JPS62126169A - Aminoalkylphenoxy derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> and R<2> are H, 1-4C alkyl or 4-8-membered heterocyclic ring which may have a substituent group as NR<1>R<2>; A is 1-4C straight-chain or branched alkyl; Z is formula II-IV; R<3> is (CH2)mR; R is phenyl, pyridyl, furanyl or thiofuranyl; m is 0-4; R<4> is H, 1-4C alkyl, alkenyl or alkynyl; R<5> is H, 1-4C alkyl or (CH2)1NR<6>R<7>; R<6> and R<7> are H or 1-4C alkyl; q is 0-4]. EXAMPLE:1-methoxy-2-[ 4-<3-( 1-piperidinomethyl )phenoxy>-cis-2-butenylamine]-1- clobutene-3,4-dione. USE:A histamine H2 receptor antagonistic agent useful for treating peptic ulcer. PREPARATION:A compound expressed by formula V is reacted with a compound expressed by formula VI (R<20> is lower alkyl; E is 0 or S) to give a compound expressed by formula VII, which is then reacted with a compound expressed by the formula R<3>NH2 to afford the aimed compound expressed by formula I (A is formula II).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to substituted aminoalkylphenoxy derivatives,
More specifically, the present invention relates to aminoalkylphenoxy derivatives having histamine H2 receptor antagonistic activity and pharmaceutically acceptable salts, hydrates and solvates thereof, which are useful in the treatment of peptic ulcers.

[Prior art]

It has long been well known that gastric acid secretion can be suppressed by blocking histamine action at histamine H2 receptors, and that gastric acid secretion can be suppressed in animals and humans using substances that have an antagonistic effect on histamine H2 receptors. There is. [Prypulkol et al., J, IntoMed
, Res., 3, 86.1975] Among these histamine H2 receptor antagonists, cimetidine is particularly known as the first to be commercialized as a therapeutic agent for peptic ulcers.

In addition, active research has been conducted into substances that have a histamine H2 receptor antagonism superior to cimetidine, and various heterocyclic compounds have been synthesized, and their H2 receptor antagonism has been investigated (Japanese Patent Application Laid-Open No. 57-16'5348 , Japanese Patent Publication No. 59-717
7).

[Purpose of the invention]

The present invention has a superior H2 receptor antagonistic effect than conventional H2 receptor antagonistic substances, has a remarkable effect of suppressing gastric acid secretion in animals, and has further mucosal protective effect and mucus secretion promoting effect as a protective effect. The object of the present invention is to provide a novel substituted aminoalkylphenoxy derivative having the following.

That is, the compound of the present invention has the general formula (wherein R' and R2 are each independently a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, or R1 and R2 are each combined with the nitrogen atom to which they are bonded) , forming a 4- to 8-membered heterocyclic ring which may further have a substituent, A represents a straight or branched alkylene group having 1 to 4 carbon atoms, and Z is the formula (in the formula, msn , p represents 0 to 4, and X represents oxygen or sulfur), R4 is hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkenyl group, or an alkynyl group, and R5 is hydrogen or an alkyl group having 1 to 4 carbon atoms. an alkyl hydrogen or an alkyl group having 1 to 4 carbon atoms, and q represents 0 to 4). ] is an aminoalkylphenoxy derivative of

Regarding R1 and R2, examples of the lower alkyl group having 1 to 4 carbon atoms include methyl, ethyl, propyl, isopropyl, n
Examples include -butyl, S-butyl, and t-butyl.

Examples of the heterocyclic group formed with the nitrogen atom to which R1 and R2 are bonded include azetidine, pyrrolidino, piperidino, perhydroazepino, and pipera groups.

These heterocyclic groups may be substituents such as a hydroxyl group, a methoxy group, an ethoxy group, a lower alkyl group having 1 to 6 carbon atoms, and the like.

Examples of the alkylene group of A are methylene, ethylene,
Examples include propylene, isopropylene, and isobutylene groups.

Regarding R4-R5 in each formula represented by Z, carbon number 1
Examples of the alkyl group of ~4 include methyl, ethyl, n-propyl, 15O-propyl, n-butyl, 5ec-butyl, t-butyl, etc., and examples of the alkenyl group include ethylene, 2-propynyl, 2- Examples of butenyl, 3-butenyl, and alkynyl groups include 2-propargyl.

R3 represents an aralkyl group, and examples of the aralkyl group include benzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, and 2-furanomethyl. Further, R3 is preferably hydrogen, dimethylaminomethyl, diethylaminomethyl, piperidinomethyl, or pyrrolidinomethyl.

In general formula (1), the geometric isomerism of the double bond portion can be either cis or trans.

Representative examples of the compound of general formula (1) provided by the present invention include the following in addition to those listed in Examples below.

1-(2-pyridylmethylamino)-2-[4-<3-
(1-pyrrolidino-methyl)phenoxy〉-cis
-2-butenylaminoco-1-cyclobutene-3,4-
Dione; 1-(3-pyridylmethylamino)-2-[4-<3-
(1-pyrrolidino-methyl)phenoxy〉-cis-
2-butenylaminoco-1-cyclobutene-3,4-dione; 1-(4-pyridylmethylamino)-2-44-<3-
(1-pyrrolidino-methyl)phenoxy〉-cis-
2-butenylamino-1-cyclobutene-3,4-dione; ■-Benzylamino-2- C4-<3. (dimethylaminomethyl)phenoxy>-cis-2-butenylaminoco-1-cyclobutene-3,4-dione: ■-(2-furanylmethylamino)-2-[4-<3-
(1-pyrrolidino-methyl)phenoxy〉-trans
-2-butenylaminoco-1-cyclobutene-3,4
-dione; 1-(3-furanylmethylamino)-2'-[4-<3
-(1-pyrrolidino-methyl)phenoxy>-tran
s -2-butenylaminoco-1-cyclobutene-3,
4-dione; 1-(2-thiofuranylmethylamine)-2-[:4-
<3-(1-pyrrolidino-ethyl)phenoxy>-c
is-2-butenylaminoco-1-cyclobutene 3.4
-dione; ■-(3-thiofuranylmethylamino)-2-C4-<
3-(1-pyrrolidino-ethyl)phenoxy>-ci
s-2-butenylaminoco-1-cyclobutene-3,4
-dione; 1-(4-pyridylmethylamino)-2-(4-<3-
(1-perhydroazepinylmethyl)phenoxy>-
cis-2-butenylaminoco-1-cyclobutene-3
,4-dione: 2-amino-3-[4-<3- (1-piperidinomethyl)phenoxy>-trans -2-butenylaminoco-pyrazine; 2-methylamino-3-C4-<3- (1-piperidinomethyl) phenoxy> -4rans -2-butenylaminoco-pyrazine; 2-amino-3-C4-<3- (1-pyrrolidinomethyl)phenoxy>-cis-2-butenylaminoco-pyrazine; 2-methylamino-3-[4- <3-(1-pyrrolidinomethyl)phenoxy>-cis-2-butenylaminoco-pyrazine;2-ethylamino-3-[4-<3-(1-piperidinomethyl)phenoxy>-cis-2-butenylaminoco-pyrazine;2-amino-3-[4-<3- (3-hydroxy-1
-pyrrolidinomethyl)phenoxy>-cis-2-butenylaminoco-pyrazine;2-amino-3-[4-<3- (3-hydroxy-1
-piperidinomethyl)phenoxy>-cis-2-butenylaminoco-pyrazine; 2-methylamino-3-[4-(3-dimethylaminomethylphenoxy) -cis-2-butenylaminoco-pyrazine; 2- [4-<3- ( 1-piperidinomethyl)phenoxy>-cis-2-butenylamino]-IH-quinazolin-4-one;2-C4-<3-(1-piperidinomethyl)phenoxy>-cis-2-butenylamino-6-dimethylaminomethyl-IH-quinazolin-4-one; 2- [4-<3- (1-pyrrolidinomethyl)phenoxy>-cis-2-butenylamino]-IH-quinazolin-4-one; 2- [4-<3- ( 1-pyrrolidinomethyl)phenoxy>-cis-2-butenylamino]-IH-quinazolin-4-one;2-C4-<3-(dimethylaminomethyl)phenoxy>-cis-2-butenylamino]-IH-quinazoline-4-one;2-C4-<3-(1-piperidinomethyl)phenoxy> -trans -2-butenylamino-IH-
6-dimethylaminomethyl-IH-quinazolyso4-
2-[4-<3-(1-piperidinomethyl)phenoxy>-trans-2-butenylamino-IH-
Quinazolin-4-one; 2- [4-<3-(1-piperidinomethyl)phenoxy> -trans -2-butenylaminoco-6=
Dimethylamino-IH-quinazolin-4-one: The compound represented by the general formula (1) of the present invention or a salt thereof can be produced by various production methods described below depending on the type of substituent Z.

First step Second step H In each of the above formulas, R', R'', R3 are as described above, R20 is lower alkyl, preferably methyl, and E is 10- or -5-1 preferably It is 10-.

Although each of the above steps may be carried out separately, it is preferable to carry out them continuously. In the first step, it is preferable to use both raw materials in equimolar amounts, and in the second step, the amine 82N-
It is preferred to use R' in excess, ie 2 to 5 times the number of moles.

Both steps can be carried out for 30 minutes, and when a solvent is used, an inert organic solvent such as methanol, ethanol, propatool, acetonitrile, chloroform, etc. can be used. The reaction temperature ranges from 0°C to below the boiling point of each solvent (generally 50°C
150°C), preferably at room temperature to 80°C.

Although the reaction time varies depending on the temperature, both steps are completed in 30 minutes to 24 hours.

Examples of raw materials for the first step include the following known substances.

The compound is prepared by the method described in JP-A-57-165348, and its derivatives are prepared by a method similar to the method.

88 (7), 1533 (1966).

(In the formula, R1, R2, R4, A are as described above,
B is R30S-(R''. is alkyl, preferably the above reaction is carried out without a solvent or in an inert organic solvent, from 50° to 150°
It can be carried out at ℃. This can be carried out using an alcohol as an inert solvent, preferably methanol, ethanol, or propatool, under reflux.

Francis G. McDonald et al., Journal of the American Chemical Society (Francis G.
McDonald et al, J. Am, Ch.
em.

Soc,), 69.1034~? (1947)
It was synthesized using the method described in .

(In the formula, R1, R2, R5, A are as described above, and D
are halogen (chlorine, bromine, iodine) atoms, lower alkylthio groups).

2-Methylthio-IH-quinazolin-4-one derivatives have been described by Seth, M. et al., Indian Journal Chemistry Section B (Indian J, Ch.
em.

5ect, B) can be produced according to the method described in 1976.14B(7), 536. This reaction is carried out without a solvent or in a solvent. Methanol, ethanol, water, DMF, DMSOl, etc. can also be used as a solvent. The reaction is carried out by stirring at 50'' to 150°C for 5 minutes to 24 hours.

As another method for producing the compound of general formula (1) (wherein R
', R2, A and Z are as described above, M is an alkali metal (sodium and potassium are preferred), and X is a halogen (chlorine, bromine, iodine) atom), or (formula (R', R2, ASX, MSZ have the same meanings as above) can also be used.

Pharmacological Effects of the Compounds of the Invention Several of the compounds of the invention were compared in various tests with cimetidine, which is widely used clinically as a peptic ulcer agent having an antagonistic effect on the histamine H2 receptor.

This test was conducted by Tsukomi et al., Applied Pharmacology, 1969, Vol. 3 (1), 7.
The method on pages 1 to 14 was modified and carried out.

Wistar (1') weighing around 160g fasted for 24 hours
Urethane 1.2g/kg to 1ister) male rats
was injected intraperitoneally and anesthetized. After ligating the esophagus and the pylorus of the stomach, an incision was made in the anterior and dorsal region, and a double polyethylene cannula was attached. The stomach wall was washed with physiological saline at 5 mA every 30 minutes, and the amount of gastric acid contained in this wash was measured by titration.

First, basal acid secretion was measured three times, then 0.2 mg/kg of the compound of the present invention was subcutaneously injected, and 30 minutes later, 3 mg/kg of histamine was subcutaneously injected.

Gastric acid secretion was measured for up to 3 hours thereafter. The three points showing the highest increase in acid secretion were selected in each time period, and the average value was taken as the increase in acid secretion for each sample group, and the inhibition rate relative to the control group was calculated by comparing it with the increase in acid secretion in the control group. .

(Experimental values show the average value of 5 cases.) In addition, a sample of a compound with a strong acid secretion suppressing effect was administered into the duodenum of rats 30 minutes before subcutaneous injection of histamine, and the histamine-induced increase in gastric acid secretion was inhibited by 50%. The dose <ED5o) was determined. The results are shown in Table 2.

A male Hartley guinea pig weighing approximately 400 g was sacrificed by exsanguination, and the right atrium was removed.

Modified Ringer's solution
The rats were suspended in a 50 ml organbath containing a gel solution, a tension of 1 g was applied, and the heart rate was recorded using a polygraph.

First, histamine was applied cumulatively from 1X10-7 mol to 3X10-' mol, and a dose-response curve was drawn. Next, draw a dose-response curve for histamine in the same manner in the presence of 5 x 10-'' to 1 x 10-6 moles of the sample injected 3 minutes earlier. The negative logarithm of concentration (pΔ2) value was calculated.

The results are shown in Table 1.

As shown in Table 1, the inhibitory effect of the subcutaneously injected compound of the example on histamine gastric acid secretion enhancement was clearly stronger than that of cimetidine. In addition, the histamine H2 receptor antagonism using isolated right atrium specimens from guinea pigs showed a strong efficacy comparable to or even greater than that of cimetidine.

Another feature of the compound of the present invention is that its effect on suppressing histamine gastric acid secretion in rats by intraduodenal administration, which is similar to oral administration, was extremely strong. That is, Table 2
As shown in the E D5 of each compound of Example 2.3.6
．． Values are EDs of cimetidine. Approximately 97 each compared to the value
．． It was 180.55 times more potent. (Table 2) Therefore, the compound of the present invention has a strong histamine H2 receptor inhibitory effect and a gastric acid secretion suppressing effect, and has low toxicity, making it an extremely useful compound as an anti-ulcer agent.

Example 1 4-[3-(1-piperidinomethyl)phenoxy]
-cis-2-butenylamine 1 g (0,003
dimethyl squarate (Sidney Cohen et al., j,
8mer, Chem, Sac,, Vol.
88. 1533. 1966 Produced by the method described. )0.55g (0,00387 mol) was added and stirred at room temperature for 4 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, eluting with a mixture of ethyl acetate and methanol in a ratio of 4:1. 1.15 g (yield: 810%) of the title compound was obtained as a pale yellow oil.

IR (neat, cm-'): 2950.1805
．． 171B, 1610.1280°1120, 102
0.10.00.870.750°700, 66O N+, IR (CDCβ3.pflm): 1
．． 2-1.9(61-1, lwa, 2.1~2.6(
41t! , l), 3.35 (3H,S),
3. =IO(2H,S), 4.3~4.5(2H,
M＞.

5.5~5.7(2H,!,D, 6.5~7.3(
4H.

M>, 7.9 (LH, disappeared with 8 heavy water) Example 2 1-Methoxy-2-[:4-<
3-(1-piperidinomethyl)phenoxy>-cis
-2-butenylamino)-1-cyclobutene-3,4-
Zeon 2. Og (0,0054 mol) and 1.17 g (0,0108 mol) of 3-aminomethyl-pyridine were dissolved in 25 ml of absolute ethanol and stirred at room temperature for 4 hours. After the reaction, the precipitated crystals were recrystallized from ethanol to give 1.65 g of colorless crystals with a melting point of 191-3°C (yield: 6
8.5%).

Elemental analysis C2s H30N 403 Calculated value: H, 6,77; C, 69,93: N,
12.55 Measured value: H, 6,79; C, 68,78
; N, 12.35IR (KBr, cm-'):
3190. 2950. 1800. 1622°1560, 1430. 1350. 1260°11
50, 1050. 770. 718NMR(DMS
Ods, 29m): 1.2~1.8(6H
, m), 2.05-2.6 (4H, m), 3.
25 (2H, s), 3.3 (2H, s), 4.
1-4.4 (2H, m).

4.4-4.9 (3tl, m), 5.57-5
．． 9(2)1. m), 6.6-6.9 (2
H, m).

6,9-8.6 (8H,m) Example 3 l-(4-pyridylmethylamino)-2-[4-<3-
(1-piperidinomethyl)phenoxy〉-cis-2
-butenylryomino]-1-cyclobutene-3,4-dione The title compound was prepared in the same manner as in Example 2 except that 3-aminomethylpyridine in Example 2 was replaced with 4-aminomethylpyridine. .

Colorless crystals, melting point 186-190°C, yield 56%.

Elemental analysis C26H30N 40 s Calculated value: H, 6,77; C, 69,93; N,
12.55 Measured values: H, 6,74, C, 69,92;
N, 12.411R (KBr, cm-Re: 3
200. 2950. 1810. 1650°156
0, 1490. 1430. 1280°1040,
800. 700. 62ONMR (DMSO-ds
, ppm): 1.3 to 1.7 (6H, m),
2.05-2.45 (4H, m), 3.3 (2H
,s), 3.4(2H,s), 4.6-4.
9 (2H, m).

4, 1-4.5 (2N, m), 5.6-5.
9 (2H.

m), 6.6~8.6 (9N, m IH with heavy water treatment
Example 4 l-(4-pyridylmethyl)-2-[4-(3-<1-
(2-methylpiperidino)-methyl〉phenoxy) −
cis-2-butenylaminoco-1-cyclobutene-3
,4-dione pale yellow oil IR (neat, cm-'): 3200.29
50.2560.1800°1670, 1600.12
60.1030°9O NIJR (CDCj23.ppm) 4. L~1.4
(31(,d), 1.3-2.0(6H,m), 4
．． 1-4.55 (211, m>.

4.5-5.0 (4)1. m), 5.6-6.0(
2tl, m), 6.2-7.5 (5H, m).

8.35-8.8 (2N, d).

M"=460 Example 5 ■-(4-pyridylmethyl)-2-[4-(3-<1-
(4-methylpiperidino)-methyl〉phenoxy) −
cis -2-butenylaminoco-1-cyclobutene-
3,4-dione pale yellow oil IR (neat, cm-'): 3250.29
60.1805.1680°1600, 1540.
1365. 1330°1270, 1170.1040
．． 800,70ONMR ((:DCj! 3.ppm)
'0.8~1. H3)1. s), 1.3-1.
9 (6H, m), 2.4-3.4 (3H, m>.

3.86 (2H, s), 4.1-4.5 (2) 1. m
).

4.55-5.0 (2H, m), 5.5-6.0 (2
fl, m), 6.7-8.6 (IH disappeared by treatment with 9H, m heavy water) Example 6 2-amino-3-[4-<3-(1-piperidinomethyl)phenoxy>-cis-2-butenylamino ]-Pyrazine IR (neat, cm-'): 3310.
2960. 1660. 1550°1450. 12
60. 1160. 1040°870, 780.
70O NEAR (CDCβ3.ppm): 1.3-1.
8 (6)1. s), 2.2-2.6 (4H
, m), 3.45 (28, s>, 3.8-4.
2 (2H, m) 4.5-4.8 (2H, m).

5.5-6.0 (2H, m), 6.6-7.4 (6
tl.

m) Example 7 2-[4-<3-(1-piperidinomethyl)phenoxy>-cis-2-butenylaminoco-6-dimethylaminomethyl-IH-quinazolin-4-one 4-<3-(1-piperidinomethyl ) Phenoxy>-
1.0 g (3.85 mmol) of cis-2-butenylamine and 2-methylthio-6-dimethylamino, -methyl-
IH-quinazolin-4-one (melting point 195-197°C (
d) 0.96 g (3.86 mmol) was melted at 100° C. and stirred for 24 hours. After the reaction is completed, 6mj! was dissolved in methanol and subjected to column chromatography using silica gel. Purification was carried out by elution with ethyl acetate ethanol:ammonia=6:1:1 to obtain the title compound as a pale yellow oil.

IR (neat, cm-'): 3210.16
70.1620.1500°1460, 1390.13
50.1260°1125, 1040.990.860
°825, 770.690.56O NMR (CDCj23.ppm): 1.3-1.8
(6H, m), 19 (6tl.

s), 2,1-2.7 (6H, m), 3.4 (
2H,s), 4. (r5.0 (2H, m).

5.6~6.0 (28, m), 6.1~6.6 (L
H.

bro, disappeared by heavy water treatment), 6.7 to 8.1 (8
1 (, m)

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (1) (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 R^1
and R^2, together with the nitrogen atom to which they are bonded, form a 4- to 8-membered heterocyclic ring which may further have a substituent, and A
indicates a linear or branched alkylene group having 1 to 4 carbon atoms, and Z is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ▲ Numerical formulas, chemical formulas,
There are tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼
There are tables, etc. ▼ (In the formula, m, n, p represent 0 to 4, and X represents oxygen or sulfur), and R^4 is hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkenyl group, or It is an alkynyl group, R^5
is hydrogen, alkyl group having 1 to 4 carbon atoms, ▲ mathematical formula, chemical formula,
There are tables, etc. ▼ (In the formula, R^6 and R^7 are hydrogen or an alkyl group having 1 to 4 carbon atoms, and q represents 0 to 4). ] Aminoalkylphenoxy derivative.