JPH01156948A - Novel phenoxyalkylamine derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R1 and R2 are lower alkyl or R1 and R2 together with adjacent N further form 5-7-membered nitrogen- containing heterocyclic ring which may be replaced with lower alkyl; R3 is H or lower alkylene; m is 3 or 4; n is 1-3; Z is group shown by formula II) or a salt thereof. EXAMPLE:1,3,5-Benzenetricarbonyloxytri-[N-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]acetamide. USE:An antitumor agent showing excellent and durable inhibitory action on secretion of acid in the stomach. PREPARATION:A compound shown by formula III is reacted with a compound shown by formula IV (X1 is halogen, especially chlorine) to give a compound shown by formula I.

Description

Detailed Description of the Invention The present invention relates to a novel phenoxyalkylamine derivative, and more specifically, in the following general formula, R and R2 each independently represent a lower alkyl group, or R1 and R8 are bonded together. together with the nitrogen atom, forming a 5- to 7-membered nitrogen-containing heterocycle which may be further substituted with a lower alkyl group: R1 represents a hydrogen atom or a lower alkyl group; m is 3 or 4; n is an integer of 1 to 3; Z represents a trivalent group represented by the following formula; and salts thereof.

The compound of formula (I) and its salts exhibit excellent and long-lasting suppressive action on gastric acid secretion, and are useful as active ingredients of anti-ulcer agents.

By the way, one of the major causes of ulcers in the stomach or duodenum is the secretion of abnormally large amounts of gastric acid, and the conventional anti-ulcer drugs to deal with this are those that have the effect of neutralizing gastric acid and those that have anticholinergic effects. It is broadly divided into those with . However, the type that neutralizes gastric acid has poor sustainability and is weakly effective, and the type that has anticholinergic effects is strongly undesirable for MII use.

On the other hand, it is already known that gastric acid secretion is stimulated via histamine H2 receptors, and recently a new type of gastric acid secretion inhibitor that has this histamine H2 receptor antagonistic effect has been developed, and several proposals have been made. [For example, Japanese Patent Publication No. 53-24422, Japanese Patent Application Laid-open No. 53-18557
Publication No. 149936/1983, Japanese Patent Application Laid-Open No. 1983-149936
-109963, JP-A-55-115860, JP-A-56-8352, etc.].

The compound of formula (I) provided by the present invention is a novel compound that has not been described in conventional literature, and has excellent gastric acid secretion suppressing action and long-lasting action based on histamine H7 receptor antagonism. It is a useful compound as a new type of anti-ulcer agent.

The term "lower" as used herein means that the compound or group to which this term is attached has no more than 6 carbon atoms, preferably no more than 4 carbon atoms.

Thus, a "lower alkyl group" can be either linear or branched, for example methyl, ethyl, n
-propyl, isopropyl% n-butyl, isobutyl,
Included are 5ec-butyl, Lθrt-butyl groups, and the like.

In the above formula (I), the "5- to 7-membered nitrogen-containing heterocycle" that can be formed by R and R2 together with the nitrogen atom to which they are bonded includes a heteroatom other than the nitrogen atom. It is desirable that there be no ring, and it is preferable that the ring is saturated. Specific examples of such heterocyclic groups include l-pyrrolidinyl, 1-piperidinyl, and 1-perhydroazepinyl groups. These nitrogen-containing heterocyclic groups may be further substituted (preferably mono-substituted) with a lower alkyl group, and specific examples of such substituted nitrogen-containing heterocyclic groups include 2-methyl-1- piperidinyl, 3-methyl-
Included are 1-piperidinyl and 4-ethyl-I-piperidinyl groups.

This group includes dimethylamino, 1-pyrrolidinyl, ■-piperidinyl, ■-perhydroazepinyl, and 3-methyl-1-piperidinyl groups, among which especially 1
-pyrrolidinyl, -piperidinyl and l-perhydroazepinyl groups are preferred.

Further, as the group R3, a hydrogen atom, a methyl group and an ethyl group are preferable. Thus, the groups ■-(l-pyrrolidinyl)ethyl, 1-(1-pyrrolidinyl)propyl, l-piperidinylmethyl and l-perhydroazepinylmethyl groups may be mentioned.

In addition, in the formula (I), m is preferably 3, and n is preferably 1.

According to the invention, salts of the compounds of formula (I) above are also provided. Examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids such as acetic acid, propionic acid, oxalic acid, lactic acid, citric acid, tartaric acid, p-toluenesulfonic acid, etc. Among these, pharmacologically acceptable salts are suitable.

The compound of the formula (I) is a compound of the following formula, in which R1, R3, R, m and n have the above-mentioned meanings. represents a chlorine atom, 2 has the above meaning, and can be produced by reacting with a compound of the following.

The reaction between the compound of formula (I[) and the compound of formula (I[I)] can be carried out in the absence of a solvent or in a suitable inert solvent such as alcohols such as methanol and ethanol; aromatic hydrocarbons such as benzene and toluene. ; ethers such as tetrahydro7rane and dioxane; amides such as dimethylformamide and dimethylacetamide; dimethyl sulfoxide; It can be carried out at a temperature of

The amount of the compound of formula (II) to be used is not critical and can vary widely depending on the type of starting material used, etc., but in general, the amount of the compound of formula (If) is 1 mole of the compound of formula (I It can be used in an amount of at least 3 mol, preferably 3 to 6 mol, more preferably 3 to 3.5 mol.

In the above reaction, the reaction may be carried out in the presence of a condensing agent if necessary, and examples of condensing agents that can be used include organic bases such as pyridine and triethylamine; and inorganic bases such as sodium carbonate.

The compounds of formula CI) prepared by the methods described above can be converted into the corresponding salts.

The salt-forming reaction can be easily carried out by treating the compound of formula (I) with the above-mentioned inorganic or organic acid according to a method known per se.

Thus, said formula (I) prepared according to the method of the invention
The compound or a salt thereof can be isolated and/or purified from the reaction mixture by means known per se, such as recrystallization, distillation, column chromatography, thin layer chromatography, etc.

The phenoxyalkylamine derivative represented by formula (1) of the present invention and its salt as explained above have a long-lasting suppressive effect on gastric acid secretion based on its excellent histamine H2 receptor antagonism, and suppresses gastric acid secretion caused by gastric acid. It is a very useful compound in the treatment of diseases such as gastric or duodenal ulcers.

The following animal experiments demonstrate that the compound represented by formula (I) of the present invention has excellent histamine H2 receptor antagonism.

The compounds of the present invention used in the following animal experiments are represented by the following symbols.

Compound A: 1.3.5-benzenetricarbonyloxytri[N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]azedamide].

The head of a Hartley guinea pig (male: 400-550, ?) was bruised and exsanguinated, and the heart was removed. The right atrium was dissected in oxygen-saturated Tyrode's solution and silk sutures were attached to both ends. A tension cuff was placed in a Magnus tube (25 mβ) containing Tyrode's solution kept at 36°C and aerated with a mixed gas (95% oz. 20025%) using silk thread attached to both ends.
The atrium was suspended with mg. A force displacement transducer (Force) measures the contraction movement of the atrium.
-d i sp lacement-transduc
er) and the heart rate was calculated.

Histamine (used in the form of diphosphate, the same hereinafter) was administered at doses equally spaced in logarithm of the added amount in % until the maximum response of increasing heart rate was obtained. 1
Histamine dose-response curve
rve) was obtained. The inside of the Magnus tube was evacuated and cleaned several times, and the atrium was stabilized for 1 hour, and then the above procedure was repeated again to obtain a histamine dose-response curve. After washing the inside of the Magnus tube several times, the tissue was allowed to stabilize for 50 minutes. The test compound (I
X l O-'M) was added into the Magnus tube, and after 20 minutes, a dose-response curve of histamine in the presence of the test compound was obtained.

J, M from the second dose-response curve of histamine and the third dose-response curve of histamine in the presence of the test compound.
, Van Rossun+'s method (Arch, in
t, Pharmacodyn, l 43.29
9, l 963) for each test compound (the negative logarithm of the molar concentration of the test compound required to double the histamine concentration in the Magnus tube required to produce a given reaction). )
) was calculated. The results are shown in Table 1 below.

Table 1 Compound 4 A 5.97 Thus, the compound represented by formula (I) of the present invention can be administered orally or parenterally as an anti-ulcer agent for the treatment and treatment of humans and other warm-blooded animals. For example, intramuscular injection, intravenous injection,
(subcutaneous administration, rectal administration, transdermal administration, etc.), but oral administration is particularly preferred.

When used as a medicament, the compounds of the invention can be formulated into a variety of forms suitable for oral or parenteral administration.

For example, the compounds of the present invention may be incorporated into non-toxic excipients, binders, lubricants, disintegrants, preservatives, etc. commonly used in such drugs.
It can be formulated using additives such as tonicity agents, stabilizers, dispersants, antioxidants, colorants, flavoring agents, buffering agents, etc.

Such drugs may be in solid form (e.g., tablets, hard capsules, soft capsules, granules, powders, fine granules, emulsions, lozenges, etc.) or semi-solid forms (e.g., suppositories, ointments, etc.) depending on their use. ) and liquid forms (injections, emulsions, suspensions, syrups, sprays, etc.). Therefore, the non-toxic additives that can be used include, for example, starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, magnesium aluminate metasilicate, synthetic aluminum silicate, silicic anhydride, talc, stearic acid. Magnesium, methylcellulose, carboxymethylcellulose or its salts, gum arabic, polyethylene glycol, p-hydroxybenzoic acid alkyl ester, syrup, ethanol, phlopylene gellicol, petrolatum, carbowax,
Examples include glycerin, sodium chloride, sodium sulfite, sodium phosphate, citric acid, and the like. The medicament may also contain other therapeutically useful agents.

The content of the compound of the invention in the drug varies depending on the drug layer, but is generally in a concentration of 5 to 100% by weight for solid and semi-solid forms and 0.1% for liquid forms. It is desirable to contain the active compound in a concentration of ~10% by weight.

The dosage of the compound of the present invention can vary widely depending on the type of warm-blooded animal including humans, the route of administration, severity of symptoms, doctor's diagnosis, etc., but in general, the dosage is 0.2 per day. ~80mg/kH.

Suitably, it can be set to 0.5-50+og/kg. However, as mentioned above, depending on the severity of the patient's symptoms and the doctor's diagnosis, it is of course possible to administer an amount smaller than the lower limit or larger than the upper limit of the above range. The above dosage can be administered once a day or in divided doses.

The present invention will be further explained below with reference to Examples.

Example 1 N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydroxyacetamide (300 mg)
1°3.5-benzenetricarbonyl chloride (90 mg) was added to the solution in chloroform (2 ml) and reacted at room temperature for 2 hours. Aqueous sodium hydroxide solution was added, and the product was extracted with chloroform. The chloroform layer was extracted with anhydrous It was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. Ether was added, and the precipitated crystals were collected by filtration to give 1,3.5-benzenetricarbonyloxytri[N-[3-[3-
(l-piperidinylmethyl)phenoxy]propyl]acetamide] (95 mg) was obtained.

IR (liquid film, cm-'); 1735.1660°N M
R (CD CQs, δ); l-2 ~ 1.9 (18H
.

multiplet), 2.00 (6H, triplet, J-5Hz)
, 2.1-2.7 (12H, multiplet), 3.40 (6
H1-double), 3.49 (6H, quartet, J-6Hz
), 4.01 (6H, triple line, J-6Hz), 4.
78 (6H, -multiplet), 6.5-7.4 (15H9 multiplet), 8.83 (3H, -multiplet).

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ In the formula, R_1 and R_2 each independently represent a lower alkyl group, or R_1 and R_2 together with the nitrogen atom to which they are bonded. to form a 5- to 7-membered nitrogen-containing heterocycle which may be further substituted with a lower alkyl group; R_3 represents a hydrogen atom or a lower alkyl group; m is 3
or 4; n is an integer of 1 to 3; Z represents a trivalent group represented by the following formula ▲ Numerical formula, chemical formula, table, etc. ▼ Compounds and salts thereof.