JPS5910357B2 - Heterocyclic compounds - Google Patents

Description

[Detailed description of the invention] The present invention provides a solution of general formula (I) R3 useful as a medicine. [(″”−, −−~<2:゜・.

C=0R4 [In the formula, R1 and R2 are the same or different and represent a lower alkyl group or a phenyl-lower alkyl group, but one of them may be a hydrogen atom.

Furthermore, R1 and R2 may form pyrrolidine, morpholine, or 4-lower alkylpiperazine together with adjacent nitrogen atoms. R3 represents a hydrogen atom or a lower alkyl group, R4 represents a hydrogen atom, and Py represents a pyridyl group. Ring A is substituted with a halogen atom]. Compound (I) of the present invention has the general formula (
■) ゛'T゛・□人〒H-x(■) C=0R゛ [In the formula, R3, R4, Py and ring A have the same meanings as above, and X is a halogen atom or an active ester of a hydroxyl group. a compound represented by the general formula () [in the formula, R
1 and R2 have the same meanings as above].

In each of the above formulas, the lower alkyl group represented by R1 and R2 is preferably a straight chain, branched or cyclic alkyl group having about 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl. , isobutyl, Sec-butyl, tert-butyl, cyclobutyl,
Examples include pentyl, hexyl, cyclopropylmethyl, cyclopentyl, and cyclohexyl.

Examples of the phenyl-lower alkyl group represented by R1 and R2 include pentyl and phenethyl groups. R1 and R2 are both adjacent nitrogen atoms, pyrrolidine,
Morpholine or 4-lower alkylpiperazine [e.g.
-methylpiperazine, 4-ethylpiperazine]. As the lower alkyl group represented by R3, R
The same lower alkyl groups as those represented by 1 and R2 can be mentioned. As R3, among others, a hydrogen atom and a carbon number of 1 to
The lower alkyl group of No. 3 is particularly preferred. The halogen atom substituted in ring A is fluorine, chlorine, bromine and iodine. As the substituent for ring A in general formula (1),
Particularly preferred are bromine and chloro. General formula (1
) The preferred position of the substituent on ring A is the 4-position, and 4-halogen atoms, particularly 4-brome and 4-chloro, are preferred as the substituent. The halogen atom represented by Examples thereof include oxy groups, phenylsulfonyloxy groups, and arylsulfoxy groups such as p-tolylsulfonyloxy groups. Furthermore, the pyridyl group represented by Py can be represented by the formula J, especially 2
-Pyridyl group is preferred.

The reaction of the present invention is carried out by reacting the compound of general formula (1) with the compound of general formula ().

The amount of the raw material compound used is usually about 1 to 10 moles of compound () per 1 mole of compound (). Although the reaction proceeds even in the absence of a solvent, the reaction can proceed more smoothly by using a solvent. Such solvents usually include alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, etc.), aliphatic or aromatic hydrocarbons, or halogenated hydrocarbons (
Examples: benzene, toluene, xylene, chlorobenzene,
chloroform, dichloromethane, dichloroethane, etc.)
, dialkyl formamides (e.g., dimethyl- or diethyl-formamide, etc.), ketones (e.g., acetone, methyl ethyl ketone, cyclohexane, etc.), ethers (diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, etc.), pyridine, dimethyl sulfoxide, etc. used. The reaction temperature is room temperature to 15
A suitable temperature between 0° C. is selected, and if a solvent is used, usually a temperature near its boiling point. In this reaction, hydrogen halide or sulfonic acid corresponding to X in compound () is generated, but in order to capture this, the general formula ()
Alternatively, an excess amount of the compound may be used, and a suitable basic substance such as tertiary amines such as triethylamine, pyridine, alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, or Bicarbonate may be added to the reaction system. In addition, when using a compound in which X is a chlorine or bromine atom as a raw material, the reaction will proceed more smoothly if the reaction is carried out in the presence of a catalytic or equimolar amount of potassium iodide or sodium iodide. You can also do that. The compound of general formula (1) produced in this way can be treated by a treatment method known per se (
For example, it can be isolated and purified by recrystallization, column chromatography, etc. It can also be purified by recrystallizing it as a crystalline acid addition salt and then treating it with an alkali to form a free base. In addition, since the compound of general formula (1) has a basic nitrogen atom in its molecule, it cannot be used with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid) or organic acids (e.g. acetic acid, oxalic acid,
succinic acid, malonic acid, tartaric acid, fumaric acid, maleic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, etc.) by a conventional method to obtain the corresponding usually water-soluble acid addition salt. The compound (1) of the present invention or its acid addition salt produced in this way has pharmacological effects such as central nervous system depressant action, such as muscle relaxant, anticonvulsant, analgesic, anxiolytic, and hypnotic action, such as muscle relaxant, Anticonvulsants, sedatives, anti-anxiety drugs, Miner 1/Tranquilizer 1,
It is useful as a medicine such as a hypnotic agent.

When compound (1) or an acid addition salt thereof is used as a pharmaceutical, it can be used as such or mixed with appropriate pharmacologically acceptable carriers, excipients, and diluents to form powders, granules, tablets,
It can be administered orally or parenterally in the form of capsules, injections, suppositories, and the like. The dosage varies depending on the target disease, symptom, and compound, but in the case of oral administration, it is usually selected from the range of about 1 to 100 Tf1f per day for adults. Furthermore, the raw material compound of the general formula () of the present invention is
For example, it can be manufactured by the method shown below.
[In each formula, R3, R4, X, . Py and ring A have the same meanings as above, k represents lower alkyl (eg, methyl, ethyl, propyl group)] Examples of compounds included in the general formula (1) include the following compounds.

4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-methylaminomethyl-4H-1.2.4
-triazole 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-5-methyl-3-methylaminomethyl-4H-1.2.4-triazole 4-[4-
Bromo-2-(2-pyridinecarbonyl)phenyl]-
3-dimethylaminomethyl-4H-1,2,4-triazole4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-5-methyl-3-dimethylaminomethyl-4H-1,2,4 -triazole 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-5-ethyl-3-dimethylaminomethyl-4H-1.2.4-
Triazole 4-[4-promo 2-(2-pyridinecarbonyl)phenyl]-3-ethylaminomethyl-44
H-1.2.4-triazole 4-[4-promo 2-
(2-pyridinecarbonyl)phenyl]-3-ethylaminomethyl-5-methyl-4H-1,2,4-triazole4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-diethylaminomethyl- 4H-1・
2,4-triazole 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-diethylaminomethyl-5-methyl-4H-1,2,4-triazole 4
-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-diethylaminomethyl-5-ethyl-4H
-1,2,4-triazole 4-[4-bromo-2-(
2-pyridinecarbonyl)phenyl]-3-dipropylaminomethyl-4H-1,2,4-triazole4-[
4-Promo2-(2-pyridylcarbonyl)phenyl]-3-diisopropylaminomethyl-4H-1.2.
4-triazole 4-[4-bromo-2-(2-pyridylcarbonyl)phenyl]-3-pyrrolidinomethyl-4
H-1.2.4-triazole 4-[4-bromo-2-
(2-pyridinecarbonyl)phenyl]-5-methyl-
3-pyrrolidinomethyl-4H-1.2.4-triazole 4-[4-bromo-2-(2-pyridinecarbonyl)
phenyl]-3-morpholinomethyl-4H1.2.4-
Triazole 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-5-methyl-3-morpholinomethyl-4H-1,2,4-triazole 4-[4-bromo-2-(2-pyridinecarbonyl) ) phenyl]-5-
Methyl-3-(4-methylpiperazinyl)methyl-4H
-1,2,4-triazole 4-[4-bromo-2-(
2-pyridinecarbonyl)phenyl]-3-[4-(2
-hydroxyethyl)piperazinyl]methyl-4H-1
・2,4-triazole 4-[4-bromo-2-(4-
pyridinecarbonyl)phenyl]-3-dimethylaminomethyl4H-1,2,4-triazole4-[4-bromo-2-(4-pyridinecarbonyl]phenyl]-3-
Diethylaminomethyl-4H-1,2,4-triazole3-benzylaminomethyl-4-[4-promo2-(
2-pyridinecarbonyl)phenyl]4H-1・2・4
-triazole 4-[4-chloro-2-(2-pyridinecarbonyl)phenyl]-3-dimethylaminomethyl 4
H-1,2,4-triazole 4-[4-chloro-2-
(2-pyridinecarbonyl)phenyl]-5-methyl-
3-dimethylaminomethyl-4H-1.2.4-triazole 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-5-ethyl-3-pyrrolidinomethyl-4H-1.2.4 -triazole 4-[4-bromo-2
-(2-pyridinecarbonyl)phenyl]-5-ethyl-3-(4-methylpiperazinyl)methyl-4H-1.
2,4-triazole 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-(4-ethylpiperazinyl)methyl-4H-1,2,4-triazole 4
-[4-Bromo-2-(2-pyridinecarbonyl)phenyl]-3-(4-ethylpiperazinyl)methyl-5-
Methyl-4H-1,2,4-triazole3-benzylaminomethyl-4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-5-methyl-4H-1-2.
4-Triazole 4-[4-chloro-2-(2-pyridinecarbonyl)phenyl]-3-methylaminomethyl-
4H-1,2,4-triazole 4-[4-chloro-2
-(2-pyridinecarbonyl)phenyl]-3-pyrrolidinomethyl-4H1.2.4-triazole4-[4-
Chloro-2-(2-pyridinecarbonyl)phenyl]-
5-Methyl-3-pyrrolidinomethyl-4H-1, 2, 4
-Triazole 4-[4-chloro-2-(2-pyridinecarbonyl)phenyl]-3-morpholinomethyl-4H
1,2,4-triazole 4-[4-chloro-2-(2
-pyridinecarbonyl)phenyl]-5-methyl-3-
Morpholinomethyl-4H-1,2,4-triazole 4
-[4-chloro-2-(2-pyridinecarbonino(to)
phenyl]-3-(4-methylpiperazinyl)methyl-
4H-1,2,4-triazole 4-[4-chloro-2
-(2-pyridinecarbonyl)phenyl]-3-diethylaminomethyl 4H-1,2,4-triazole The present invention will now be explained in more detail with reference to Reference Examples and Examples, but the present invention is not limited by these in any way. Needless to say, it won't.

Reference example 1 2-(2-amino-5-bromobenzoyl)pyridine 8
．． 7f1 orthoacetic acid methyl ester 5.7t1 acetic acid 2.
A solution of 8 ml of benzene and 100 ml of benzene is heated under reflux for 1.5 hours while distilling off the produced alcohol azeotropically, and then cooled.

Washed sequentially with saturated sodium bicarbonate water and water, dried (Na
After 2SO4), the solvent was distilled off under reduced pressure to give 2-[2-(1
-methoxyethylideneamino)5-bromobenzoyl]
Pyridine is obtained as an oil. Add this to methanol 6
0a solution, hydrazine hittride (100%) 4
Add 1.9 ml of 4 ml of acetic acid, stir at room temperature for 3 hours, collect the precipitate, wash with methanol, and dry to obtain 3-amino-6-promo-3,4-dihydro-4-hydroxy-2.
-Methyl-4-(2-pyridyl)-quinazoline crystals are obtained. Recrystallization from methanol-chloroform gives colorless crystals. Melting point: 208 low - 210°C (decomposition) Elemental analysis
Cl4Hl3BrN4O Calculated value C5O. 46, H3.93, Nl6.82 Experimental value C5O. O2, H3.7O, Nl7. ll Reference Example 2 3-Amino-6-bromo-3,4-dihydro-4-hydroxy-2-methyl-4-(2-pyridyl)-quinazoline was added to 30 ml of dimethylformamide solution while stirring under ice-cooling. A solution of 0.517 acetic anhydride in 6 ml of dimethylformamide was added dropwise, then 30
After stirring for a minute, 250ml of water containing 4.2t of potassium carbonate.
1 solution.

This liquid is passed through a celite layer to remove any insoluble matter,
▲Extract the liquid with ethyl acetate, wash the ethyl acetate layer with water, and dry (
After distilling off the solvent and collecting the precipitate using ethyl acetate-ether, the mono-(
Crystals of the chloroacetylated product are obtained. Recrystallization from ethyl acetate gives colorless prismatic crystals. Melting point 129-1
31℃ (decomposition) elemental analysis Cl6Hl4BrClN4O
2 Calculated value C46.9O,. H3.44, Nl3.68 Experimental value C47. O7, H3.2O, Nl3.

6l Reference Example 3 3-Amino-6-bromo-3 produced in Reference Example 2 above
・4-dihythro-4-hydroxy-2-methyl-4-(
A solution of 30 ml of acetic acid containing 2.177 mono(chloroacetyl)-2-pyridyl)-quinazoline was heated to 80°C for 3 hours, and the acetic acid was distilled off under reduced pressure. The residue was dissolved in chloroform and dissolved in saturated sodium bicarbonate water, Wash sequentially with water and dry (
After that, the solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate and collected to give 4-[4-bromo-2-(2
-Pyridinecarbonyl)phenyl]-3-chloromethyl-5-methyl-4H-1,2,4-triazole crystals are obtained.

Recrystallization from benzene-ether gives colorless prismatic crystals.
Melting point 170-171.5℃ (decomposition) Elemental analysis Cl6H
l2BrClN4O Calculated value C49. O6, H3. O9, Nl4.3l Experimental value C48.85, H2.89, Nl4. l5 Reference example 4 2-(2-amino-5-bromobenzoyl)pyridine 1
After adding 4t1 and 42d of formic acid (99%) and heating under reflux for 1 hour,
The solvent was distilled off, the residue was neutralized by adding saturated sodium bicarbonate water, and the precipitated crystals of 2-(5-bromo-2-formamidobenzoyl)pyridine were taken up with F and washed with water.

Recrystallization from methanol gives yellow needle-like crystals. Melting point 116-
117°C elemental analysis Cl3H, BrN2O Calculated value C5l. l7, H2.97, N9. l8 Experimental value C5l. l2, H2.75, N9. 14 Reference example 5 Hydrazine and
After adding 10 d of Hittler (100%) and heating at 60°C for several minutes, it was left at room temperature for 5 hours, and the precipitate was collected with F, washed with methanol and ether, and dried to give 3-amino-6-bromo-4.
-Hydroxy-4-(2-pyridyl)-3,4-dihydroquinazoline crystals are obtained.

Colorless granular crystals. Melting point 185187℃ (decomposition) Elemental analysis C
l3HllBrN4O Calculated value C48.92, H3.47, Nl7.55 Experimental value C48.77, H3.35, Nl7.56 Reference example 6 3-amino-6-bromo-4-hydroxy-4-(2-
pyridyl)-3,4-dihydroquinazoline 8.5f chloroform 60ml 11 sodium carbonate 11.3P water 1
10d solution and while stirring, slowly add monochloroacetyl chloride 12f dropwise at 100-15°C and stir for 30 minutes.

After further stirring at room temperature for 30 minutes, the precipitated crystals are washed with F, chloroform, and water in sequence, and dried to obtain crystals of the di-(chloroacetylated) compound of the above compound. Recrystallization from chloroform-methanol gives colorless prismatic crystals. Melting point 148.5-149℃ (decomposition) Elemental analysis
Cl, Hl3BrCl2N4O, calculated value C43.24
, H2.77, Nll. 86 Experimental values C42.8O, H2.48, Nll. 47 Reference Example 7 3-Amino-6-bromo-4 produced in Reference Example 6 above
-Di-(chloroacetyl) compound of hydroxy-4-(2-pyridyl)-3,4-dihydroquinazoline 0.94t
Add 0.4r of monochloroacetic acid to 1 solution of benzene 19Tn, heat under reflux for 30 minutes, wash the benzene layer with water, separate the benzene layer, distill off the benzene under reduced pressure, and wash the residue with methanol-isopropyl ether. 4-[4
-Bromo-2-(2-pyridinecarbonyl)phenyl]
Crystals of -3-chloromethyl-4H-1,2,4-triazole are obtained.

Recrystallization from ethyl acetate gives colorless crystals. melting point 14
6-147℃ Elemental analysis Cl5HlOBrClN4O Calculated values C47.7O, H2.66, Nl4.83 Experimental values C47.86, H2.43, Nl4.83 Reference example 8 8-bromo-1-methyl-6-(2-pyridyl )-14H
-s-Triazolo [4.3-a] [1.4] Into a solution of 0.7 t of benzodiazepine in 5 d of 6N monohydrochloric acid, add 1.25 t of sodium nitrite and 2 ．．
Add 5a solution and stir for 1 hour.

After bringing the mixture to room temperature and stirring for another 2 hours, it was neutralized with saturated sodium bicarbonate water, extracted with chloroform, the chloroform layer was washed with water, dried with Na2SO4, and the solvent was distilled off to give 4-[
4-Bromo-2-(2-pyridinecarbonyl)phenyl]-3-hydroxymethyl-5-methyl-4H-1.2
・4-triazole and 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-chloromethyl-4
A mixture of H-1.2.4-triazoles is obtained. [
The former 3-hydroxymethyl form produced here and the latter 3
-Chloromethyl compound was subjected to silica gel chromatography and chloroform monoacetate ethyl methanol (85:1
It can be easily separated by elution and purification at a ratio of 0:5). Former 3-
When the hydroxymethyl compound is recrystallized from methanol, it becomes colorless prismatic crystals with a melting point of 203-205°C (decomposition). The latter 2-chloromethyl compound corresponds to the product of this reference example] The entire amount of the mixture obtained above was diluted with chloroform 20
After adding 4.0 ml of thionyl chloride and stirring at room temperature for 3 hours, the solvent was distilled off. Saturated sodium bicarbonate water was added to the residue and extracted with chloroform. The chloroform layer was washed with water and dried with Na2sO4, and then the solvent was distilled off. 4 when leaving
-[4-Bromo-2-(2pyridinecarbonyl)phenyl]-3-chloromethyl-5-methyl-4H-1.2.
4-triazole is obtained as colorless crystals.

Melting point 172-173°C (decomposition). This product is the same as that obtained in Reference Example 3. Reference example 9 8-bromo-6-(2-pyridyl)-4-s triazolo[4.3-a][1.4]benzodiazepine 2.50 t
in 20d solution of 6N monohydrochloric acid under ice cooling (inner temperature 5-10℃)
, add a solution of 5.0 f sodium nitrite in 10 ml of water,
After stirring for 1.5 hours, neutralize with saturated sodium bicarbonate water, extract with chloroform, wash the chloroform layer with water, and add Na
After drying with 2sO4, when the solvent is distilled off, 4-[4-bromo-
2-(2-pyridinecarbonyl)phenyl]-2-hydroxymethyl-4H-1,2,4-triazole and 4-
A mixture of [4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-chloromethyl-4H1.2.4-triazole is obtained.

The entire amount was dissolved in 50 ml of chloroform, 14 ml of thionyl chloride was added, and after stirring at room temperature for 2 hours, the solvent was distilled off, and the residue was neutralized by adding saturated aqueous sodium bicarbonate.
Extracted with chloroform, washed the chloroform layer with water, and extracted with Na2s.
After drying with O4, the solvent is distilled off to give 4-[4-bromo-2-
(2-Pyridinecarbonyl)phenyl]-3-chloromethyl-4H-1,2,4-triazole is obtained as colorless crystals. Melting point 147-149°C. This product is the same as that obtained in Reference Example 7. Reference Example 10 By the same method as in Reference Example 9, 8-fromo1
-ethyl-6-(2-pyridyl)-4H-8-triazolo[4.3-a][1.4]benzodiazepine with 6N.
When the product after reaction with sodium hydrochloride mononitrite is chlorinated with thionyl chloride, 4-[4-bromo-2-(2-
Pyridinecarbonyl)phenyl]-3-chloromethyl-
Crystals of 5-ethyl-4H-1,2,4-triazole are obtained.

Recrystallization from acetone gives pale yellow prismatic crystals. Melting point 19
9-201℃ (decomposition) Example 1 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-chloromethyl-4H-1,2,4-triazole 0.257 in 10 ml of ethanol After adding 0.5 m2 of dimethylamine and heating under reflux for 1.5 hours, the solvent was distilled off. Water was added to the residue, extracted with chloroform, the chloroform layer was washed with water, and after drying with Na2sO4, the solvent was distilled off, and the residue was transferred to a silica gel column. Chromatography 1 [Silica gel 15y, chloroform-methanol monoethyl acetate (8
5:10:5)] to give 4-[4-bromo2-(2-pyridinecarbonyl)phenyl]-3-
Crystals of dimethylaminomethyl-4H-1,2,4-triazole are obtained.

Recrystallization from acetone-n-hexane gives colorless prismatic crystals. Melting point 145-146 C elemental analysis Cl7Hl6B
rN,O Calculated value C52.86, H4. l8, Nl8. l3 Experimental value C52.74, H4. lO, Nl8. l2 Example 2 Same as Example 1, 4-[4-bromo-2-(2pyridinecarbonyl)phenyl]-3-chloromethyl-5-methyl-4H-1,2,4-triazole 0.25V of ethanol Add 0.5 ml of dimethylamine to 10 ml of solution, heat under reflux for 1.5 hours, process, wash the chloroform extract with water, dry Na2sO4, and distill off the solvent to obtain 4-[4-
Bromo-2-(2-pyridinecarbonyl)phenyl]-
3-dimethylaminomethyl-5-methyl-4H-1.2
-4 triazole is obtained as colorless crystals.

Recrystallization from acetone-n-hexane gives colorless prismatic crystals. Melting point 127-128℃ Elemental analysis Cl8Hl8Br
N5O calculated value C54. Ol, H4.53, Nl7.5O Experimental value C53.7O,. H4.55, Nl7.42 The following compound can be produced by reacting a compound corresponding to the general formula () with a compound corresponding to the general formula () in the same manner as in the above example.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 and R^2 are the same or different and represent a lower alkyl group or a phenyl-lower alkyl group,
One of them may be a hydrogen atom. Furthermore, R^1 and R^2 may form a pyrrolidine, morpholine, or 4-lower alkylpiperazine type together with the adjacent nitrogen atom. R^3 represents a hydrogen atom or a lower alkyl group, R^4 represents a hydrogen atom, and Py represents a pyridyl group. ring A is substituted with a halogen atom].