JPS62263179A - Piperazinylpyridopyrimidine compound - Google Patents

Abstract

NEW MATERIAL:A piperazinylpyridopyrimidine compound expressed by formula I [R is lower alkyl; Y is OH, -NH-NH-Ar (Ar is H or arylsulfonyl)]. EXAMPLE:8-Ethyl-5, 8-dihydro-5-oxo-2-(1-piperazinyl)-4-[N'-(p-toluenesulfonyl)hy drazino]-pyrido[2,3-d]pyrimidine-5-carboxylic acid hydrate. USE:Useful as a medicinal agent, having effect on animal and specific organs thereof and capable of exhibiting, e.g. hypotensive action, anticonvulsant action, etc. PREPARATION:A 4-aminouracil expressed by formula II is reacted with a halogenating agent and successively reacted with piperazine and an alkoxymethylenemalonic acid ester to give a compound expressed by formula III, which is further cyclized while heating, alkylated, hydrolyzed, etc., to afford the aimed compound expressed by formula I.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention relates to a novel organic compound, which has an effect on animals and their specific agents, and which It is expected to be used in various fields.

(Prior art) Compounds having the same skeleton as the compound provided by the present invention are known as compounds having antibacterial activity.
1-piperazinyl)-8-ethyl-5,8-dihydro-
A compound called 5-oxopyrido[2°3-d]pyrimidine-6-carboxylic acid (pipemidic acid) has been listed, and this compound has been introduced as a compound with excellent antibacterial activity.

(Problems to be Solved by the Present Invention) The present inventors conducted research aimed at searching for new biological activities of known compounds and creating new compounds having biological activity, and arrived at the present invention.

(Means for Solving Problems) The novel compound provided by the present invention and the biological activity of the compound were discovered as follows. That is, the compound of the present invention has the same skeleton as that of a compound conventionally known to have excellent antibacterial activity, and the present inventors have already found that it is an advantageous raw material for the production of the compound. Although it has been confirmed that similar biological activity is expected, it can be said that the antibacterial activity against various bacteria is almost negligible compared to the above-mentioned known compounds. It turns out.

It has been found that the compounds of the present invention have other activities such as hypotensive action and anticonvulsant action.

The method for producing the compound of the present invention will be described below. -4-aminouracil is reacted with a halogenating agent to produce 2,6-cyhalogeno-4-aminopyrimidine.

This is reacted with piperazine, one of which does not necessarily need to be protected, to obtain a 2-(4-!! substituted or unsubstituted -1
-piperazinyl)-4-amino-6-halogenpyrimidine is obtained. When 4-unsubstituted, it is protected with an acyl group or the like to obtain 2-(4-5!substituted-1-piperazinyl)-4-amino-6-halogenpyrimidine. The obtained compound is reacted with an alkoxymethylene malonic acid diester, and the obtained compound is ring-closed by heating, and then alkylated and hydrolyzed, or reacted with an arylsulfonylhydrazine and hydrolyzed, thereby achieving the object of the present invention. compound can be obtained. The chemical reaction formula is as follows.

(stomach)
Here Examples of the halogenating agent used for converting compound (a) to compound (b) include phosphorus oxychloride, phosphorus tribromide, thionyl chloride, and phosphorus pentachloride, and tertiary amines such as triethylamine , dimethylaniline, pyridine, etc.

Next, in order to convert compound (b) to compound (c), piperazine is reacted with or without protection on one side. Here, examples of the acyl group include acyl groups such as acetyl and benzoyl. In the conversion from compound (b) to compound (c), which halogen atom reacts at the 2-position or the 6-position is determined by C, A, 8
417272x (1976), 96199633u (
1982), the present inventors found that compound (c) can be obtained selectively.

Compound (c) is a compound obtained by subjecting it to a heating reaction with an alkoxymethylene malonic acid dialkyl ester, such as ethoxymethylene, malonic acid diethyl ester, methoxymethylene malonic acid dimethyl ester.

The obtained compound (c) is converted into compound (e) by heating to 150-200''C with a solvent such as trichlorobenzene, dichlorobenzene, xylene, kerosene, etc.

The obtained compound (e) is prepared by dimethyl sulfate in a solvent such as water, acetone, methyl ethyl ketone, methyl alcohol, ethyl alcohol, tetrahydrofuran, dioxane, toluene, etc. using a base (e.g., soda carbonate, potassium carbonate, alcoholade, etc.). , diethyl sulfate, ethyl p-toluenesulfonate, ethyl bromide, methyl iossite, and other alkylating agents can be reacted to convert it into the compound (2).

The compound thus obtained can be used directly or as a hydrazine or arylsulfonylhydrazine (e.g. p
-toluenesulfonylhydrazine, benzenesulfonylhydrazine, etc.) and then hydrolyzed to convert it into the compound of the present invention.

Hydrolysis uses caustic soda, caustic potassium, soda carbonate,
It is carried out using an aqueous solution of a basic compound such as potassium carbonate.

The present invention will be further explained in detail by describing examples below.

Example 1 2-(4-7cetyl-1-piperazinyl)-4-[N'
-(p-toluenesulfonyl)hydrazinoco-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d
l-pyrimidine-6-carboxylic acid ethyl ester 4.5g
A mixture of 16.2 g of 10% aqueous sodium hydroxide solution was stirred at 35 to 40°C for 39 hours. 30% water to the reaction mixture
ml was added thereto, the pH was adjusted to 7.0 with acetic acid, and the precipitated crystals were collected by filtration and washed with water. Dry the crystals with warm air at 25°C to obtain 8-ethyl-5.
゜8-Dihydro-5-oxo-2-(1-piperazinyl)-4-[N'-(P-toluenesulfonyl)hydrazinoco-pyrido[2,3-dlpyrimidine-6-carboxylic acid tetrahydrate3. 67gt! -I got it. Yield 81.0%
mp, 186-189°C (decomposition) Moisture was measured by Karl Fischer method and found to be 12.63%. (Calculation amount 12.88%) IR (am crab 3400 () 1.O) 3000-2000
゛(COOH group 0)() 1640 (COO
C=O> NMR of H group: H';'aOD.

1.17 (3H,t,-CH,CH,)2.12 (
3H, s, -C, H, -CH,) 2.45 to 2.95.
3.35-3.80 (8H, piperazine ring) 3.95 (2H, q, once J engineering CH,) 8.03
(LH, s, C, -H) When this crystal was dried under reduced pressure at 100°C for 2 hours, water of crystallization was released, and a new absorption was observed at 1730 am by IR. (C=O of carboxyl group) Example 2 8-ethyl-5,8-dihydro-5-oxo-2-(1
-piperazinyl) -4-(N'-(p,-toluenesulfonyl)hydrazinocopyrido[2°3-d]pyrimidine-6-carboxylic acid tetrahydrate synthesis: (a) 2-(4-acetyl -1-piperazinyl)-4-
[N'-(p-toluenesulfonyl)hydrazinoco-8-ethyl-5,8-dihydro-5-oxopyrido[
2,3-dl pyrimidine-6-carboxylic acid ethyl ester 2.33 g, 2% aqueous sodium hydroxide solution 16 rn
The mixture of 1 was stirred at 40°C for 30 hours. After washing the reaction mixture with chloroform, it was treated with activated carbon, and the pH was adjusted with dilute acid.
It was set at 3.0.

The precipitated crystals were collected by filtration, washed with water, and then washed with methanol.
-(4-acetyl-1-piperazinyl)-4-[N'-
(p-Toluenesulfonyl)hydrazinoco-8-ethyl-5,8-dihydro-5-oxopyrido [2,3-dl
2.04 g of pyrimidine-6-carboxylic acid was obtained. Yield 9
6.3% mp.

278-281°C (decomposition) IR (a++-'): 3425.3275 (NH)
1.30 (3H,t,-CH,CH,)2.07 (
3H, s, -CH,) 2.32 (3H, s, -CH,) 2.92-4.12 (8H, piperazine ring) 4.25
(2H,q,-CH3CO,)8, 75 (L
H,s,Cw-H)(b)2-(4-acetyl-1-piperazinyl)-4-[N'-(p-toluenesulfonyl)hydrazinoco-8-ethyl-5,8-dihydro-5-oxopyride [2,3-dlpyrimidine-
A mixture of 15.30 g of local phone and 20 g of 10% aqueous sodium hydroxide solution was stirred at 35 to 40°C for 40 hours. 40 ml of water was added to the reaction mixture, and the pH was adjusted to 7.0 with acetic acid.
The precipitated crystals were collected by filtration and washed with water.

The crystals were dried with warm air at 25°C to give 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)-4-[N
'-(P-toluenesulfonyl)hydrazinoco-pyrido[2,3-dlpyrimidine-6-carboxylic acid tetrahydrate 4
．． 60g was obtained. Yield: 82.1% This product was obtained in Example 1 and IR.

mp, NMR, etc. are completely consistent.

Example 3 (1) 2-(4-acetyl-1-piperazinyl)-4
-Chloro-8-ethyl-5,8-dihydro-5-oxopyrido (2,3-d) pyrimidine-6-carboxylic acid ethyl ester 0.8 g, 3% aqueous sodium hydroxide solution 15
The mixture of m1 was heated under reflux for 4 hours. Activated carbon was added, filtered, and the pH was adjusted to 6.90 with acetic acid. The precipitated crystals were collected by filtration and washed with water to give 2-(1-piperazinyl)-4-hydroxy-8-ethyl-5,8-dihydro-5-oxopyride [
0.41 g of 2<3-d]pyrimidine-6-carboxylic acid was obtained.

mp300℃ or more IRcm: 3400 (OH) p (secret, o.

NMR δp5c - 1,48 (3H, t, CH2CH,) 3.33-4.50 (8H, piperazine ring) 4-48
(2H,q-CHaCHa)9,03
(I H, s, C? H) (2) 2-
(4-ethoxycarbonyl-1-piperazinyl)-4-
A mixture of 2.19 g of chloro-8-ethyl-5,8-cyhydro-5-oxopyrido (2,3-d) pyrimidine-6-carboxylic acid ethyl ester and 24 g of 10% sodium hydroxide was stirred at 95° C. for 30 hours. Add 5 ml of water, adjust the pH to 7.0 with acetic acid, collect the precipitated crystals by filtration, wash with water,
-(1-piperazinyl)-4-hydroxy-8-ethyl-5,8-dihydro-5-oxopyrido [2°3-d]
0.95 g of pyrimidine-6-carboxylic acid was obtained. The physical properties of this compound matched the physical properties of the compound obtained in (1).

The physiological activities of the compounds obtained in Examples 1 and 2 and the compounds obtained in Example 3 were as follows. It is shown in Table 1.

Reference Example 1 2-(4-7cetyl-1-piperazinyl)-4-chloro-8-ethyl-5,8-dihydro-5-oxopyrido [
2,3-d cobyrimidine-6-carboxylic acid ethyl ester 16.30 g, p-h luenesulfonyl hydrazide 8
．． 19g, triethylamine4. ．． A mixture of 45 g of chloroform and 82 ml of chloroform was heated under reflux for 5 hours. After cooling, the reaction mixture was washed successively with water, diluted hydrochloric acid, and water. After drying the chloroform layer, it was concentrated under reduced pressure, methanol was added to the residue, and the crystals were collected by filtration to give 2-(4-acetyl-1-piperazinyl)-4-[N'-(p-toluenesulfonyl).
17.89 g of hydrazinoco-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d-copyrimidine-6-carboxylic acid ethyl ester were obtained. Yield 80.3%
If this is reconstituted with methanol, the mp will be 230-23
Indicates 1°C.

IR (Country°l): 3150 (NH) 1705 (Ester)CO
Cl.

NMR δqHs: 1.37 (6H, t, -CH, CH, X2) 2.13
(3H, s, -CH,) 2.32 (3H1s, -CH,) 3.10-4.17 (8H, piperazine ring) 3.77
~4.60 (4H1-CH,CH,X7.67~8.0
(IHl,NH)8-20 (LH,s
, Cv H) 11.65 (IH, s, >NH) Reference Example 2 2-(4-ethoxycarbonyl-1-piperazinyl)-
4-chloro-8-ethyl-5,8-dihydro-5-oxopyride [2,3-dl pyrimidine-6-carboxylic acid ethyl ester 4.38 g, P-toluenesulfonyl hydrazide 2.05 g, triethylamine 1.11 g, chloroform 22ml of the mixture was heated to reflux for 4.5 hours.

After cooling, the reaction mixture was washed successively with water, diluted hydrochloric acid, and water.

After drying the chloroform layer, it was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 2-(4-ethoxycarbonyl-1-piperazinyl)-4-[N'-(p-toluenesulfonyl)hydrazinoco-8-ethyl- 5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6
-5.51 g of white crystals of carboxylic acid ethyl ester were obtained.

Yield 93.7% mp, 240-249°C (decomposition) IR (am): 3125 (NH) 1705
(ester, urethane) ockJ NMRδa M5 ・

Claims (1)

[Claims] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R is a lower alkyl group, Y is OH or -NH-N
A piperazinylpyridopyrimidine compound represented by H-Ar (Ar represents a hydrogen atom or an arylsulfonyl group).