JPH0440346B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to pyridyloxybutenylamine derivatives, and more particularly to aminoalkylpyridyloxy derivatives having histamine _H2 receptor antagonistic activity that are useful in the treatment of peptic ulcers, and their pharmaceutically acceptable The present invention relates to pyridyloxybutenylamine derivatives, which are important intermediate raw materials for producing salts, hydrates, and solvates, and methods for producing the same. (Prior art) Gastric acid secretion is suppressed by blocking histamine action at histamine _H2 receptors.
Furthermore, it has been well known that gastric acid secretion can be suppressed in animals and humans using substances that have an antagonistic effect on the histamine H ₂ receptor (Priebcol et al., J.Int.Met.Res., 3, 86, 1975.). Among the antagonists of this histamine H ₂ receptor, cimetidine is particularly known as being the first to be commercialized as a therapeutic agent for peptic ulcers. Histamine _H2 even better than cimetidine
Substances with receptor antagonistic effects have been researched, various heterocyclic compounds have been synthesized, and their H ₂ receptor antagonistic effects have been investigated. (Object of the Invention) The present invention provides pyridyloxybutenylamine derivatives, which are important intermediate raw materials for producing aminoalkylpyridyloxy derivatives that have _H2 receptor antagonistic activity superior to conventional _H2 receptor antagonistic substances. The present invention provides a method for manufacturing the same. That is, the compound of the present invention has the general formula () (In the formula, R ¹ and R ² are each independently a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, or
Together with the nitrogen atom to which they are bonded, R ¹ and R ² form a 4- to 8-membered heterocyclic ring which may further have a substituent, and A is a straight or branched chain having 1 to 4 carbon atoms. It is a pyridyloxybutenylamine derivative (representing an alkylene group). In the compound of formula (), examples of the lower alkyl group having 1 to 4 carbon atoms include methyl, ethyl, propyl, n-butyl, S-butyl, and t-butyl. Examples of the heterocyclic group formed with the nitrogen atom to which R ¹ and R ² are bonded include azetidino, pyrrolidino, piperidino, and perhydroazetidino groups. These heterocyclic groups may have a substituent such as a hydroxyl group, a methoxy group, an ethoxy group, or a lower alkyl group having 1 to 6 carbon atoms. Examples of the alkylene group of A include methylene, ethylene, propylene, isopropylene, and isobutylene groups. In the general formula (), the geometric isomerism of the double bond portion can be either cis or trans configuration. The pyridyloxybutenylamine derivative () of the present invention is a new substance, and can be produced, for example, by the method below. (In the formula, R ¹ , R ² , A, and M are as described above,
X represents chlorine, bromine, iodine, fluorine, especially chlorine,
Bromine is preferred. ) can be manufactured by Examples of other manufacturing methods include: (wherein R ¹ , R ² and A are as defined above, Y, Q and N-B represent active functional groups or leaving groups that can be easily utilized by those skilled in the art) It can also be manufactured by twisting. For example, Y is an acetoxymethyl group, Q is a chloro group, N-B
An example of this group is a phthalimide group. The compound of general formula () is a known compound, and the method described in JP-A-57-91986 can be used or
Alternatively, it can be produced using reactions obvious to those skilled in the art. 4-Amino-cis or trans-2-buten-1-ol, which is a raw material for the compound represented by the general formula (), is a known compound and can be prepared using known methods (for example, Andree Marszak-Fleury etal., Bull.
It can be produced using the method described in Soc. Chim. France, 1963 (6), p. 1270-2. Examples of solvents to be used include dimethyl sulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), toluene, xylene, diglyme, ethanol, pyropanol, butanol, etc. In particular, DMSO, THF, DMF, etc. preferable. 4-Amino-2-buten-1-ol is reacted as an alkali metal salt, e.g. sodium salt, potassium salt, and the alkali metal compound used for producing the metal salt is an oily alkali metal hydride, e.g. oily sodium hydride. is preferred. Although the reaction temperature and reaction time vary depending on the raw materials and solvent used, it is usually sufficient to carry out the reaction at 50° C. to 150° C. for 2 hours to 150 hours. For example, in the general formula (), use a compound in which X is chlorine and R ¹ , R ² and A are piperidinomethyl groups, and as a solvent
When using DMSO, the reaction temperature is 50-60℃
By stirring for 5 hours, the compound of the present invention can be obtained in high yield. The compound of the present invention is a useful production intermediate for producing a therapeutic agent for peptic ulcers having a histamine H ₂ receptor inhibitory effect and a gastric acid secretion suppressing effect. An example of use as a production intermediate is shown in the scheme below. In each of the above formulas, R ¹ and R ² are as described above, and R ²⁰ is lower alkyl, preferably methyl,
is ethyl, E is -O- or -S-, preferably -O-, and R ³ and R ⁴ are independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, an alkenyl group, or an alkynyl group; , R ³ and R ⁴ form a 4- to 8-membered heterocyclic ring together with the nitrogen atom to which they are bonded. The heterocyclic ring is preferably azetidino, pyrrolidino or piperidino. (Effect of the invention) Therefore, the compound of the present invention has a strong histamine effect.
It is an extremely useful compound as an important intermediate raw material in the production of therapeutic agents for peptic ulcers, which have H ₂ receptor inhibitory effects and gastric acid secretion suppressing effects. As described above, the compound of the present invention can be easily produced industrially, and the above-mentioned peptic ulcer agent can be produced in a short process by using the present intermediate raw material, making it an extremely useful compound. Examples Example 1 4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamine. 12 g of 60% sodium hydride was suspended in 481 ml of anhydrous tetrahydrofuran, and 24 g (0.276 mol) of 4-amino-cis-2-buten-1-ol was slowly added. The reaction solution was stirred at 50°C for 30 minutes, then cooled.
Next, add 2-bromo to 40 ml of tetrahydrofuran.
4-(1-piperidinomethyl)pyridine (JP-A-Sho
It was manufactured using the method described in No. 58-170779. )
44 g (0.173 mol) was slowly added and stirred under reflux for 40 hours. After the reaction, the solvent was distilled off and the residue was dissolved in water.
The mixture was poured into 200ml and extracted four times with 200ml of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography and eluted with MeOH-ethyl acetate (1:4). 38.7 g (85.9%) of the title compound was obtained as a light brown oil. IR (neat, cm ^-1 ): 3400, 3300, 2950, 1620,
1563, 1480, 1420, 1315, 1040, 830 NMR ( _CDCl3 , ppm): 1.2-1.9 (6H, m), 2.1
~2.6 (4H, m), 2.9 (2H, s), 3.2 ~ 3.7 (4H,
m), 4.7-5.0 (2H, d), 5.6-5.9 (2H, s),
6.65 (1H, S), 6.7-6.9 (1H, d), 7.9-8.1 (1H,
d). Example 2 4-(4-dimethylaminomethylpyridyl-2
-oxy)-cis-2-butenylamine. The same operation as in Example 1 was carried out except that 44 g of 2-bromo-4-(1-piperidinomethyl)pyridine was replaced with 37.2 g (0.173 mol) of 2-bromo-4-dimethylaminomethylpyridyl, and the title compound was obtained as a light brown oil. 27.1g (74.2%) was obtained. IR (neat, cm ^-1 ): 3400, 3200, 2950, 2800,
1600, 1620, 1560, 1410, 1290, 1155, 1020,
820 NMR (CDCl ₃ , ppm): 2.05 (2H, s, disappeared in heavy water), 2.2 (6H, s), 3.2~3.7 (4H, m), 4.7~
5.1 (2H, d), 5.5-6.0 (2H, t), 6.6 (1H, s),
6.7-6.9 (1H, d), 7.9-8.2 (2H, d). Example 3 4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-tran-2-butenylamine. Instead of 24 g (0.276 mol) of 4-amino-cis-2-buten-1-ol used in Example 1, 24 g of 4-amino-trans-2-buten-1-ol (bp ₁₆ 115-116°C) ( 2-bromo-4-(1-piperidinomethyl) using
From 44 g (0.173 mol) of pyridine, 32.5 g (yield 72%) of the title compound was obtained as a pale brown oil. IR (neat, cm ^-1 ): 3400, 2950, 1610, 1560,
1420, 1020, NMR (CDCl ₃ , ppm): 1.1-1.9 (6H, m), 2.1
~2.7 (4H, m), 3.1 ~ 3.7 (2H, m), 3.37 (2H,
s), 4.1-5.0 (2H, m), 5.7-6.1 (2H, m),
6.65 (1H, s), 6.77 (1H, d), 7.95 (1H, d). Reference example 1 1-amino-2-[4-<4-(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-
Butenylamino]-1-cyclobutene-3,4
-Dione 1-methoxy-2-[4-<4(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1-cyclobutene-3,4-dione. 1.42 g (0.01 mol) of dimethyl squarate (manufactured by the method described by J. Cohen et al., J. Amer. Chem. Soc., Vo188, 1533, 1966) was dissolved in 50 ml of anhydrous methanol and cooled to 5°C. did.
Next, 4-<4- produced by the method described in Example 1
(1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamine 2.61 g (0.01 mol)
A 20 ml solution of anhydrous methanol was added dropwise to the mixture while stirring at an internal temperature of 5°C, and the mixture was further stirred at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by chromatography on a silica gel column, and eluted with a mixture of ethyl acetate and methanol = 4:1. Title compound 3.4 as a pale yellow oil
g (yield 91.6%) was obtained. IR (neat, cm ^-1 ) 3250, 2950, 1720, 1620,
1405, 1040, 1000, 925, 830, 785 NMR ( _CDCl3 , ppm): 1.1-1.8 (5H, m), 2.1
~2.6 (4H, m), 3.35 (2H, s), 4.0 ~ 4.5 (2H,
m), 4.3 (3H, s), 4.7~5.0 (2H, d), 4.9~5.5
(2H, m), 6.6 (1H, s), 6.7~6.9 (1H, d),
7.8-8.2 (1H, d). 1-amino-2-[4-<4-(1piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1-cyclobutene-3,4-dione. 1-Methoxy-2-[4-<4-
1.2 g (3.2 mmol) of (1-piperidinomethyl)pyridyl-2-oxy>-cis-2-butenylamino]-1-cyclobutene-3,4-dione was dissolved in 25 ml of anhydrous methanol, and dried ammonia was added at a reaction temperature of 5°C. Gas was introduced for 20 minutes, and the mixture was further stirred at room temperature for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure.
The residue was purified by chromatography on a silica gel column and eluted with a mixture of ethyl acetate:methanol=4:1. Further recrystallization from methanol gave the title compound as colorless crystals, 0.75g (yield 65.2%) (melting point 225-30℃(d))
I got it. IR (KBr, cm ^-1 ): 3110, 2950, 1810, 1650,
1550, 1435, 1400, 1360, 1150, 1030, 640 NMR ( _CDCl3 , ppm): 1.2-1.8 (6H, m), 2.1
~2.6 (4H, m), 3.3 (2H, s), 4.1 ~ 4.5 (2H,
m), 4.8-5.1 (2H, d), 5.5-5.9 (2H, m), 6.6
(1H, s), 6.7-6.9 (1H, d), 7.0-7.5 (2H,
m, disappeared in heavy water) 7.8-8.1 (1H, d). Reference Example 2 Regarding the compound of Reference Example 1, cimetidine, which is widely used clinically as a peptic ulcer agent with histamine H ₂ receptor antagonistic action,
Various tests were conducted and compared. A. Inhibitory effect of histamine on increased gastric acid secretion in pylorus-ligated rats This study was conducted by Watanabe et al., Applied Pharmacology, 1969, Vol. 3(1), 7.
The method on pages 14 to 14 was modified and implemented. Male Wistar rats weighing approximately 160 g that had been fasted for 24 hours were anesthetized by intraperitoneal injection of 1.2 g/Kg of urethane. After ligating the esophagus and the pylorus of the stomach, an incision was made in the forestomach and a double polyethylene cannula was installed. 5 every 30 minutes
The stomach wall was washed with ml of physiological saline, and the amount of gastric acid contained in this wash was measured by titration. First, after measuring the basal acid secretion three times, reference example 1
The compound was injected subcutaneously at 0.2 mg/Kg, and 30 minutes later, histamine was injected subcutaneously at 3 mg/Kg. Gastric acid secretion was measured for up to 3 hours thereafter. In addition, select the three points at which the highest increase in acid secretion is shown in the time period, and use the average value as the amount of increase in acid secretion for each sample group.
The inhibition rate relative to the control group was calculated by comparing the amount of increase in acid secretion in the control group. Acid secretion inhibition rate (%) = - {1 - increase in acid secretion in sample group / increase in acid secretion in control group} × 100 (Experimental values show the average value of 5 cases.) Furthermore, the sample was injected with histamine into the duodenum of rats. It was administered 30 minutes before subcutaneous injection, and the dose (ED ₅₀ ) that suppressed histamine-induced gastric acid secretion increase by 50% was determined. B Histamine from isolated guinea pig right atrium specimen
Measurement of H ₂ Acceptance vs. Inhibition Effect Male Hartley guinea pigs weighing approximately 400 g were sacrificed by bloodletting, and the right atrium was removed. Modified Ringer's solution
A 50 ml organbath containing Ringer solution was suspended, a tension of 1 g was applied, and the heart rate was recorded using a polygraph. First, histamine was applied cumulatively from 1 x 10 ^-7 mol to 3 x 10 ^-4 mol, and a dose-response curve was drawn. Next, the sample injected 3 minutes before 5×10 ^-8 ~5×
A dose-response curve of histamine was similarly drawn in the presence of 10 ^-6 mol, and the negative logarithm (pA ₂ ) of the molar concentration of the specimen required to shift the curve of histamine alone to the right by two times the concentration was calculated.

[Table] Ri

[Table] As shown in Table 1, the compound of Reference Example 1 (0.2
The inhibitory effect of cimetidine (subcutaneous injection at 2 mg/Kg) on histamine gastric acid secretion was comparable to that of cimetidine (subcutaneous injection at 2 mg/Kg). In addition, the histamine of the same compound was detected in isolated right atrium specimens from guinea pigs.
The H ₂ receptor antagonism was comparable to that of cimetidine. Furthermore, intraduodenal administration of the same compound, which is similar to oral administration, had an extremely strong effect on suppressing histamine gastric acid secretion in rats.

Claims (1)

[Claims] 1. A compound represented by the following general formula () and a salt thereof. (In the formula, R ¹ and R ² are each independently a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, or
Together with the nitrogen atom to which they are bonded, R ¹ and R ² form a 4- to 8-membered heterocyclic ring which may further have a substituent, and A is a straight or branched chain having 1 to 4 carbon atoms. It is an alkylene group, and the double bond configuration of the butenyl group has cis type and trans type. ) 2 A compound represented by the following general formula () or a salt thereof (In the formula, R ¹ and R ² are each independently a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, or
Together with the nitrogen atom to which they are bonded, R ¹ and R ² form a 4- to 8-membered heterocyclic ring which may further have a substituent, and A is a straight or branched chain having 1 to 4 carbon atoms. It is an alkylene group, and the double bond configuration of the butenyl group has cis type and trans type. ), the general formula () is (wherein, R ¹ and R ² have the same meanings as above, and X represents chlorine, bromine, iodine, or fluorine) and a compound of the general formula () MO-CH ₂ -CH=CH-CH ₂ -NH ₂ ( ) (wherein M represents an alkali metal).