JPH0346470B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to certain pyrimidone derivatives, processes for their preparation, compositions containing them and histamine H ₁
- Concerning its use as an antagonist. 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 Schield, Birt.J.
Pharmac. 1966, 27 , 427), the action of histamine at these receptors is inhibited by drugs commonly called "antihistamines" (histamine H ₁ -antagonists), of which mepyramine is a common example. The second type of histamine receptor is known as the _H2 -receptor (Black et al Nature 1972, 236 ,
385). The effects of histamine on these receptors are not inhibited by mepyramine, but are inhibited by primamide. Compounds that suppress the action of histamine at histamine- _H2 -receptors are called histamine _H2 -antagonists. British Patent No. 1595291 contains the formula: 2-pyridyl, in particular 2-pyridyl unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, amino or hydroxy, or disubstituted by lower alkoxy; Z is methylene, X is oxygen, -(CH ₂ ) _n W(CH ₂ ) _o - is -CH ₂ -, A is 1,
3-benzodioxolyl or one or more lower alkyl, lower alkoxy, halogen, arylalkoxy, hydroxy, lower alkoxy-lower alkoxy, trifluoromethyl, di(lower alkyl)amino, phenoxy, halophenoxy, alkoxyphenoxy, Phenyl, phenyl substituted by halophenyl or alkoxyphenyl, compounds where Y ³ is hydrogen or lower alkyl, and pharmaceutically acceptable salts thereof are disclosed. These compounds are described as having both histamine H ₁ -antagonistic and histamine H ₂ -antagonistic effects. We have now found a group of compounds that have increased relative levels of H ₁ to H ₂ activity. These compounds are useful as histamine H ₁ -antagonists, i.e. in the treatment of diseases whose symptoms are transmitted through the action of histamine at H ₁ -receptors, such as bronchial asthma, rhinitis, hay fever and algic eczema. Useful. Thus, the present invention provides the formula: [In the formula, R ¹ is a halogen, nitro, amino, or a pharmaceutically acceptable amino group derivative that can be converted into amino in vivo, or an alkyl having 1 to 4 carbon atoms, and R ² is a halogen, nitro, amino, or an amino group that can be converted into amino in vivo. a pharmaceutically acceptable amino group derivative that can be converted into a C1-C4 alkyl or a C3-4 alkoxy, ^R3 is an alkylene having a C1-3, and ^R4 is an unsubstituted or substituted phenyl (substituted or The groups may be the same or different and include 1 or 2 halogens, hydroxy, alkyl having 1 to 4 carbon atoms, and 1 to 4 carbon atoms.
4 (alkoxy or methylenedioxy)] and pharmaceutically acceptable salts thereof. The pharmaceutically acceptable derivatives R ¹ and R ² that can be converted into amino in vivo mean derivatives that are hydrolyzed or metabolized in vivo to generate free amino groups. Examples of such derivatives include C1-C4 alkylaminos, such as methylamino, and C1-4 alkanoylaminos, such as acetamino. The halogen for R ¹ and R ² includes fluorine, chlorine, bromine or iodine. Preferably R ¹ is halogen, especially bromine. Examples of alkyl having 1 to 4 carbon atoms for R ¹ and R ² include methyl, ethyl, n-propyl, isopropyl, n-butyl and t-butyl. Preferably, R ² is alkyl having 1 to 4 carbon atoms,
In particular methyl or amino. Examples of alkoxy having 3 to 4 carbon atoms in R ² are:
Mention may be made of n-propoxy and n-butoxy. Examples of ^R3 include methylene, 1,2-ethanediyl or 1,3-propanediyl. The phenyl of R ⁴ may be unsubstituted, and if substituted, the substituent is preferably in the meta and/or para position relative to the position attached to the CH ₂ group. Thus, specific examples of R ⁴ include phenyl, 3-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl or 5
-(1,3-benzodioxolyl). Examples of compounds within the scope of the invention include 2-[4-(5-bromo-3-methylpyridine-
2-yl)butylamino]-5-benzyl-4-
Pyrimidone, 2-[4-(5-bromo-3-methylpyridine-
2-yl)butylamino]-5-(3-methoxybenzyl)-4-pyrimidone, 2-[4-(5-bromo-3-methylpyridine-
2-yl)butylamino]-5-(4-chlorobenzyl)-4-pyrimidone, 2-[4-(5-bromo-3-methylpyridine-
2-yl)butylamino]-5-(4-fluorobenzyl)-4-pyrimidone, 2-[4-(5-bromo-3-methylpyridine-
2-yl)butylamino]-5-(4-hydroxybenzyl)-4-pyrimidone, 2-[4-(5-bromo-3-methylpyridine-
2-yl)butylamino]-5-(4-methoxybenzyl)-4-pyrimidone, 2-[4-(5-bromo-3-methylpyridine-
2-yl)butylamino]-5-[5-(1,3-
benzoxolyl)methyl]-4-pyrimidone, 2-[4-(5-bromo-3-aminopyridine-)
2-yl)butylamino]-5-(4-fluorobenzyl)-4-pyrimidone, and pharmaceutically acceptable salts thereof. Although the compound of formula (2) is shown as a 4-pyrimidone, it exists in equilibrium with the corresponding 6-one tautomer. In addition, these compounds are
To a lesser extent, it also exists as a hydroxy tautomer, and the pyrimidine ring can also exist in the following tautomeric forms: The present invention includes all of these tautomeric forms. The compound of formula (2) forms a pharmaceutically acceptable salt with a pharmaceutically acceptable acid. Examples of these acids are hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, tartaric acid,
Citric acid, maleic acid, lactic acid, 2-hydroxyethanesulfonic acid, methanesulfonic acid, toluene-
Mention may be made of 4-sulfonic acid, ethanedisulfonic acid, ethanesulfonic acid and camphorsulfonic acid. Compounds of the invention have the formula: [In the formula, R ³ is the same as above, R ⁵ is the same as R ¹ or a protected amino group, and R ⁶ is the same as R ² or a protected amino group.] A compound or a salt thereof represented by the formula: [In the formula, R ⁴ is the same as above, R ⁷ means a group that can be substituted with an amine.] If necessary, the protecting group is removed from the protected amino group of the obtained product. ,
If desired, the amino group of the obtained product is converted into a pharmaceutically acceptable derivative that can be converted into amino in vivo, and if desired, the obtained compound represented by formula (2) is converted into a pharmaceutically acceptable salt. It can be manufactured by a method consisting of changing. In the amino protecting group for R ⁵ or R ⁶ , the protecting group can be any standard amino protecting group suitable for the reaction conditions. For example, carbon number 1
-4 alkanoyl, benzyl or benzoyl. These protecting groups can be introduced and removed by standard methods. If the protecting group is not pharmaceutically acceptable or cannot be converted to amino in vivo, it is removed. If the protecting group can be converted to amino in vivo, there is no need to remove it unless a free amino compound is needed. Free amino groups can be converted to pharmaceutically acceptable derivatives that can be converted to amino in vivo by standard methods. This method depends on the nature of the derivative. For example, an amino group can be alkylated or acylated. Pharmaceutically acceptable salts of compounds of formula (2) can be prepared by standard methods, eg, by reacting a solution of a compound of formula (2) with a solution of an acid. Examples of ^R7 include alkylthio having 1 to 4 carbon atoms (especially methylthio), benzylthio, chlorine,
Mention may be made of bromine and nitroamino. Preferably R ⁷ is nitroamino. The reaction is carried out in the absence of a solvent at elevated temperatures, e.g.
It can be carried out at 170°C, preferably from 120 to 140°C, or in a solvent at an elevated temperature, for example at the reflux temperature of the reaction mixture. The choice of solvent is influenced by the solubility characteristics of the reactants and the nature of ^R7 . Preferably, the solvent is pyridine, picoline or a mixture of picolines, an alkanol having 1 to 4 carbon atoms, preferably
ethanol, 1-propanol or 1,2-ethanediol, ketones such as acetone or 2-butanone, high-boiling alkoxyaryl ethers such as anisole, or polar aprotic solvents such as dimethylformamide, dimethylacetamide, dimethyl Sulfoxide, hexamethylphosphoramide, sulfolane, acetonitrile or nitromethane. Formula (2) of phenyl in which R ⁴ is substituted with hydroxy
and their salts can also be prepared by reacting a compound of formula (2) in which R ⁴ is phenyl substituted with methoxy with boron tribromide and then optionally converting the resulting product into an acid addition salt. It can also be manufactured by different methods. The compound represented by formula (3) has been disclosed in European patent application no.
It can be produced by the method described in 0068833 and 0068834 or similar methods. Further, the compound of formula (3) in which one of R ⁵ and R ⁶ is amino and neither of R ⁵ and R ⁶ is nitro,
It can be manufactured as follows according to the description in British Patent Application No. 8309481. formula:

[expression] or

[Formula] [In the formula, R ⁸ means halogen, alkyl having 1 to 4 carbon atoms, or alkoxy having 3 to 4 carbon atoms, and R ⁹ means halogen or alkyl having 1 to 4 carbon atoms]
A compound represented by is reacted with hydrazine and a transition metal catalyst to form the formula:

[expression] or

[In the formula, R ⁸ and R ⁹ are the same as above]

The compound represented by formula (7) or formula (8) is then further reacted with hydrazine and Raney nickel. This reaction is carried out at moderate temperatures, e.g. 5°C to about 70°C.
C, preferably at about 10 C to room temperature. The first hydrazine reduction to produce compounds of formula (7) and formula (8) can be carried out using a hydrogenation catalyst that is milder than Raney nickel. Examples of mild catalysts for this step include palladium on an inert support, specifically palladium on activated carbon. The reaction temperature depends on the catalyst. When using milder catalysts, higher temperatures can be employed, for example 55-70°C.
For example, when using stronger catalysts such as Raney nickel, the reaction temperature should not exceed 55°C. Preferably, the reaction is carried out at 5°C to room temperature, regardless of the catalyst used. After carrying out the first step, the compound of formula (7) or formula (8) is recovered by removing the catalyst, for example by filtration, and then evaporating the solvent. be able to. Then, the obtained formula
A second step can be carried out by redissolving the compound of (7) or formula (8) in the same or different solvent and reacting with Raney nickel and further with hydrazine. Preferably, the reactions are carried out in the same system. That is, a compound of formula (5) or (6) is reacted with a sufficient amount of hydrazine and a catalyst to produce a compound of formula (7) or (8) in the reaction system, and the catalyst of the first step is Raney nickel. If not, the catalyst is removed, for example by filtration, and then Raney nickel and a sufficient amount of hydrazine are added to convert the compound of formula (7) or (8) to the corresponding compound of formula (3). The first or second step reaction can be carried out in the presence of a solvent, the choice of which is not particularly limiting, but which is substantially inert to the reagents and products. Examples of solvents used in this method include alkanols having 1 to 6 carbon atoms, especially methanol and ethanol. The reaction time in each step depends on the nature of the reagent, the reaction temperature and, in the first step, the catalyst used until the reaction is completed. The progress of the reaction can be monitored by standard techniques, e.g., thin layer chromatography, and once the reaction is complete, the product can be monitored by standard techniques, e.g., removing the catalyst and then evaporating the solvent. It can be isolated by formula: [In the formula, R ⁴ and R ⁷ are the same as above] The compound represented by the formula is known or can be produced in a similar manner to a known method as disclosed, for example, in British Patent No. 1595291. can. The compound represented by formula (2) also has the formula: [In the formula, R ¹ , R ² and R ³ are the same as above] The guanidine represented by the formula: [In the formula, R ⁴ is the same as above, R ¹⁰ means alkyl having 1 to 4 carbon atoms, (especially ethyl), benzyl or phenyl] It can also be produced by reacting with a compound represented by the following: I can do it. This reaction can be carried out using a solvent, for example, formula (10).
in an alcohol corresponding to the ester group of the compound, i.e. R ¹⁰ OH, at elevated temperature, preferably a base,
In particular, this is carried out by heating the guanidine of formula (9) and the compound of formula (10) in the presence of a sodium alkoxide corresponding to the ester group of the compound of formula (10), ie, NaOR ¹⁰ . The guanidine represented by formula (9) is the amine of formula (3), which is represented by the formula: [In the formula, R ¹¹ means a leaving group such as methylthio] It can be produced by reacting with a compound represented by the following formula. The histamine H ₁ -antagonistic activity of the compound of formula (2) is demonstrated in vitro in the guinea pig ileal test. In this test, the isolated portion of the guinea pig ileum was fixed in a 10 ml tissue bath between the fixation part and the transducer under 500 mg of tension, and a magnesium-free sample was placed at a temperature of 30°C with constant aeration. Soak in Tyrode solution. Amplify the output from the transducer. The amplified output is sequentially supplied to a flat bass recorder. A predetermined amount of histamine is added to the tissue bath and the histamine concentration is increased stepwise until maximum contraction is reached. The tissue bath is flushed out and filled with fresh magnesium-free Tyrode's solution containing the test compound. The solution is left in contact with the tissue for 8 minutes and a predetermined amount of histamine is added again until maximum contraction is recorded. Repeat the analysis with increasing concentrations of test compound and record the histamine dose that gives 50% of maximal contraction. The dose ratio (DR) is calculated by comparing the histamine concentration required to produce 50% of the maximal response in the absence and presence of a histamine antagonist. LogDR-1 is plotted against LogD (concentration of test compound) and the intersection with the Log(DR-1) ordinate axis is taken as a measure of activity (pA ₂ value). The compounds of Examples 1 to 7 below have a pA ₂ of 8 or more.
has value. The histamine H ₂ -antagonistic activity of the compound represented by formula (1) was demonstrated in vitro in the guinea pig atrial test.
It is indicated by. In this test, the isolated right atrium of a naturally beating guinea pig was placed under 300mg of tension.
It is fixed in a 15 ml tissue bath between the fixation part and the transducer and immersed in Mc Ewens solution at a temperature of 37°C with constant ventilation. Amplify the output from the transducer.
The output is sequentially supplied to a flatbed recorder. A predetermined amount of histamine is added to the tissue bath and the histamine concentration is increased stepwise until the maximum beat rate is reached. The bath is flushed and filled with fresh McEvans solution containing the test compound. The solution is left in contact with the tissue for 60 minutes and a predetermined amount of histamine is added again until the maximum beat rate is recorded. Repeat the analysis with increasing concentrations of the test compound until the maximum number of beats is 50.
Record the dose of histamine giving %. 50% of maximal response in the absence or presence of antagonist
The dose ratio (DR) is calculated by comparing the histamine concentration required to produce . Plot LogDR-1 against LogD (concentration of test compound) and log
(DR-1) The intersection with the ordinate axis is the measure of activity (pA ₂
value). The compounds of Examples 1 to 7 below are 5
It has a _pA2 value of: The activity of the compound of formula (2) as a histamine H ₁ -antagonist is demonstrated in vivo by inhibition of histamine-induced bronchoconstriction. Guinea pigs of either sex are anesthetized by intraperitoneal injection of sodium pentobarbitone 9 mg/Kg. Insert a cannula into the trachea. The animal is artificially breathed with a volume of air just adequate to inflate the lungs. The pressure required to inflate the lungs is monitored from the breathing system using a low pressure transducer. Intravenous injection of histamine produces a dose-dependent pressure increase that inflates the lungs in response to the bronchoconstrictive action of histamine. The response to histamine can be antagonized using histamine H ₁ -receptor antagonists. The dose-response curve for histamine is 20,
Prepared at 40, 80, 160 and 320 nanomoles/Kg.
The antagonist was then administered by intravenous injection, and
Minutes later, the dose of histamine is increased as needed to generate a new histamine dose-response curve. The effect of an antagonist can be quantified by the shift of the histamine dose-response curve to the right, by giving each animal a series of doses of the antagonist, expressed as a dose ratio, and increasing the Dose ratios can be calculated. The activity of the compound of formula (2) as a histamine H ₂ -antagonist is demonstrated in vivo by inhibition of histamine-stimulated gastric acid secretion from the rumen-perfused stomach of urethane-anesthetized rats. This method uses Ash and Schild.
Birt.J.Pharmac.Chemother., 27 , 247 (1966))
reported by. For use of the compounds of the invention as histamine _H1 -antagonists, the compounds can be formulated as pharmaceutical compositions using standard pharmaceutical techniques. The present invention also encompasses a pharmaceutical composition comprising a compound of formula (2) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The compound of formula (2) and its pharmaceutically acceptable salts can be administered locally or systemically. Topical formulations for transdermal administration include lotions and creams. Topical formulations for administration to the respiratory tract include solutions or inhalable fine powders administered by nebulizer or as an aerosol. The active ingredient of the inhalable powder has a small particle size, ie a particle size of less than 50 microns, preferably less than 10 microns. The active ingredient is associated with a solid carrier, for example lactose having a particle size of 50 microns or less. Systemic administration can be carried out rectally, orally or parenterally. A typical suppository formulation consists of an active compound of the invention and a binder and/or lubricant such as gelatin, cocoa butter, other low melting vegetable fats or oils. Typical parenteral compositions consist of a solution or suspension of the active agent in a sterile aqueous carrier or parenterally acceptable oil. Orally active compounds of formula (2) can be formulated as syrups, tablets, capsules and lozenges. Syrup formulations generally consist of a suspension or solution of the compound in a liquid carrier, such as ethanol, glycerin or water, containing flavoring and coloring agents. If the composition is in capsule form, the solid in granule form, optionally containing a binder, is encapsulated in a gelatin shell. When the composition is in tablet form, any suitable pharmaceutical carrier commonly used in the manufacture of solid formulations can be used. Examples of such carriers include magnesium stearate, starch, lactose, dextrose, sucrose and cellulose. Preferably, the composition is in a single dose form, such that the patient himself can take a single dose, e.g.
Form into tablets, capsules or metered aerosol. If appropriate, small doses of bronchodilators and anti-asthmatic agents, such as sympathomimetic amines, especially
Isoprenaline, isoethaline, salbutamol, phenylephrine and efuedrin, xanthine derivatives, especially thiophylline and aminophylline, corticosteroids, especially prednisolone, and adrenal stimulants, especially,
ACTH can be included. As is customary, the composition may be accompanied by a label for use in the treatment concerned, and in the case of the present invention:
For example, it can be a histamine H ₁ -antagonist for the treatment of asthma, hay fever, rhinitis or allergic eczema. Each unit dose for oral administration preferably contains between 5 and
Contains 200 mg of a compound of formula (2) or a pharmaceutically acceptable salt thereof in terms of free base. The pharmaceutical composition of the present invention is generally used to treat rhinitis, hay fever,
Administered to humans for the treatment of bronchial asthma or allergic eczema. For adult patients, 15 mg to 400 mg per oral administration, preferably
Doses of 15 to 200 mg, for intravenous, subcutaneous or intramuscular administration, 1 mg to 50 mg, preferably 1 mg to 10 mg.
of a compound of formula (2) or a pharmaceutically acceptable base thereof, calculated as the free base, and the composition is administered from 1 to 4 times per day. Next, the present invention will be explained in more detail using Examples. Example 1 0.73 g of 5-bromo-2-(4-aminobutyl)-3-methylpyridine was dissolved in 2-methylthio-5-(4
-Chlorobenzyl)-4-pyrimidone (0.75 g) at 160-170°C and heating continued for 6 hours. The mixture was cooled and recrystallized from chloroform/petroleum ether (boiling point 60-80°C) to give 2-[4-(3-methyl-5-promopyridin-2-yl)butylamino]-5-(4-chloro 1.0 g of benzyl)-4-pyrimidone is obtained. Melting point 149-150℃. Elemental analysis value, theoretical value (%) as C ₂₁ H ₂₂ BrClN ₄ O: C, 54.50; H, 4.79; N, 12.11;
Total halogen 24.93 Actual value (%): C, 54.30; H, 4.94; N, 12.03;
Total halogens 24.79 Example 2 (a) 105 g of 5-(4-methoxybenzyl)-2-thiouracil are refluxed for 3 hours in 800 ml of glacial acetic acid and 400 ml of 48% aqueous hydrobromic acid. The solution at about 35℃
53 ml of methyl iodide are added and the solution is refluxed for a further 2 hours. The mixture is evaporated to dryness under vacuum and 500 ml of water are added to the residue. Add sodium hydroxide to bring the pH to about 5. The resulting solid was collected by filtration and recrystallized from ethanol to give 5-
(4-hydroxybenzyl)-2-methylthio-
43.1 g of 4-pyrimidone are obtained. Melting point 243-244
℃. (b) 5-bromo-2-(4-aminobutyl)-3-
0.875 g of methylpyridine and 0.745 g of 5-(4-hydroxybenzyl)-2-methylthio-4-pyrimidone are refluxed in 3 ml of pyridine for 24 hours. Evaporate the pyridine under vacuum. The remaining pyridine is removed from the residue by azeotroping with water under vacuum and then drying with ethanol. Add 20ml of water and lower the pH to 6 with dilute hydrochloric acid. The resulting solid was recrystallized from ethanol/water, dimethylformamide/water, and finally acetic acid/water.
-[4-(5-bromo-3-methylpyridine-2
0.54 g of -yl)butylamino]-5-(4-hydroxybenzyl)-4-pyrimidone is obtained. Melting point 232-234℃. NMR (DMSO- _d6 ): _{( CH2} ) _2CH2NH2 , _1.62 ,
m; 3-CH ₃ , 2.27, s; CH ₂ (CH ₂ ) ₃ NH ₂ ,
2.70, m; CH ₂ NH ₂ , about 3.2, m; CH ₂ (benzyl), 3.38, s; NH, about 6.3, broad; 3-H
+5-H phenyl, 6.63, m; 2-H+6-H phenyl, 6.98, m; 6-H pyrimidyl, 7.37,
s; 4-H pyridyl 7.76, d; 6-H pyridyl,
8.38, d; OH, 8.96, broad s; NH, 10.5,
Broad Example 3 0.875 g of 5-bromo-2-(4-aminobutyl)-3-methylpyridine and 0.786 g of 5-(4-methoxybenzyl)-2-methylthio-4-pyrimidone
reflux in 3 ml of pyridine for about 20 hours. Evaporate the pyridine under vacuum. The remaining pyridine is removed from the residue by azeotroping with water under vacuum and then drying with ethanol. Add 10 ml of water and 1 ml of ethanol to obtain a colorless solid. This was recrystallized from ethanol and then methanol.
-[4-(5-bromo-3-methylpyridine-2-
0.97 g of yl)butylamino]-5-(4-methoxybenzyl)-4-pyrimidone is obtained. Melting point 149~
150℃. Elemental analysis value, theoretical value (%) as C ₂₂ H ₂₅ BrN ₄ O ₂ : C, 57.7; H, 5.51; N, 12.25;
Br, 17.47 Actual value (%): C, 57.85; H, 5.50; N, 12.33;
Br, 17.40 Example 4 0.88 g of 5-bromo-2-(4-aminobutyl)-3-methylpyridine and 0.75 g of 5-(4-fluorobenzyl)-2-methylthio-4pyrimidone
is refluxed in 3 ml of pyridine for 24 hours. The pyridine is removed under vacuum and the residue is triturated with 5 ml of ethanol to give a colorless solid. The solid was recrystallized from methanol to give 2-[4-(5-bromo-3-methylpyridin-2-yl)butylamino]-5-
(4-fluorobenzyl)-4-pyrimidone 0.96g
get. Melting point 172-173℃. Elemental analysis value, theoretical value (%) as C ₂₁ H ₂₂ BrFN ₄ O: C, 56.64; H, 4.98; N, 12.58;
Br17.94 Actual value (%): C, 56.64; H, 5.22; N, 12.58;
Br, 17.59 The 4-methoxybenzyl- and 4-fluorobenzyl-2-methylthio-4-pyrimidone used in Examples 3, 4, and 8 were converted to 4-methoxybenzaldehyde by the method described in U.S. Pat. No. 4,145,546. and 4-fluorobenzaldehyde. Example 5 0.58 g of 5-bromo-2-(4-aminobutyl)-3-methylpyridine and 0.51 g of 5-(3-methoxybenzyl)-2-methylthio-4-pyrimidone
reflux in 3 ml of pyridine for 30 hours. Pyridine is removed under vacuum. The residue is recrystallized from ethanol/water to obtain 0.60 g of 2-[4-(5-bromo-3-methylpyridin-2-yl)butylamino]-5-(3-methoxybenzyl)-4-pyrimidone.
Softens at 65℃ and melts at 73℃. Elemental analysis value _{, C22H25BrN4O20.7H2O} , theoretical value ( _% ): C, _56.22 ; H, 5.66; _N , 11.92;
Br, 17.00 Actual value (%): C, 56.17; H, 5.60; N, 12.08;
Br17.06 Weight loss 30-180°C = 2.7% = _0.7H2O Example 6 0.88 g of 5-bromo-2-(4-aminobutyl)-3-methylpyridine and 5-(3,4-methylenedioxy 0.83 g of benzyl)-2-methylthio-4-pyrimidone is refluxed in 3 ml of pyridine for 24 hours. The pyridine was removed under vacuum and the resulting brown oil was triturated with ethanol to give a cream solid, which was recrystallized from dimethylformamide/ethanol to give a colorless solid of 2-[4-(5-
1.1 g of bromo-3-methylpyridin-2-yl)butylamino]-5-(3,4-methylenedioxybenzyl)-4-pyrimidone are obtained. Melting point 145-146
℃. Elemental analysis value, theoretical value (%) as C ₂₂ H ₂₃ BrN ₄ O ₃ : C, 56.06; H, 4.92; N, 11.89;
Br, 16.95 Actual value (%): C, 56.17; H, 4.90; N, 12.08;
Br, 16.65 Example 7 0.88 g of 5-bromo-2-(4-aminobutyl)-3-methylpyridine and 0.74 g of 5-benzyl-2-nitroamino-4-pyrimidone were added to pyridine 3
ml for 4 hours. Remove the solvent under vacuum;
Partition the remaining oil between chloroform and water at PH5. The chloroform extract is dried over magnesium sulfate and evaporated to an oil. Recrystallization from ethanol/ethyl acetate gave 2-[4-(5-bromo-3-methylpyridin-2-yl)butylamino]-5-
0.65 g of benzyl-4-pyrimidone is obtained. melting point
138-139℃. Elemental analysis value, theoretical value (%) as C ₂₁ H ₂₃ BrN ₄ O: C, 59.02; H, 5.42; N, 13.11;
Br18.70 Actual value (%): C, 58.81; H, 5.49; N, 13.09;
Br, 18.82 Example 8 (a) A mixture of 35 ml of concentrated sulfuric acid and 35 ml of concentrated nitric acid was
2-Amino-5 in 240 ml of concentrated sulfuric acid cooled to
- Add dropwise to a solution of 50.3 g of bromopyridine under stirring, maintaining the temperature of the reaction mixture at 5-6° C. during the addition. Once the addition is complete, the reaction mixture is stirred for an additional hour at 5-8°C, warmed to 30°C and left for about 18 hours. Furthermore, add 35 ml of concentrated nitric acid at a temperature of 30~30°C while stirring.
Add to the reaction mixture in portions while maintaining the temperature at 40°C. A 50 ml portion of the solution is poured into 100 ml of hot water (approximately 70°C) with rapid stirring and the mixture is heated to 120°C. Gas is released. Once gas evolution has stopped, add another 75 ml of the reaction mixture to the temperature
Add while maintaining the temperature at 120℃. Once the addition is complete, the resulting solution is poured into 1 Kg of ice and cooled in a saline/ice bath. Fine orange crystals form,
It was collected and recrystallized from dimethylformamide/water to give 2-hydroxy-3-nitro-5-
23.5 g of bromopyridine are obtained. Melting point 240-243
℃. (b) 2-hydroxy-3 in 16 ml of phosphoryl chloride
- A solution of 23.4 g of nitro-5-bromopyridine
Heat to reflux for 2.5 hours. Pour the reaction mixture into ice/water to form a brown solid, which is collected.
This solid is dissolved in chloroform, dried over magnesium sulfate, and decolorized by heating over activated carbon for about 30 minutes. Evaporation of the solvent from the decolorized solution gives 24.0 g of a yellow solid, which is recrystallized from ether/petroleum ether (40-60°C) to give 19.4 g of 2-chloro-3-nitro-5-bromopyridine. Melting point 66-68℃. (c) A solution of 24.2 g of 2-(2-cyanoethyl)malonic acid diethyl ester in 15 ml of tetrahydrofuran was dissolved in tetrahydrofuran at 20°C under a nitrogen atmosphere.
Add to a suspension of 2.45 g of sodium hydride in 30 ml. To this was added 22 g of 2-chloro-3-nitro-5-bromopyridine, and the resulting mixture was
Heat to ~95°C. A small amount of tetrahydrofuran is distilled off. The mixture is heated to reflux for 2.5 hours.
The reaction mixture is poured into water and neutralized to pH 7 with concentrated hydrochloric acid. The aqueous layer is extracted with chloroform, dried over magnesium sulfate, decolorized with activated carbon, and then filtered through a silica column. Evaporate the chloroform eluate to obtain an oil. This crystallizes slowly. Petroleum ether crystals (40-60℃)
4-(5-bromo-3-
28 g of nitropyridin-2-yl)-4,4-bis(carboethoxy)butyronitrile are obtained.
Melting point 58-62℃. (d) 4-(5-bromo-3-nitropyridine-2
21.8 g of -yl)-4,4-bis-(carboethoxy)butyronitrile are added to a mixture of 263.6 ml of 1M aqueous sodium hydroxide solution and 635 ml of methanol. The resulting mixture is stirred for 18 hours. The mixture was made acidic to PH 1.5 by addition of concentrated hydrochloric acid;
Heat at 50°C for 4.75 hours. The solution is neutralized to pH 7 with sodium hydroxide solution and the methanol is distilled off. Extract the remaining aqueous solution with chloroform to form an oil.
11.2 g were obtained which was chromatographed on a silica column and eluted with chloroform to give a yellow solid of 5-bromo-3-nitro-2-(3
9.6 g of -cyanopropyl)pyridine are obtained. Melting point 73-76℃. (e) 34 g of Raney nickel moistened with ethanol.
is added to a suspension of 8.4 g of finely ground 5-bromo-3-nitro-2-(3-cyanopropyl)pyridine in 350 ml of ethanol under a nitrogen atmosphere.
The mixture was cooled to 10 °C and a solution of 2.34 ml of hydrazine hydrate in 10 ml of ethanol was added to the reaction temperature at 12 °C.
Add while maintaining at ~15°C. The reaction mixture was warmed to room temperature with constant stirring and added with ethanol 3
2.3 ml of hydrazine hydrate per ml was added dropwise at regular intervals over a period of 46 hours to obtain a total of 15.5 ml of hydrazine hydrate.
Add ml. Cool the reaction mixture to 15° C. before each addition. 23 hours later, 6 more Rane Nickels
Add g. After 47 hours, stop the reaction. The reaction mixture is passed through a pad of diatomaceous earth to remove the catalyst. Evaporation of the solvent gave 7.9 g of an oil, which was chromatographed on a silica column with ethyl acetate/ethanol/0.880 ammonia (15:
10:2) to give 4.0 g of oily 3-amino-5-bromo-2-(4-aminobutyl)pyridine.
get. (f) 3-amino-2-(4-aminobutyl)-5-
0.5 g of bromopyridine and 2-methylthio-
5-(4-fluorobenzyl)-4-pyrimidone
0.51 g is refluxed in 1.5 ml of pyridine for 205 hours.
The pyridine was removed under vacuum and the residue was reevaporated twice with 20 ml of n-propanol to give 1.12 g of a brown oil.
get. This oil is chromatographed on silica and eluted with ethyl acetate/ethanol/0.880 ammonia (15:10:2). The product was crystallized from acetonitrile/water (9:1) to give 2-[4-(3-amino-5-bromopyridine-
0.53 g of 2-yl)butylamino]-5-(4-fluorobenzyl)-4-pyrimidone is obtained. Melting point 146-148℃.

Claims (1)

[Claims] 1 Formula: [In the formula, R ¹ is halogen, nitro, amino, or a pharmaceutically acceptable derivative of an amino group that can be converted into amino in vivo, or an alkyl having 1 to 4 carbon atoms; R ² is halogen, nitro, amino, or A pharmaceutically acceptable derivative of an amino group that can be converted into amino, alkyl having 1 to 4 carbon atoms or alkoxy having 3 to 4 carbon atoms; R ³ is alkylene having 1 to 3 carbon atoms; and R ⁴ is unsubstituted or substituted phenyl. (The substituents may be the same or different, and include 1 or 2 halogens, hydroxy, alkyl having 1 to 4 carbon atoms, 1 to 4 carbon atoms,
4 alkoxy or methylenedioxy) or a pharmaceutically acceptable salt thereof. 2. The compound of item 1 above, wherein R ¹ is halogen. 3. The compound of item 1 or 2 above, wherein R ¹ is bromine. 4. The compound according to any one of items 1 to 3 above, wherein R ² is alkyl having 1 to 4 carbon atoms. 5. The compound of item 4 above, wherein R ² is methyl. 6. The compound according to any one of items 1 to 3 above, wherein R ² is amino. 7 R ⁴ is phenyl, 3-methoxyphenyl, 4
-chlorophenyl, 4-fluorophenyl, 4-
7. The compound according to any one of items 1 to 6 above, which is hydroxyphenyl, 4-methoxyphenyl or 5-(1,3-benzoxolyl). 8 2-[4-(5-bromo-3-methylpyridin-2-yl)butylamino]-5-benzyl-4
- The compound of item 1 above which is a pyrimidone or a pharmaceutically acceptable salt thereof. 9 2-[4-(5-bromo-3-methylpyridin-2-yl)butylamino]-5-(3-methoxybenzyl)-4-pyrimidone or a pharmaceutically acceptable salt thereof, item 1 above. compound. 10 2-[4-(5-bromo-3-methylpyridin-2-yl)butylamino]-5-(4-chlorobenzyl)-4-pyrimidone or a pharmaceutically acceptable salt thereof, item 1 above. compound. 11 2-[4-(5-bromo-3-methylpyridin-2-yl)butylamino]-5-(4-fluorobenzyl)-4-pyrimidone or a pharmaceutically acceptable salt thereof, item 1 above. compound. 12 2-[4-(5-bromo-3-methylpyridin-2-yl)butylamino]-5-(4-hydroxybenzyl)-4-pyrimidone or a pharmaceutically acceptable salt thereof, item 1 above. compound. 13 2-[4-(5-bromo-3-methylpyridin-2-yl)butylamino]-5-(4-methoxybenzyl)-4-pyrimidone or a pharmaceutically acceptable salt thereof, item 1 above. compound. 14 2-[4-(5-bromo-3-methylpyridin-2-yl)butylamino]-5-[5-(1,
3-Benzoxolyl)methyl]-4-pyrimidone or a pharmaceutically acceptable salt thereof;
compound of term. 15 2-[4-(5-bromo-3-aminopyridin-2-yl)butylamino]-5-(4-fluorobenzyl)-4-pyrimidone or a pharmaceutically acceptable salt thereof, item 1 above. compound. 16. The compound according to any one of items 1 to 15 above, which is a hydrochloride. 17 Formula: [In the formula, R ³ is the same as below, R ⁵ means R ¹ group or protected amino shown below, and R ⁶ means R ² group or protected amino shown below] A compound or a salt thereof represented by the formula : [In the formula, R ⁴ is the same as below, R ⁷ means a group that can be substituted with an amine] React with a compound represented by the following, and if necessary, remove the protecting group from the protected amino group of the obtained product. ,
Then, if desired, the obtained compound of formula (2) shown below is converted into a pharmaceutically acceptable salt, characterized in that the formula: [In the formula, R ¹ is halogen, nitro, amino, or a pharmaceutically acceptable derivative of an amino group that can be converted into amino in vivo, or an alkyl having 1 to 4 carbon atoms; R ² is halogen, nitro, amino, or A pharmaceutically acceptable derivative of an amino group that can be converted into amino, alkyl having 1 to 4 carbon atoms or alkoxy having 3 to 4 carbon atoms; R ³ is alkylene having 1 to 3 carbon atoms; and R ⁴ is unsubstituted or substituted phenyl. (The substituents may be the same or different, and include 1 or 2 halogens, hydroxy, alkyl having 1 to 4 carbon atoms, 1 to 4 carbon atoms,
4 (alkoxy or methylenedioxy)] or a pharmaceutically acceptable salt thereof. 18 The obtained compound of formula (2) in which R ⁴ is phenyl substituted with methoxy is reacted with boron tribromide and optionally converted to its salt to form the corresponding R ⁴
said first step to obtain a phenyl compound of formula (2) substituted with hydroxy or a pharmaceutically acceptable salt thereof;
Manufacturing method in Section 7.