7 .98, N16.76 Production Example The following compounds were obtained from the corresponding raw material compounds in the same manner as in Reference Examples (1) and (2). (1) 2-(4-chlorophenyl)-4-(N,N-
Dimethylamino)-3-methyl-2-(6-methylpyridin-2-yl)butyronitrile monohydrochloride monohydrate. mp125~132℃. IR (Nujiyor): 3400, 2600, 2450, 1595,
1575, 1490 cm ^-1 NMR (DMSO−d ₆ , δ): 1.19-1.29 (3H,
m), 2.55 (3H, s), 2.76 (3H, s), 2.80
(3H, s), 2.6-3.4 (2H, m), 3.48-3.83
(1H, m), 7.18-7.82 (7H, m), 10.86 (1H,
m) Elemental analysis: (C ₁₉ H ₂₂ ClN ₃・HCl・H ₂ O Calculated value: C59.69, H6.59, N10.99 Actual value: C60.79, H6.33, N11.27 (2) 2 -(4-chlorophenyl)-4-(N,N-
dimethylamino)-2-(6-methylpyridine-
2-yl)valeronitrile monohydrochloride hemihydrate. mp92~98℃. IR (Nujiyor): 3350, 2600, 2400, 1590,
1570cm ^-1 NMR (DMSO-d ₆ , δ): 1.12-1.3 (3H, m),
2.52 (3H, s), 2.67 (6H, broad s),
2.40~2.92 (1H, m), 3.00~3.44 (2H, m),
7.20-7.88 (7H, m), 11.44 (1H, m) Elemental analysis: (C ₁₉ H ₂₂ ClN ₃・HCl・1/2H ₂ O) Calculated value: C61.13, H6.48, N11.26 Actual value : C60.12, H6.52, N11.23 Example 1 4-(N,N-dimethylamino)-2-phenyl-2-(2-pyridyl)valeronitrile (6.3g)
Add concentrated sulfuric acid (11 ml) to the solution at 0°C, then add water (1 ml) to the solution at 0°C.
ml). After stirring at 90℃ for 3 hours, the reaction solution was poured into ice water and adjusted to pH 10 with 10% aqueous sodium hydroxide solution.
and extracted three times with ethyl acetate (50 ml).
The extracts are combined, washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. When the obtained crude crystals are recrystallized from diethyl ether, 4-
(N,N-dimethylamino)-2-phenyl-2-
(2-pyridyl)valeramide (1.89 g) is obtained.
mp132-134℃. IR (Nujiyor): 3200, 1675, 1635, 1585,
1490cm ^-1 NMR (CDCl ₃ , δ): 0.72 (3H, d, J = 6.5Hz),
2.13 (6H, s), 2.0~3.46 (3H, m), 5.87 (1H,
m), 6.87-7.63 (8H, m), 8.37-8.63 (1H,
m), 10.63 (1H, m) Elemental analysis: (C ₁₈ H ₂₃ N ₃ O) Calculated values: C72.69, H7.80, N14.13 Actual values: C72.47, H7.83, N14.17 Implemented Example 2 The following compounds were obtained from the corresponding raw material compounds in the same manner as in Example 1. (1) 4-(N,N-dimethylamino)-3-methyl-2-phenyl-2-(2-pyridyl)butyramide dihydrochloride 1/2 hydrate. mp135~145℃. IR (Nujiyor): 3370, 2700, 1675, 1610,
1530cm ^-1 NMR (DMSO-d ₆ , δ): 1.03 (3H, d, J=
6Hz), 2.0~3.53 (8H, m), 3.53~4.13 (1H,
m), 6.30-6.90 (3H, m), 6.90-8.30 (8H,
m), 8.47-8.77 (1H, m), 10.37 (1H, m) Elemental analysis: (C ₁₈ H ₂₃ N ₃ O・2HCl・1/2H ₂ O Calculated value: C57.00, H6.91, N11. 08 Actual value: C56.87, H7.08, N10.37 (2) 2-(4-chlorophenyl)-4-(N,N-
dimethylamino)-3-methyl-2-(6-methylpyridin-2-yl)butyramide. IR (Nujiyor): 3440, 3350, 3140, 1675,
1645cm ^-1 NMR (CDCl ₃ , δ): 0.98 (3H, d, J = 6.5
Hz), 1.30-2.20 (2H, m), 2.22 (6H, s),
2.53 (3H, s), 2.92~3.48 (1H, m), 6.70~
7.60 (7H, m) Elemental analysis: (C ₁₉ H ₂₄ ClN ₃ O) Calculated value: C65.98, H6.99, N12.15 Actual value: C65.56, H6.90, N11.70 (3) 2 -(4-chlorophenyl)-4-(N,N-
dimethylamino)-2-(6-methylpyridine-
2-yl)valeramide. mp162~167℃. IR (Nujiyor): 3220, 1660, 1590, 1575,
1490cm ^-1 NMR (CDCl ₃ , δ): 0.75 (3H, d, J = 6
Hz), 2.12 (6H, s), 1.90~2.90 (3H, m),
2.50 (3H, s), 5.90 (1H, m), 6.90~7.65
(7H, m), 10.70 (1H, m) Elemental analysis: (C ₁₉ H ₂₄ ClN ₃ O) Calculated value: C65.98, H6.99, N12.15 Actual value: C66.06, H7.12, N12 .06

Claims (1)

[Claims] 1. General formula (In the formula, R ² is hydrogen or halogen, R ³ is hydrogen or a lower alkyl group, one of R ⁴ and R ⁵ is hydrogen and the other is a lower alkyl group, R ⁶ is a lower alkyl group, R ⁷ is a lower α-aryl-α-pyridyl fatty acid derivatives and salts thereof represented by: 2. The compound according to claim 1, wherein R ² and R ³ are each hydrogen. 3. The compound according to claim 2, wherein R ⁴ is hydrogen and R ⁵ is a lower alkyl group. 4. The compound according to claim 3, which is 4-(N,N-dimethylamino)-2-phenyl-2-(2-pyridyl)valeramide. 5 General formula (In the formula, R ² is hydrogen or halogen, R ³ is hydrogen or a lower alkyl group, one of R ⁴ and R ⁵ is hydrogen and the other is a lower alkyl group, R ⁶ is a lower alkyl group, R ⁷ is a lower α-aryl-α-pyridylacetonitrile derivatives or salts thereof represented by the formula (wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meanings as above) α−
A method for producing an aryl-α-pyridyl fatty acid derivative. 6 General formula (In the formula, R ² is hydrogen or halogen, R ³ is hydrogen or a lower alkyl group, one of R ⁴ and R ⁵ is hydrogen and the other is a lower alkyl group, R ⁶ is a lower alkyl group, R ⁷ is a lower An anti-ulcer agent containing an α-aryl-α-pyridyl fatty acid derivative or a salt thereof as an active ingredient.