JPS6129355B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a heterocyclic compound having medicinal efficacy, a method for preparing the compound, a pharmaceutical composition containing the compound, and a method for administering the compound to block histamine _H2 -receptors. Although the compounds can also exist as acid addition salts, for convenience, the parent compound is described herein. Many physiologically active substances exert their biological effects through specific sites known as receptors. Histamine is also such a substance and has many biological effects. The biological effects of histamine, which are usually inhibited by antihistamines such as mepyramine, diphenhydramine, and chloropheniramine, are directed to the histamine _H1 -receptor [Ash and Schild, Brit. J. Pharmac.
Chemother, vol. 27, p. 427 (1966)], and drugs having such an action are hereinafter referred to as histamine H ₁ -antagonists. However, other biological effects of histamine are not suppressed by histamine H ₁ -antagonists, and this type of effect has been reported by Black et al., Nature, vol. 236, p. 385 (1972).
Histamine H ₂ was suppressed by a compound called primamide, which was described by
-Exercised through receptors defined as receptors.
Thus, the histamine _H2 -receptor can be defined as a histamine receptor that is not inhibited by mepyramine but is blocked by brimamide. Histamine _H2 - Compounds that block receptors are histamine _H2
-It is called an antagonist. Blockade of histamine _H2 -receptors is histamine _H1
- Useful in inhibiting the biological effects of histamine that are not inhibited by antagonists. Therefore, histamine H ₂ -antagonists are useful as drugs that act on the cardiovascular system, such as gastric acid secretion inhibitors, anti-inflammatory agents, and agents that suppress the effect of histamine on blood pressure. Combinations of histamine _H1- and _H2 -antagonists are useful in treating certain conditions such as inflammation and inhibiting the effects of histamine on blood pressure. The compounds of the present invention have both histamine H ₁ -antagonistic activity and histamine H ₂ -antagonistic activity, and can also be used in the treatment of symptoms for which histamine H ₂ -antagonists are effective.
It is also useful for treating conditions for which a combination of histamine H ₁ - and H ₂ - antagonists is effective. Compounds of the invention have the formula: [In the formula, Het is a lower alkyl (preferably methyl) substituted 4-imidazolyl ring, a 2-pyridyl ring (optionally substituted with lower alkoxy, preferably methoxy, halogen, preferably chlorine or bromine, or amino) good) or 2-
Thiazolyl ring; Y is sulfur or methylene group; Z is hydrogen or lower alkyl (preferably methyl);
Het' is 2-, 3- or 4-pyridyl (optionally substituted with lower alkyl or lower alkoxy), 2-thienyl, 2-thiazolyl or 3
- quinolyl] or a pharmaceutically acceptable salt thereof. Preferred Het is 2-thiazolyl, 5-methyl-
4-imidazolyl, 3-bromo-2-pyridyl,
3-chloro-2-pyridyl or 3-methoxy-
It is a 2-pyridyl ring. Preferred Y is sulfur, and preferred Z is hydrogen. Preferred Het' are 2-thienyl, 2-pyridyl,
It is a 3-pyridyl, 4-pyridyl or 2-thiazolyl ring. A particularly preferred Het' is a 3-pyridyl ring. In this specification, the term "lower alkyl" refers to an alkyl group having 1 to 4 carbon atoms, and the term "lower alkoxy" refers to an alkoxy group having 1 to 4 carbon atoms. The compound of formula [1] is 4-pyrimidone and 4-
Although shown as thione derivatives, these derivatives exist in equilibrium with the corresponding 6-one and 6-thione tautomers. These compounds also exist to some extent as mercapto and hydroxy tautomers, and the pyrimidine ring also exists in the following tautomeric forms. Certain Het and Het' may also exist in several tautomeric forms, all of which are within the scope of this invention. Hydrates of the compound of formula [1] and pharmaceutically acceptable hydrated salts of the compound of formula [1] are also within the scope of the present invention. Compounds within the scope of the present invention include 2-[2-(5-
Methyl-4-imidazolylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone, 2-[2-(2-thiozolylmethylthio)ethylamino]-5-(4-pyridylmethyl)- 4-
Pyrimidone, 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone, 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl Amino]-5-(2-thienylmethyl)-4-pyrimidone, 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-pyridylmethyl)-4-pyrimidone, 2- [2-(5-methyl-4-imidazolylmethylthio)ethylamino]
-5-(3-pyridylmethyl)-4-pyrimidone,
2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(2-pyridylmethyl)
-4-pyrimidone, 2-[2-(5-methyl-4-
imidazolylmethylthio)ethylamino]-5-
(2-thiazolylmethyl)-4-pyrimidone, 2-
[2-(2-thiazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone, 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-( 3-pyridylmethyl)-4-pyrimidone. The compound of formula [1] has the formula: [wherein Z and Het' are the same as in formula [1]; Q means a group conveniently substituting lower alkylthio, benzylthio, halogen or amine] isocytosine represented by the formula: Het-CH ₂ -Y- (CH ₂ ) ₂ -NH ₂ [3] [In the formula, Het and Y are the same as in the formula [1]] It can be produced by treatment with an amine represented by the following formula. Preferably, the reaction is carried out without a solvent at an elevated temperature, for example 150°C, or in the presence of a solvent such as in refluxing pyridine. An intermediate of formula [2] (compound of formula [6] below) in which Z is hydrogen and Q is lower alkylthio can be produced according to the following reaction formula 1. Reaction formula 1 [In the formula, Het' is the same as in formula [1]; a is 0; Alk means lower alkyl] The ester of formula [4] can be produced by a known method,
For example, in the presence of pyridine and piperidine, the formula
It can be produced by condensing the aldehyde of Het'-CHO with malonic acid, hydrogenating it, and esterifying the product. An intermediate of formula [2] (compound of formula [7] described below) in which Z is lower alkyl and Q is lower alkylthio can be produced according to Reaction Scheme 2. Reaction formula 2 [In the formula, Het′ is the same as the formula [1]; a is 0; Hal is chlorine or bromine; Alk means lower alkyl] Intermediate of formula [2] where Q is halogen (formula below)

Compound [9]) can be produced according to Reaction Scheme 3. Reaction formula 3 [Wherein Het' and Z are the same as in formula [1]; a is 0; Hal means chlorine or bromine] The amine of formula [3] is described in British Patent Nos. 1305547 and 1338169 and British Patent Application No. 31968/75
and No. 31970/75 (each patent application 1986-092242)
No. 51-092245). The compound of formula [1] blocks histamine _H2 -receptors. That is, the compound inhibits the biological effects of histamine that are not inhibited by histamine H ₁ -antagonists such as mepyramine, but are inhibited by brimamide. For example, the compounds of the present invention were found to inhibit histamine-stimulated secretion of gastric acid from the rumen-perfused stomach of urethane-anesthetized rats when administered intravenously at doses of 0.5 to 16 micromol/Kg. This method is described in Ash and Schild, supra. Also, these compounds histamine
The action as an H ₂ -antagonist is demonstrated by the ability to suppress other effects of histamine which are not mediated by histamine H ₁ -receptors, according to the above-mentioned reference by Archu and Shields. For example, the compound suppresses the effects of histamine on isolated atria of guinea pigs and uteri of rats. The compounds of the invention inhibit basal and pentagastrin or food stimulated secretion of gastric acid. Furthermore, the compound of the present invention exhibits anti-inflammatory activity in conventional tests such as the rat paw edema test in which edema is induced by irritants, and subcutaneous injection of the compound of formula [1] causes swelling in rat paws. Decrease. Routine tests, such as measuring blood pressure in anesthetized cats, can also demonstrate the effect of the compounds of the invention in inhibiting the vasodilatory effects of histamine. The activity level of the compounds of the present invention is determined by the effective dose to inhibit gastric acid secretion by 50% in anesthetized rats (many compounds of formula [1] are 1-10 micromol/Kg) and histamine-induced in isolated guinea pig atrium. It is indicated as an effective dose that suppresses frequent sweating by 5%. Compounds of formula [1] also block histamine H ₁ -receptors. That is, the compound inhibits the biological effects of histamine that are inhibited by mepyramine, diphenhydramine and chloropheniramine. For example, it has been found that the compounds of the present invention suppress the effects of histamine in the isolated guinea pig ileum. Many of the compounds of formula [1] suppress histamine-stimulated contractions of the guinea pig ileum at doses from 10 ^-5 molar. For therapeutic use, the medicinally active compounds of the invention include:
Usually, at least one of the basic form or pharmaceutically acceptable acid addition salt of the compound is an essential active ingredient;
It is administered as a pharmaceutical composition comprising this and a pharmaceutical carrier. Such addition salts include hydrochloric acid, hydrobromic acid,
This includes salts with hydroiodic acid, sulfuric acid, maleic acid, etc., and can be prepared from the corresponding base of formula [1] by a conventional method, for example, by treating the base with an acid in a lower alkanol or using an ion exchange resin. The desired salts are conveniently obtained directly from the base or by forming the desired salts from other addition salts. A pharmaceutical composition comprising a compound of formula [1] or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutical carrier, and a compound of formula [1] or a pharmaceutically acceptable acid addition salt thereof are administered to induce histamine H ₂ -reception. Methods of isolating the body are also within the scope of this invention. The pharmaceutical carrier used may be, for example, solid or liquid. Examples of solid carriers include lactose, white porcelain, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Liquid carriers include syrup, peanut oil, olive oil, water, and the like. Various dosage forms can be employed. Thus, when a solid carrier is used, it can be a tablet, a powder or granules in a hard gelatin capsule, or a troche or lozenge. The amount of solid carrier can vary widely, but is preferably from about 25 mg to about 1 g. When using a liquid carrier, syrup,
They may be sterile injectable solutions, such as emulsions, soft gelatin capsules, ampoules, or aqueous or non-aqueous suspensions. The pharmaceutical compositions are manufactured by conventional methods including steps such as mixing, granulating, and tabletting or dissolving the ingredients appropriate to the desired product. The active ingredient is present in the composition in an effective amount to block histamine _H2 -receptors. Administration can be carried out orally or parenterally. Preferably, each dosage unit contains about 50 to about 250 mg of active ingredient. Preferably, the active ingredient is administered from 1 to 6 times per day. A daily dose of about 150 to about 1500 mg is preferred. Advantageously, the composition is adapted to the desired method of administration, for example as a tablet, capsule, injection solution or topical cream or ointment. Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto. In each example, pA ₂ (ileum) is histamine
The value in the contraction inhibition test due to histamine stimulation of the guinea pig ileum showing H ₁ -antagonism,
pA ₂ (atrial) is the value in the above-mentioned guinea pig atrium histamine-induced acid secretion suppression test showing histamine H ₂ -antagonism, and ED ₅₀ is the value in the gastric acid secretion suppression test by histamine stimulation from the rumen-perfused stomach of the rat (micromolar). /Kg). Furthermore, LD ₅₀ is the value (micromol/Kg) when administered intravenously to mice. Example 1 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone trihydrochloride (i) β-(4-pyridyl)propionic acid ethyl
43.45 g and 19.6 g of ethyl formate are added over a period of 6 hours to a stirred mixture of 5.6 g of sodium wire and 150 ml of dry ether cooled in an ice-salt bath.
The mixture is stirred at room temperature for 18 hours, evaporated to dryness and the residue is treated with 18.45 g of thiourea and 130 ml of ethanol and refluxed for 7 hours. The mixture is evaporated to dryness, the residue is dissolved in water and glacial acetic acid is added to bring the pH _{to 4} to precipitate the solid product. Take this white solid and wash it with ethanol.
-(4-pyridylmethyl)-2-thiouracil is obtained. Melting point 320-324°C (decomposed) (ii) 11.0 g of 5-(4-pyridylmethyl)-2-thiouracil, 7.2 g of methyl iodide and 2.1 g of sodium hydroxide in 50 ml of water and 100 ml of ethanol.
The medium solution is stirred at 60° C. for 30 minutes, cooled and filtered to give 5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone. Melting point 179-182°C (ethanol) (iii) 5.9 g of 5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone and 2-(5-methyl-4-imidazolylmethylthio)ethylamine
Heat 4.3 g of the homogeneous mixture at 145-150° C. for 5 hours and cool. Trituration of the residue with water and treatment with ethanolic hydrogen chloride gives the title compound. Melting point _: 228-233°C Elemental analysis, _{C17H23Cl3N6OS} , actual value (%): _C , 43.6; _H , 51.1;
N, 17.6; S, 7.2; Cl, 21.95 Theoretical value (%): C, 43.8; H, 5.0;
N, 18.0; S, 6.9; Cl, 22.8 _LD50 : 161, _pA2 (ileum) 4.75, _pA2 (atrial):
6.46, ED ₅₀ : 1.15 Example 2 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone trihydrochloride hemihydrate 5-(4 -pyridylmethyl)-2-methylthio-
1.55 g of 4-pyrimidone and 1.16 g of 2-(2-thiazolylmethylthio)ethylamine are heated at 135-140° C. with occasional stirring. After cooling, the reaction mixture is tritiated with water, acidified with dilute ethanolic hydrogen chloride, evaporated to dryness and the residue is recrystallized from methanol to give the title compound.
Melting point _: 190-195℃ Elemental analysis, _{C16H17N5OS2.3HCl.0.5H2O} , actual _value (%): _C , _40.3 ; H, 4.4;
N, 14.5; S, 13.3; Cl, 21.7 Theoretical value (%): C, 40.2; H, 4.4;
N, 14.7; S, 13.4; Cl, 22.3 pA ₂ (ileum): 6.75, pA ₂ (atrial) 6.36, ED ₅₀ :
2.4 Example 3 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone dihydrochloride Following the method of Example 2 above, 5 -(4-pyridylmethyl)-2-methylthio-4-pyrimidone
1.1 g are reacted with 1.15 g of 2-(3-bromo-2-pyridylmethylthio)ethylamine. The reaction mixture is tritiated with hot water, acidified with dilute ethanolic hydrogen chloride, evaporated to dryness and the residue is recrystallized from ethanol to give the title compound. Melting point: 211-215℃ (decomposed) Elemental analysis, as C ₁₈ H ₁₈ BrN ₅ OS・2HCl, Actual value (%): C, 42.65; H, 3.9;
N, 13.9; S, 6.3 Theoretical value (%): C, 42.8; H, 4.0;
N, 13.9; S, 6.35 LD ₅₀ : 241, pA ₂ (ileum): 6.69, pA ₂ (atrial):
6.44, ED ₅₀ : 2.13 Example 4 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-thienylmethyl)-4-pyrimidone dihydrochloride (i) 2-thienyl 33.3 g of ethyl propionate, 14.1 g of ethyl formate and 4.2 g of sodium are reacted in 120 ml of ether and the mixture is cooled in an ice-salt bath. The ether is evaporated and the residue is refluxed with 13.8 g of thiourea and 100 ml of ethanol. Evaporate the ethanol, dissolve the residue in water, and add acetic acid to precipitate 5-(2-thienylmethyl)-2-thiouracil (38
%). Melting point: 212-215°C (ethanol) (ii) 4.5 g of 5-(2-thienylmethyl)-2-thiouracil was heated at 65°C with a mixture of 2.8 g of methyl iodide, 0.8 g of sodium hydroxide, 75 ml of water and 150 ml of ethanol. to give 5-(2-thienylmethyl)-2-methylthio-4-pyrimidone (89%). Melting point: 170.5-171.5°C (ethanol) (iii) A homogeneous mixture of 1.43 g of 5-(2-thienylmethyl)-2-methylthio-4-pyrimidone and 1.03 g of 2-(5-methyl-4-imidazolylmethylthio)ethylamine Heat at 140℃ for 6 hours. The cooled residue is washed with water and treated with dilute ethanolic hydrogen chloride to give the title compound. yield
40%, mp 172-176 °C (ethanol-acetonitrile) The dihydrochloride was passed through an IRA400 ion exchange column, eluted with 1N hydrobromic acid, the eluate was evaporated to dryness, and recrystallized from ethanol-acetonitrile. The corresponding dihydrobromide salt is obtained. Melting point 199
~203℃ Elemental analysis, _{C16H19N5OS2 ・ 2HBr} Actual value (%): C, 36.7; _H , 4.2;
N, 13.5; S, 12.1; Br, 30.6 Theoretical value (%): C, 36.7; H, 4.0;
N, 13.4; S, 12.2; Br, 30.5 LD ₅₀ : 1.5, pA ₂ (atrial): 6.38, ED ₅₀ : 0.1 Example 5 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]- 5-(2-pyridylmethyl)-4-pyrimidone trihydrochloride hemihydrate (i) Ethyl β-(2-pyridyl)propionate
19.24 g and 8.5 g of ethyl formate were heated in a sodium wire cooled with carbon dioxide over a period of 1.75 hours.
Add to a stirred mixture of 2.5 g and 80 ml of dry ether. The mixture is stirred at room temperature for 21 hours, evaporated to dryness and the residue is treated with 8.2 g of thiourea and 70 ml of ethanol and refluxed for 7.5 hours.
The mixture is evaporated to dryness, the residue is dissolved in water and glacial acetic acid is added to bring the pH to 5. The white precipitate is collected, washed with water, and recrystallized from water-acetic acid to obtain 5(2-pyridylmethyl)-2-thiouracil. Melting point 262-267°C (decomposition) (ii) 6.6 g of 5-(2-pyridylmethyl)-2-thiouracil, 4.3 g of methyl iodide and 2.5 g of sodium hydroxide in 100 ml of water and 100 ml of ethanol.
The medium solution is stirred at 70° C. for 30 minutes, cooled and glacial acetic acid is added to bring the pH to 5. Evaporate a portion of this solution and cool in an ice bath. The precipitate is collected and recrystallized from ethanol to obtain 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone. Melting point: 195-197.5°C (iii) 4.7 g of 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone and 2-(5-methyl-4-imidazolylmethylthio)ethylamine
Heat 3.4 g of the homogeneous mixture at 130-135° C. for 7 hours. Trituration of the cooled residue with hot water and treatment with dilute ethanolic hydrogen chloride gives the title compound. Melting point: 207-210℃ ( _aqueous ethanol) Elemental analysis, as _C17H20N6OS・_3HCl・_0.5H2O , actual value (%): C, 42.8; H, 4.9;
N, 17.8; S, 6.9; Cl ^- , 21.8 Theoretical value (%): C, 43.0; H, 5.1;
N, 17.7; S, 6.8; Cl ^- , 22.4 LD ₅₀ : 19.8, pA ₂ (ileum): 4.9, pA ₂ (atrial)
7.22, ED ₅₀ : 0.2 Example 6 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone trihydrochloride (i) β-( Ethyl 3-pyridyl)propionate
38.9 g and 17.0 g of ethyl formate are added over a period of 2.25 hours to a stirred mixture of 5.0 g of sodium wire and 150 ml of dry ether cooled in an ice bath. The mixture is stirred at room temperature for 22 hours, evaporated to dryness and the residue is treated with 16.5 g of thiourea and 130 ml of ethanol and refluxed for 8 hours. The mixture is evaporated to dryness, the residue is dissolved in water and acetic acid is added to bring the pH to 5 to give 5-(3-pyridylmethyl)-2-thiouracil. Melting point 271-274
°C (decomposition) (acetic acid-water) (ii) 11.0 g of 5-(3-pyridylmethyl)-2-thiouracil, 7.1 g of methyl iodide and 4.2 g of sodium hydroxide in 150 ml of water and 150 ml of ethanol.
The solution in ml was stirred at 65° C. for 40 minutes, cooled and acetic acid was added to bring the pH to 5. Part of this solution was evaporated,
Cool, filter, 5-(3-pyridylmethyl)-
2-methylthio-4-pyrimidone is obtained. melting point
247-249°C (ethanol-acetic acid) (iii) A homogeneous mixture of 6.55 g of 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone and 4.8 g of 2-[5-methyl-4-imidazolylmethylthio)ethylamine. Heat at 130-135℃ for 7 hours. The cooled mixture is tritiated with hot water and treated with dilute ethanolic hydrogen chloride to give the title compound. Melting point: 237-241°C ( _{ethanol-water) Elemental analysis, as C17H20N6OS ・ 3HCl} , Actual value (%): C, 43.7; H, 5.2;
N, 17.4; S, 6.5; Cl ^- , 22.0 Theoretical value (%): C, 43.8; H, 5.0;
N, 18.0; S, 6.9; Cl ^- , 22.8 LD ₅₀ : 24.7, pA ₂ (atrial): 6.98, ED ₅₀ : 0.05 Example 7 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino] -5-(2-pyridylmethyl)-4-pyrimidone trihydrobromide 5-(2-pyridylmethyl)-2-methylthio-
1.5 g of 4-pyrimidone and 2-(3-bromo-2
A homogeneous mixture of 1.6 g of pyridylmethylthio)ethylamine is heated at 130° C. for 6 hours. After cooling,
Trituration of the residue with hot water and treatment with dilute hydrobromic acid gives the title compound. Yield 44.5%, melting point
225-230℃ (decomposition) (methanol-water) Elemental _analysis , _C18H18BrN5OS・3HBr Actual value (%): C, _32.1 ; H, 3.1;
N, 10.5; S, 4.8; Br ^- , 35.0 Theoretical value (%): C, 32.0; H, 3.1;
N, 10.4; S, 4.8; Br ^- , 35.5 LD ₅₀ : 80.7, pA ₂ (ileum) 6.25, pA ₂ (atrial)
6.79, ED ₅₀ : 2.72 Example 8 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-thiazolylmethyl)-4-pyrimidone trihydrochloride (i) 2-thiazole acrylic A solution of 26.76 g of acid and 10 ml of concentrated sulfuric acid in 150 ml of ethanol is refluxed for 18 hours. This solution is partially evaporated and dissolved in water. The solution is extracted with ether and the ether extract is evaporated to give ethyl 2-thiazole acrylate. (ii) 14.8 g of ethyl 2-thiazole acrylate is dissolved in 170 ml of ethanol and hydrogenated using 10% paldium-carbon at 40° C. and 50 psi to obtain ethyl 2-thiazole propionate. (iii) 14.2 g of ethyl 2-thiazolepropionate and 5.9 g of ethyl formate over a period of 2.25 hours;
Add to a stirred mixture of 1.8 g of sodium wire and 65 ml of dry ether cooled in an ice bath. The mixture was stirred at room temperature for 21 hours, evaporated to dryness, treated with 5.8 g of thiourea and 60 ml of ethanol, and
Let time flow. A solid product is obtained according to the method of Example 5(i) above to obtain 5-(2-thiazolemethyl)-2-thiouracil. Melting point 275-280
°C (decomposition) (acetic acid) (iv) 4.8 g of 5-(2-thiazolemethyl)-2-thiouracil, 3.0 g of methyl iodide and 0.9 g of sodium hydroxide in 75 ml of water and 150 ml of ethanol.
Stir the medium solution at 70 °C for 30 min. Said Example 5
A solid product was obtained according to method (ii), and 5-(2-
Thiazolemethyl)-2-methylthio-4-pyrimidone is obtained. Melting point: 181-1182.5°C (ethanol) (v) A homogeneous mixture of 1.4 g of 5-(2-thiazolemethyl)-2-methylthio-4-pyrimidone and 1.0 g of 2-(5-methyl-4-imidazolylmethylthio)ethylamino. Heat at 145-150℃ for 6 hours. Trituration of the cooled residue with hot water and treatment with dilute ethanolic hydrogen chloride gives the title compound. Melting point 208-211℃ (ethanol-water) Elemental analysis, C ₁₅ H ₁₈ N ₆ OS _2.3HCl Actual value (%): C, 38.9; H, 4.7;
N, 17.9; S, 13.5; Cl, 21.6 Theoretical value (%): C, 38.2; H, 4.5;
N, 17.8; S, 13.6; Cl22.5 LD ₅₀ : 16.5, pA ₂ (ileum): 5.05, pA ₂ (atrial): 7.38, ED ₅₀ : 0.07 Example 9 2-[2-(2-thiazolyl) Methylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone trihydrobromide 5-(3-pyridylmethyl)-2-methylthio-4- pyrimidone
1.74 g are reacted with 1.30 g of 2-(2-thiazolylmethylthio)ethylamine. The reaction mixture is tritiated with hot water and treated with dilute hydrobromic acid to give the title compound. Melting point _{: 229-233.5℃ (methanol-water) Elemental analysis, C16H17N5OS2.3HBr Actual value} (%): C, _32.1 ; H, 3.4;
N, 11.7; S, 10.3; Br ^- , 39.9 Theoretical value (%): C, 31.9; H, 3.4;
N, 11.6; S, 10.7; Br ^- , 39.8 LD ₅₀ : 141, pA ₂ (ileum): 6.08, pA ₂ (atrial)
7.24, ED ₅₀ : 0.09 Example 10 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone trihydrobromide Said example 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone according to method 2.
1.27 g are reacted with 1.35 g of 2-(3-bromo-2-pyridylmethylthio)ethylamine. The reaction mixture is tritiated with hot water and treated with dilute hydrobromic acid to give the title compound. Melting point 217~
220.5℃ (methanol) Elemental _analysis , _C18H18BrN5OS・_3HBr Actual value (%): C, 32.1; H, 3.2;
N, 10.2; S, 45; Br, 47.5 Theoretical value (%): C, 32.0; H, 3.1;
N, 10.4; S, 4.8; Br47.4 LD ₅₀ : 56.3, pA ₂ (ileum): 7.03, pA ₂ (atrial): 6.89, ED ₅₀ : 0.36 Example 11 In the method of Example 6, 2-( Instead of 5-methyl-4-imidazolylmethylthio)ethylamine, (a) 2-(3-methoxy-2-pyridylmethylthio)ethylamine (b) 2-(3-chloro-2-pyridylmethylthio)ethylamine (c) 2 -(3-fluoro-2-pyridylmethylthio)ethylamine (d) Using 2-(3-iodo-2-pyridylmethylthio)ethylamine, (a) 2-[2-(3-methoxy-2-pyridylmethylthio) ) ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone, melting point 155-156.5℃
(pA ₂ (ileum): 6.24, pA ₂ (atrial): 7.25,
ED ₅₀ : 0.11) (b) 2-[2-(3-chloro-2-pyridylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone, melting point 134-135.5°C
(pA ₂ (ileum): 6.9, pA ₂ (atrial): 7.34,
ED ₅₀ : 0.13) (c) 2-[2-(3-fluoro-2-pyridylmethylthio)ethylamino]-5-(3-pyridylmethyl-4-pyrimidone, melting point 107.5-109.5°C
(pA ₂ (ileum): 5.78, pA ₂ (atrial): 7.52,
ED ₅₀ : 0.14) (d) 2-[2-(3-iodo-2-pyridylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone, melting point 118-125.5°C
(pA ₂ (ileum): 7.32, pA ₂ (atrial): 6.89,
ED ₅₀ : 0.21). Example 12 (i) Reaction of 2-chloro-3-nitropyridine with 2-(2-cyanoethyl)malonic acid diethyl ester and sodium hydride in tetrahydrofuran to form 1-(3-nitro-2-pyridyl)-1 - 1-bis(carboethoxy)butyronitrile (melting point 93.5-94.5°C) is obtained, alkaline hydrolyzed and acidified to obtain 2-(3-cyanopropyl)-3-nitropyridine hydrochloride.
(Melting point 142-145.5℃). Cyclization with hydrogen on palladium-carbon gives 3-amino-2-(3-cyanopropyl)pyridine, which is treated with sodium nitrite and sulfuric acid and heated to give 2-(3-cyanopropyl)pyridine. -3-hydroxypyridine is obtained. Alkylation with methyl iodide and sodium ethoxy in dimethyl sulfoxide followed by cyclization with lithium aluminum hydride gave 4.
-(3-methoxy-2-pyridyl)butylamine is obtained. Alternatively, it is alkylated with ethylene iodide and sodium ethoxide in dimethyl sulfoxide, and then reduced with lithium aluminum hydride to obtain 4-(3-ethoxy-2-pyridyl)butylamine. 3-amino-2-
4-(3-Amino-2-pyridyl)butylamine is obtained by reducing (3-cyanopropyl)pyridine with lithium aluminum hydride. 4-
(3-Amino-2-pyridyl)butylamine was diazotized with cuprous chloride in hydrochloric acid or cuprous bromide in hydrobromic acid to give 4-(3-chloro-2-pyridyl)butylamine and 4-(3-chloro-2-pyridyl)butylamine, respectively. −
(3-bromo-2-pyridyl)butylamine is obtained. (ii) In the method of Example 6 above, in place of 2-(5-methyl-4-imidazolylmethylthio)ethylamine, (a) 4-(5-methyl-4-imidazolyl)butylamine (b) 4-(3 -methoxy-2-pyridyl)butylamine (c) 4-(3-ethoxy-2-pyridyl)butylamine (d) 4-(3-chloro-2-pyridyl)butylamine (e) 4-(3-bromo-2- (f) Using 4-(3-amino-2-pyridyl)butylamine, (a) 2-[4-(5-methyl-4-imidazolyl)butylamino]-5-(3-pyridyl) Methyl-4-pyrimidone trihydrochloride, melting point 242
~246℃ (pA ₂ (ileum): 5.78, pA ₂ (atrial): 6.62, ED ₅₀ : 0.125) (b) 2-[4-(3-methoxy2-pyridyl)butylamino]-5-(3- pyridylmethyl)-
4-pyrimidone, melting point 117-118℃ (LD ₅₀ :
88.4, pA ₂ (ileum): 7.84, pA ₂ (atrial):
7.37, ED ₅₀ : 0.23) (c) 2-[4-(3-ethoxy-2-pyridyl)
Butylamino]-5-(3-pyridylmethyl)
-4-pyrimidone, melting point 135-136°C (pA ₂
(ileum): 7.65, _pA2 (atrial): 6.71,
ED ₅₀ : 1.10) (d) 2-[4-(3-chloro-2-pyridyl)butylamino]-5-(3-pyridylmethyl)-
4-pyrimidone, melting point 146-147.5°C (pA ₂
(ileum): 8.23, _pA2 (atrial): 6.78,
ED ₅₀ : 0.56) (e) 2-[4-(3-bromo-2-pyridyl)butylamino]-5-(3-pyridylmethyl)-
4-pyrimidone, melting point 159-162℃ (pA ₂ (ileum): 8.67, pA ₂ (atrial): 6.5, ED ₅₀ :
0.4) (f) 2-[4-(3-amino-2-pyridyl)butylamino]-5-(3-pyridylmethyl)-
4-pyrimidone, melting point 130-131.5℃ (LD ₅₀ :
141, pA ₂ (ileum): 8.84, pA ₂ (atrial):
6.64, ED ₅₀ : 0.42). Example 13 (i) A solution of 63.71 g of 3-quinolyl acrylic acid and 25 ml of concentrated sulfuric acid in 350 ml of ethanol is refluxed for 18 hours. The product is isolated according to the method of Example 8(i) above to yield ethyl 3-quinolyl acrylate. Melting point 86.5-88℃ (ethanol-water) Elemental analysis, as C ₁₄ H ₁₃ NO ₂ Actual value (%): C, 73.8; H, 5.8; N, 6.0 Theoretical value (%): C, 74.0; H, 5.8 ;N, 6.2 (ii) Ethyl 3-(3-quinolyl)acrylate 5168
g in 170 ml of ethanol and hydrogenated using 10% palladium on carbon at 37° C. and 50 psi to obtain ethyl 3-(3-quinolyl)propionate. (iii) 3-(3-quinolyl)propionic acid ether
47.99 g and 16.3 g of ethyl acid are added to a stirred mixture of 4.8 g of sodium wire and 150 ml of dry ether cooled in an ice bath over a period of 3 hours. The mixture is stirred at room temperature for 20 hours, evaporated to dryness and the residue is treated with 15.9 g of thiourea and 130 ml of ethanol and refluxed for 7 hours. The mixture is evaporated to dryness, the residue is dissolved in water and acetic acid is added to bring the pH to 4. Pass the mixture to obtain 5-(3-quinolylmethyl)-2-thiouracil. Melting point 281-286
°C (decomposition) (acetic acid-water) (iv) In 200 ml of water and 200 ml of ethanol, 5-(3
-quinolylmethyl)-2-thiouracil 17.5
A solution of 9.2 g of methyl iodide and 5.4 g of sodium hydroxide was stirred at 75°C for 1 hour and allowed to cool.
Add acetic acid to adjust the pH to 4, remove the solid and give 5-
(3-quinolylmethyl)-2-methylthio-4-
Get pyrimidone. Melting point 215.5-218°C (ethanol) (v) 2.1 g of 5-(3-quinolylmethyl)-2-methylthio-4-pyrimidone and 2-(5-methyl-4-imidazolylmethylthio)ethylamine
Heat 1.3 g of the homogeneous mixture at 150-155° C. for 6 hours. The cooled mixture was tritiated with hot water and treated with dilute ethanolic hydrogen chloride to give 2-
[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-quinolylmethyl)-4-pyrimidone trihydrochloride is obtained. Melting point 184-189℃ (ethanol-water), LD ₅₀ :
129, pA ₂ (ileum): 5.93, pA ₂ (atrial):
6.12, ED ₅₀ : 0.34 Example 14 5-(3-quinolylmethyl)-2-methylthio-
A homogeneous mixture of 2.0 g of 4-pyrimidone and 1.2 g of 2-(2-thiazolylmethylthio)ethylamine is heated at 145° C. for 4 hours. After cooling, the residue was triturated with hot water and treated with dilute ethanolic hydrogen chloride to give 2-[2-(2-thiazolylmethylthio)
ethylamino]-5-(3-quinolylmethyl)-4
- Obtain pyrimidone trihydrochloride. Melting point 202~205
°C (ethanol-water), pA ₂ (ileum): 6.17, pA ₂
(Atrial): 6.28, ED ₅₀ : 1.49 Example 15 (i) 48 g of pyridine-3-carboxaldehyde,
A mixture of 52 g of ethyl acetoacetate, 4.8 g of 40% aqueous piperidine acetate, and 5% palladium on carbon (50% wet, 2.48 g) is hydrogenated at 100 psi at 30° C. for 22 hours. dilute the mixture with ether,
filtrate, evaporate the liquid and distill under reduced pressure to give 2
-(3-pyridylmethyl)ethyl acetoacetate is obtained. Boiling point 146℃/1mmHg. This ester,
Reflux in ethanol with thiourea and sodium ethoxide and then acidify the mixture to yield 5-(3-pyridylmethyl)-3-methyl-2-thiouracil. Melting point 328-331℃ (ii) 5-(3-pyridylmethyl)-6-methyl-2
- Thiouracil was treated with methyl iodide and sodium ethoxide in ethanol at 0°C and then acidified to give 2-methylthio-5-
(3-pyridylmethyl)-6-methyl-4-pyrimidone is obtained. Melting point 208-211℃ (iii) 2-methylthio-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone at 160-211℃
At 170°C, condensation with (a) 2-(2-thiazolylmethylthio)ethylamine (b) 2-(3-bromo-2-pyridylmethylthio)ethylamine yields (a) 2-[2-( 2-thiazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-
6-methyl-4-pyrimidone, melting point 118-121
°C ( _pA2 (ileum): 5.68, _pA2 (atrial):
6.72, ED ₅₀ : 2.0) (b) 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone, melting point 159-162 °C (pA ₂ ileum): 6.34, pA ₂ (atrial): 6.87, ED ₅₀ : 1.1). (iv) 2-Methylthio-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone was treated with 2-(5-methyl-4-imidazolylmethylthio)ethylamine in refluxing pyridine for 25 hours, then mixed. The liquid was evaporated and the residue was chromatographed on silica gel and chloroform-
Elute with methanol (5:1) to give 2-[2-
(5-methyl-4-imidazolylmethylthio)
ethylamino]-5-(3-pyridylmethyl)-
6-methyl-4-pyrimidone is obtained. Melting point 128
~131℃, _pA2 (ileum): 5.33, _pA2 (atrial):
6.62, ED ₅₀ : 0.34) Example 16 (i) 6-Methylpyridine-2-carboxaldehyde is condensed with malonic acid in pyridine using piperidine catalyst to give 2-(6-methyl-3-pyridyl)acrylic acid. (melting point 213-215.5
°C), which is converted into the corresponding ethyl ester (melting point 36
~37°C). This is reduced with hydrogen and palladium-carbon to obtain oily ethyl 3-(6-methyl-3-pyridyl)propionate. (ii) Following the method of Example 1(i) above, ethyl 3-(6-methyl-3-pyridyl)propionate was treated with sodium and ethyl formate to form 5-(6
-Methyl-3-pyridylmethyl)-2-thiouracil is obtained (melting point 240-241°C). This was prepared by the method of Example 1(ii) above.
-pyridylmethyl)-2-methylthio-4-pyrimidone. Melting point: 197-198.5°C (iii) According to the method of Example 1(iii) above, 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone was converted into (a) 2-(5-methyl -4-Imidazolylmethylthio)ethylamine (b) 2-(2-thiazolylmethylthio)ethylamine (c) 2-(3-bromo-2-pyridylmethylthioethylamine) (d) 4-(5-methyl-4-imidazolyl) Butylamine (e) 4-(3-methoxy-2-pyridyl)butylamine (f) 4-(3-chloro-2-pyridyl)butylamine (g) 4-(2-pyridyl)butylamine (h) 4-(3- (a) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4, respectively, upon treatment with ethoxy-2-pyridyl)butylamine. -Pyrimidone trihydrochloride, melting point 210-214℃ (LD ₅₀ :
121, pA ₂ (ileum): 5.49, pA ₂ (atrial):
7.05, ED ₅₀ : 0.09) (b) 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrochloride,
Melting point 187-190℃ (LD ₅₀ : 476, pA ₂ (ileum): 6.48, pA ₂ (atrial): 7.21, ED ₅₀ :
0.27) (c) 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(6-methyl-
3-pyridylmethyl)-4-pyrimidone trihydrochloride, melting point 193-196°C (LD ₅₀ : 124,
pA ₂ (ileum): 7.15, pA ₂ (atrial): 6.85,
ED ₅₀ : 0.18) (d) 2-[4-(5-methyl-4-imidazolyl)butylamino]-5-(6-methyl-3-
(pyridylmethyl)-4-pyrimidone trihydrochloric acid, melting point 189-190°C (pA ₂ (ileum):
6.7, pA ₂ (atrial): 6.45, ED ₅₀ : 0.16) (e) 2-[4-(3-methoxy-2-pyridyl)
butylano]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrochloride,
Melting point 209-210℃ (LD ₅₀ : 318, pA ₂ (ileum): 7.77, pA ₂ (atrial): 6.66, ED ₅₀ :
0.21 (f) 2-[4-(3-chloro-2-pyridyl)butylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone free base, melting point
132-133℃ ( _LD50 : 237, pA (ileum):
8.6, pA ₂ (atrial): 6.94, ED ₅₀ : 0.73) (g) 2-[4-(2-pyridyl)butylamino]
-5-(6-methyl-3-pyridylmethyl)-
4-pyrimidone free base, melting point 156.5-157.5
°C ( _pA2 (ileum): 7.28, _pA2 (atrial):
6.5, EP ₅₀ : 0.4) (h) 2-[4-(3-ethoxy-2-pyridyl)
Butylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone free base, melting point 104-105°C (pA ₂ (atrial): 6.82, ED ₅₀ :
1.11). Example 17 (i) A mixture of 111 g of ethyl formate and 108 g of 2-butanone is added dropwise to a stirred mixture of sodium hydride in oil (50% w/w, 72 g) and the mixture is allowed to stand overnight. Add 800 ml of ether and take 101 g of solid. Cyanoacetamide 69.5 in this solid
g, piperidine acetate (prepared by adding piperidine to 7 ml of acetic acid and 18 ml of water until the mixture is basic) and 400 ml of water are added and the mixture is heated under reflux for 2 hours and allowed to cool. The mixture was acidified with acetic acid and the precipitated solid was recrystallized from aqueous ethanol to give 3-cyano-5,6-dimethyl-2.
-43.5 g of hydroxypyridine are obtained. (ii) A homogeneous mixture of 42 g of 3-cyano-5,6-dimethyl-2-hydroxypyridine and 81 g of phosphorus pentachloride is heated at 140-160°C for 2 hours. The phosphoryl chloride is distilled off under reduced pressure and 500 g of ice-water are added to the residue. The mixture is adjusted to pH 7 with aqueous sodium hydroxide and extracted with ether. The ether extract was distilled to obtain an oil, which was crystallized from petroleum ether (boiling point 60-80°C) to give 2-chloro-3-cyano-5,6-dimethylpyridine25.3
get g. Melting point 83-87℃ (iii) 2-chloro-3-cyano-5,6-dimethylpyridine 21.5g, semicarbazide hydrochloride 24.0g
A mixture of 42.3 g of sodium acetate, 225 ml of water and 475 ml of methanol was mixed with Raney-nickel catalyst 5.
hydrogenate at 50 psi and 50° C. Add the mixture to 750 ml of water and filter. The solid was taken and suspended in 130 ml of water, 70 ml of concentrated hydrochloric acid was added, and the mixture was heated at 100°C for 1 hour. Add 120 ml of 40% w/w formalin and further heat the mixture at 100℃.
Heat for 0.5 hours and leave to cool. sodium acetate 95
g and 250 ml of water were added, the mixture was extracted with ether, the extract was washed with 5% aqueous potassium carbonate and evaporated to give 13.24 g of 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde.
(60%). Melting point 69-70℃ (iv) 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde 16.85g, malonic acid
11.45g, piperidine 10ml and pyridine 100ml
The mixture is heated under reflux for 1 hour and evaporated to give an oil. Dissolve this oil in 2N sodium hydroxide solution and extract with chloroform (discard). The aqueous layer is made acidic with hydrochloric acid and extracted with chloroform. The chloroform extract was washed with water and evaporated to give 3-(2-chloro-5,6-dimethyl-
18.3 g (87%) of 3-pyridyl)acrylic acid are obtained. Melting point 150-158℃. This acid is esterified using ethanol and sulfuric acid to obtain the ethyl ester. Melting point 85-88℃ (v) 3-(2-chloro-5.
32.7 g of ethyl 6-dimethyl-3-pyridyl)acrylate is hydrogenated with 3 g of 5% palladium-carbonate at 25-30° C. and 50 psi. The mixture is filtered and the liquid is evaporated to give an oil, which is partitioned between chloroform and N-hydrochloric acid. The aqueous layer is made basic with aqueous sodium hydroxide, extracted with chloroform, and the chloroform extract is evaporated to yield 21.8 g (80%) of ethyl 3-(5,6-dimethyl-3-pyridyl)propionate as an oil. . (vi) According to the method of Example 13(iii) above, 3-(5.6
-Ethyl dimethyl-3-pyridyl)propionate is reacted with ethyl formate and sodium hydride in dimethoxyethane to give ethyl 3-(5,6-dimethyl-3-pyridyl)-2-formylpropionate. Melting point 148-149℃. This ester was treated sequentially with thiourea and methyl iodide according to the method of Example 1(i) and (ii) above to obtain 5-(5,6-dimethyl-3-pyridylmethyl)-2-methylthio-4 -pyrimidone was obtained, and this compound was reacted with 2-(3-bromo-2-pyridylmethylthio)ethylamine at 140°C for 6 hours to obtain 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5. -(5・6
-dimethyl-3-pyridylmethyl)-4-pyrimidone is obtained. Melting point 105-107°C, pA ₂ (atrial): 8.10, ED ₅₀ : 0.04 Example 18 (i) 2-methoxy-5-cyanopyridine 61.26
g, semicarbazide hydrochloride 76.4g, sodium acetate 74.92g, ethanol 1300ml and water 400ml
The mixture was hydrogenated using 1.0 g of Raney Nickel catalyst at 50 p.si. Mixed liquid capacity 500
ml, add 1000ml of water, and cool the mixture to 0°C.
Leave it overnight. Filter the mixture, wash the solid with water, and dissolve in 1000 ml of 10% hydrochloric acid. Add 450 ml of 36% w/v formaldehyde solution, warm the mixture for 15 minutes, allow to cool, and dilute with sodium acetate in 900 ml of water.
Add to 298.5g of solution. The mixture was extracted three times with 500 ml of ether, the oil extracts were combined, washed successively with aqueous potassium carbonate and water, dried and evaporated to yield 31.5 g (50%) of 6-methoxypyridine-3-carboxaldehyde. get. Melting point 48~
(ii) A mixture of 2.34 g 6-methoxypyridine-3-carboxaldehyde, 4.51 g monoethyl malonate, 12 ml pyridine and 6 drops of piperidine is heated under reflux for 5 hours and evaporated to give an oil. This oil is partitioned between ether and dilute aqueous ammonia. The ether layer was washed with water and evaporated to give an oil which was left to crystallize to yield 2.8 ethyl 3-(6-methoxy-3-pyridyl)acrylate.
g (79%). Melting point: 49-52℃ (iii) 3-(6-methoxy-3) in 160ml of ethanol
- 32.33 g of ethyl pyridyl acrylate, 5
% palladium-carbon using 0.2 g, 50 p.si, 40
Hydrogenate at °C. The mixture was filtered and the liquid was evaporated to give 32.7 g of ethyl 3-(6-methoxy-3-pyridyl)propionate as an oil. (iv) 32.74 g of ethyl 3-(6-methoxy-3-pyridyl)propionate and 17.22 g of ethyl formate.
Sodium hydride (50 ml) in oil was added to 50 ml of 1,2-dimethoxyethane cooled to -2°C.
%) into 9.38 g of a stirred suspension over a period of 1.5 hours, left overnight at room temperature, and poured onto ice. Extract the mixture with ether (discard) and adjust the aqueous layer to pH 5 with 2N sulfuric acid. The oil precipitates and crystallizes on standing to form 2-formyl-3-(-6methoxy-
Ethyl 3-pyridyl)propionate 25.9g (70
%). Melting point 91.5-94℃. Sample recrystallized from aqueous ethanol, melting point 93-94°C. methyl)-2-methylthio-4-pyrimidone,
This compound was reacted with (a) 2-(5-methyl-4-imidazolylmethylthio)ethylamine (b) 2-(2-thiazolylmethylthio)ethylamine at 140°C for 6 hours to give (a) each 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone trihydrochloride, melting point 205-209°C (LD ₅₀ :
230, pA ₂ (ileum) 5.53, pA ₂ (atrial) 6.86,
ED ₅₀ : 0.06) (b) 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone, melting point 95-97
°C ( _LD50 : 236, _pA2 (ileum): 6.18, _pA2
(Atrial): 6.72, _ED50 : 0.34). Example 19 (i) 20.8 g of sodium are dissolved in 285 ml of methanol, a solution of 115.53 g of 2-chloro-4-cyanopyridine in 850 ml of methanol dioxane (1:1) is added and the mixture is boiled under reflux for 2.5 hours. , leave to cool. Filter the mixture, reduce the volume to 200 ml by evaporating the liquid, and add 400 ml of water. The precipitated solid was collected to obtain 57.2 g (51%) of 2-methoxy-4-cyanopyridine. Melting point 93~
95.5℃ (ii) 57.2g of 2-methoxy-4-cyanopyridine,
A mixture of 71.25 g of semicarbazide hydrochloride, 69.86 g of sodium acetate, 1200 ml of ethanol, and 370 ml of water was mixed with 1.0 g of Raney-nickel catalyst.
Hydrogenate at 50 p.si. The mixture is evaporated to a volume of 450 ml, 900 ml of water is added and the mixture is left overnight at 0°C. Filter the mixture, wash the solid with water,
Dissolve in 950ml of % hydrochloric acid. 420 ml of 36% w/v formaldehyde solution are added, the mixture is warmed for 30 minutes, allowed to cool and added to a solution of 280 g of sodium acetate in 840 ml of water. The mixture was extracted three times with 500 ml of ether, the extracts were combined, washed successively with aqueous potassium carbonate and water, dried and evaporated to give 2-methoxypyridine-4-carboxaldehyde.
Obtain 20.53g (35%). Melting point 33-35℃. Melting point of sample recrystallized from petroleum ether: 33-36°C (iii) In the method of Example 18(ii)-(iv), 6-
Using 2-methoxypyridine-4-carboxaldehyde in place of methoxypyridine-3-carboxaldehyde, oily ethyl 2-formyl-(2-methoxy-4-pyridyl)propionate is obtained. This ester was treated sequentially with thiourea and methyl iodide according to the method of Example 1(i) and (ii) above to yield 5-(2-methoxy-4-pyridylmethyl)-2-methylthio-4-pyrimidone. , this compound was reacted with (a) 2-(5-methyl-4-imidazolylmethylthio)ethylamine (b) 2-(2-thiazolylmethylthio)ethylamine at 140°C for 6 hours to produce (a) ) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone, melting point 177-178°C (LD ₅₀ : 240, pA ₂ (ileum): 4.84, _pA2 (atrial): 6.84, _ED50 :
0.06) (b) 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone, melting point 105.5~
106.5℃ (pA ₂ (ileum): 5.78, pA ₂ (atrial)
6.57, ED ₅₀ : 0.32). Example 20 (i)(a) 2-(4-Methylpyridin-2-ylmethylthio)ethylamine dihydrobromide A mixture of 3.75 g of 2-hydroxymethyl-4-methylpyridine and 3.5 g of cysteamine hydrochloride Reflux in 60 ml of 48% hydrobromic acid for 7 hours and remove the solvent under vacuum. Recrystallize the product from ethanol to obtain the title compound in the form of needles.
Obtain 5.13g. Melting point 173-174°C (b) 2-[2-(4-methylpyridin-2-ylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone 1.6 g of the product from (a) dilute sodium hydroxide
Dilute to 10 ml and extract with chloroform (3 x 10 ml). The chloroform extract was dried over magnesium sulfate, the solvent was removed, and the product was purified with 2-
Nitroamino-5-(3-pyridylmethyl)-4
- 10 ml of ethanol containing 1.0 g of pyrimidone
Reflux for 36 hours inside. The solvent is removed and the product is chromatographed on silica gel, eluting with 10% w/w methanol in chloroform. Recrystallization from ethanol-diethyl ether gives 0.95 g of the title compound. Melting point 128
~129℃ Elemental analysis, as CC ₁₉ H ₂₁ N ₅₀ S, actual value (%): C, 61.73; H, 5.76;
N, 19.01; S, 8.90 Theoretical value (%): C, 62.10; H5.76;
N, 19.06; S, 8.70 Example 21 (a) 4-(3-benzyloxypyridin-2-yl)butylamine 0.88 g of sodium hydride in 45 ml of dimethyl sulfoxide was dissolved in 3-hydroxy-2-3-cyanopropyl)pyridine. Add to 6.0 g of solution over 30 minutes at 20°C. This solution was stirred for 40 minutes and 4.4% of benzyl bromide was added in 10ml of dimethyl sulfoxide.
ml and stir the resulting solution for 2 hours. Remove the solvent under vacuum and dissolve the residue in 75 ml of water;
Extract with chloroform (3 x 75 ml). Combine the chloroform extracts, dry over magnesium sulfate and remove the solvent to obtain an oil. Dissolve this in 100 ml of dry tetrahydrofuran, and add lithium aluminum hydride to 60 ml of tetrahydrofuran.
Add dropwise to 3.75 g of suspension. This suspension was stirred for 2 hours, then 40 ml of tetrahydrofuran was added.
Add 3.75ml of water over 50 minutes, and
3.75ml of 16% sodium hydroxide solution and water
Add 11.25ml. Filter the mixture, concentrate to dryness, and partition the residue between water and chloroform. The product is extracted with chloroform at pH 11 to obtain 6.2 g of the title compound as an oil. (b) 2-[4-(3-benzyloxypyridine-2
-yl)butylamino]-5-(6-methylpyridin-3-ylmethyl)-4-pyrimidone In 15 ml of pyridine, 2.77 g of 4-(3-benzyloxypyridin-2-yl)butylamine and 2-nitroamino-5 -(6-methylpyridin-3-ylmethyl)-4-pyrimidine 2.61g
The mixture is refluxed for 18 hours. The solvent is removed under vacuum and the residue is chromatographed on silica gel, eluting with 10% ethanol in chloroform. Recrystallization from ethanol-ether water gives the trihydrate of the title compound. Melting point 55-60
(c) 1.25 g of the product of 2-[4-(3-hydroxypyridin-2-yl)butylamino]-5-(6-methylpyridin-3-ylmethyl)-4-pyrimidone (b) was added to 10 % palladium-carbon
Dissolve in 50 ml of ethanol containing 0.5 g and 1 ml of triethylamine and shake for 18 hours under a hydrogen atmosphere at 350 kPa. The solution is filtered, concentrated and the resulting product is recrystallized from ethanol to give 0.6 g of the title compound. Melting point 192
~194°C Example 22 Pharmaceutical composition Ingredient Amount 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone)-4-pyrimidone tri Hydrochloride 75mg Sucrose 75mg Starch 25mg Talc 5mg Stearic acid 2mg Pass the ingredients through a sieve, mix and place in a hard gelatin capsule. Example 23 Pharmaceutical composition Ingredient Amount 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone trihydrochloride 100mg Lactose 100mg Ingredients Pass through a sieve, mix and place into hard gelatin capsules. Other compounds of formula [1] can also be formulated into pharmaceutical compositions by the methods of Examples 22 and 23. The pharmaceutical composition obtained in the above example is orally administered in the above doses to block histamine _H2 -receptors.

Claims (1)

[Claims] 1 Formula: [Wherein, Het is a lower alkyl-substituted 4-imidazolyl ring, 2-pyridyl ring (which may be substituted with lower alkoxy, halogen or amino) or 2-thiazolyl ring; Y is sulfur or methylene group;
Z is hydrogen or lower alkyl; Het' is 2-, 3-
or 4-pyridyl (which may be substituted with lower alkyl or lower alkoxy), 2-thienyl, 2-thiazolyl or 3-quinolyl] or a pharmaceutically acceptable salt thereof . 2. The compound of claim 1, wherein Y is sulfur. 3. The compound according to claim 1 or 2, wherein Z is hydrogen or methyl. 4. The compound of claim 3, wherein Z is hydrogen. 5. The compound of claim 1 which is 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone. 6. The compound of claim 1 which is 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone. 7 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone Claim 1
compound of term. 8. The compound of claim 1 which is 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-thienylmethyl)-4-pyrimidone. 9. The compound of claim 1 which is 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-pyridylmethyl)-4-pyrimidone. 10 The compound of claim 1 which is 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone. 11 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(2-pyridylmethyl)-4-pyrimidone Claim 1
compound of term. 12 The compound of claim 1 which is 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-thiazolylmethyl)-4-pyrimidone. 13 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-
A compound according to claim 1 which is a pyrimidone. 14 Claim 1 which is 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone
compound of term. 15 Formula: [Wherein, Het is a lower alkyl-substituted 4-imidazolyl ring, 2-pyridyl ring (which may be substituted with lower alkoxy, halogen or amino) or 2-thiazolyl ring; Y is sulfur or methylene group;
Z is hydrogen or lower alkyl; Het' is 2-, 3-
or 4-pyridyl (which may be substituted with lower alkyl or lower alkoxy), 2-thienyl, 2-thiazolyl or 3-quinolyl] or a pharmaceutically acceptable salt thereof Histamine H ₂ − is an essential active ingredient, which is combined with a pharmaceutical carrier.
Pharmaceutical composition for antagonism or histamine _H1- and _H2 -antagonism. 16 Formula: [In the formula, Z and Het' are the same as below; Q means a group that can be substituted with lower alkylthio, benzylthio, halogen or other amine.] Isocytosine represented by the formula: Het-CH2 _- Y-(CH ₂ ) A formula characterized by treatment with an amine represented by ₂ -NH ₂ [In the formula, Het and Y are the same as described below]: [Wherein, Het is a lower alkyl-substituted 4-imidazolyl ring, 2-pyridyl ring (which may be substituted with lower alkoxy, halogen or amino) or 2-thiazolyl ring; Y is sulfur or methylene group;
Z is hydrogen or lower alkyl; Het' is 2-, 3-
or 4-pyridyl (which may be substituted with lower alkyl or lower alkoxy), 2-thienyl, 2-thiazolyl or 3-quinolyl] or a pharmaceutically acceptable salt thereof manufacturing method. 17 Claim 1 in which Q is methylthio
Manufacturing method in Section 6.