JPH0441142B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to dioxocyclobutene derivatives having a 4-mannituhypyridin-2-yl group, processes for their preparation, pharmaceutical compositions containing them and their use as histamine antagonists. .

Histamine is a biologically active compound endogenous to mammals that exerts its activity through interaction with certain sites called receptors. One type of receptor is known as a histamine H ₁ -receptor (Ash and Schild, Brit. J. Pharmac.
Chemorhen. 27 427 (1966)), the effects of histamine transmitted through these receptors can be blocked by drugs commonly called "antihistamines" (histamine H ₁ -antagonists), of which mepyramine is a common example. be done. The second type of histamine receptor is known as the _H2 -receptor (Black
etal.Nature 1972, 236 , 385). These receptors are blocked by brimamide but not by mepyramine. These histamines
A compound that blocks H ₂ − receptors is histamine H ₂ −
called an antagonist.

Histamine _H2 -antagonists are used _to treat disease states caused by the biological effects of histamine transmitted via _H2 -receptors, e.g. as gastric acid secretion inhibitors. and as an inhibitor of the effects of histamine on blood pressure, such as drugs acting on the cardiovascular system, such as histamine, which is transmitted through the _H2 -receptor.

Cimetidine has proven useful in the treatment of duodenal, gastric, recurrent and marginal ulcers and ruminant esophagitis, and in the treatment of patients who are at high risk due to upper gastrointestinal bleeding.

In some physiological conditions, the biological effects of histamine are transmitted through both histamine _H1- and _H2 -receptors, and blockade of both types of receptors is useful. These conditions include histamine-mediated inflammation, such as dermatitis;
and hypersensitization reactions due to the action of histamine at H ₁ - and H ₂ -receptors, such as allergies.

The present invention is based on the formula: [In the formula, R ¹ and R ² are each alkyl having 1 to 6 carbon atoms, or a -(CH ₂ ) _o - bond with n of 4 to 6, and together with the nitrogen atom to which they are bonded, R 1 and R 2 are alkyl having 1 to 6 carbon atoms; forms a 7-membered ring].

Preferred R ¹ is methyl, ethyl, n-propyl or isopropyl. Preferred R ² is methyl,
Ethyl or n-propyl. In one preferred embodiment, R ¹ R ² N- represents dimethylamino. In other preferred embodiments, preferably R ¹
R ² NCH ₂ − represents pyrrolidinomethyl, piperidinomethyl or hexahydroazepinomethyl. Particularly preferred is piperidinomethyl.

The activity of compounds of formula () as histamine _H2 -antagonists is due to their ability to inhibit histamine-stimulated gastric acid secretion from the rumen-perfused stomach of urethane-anesthetized rats and histamine-induced inhibition of contractions of isolated rat uteruses. can be demonstrated by their ability to reverse. These are Ash and Shield.
Schield, Birt. J. Pharmac. Chemother. 27 247
(1966)), this is an effect of histamine that is not transmitted through histamine H ₁ -receptors.

The histamine _H2 -antagonistic activity of the compound also
It can also be demonstrated by suppressing gastric acid secretion induced by histamine stimulation in Heidenhain small stomach dogs, by suppressing histamine-induced tachycardia in the isolated right atrium of guinea pigs, and by suppressing histamine-induced vasodilation in anesthetized cats.

The measurement of suppression of gastric acid secretion induced by histamine stimulation from the rumen-perfused stomach of rats anesthetized with urethane and the suppression of histamine-induced tachycardia in the isolated right atrium of guinea pigs are described in European Patent Application Publication No. 0049173 by the applicant. It is detailed in

To demonstrate the level of activity of the compounds of the present invention, the inventors have demonstrated that the products of the examples below have an ED ₅₀ value of less than 1 micromolar Kg (intravenously) in the rumen perfusion rat test and in the guinea pig atrial test. It was determined to have a pA ₂ value of 6 or higher.

The compounds of the invention are much more active and have a longer duration of activity than related compounds in which the R ¹ R ² NCH ₂ - group is a 6-substituent of the pyridyl group.

Furthermore, we found that the compound of Example 1 had significantly increased activity over cimetidine after intravenous administration to Heidenhain dogs when the dose level was adjusted to produce a peak response similar to that of cimetidine. It was found that the duration of

For use of compounds of formula () or pharmaceutically acceptable salts thereof as medicaments, they are usually formulated as pharmaceutical compositions according to standard formulation methods.

Furthermore, the present invention provides a pharmaceutical composition comprising the compound of formula () or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Compounds of formula () and pharmaceutically acceptable salts thereof can be administered orally, parenterally, transdermally or rectally.

Orally active compounds of formula () and their pharmaceutically acceptable salts can be formulated as syrups, tablets, capsules and lozenges.
Syrup formulations generally consist of a suspension or solution of the compound or salt in a suitable liquid carrier such as ethanol, glycerin or water and a flavoring or coloring agent. If the composition is in tablet form, any suitable pharmaceutical carrier commonly used in the manufacture of solid formulations may be employed. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A typical parenteral composition consists of a solution or suspension of the compound or salt in a sterile aqueous carrier or parenterally acceptable oil.

Typical compositions for transdermal administration include lotions and creams containing a compound of formula () or a salt thereof in a liquid vehicle.

A typical suppository formulation will include a compound of formula () or a pharmaceutically acceptable salt thereof which is active in the method of administration and a binder such as gelatin, cocoa butter or other low melting vegetable wax or oil and/or
or consisting of lubricants.

Preferably, the composition is in unit dosage form, such as a tablet or capsule, so that the patient can administer a single dose himself.

The pharmaceutical compositions of the present invention are generally administered at dosage levels similar to those used for known histamine _H2 -antagonists, at dosage levels tolerable considering the efficacy of the compounds of the present invention for known histamine _H2 -antagonists. It is administered to humans in the usual manner for the treatment of peptic ulcers and other conditions caused or exacerbated by gastric acidity. For example, an adult patient may receive a single dose of 15 to 1500 mg, preferably 20
~250 mg orally or 1.5 to 150 mg, preferably 5 to 20 mg intravenously, subcutaneously or intramuscularly, and the composition is administered 1 to 6 times a day.

The compounds of the invention do not show any obvious signs of toxicity at the level of administration to patients.

In other embodiments of the invention, compounds of formula () and pharmaceutically acceptable acid addition salts thereof are, for example, of formula: [In the formula, R ¹ and R ² are the same as above] A compound represented by the formula: [In the formula, Q means a group capable of substituting with an amine] It can be produced by a method comprising reacting with a compound represented by the following and, if necessary, forming a pharmaceutically acceptable acid addition salt. can.

The compound of formula () has been published in European Patent Application No.
It can be manufactured by the method of No. 0049173. formula()
The compound can be prepared by the method of British Patent Specification No. 1,563,090.

Suitable Q is alkoxy having 1 to 6 carbon atoms, halogen or alkylthio having 1 to 6 carbon atoms, for example,
Methylthio, methoxy or ethoxy. Among them, methoxy is preferred. The reaction can be carried out in the absence of a solvent or in a solvent such as methanol, ethanol or acetonitrile. In the presence of a solvent, the reaction temperature can be, for example, from room temperature to reflux temperature. In the absence of solvent, the reaction temperature is elevated, e.g. about 120-160°C
is convenient.

Pharmaceutically acceptable acid addition salts of compounds of formula () can be prepared from the corresponding bases of compounds of formula () in conventional manner. For example, the base can be reacted with an acid in an alkanol having 1 to 4 carbon atoms, or an ion exchange resin can be used. Salts of compounds of formula () can be interconverted using ion exchange resins. Therefore, even pharmaceutically unacceptable salts can be converted into pharmaceutically acceptable salts and can therefore be used.

Suitable pharmaceutically acceptable acid addition salts of compounds of formula () include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
Included are the salts formed with acetic acid, citric acid, maleic acid, lactic acid, ascorbic acid, fumaric acid, oxalic acid, methanesulfonic acid and ethanesulfonic acid.

During the methods described herein, optionally
Either group can be appropriately protected, if necessary, by conventional methods.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 1-[3-[4-(piperidinomethyl)pyridin-2-yloxy]propan-1-ylamino]-2-aminocyclobutan-1-ene-3,
4-dione 1-amino-2-methoxycyclobutane-1-
0.5 g of ene-3,4-dione (UK patent specification no.
1563090) and 3-[4-
(piperidinomethyl)pyridin-2-yloxy]
1.05g of propan-1-ylamine and 25g of ethanol
ml for 4 hours. A solid forms during the reaction. The reaction mixture is cooled and the solids are collected by filtration. The solid is recrystallized from ethanol/methanol to give 0.88 g of the title product. Melting point 226-228℃. Example 2 1-[3-[4-dimethylaminomethyl)pyridin-2-yloxy]propan-1-ylamino]-2-aminocyclobutan-1-ene-3,
4-dione 1-amino-2-methoxycyclobutane-1-
0.5 g of ene-3,4-dione and 3-[4-(dimethylaminomethyl)pyridin-2-yloxy]propan-1-ylamine are refluxed in ethanol in the same manner as in Example 1. The solid obtained is recrystallized from ethanol to give 0.79 g of the title product. Melting point 212-214℃.

Example 3 1-[3-[4-(dimethylaminomethyl)pyridin-2-yloxy]propan-1-ylamino]-2-aminocyclobutan-1-ene-
3,4-dione 1-amino-2-methoxycyclobutane-1-
Ene-3,4-dione in dry pyridine with 3-
mixed with [4-(dimethylaminomethyl)pyridin-2-yloxy]propan-1-ylamino,
Heating to reflux temperature gives the title product.

Example 4 1-[3-[4-(piperidinomethylpyridine-
2-yloxy]propan-1-ylamino]
-2-aminocyclobutan-1-ene-3,4
-dione 1-amino-2-methoxycyclobutane-1-
Ene-3,4-dione in dry pyridine with 3-
Mixing with [4-(piperidinomethyl)pyridin-2-yloxy]propan-1-ylamine and heating to reflux gives the title product.

Example 5 Pharmaceutical composition for oral administration A pharmaceutical composition for oral administration is obtained according to the following formulation.

Ingredients % (w/w) Product of Example 1 55. Dibasic Calcium Phosphate Dihydrate 20 Colorant 0.5 Polyvinylpyrrolidone 4.0 Microcrystalline Cellulose 8.0 Corn Starch 8.0 Sodium Glycolate 4.0 Magnesium Stearate 0.5 of Example 1 Mix the product, dibasic calcium phosphate dihydrate and colorant, add a concentrated solution of polyvinylpyrrolidone, granulate, dry and pass the dry granules through a sieve. Cellulose, starch, sodium glycolate and magnesium stearate are added to the granules and compressed into tablets containing 100 mg, 150 mg or 200 mg of the free base of the product of Example 1.

Example 6 Pharmaceutical Composition for Injection The product of Example 1 was converted into its hydrochloride salt, which was dissolved in water for injections (EP) at a concentration of 1-5% (w/
w) Obtain a solution. The solution is clarified by filtration, filled into vials, sealed and sterilized to obtain a vial containing 2 ml of the solution for injection.

Reference example 1 1-amino-2-(3-hydroxypropylamino)cyclobutan-1-ene-3,4-dione 1-amino-2-methoxycyclobutane-1-
1.27 g of ene-3,4-dione and 0.75 g of 3-hydroxypropylamine are refluxed in 25 ml of ethanol for 4 hours. The reaction mixture is cooled and the solid product is collected by filtration. Wash this with ethanol,
After drying, 1.3 g of the title compound was obtained. Melting point 256−258
℃.

get.

Elemental analysis value, calculated value (%): C49.41, H5.92, N16.46 Actual value (%): C49.27, H5.88, N16.38 NMR: δ = 1.69 (2H, m), 3.4 ~3.7 (4H, m),
4.47 (1H, t, OH), 7.32 (3H, broad, amino proton) ppm.

Claims (1)

[Claims] 1 Formula: [In the formula, R ¹ and R ² each have 1 to 6 carbon atoms
alkyl, or -(CH ₂ ) _o - where n is 4 to 6
A compound represented by the following formula or a pharmaceutically acceptable salt thereof. 2. The compound of item 1 above, which is R ¹ R ² N-dimethylamino. 3. The compound of item 1 above, wherein R ¹ R ² N- is piperidino. 4 1-[3-[4-(piperidinomethyl)pyridin-2-yloxy]propan-1-ylamino]-2-aminocyclobutan-1-ene-3,
4-dione or a pharmaceutically acceptable salt thereof, or 1-[3-[4-(dimethylaminomethyl)pyridin-2-yloxy]propan-1-ylamino]-2-aminocyclobutan-1-ene-3,
The compound according to item 1 above, which is a 4-dione or a pharmaceutically acceptable salt thereof. 5 Formula: [In the formula, R ¹ and R ² each have 1 to 6 carbon atoms
alkyl, or -(CH ₂ ) _o - where n is 4 to 6
A histamine H ₂ comprising a compound represented by the following formula or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. - Antagonist composition. 6 formula: [In the formula, R ¹ and R ² are the same as below] A compound represented by the formula: [In the formula, Q means a group that can be substituted with an amine] A compound represented by the following formula: [In the formula, R ¹ and R ² each have 1 to 6 carbon atoms
alkyl, or -(CH ₂ ) _o - where n is 4 to 6
form a 5- to 7-membered ring together with the nitrogen atom to which they are bonded] or a pharmaceutically acceptable salt thereof.