JPH04103580A - Pyridine compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R1 is group shown by formula II or formula III; R2, R3 and R5 are H, halogen, lower alkyl or lower alkoxy; R4 is H or lower alkyl; A and B are H or lower alkyl or A and B together with adjoining C a bonded to form group shown by formula TV (R6 and R7 are H, lower alkyl or R6 and R7 are bonded lower alkylene; (m)is 3-9]. EXAMPLE:1-[2-[4-(4-Fluorophenyl)-6,7-dihydro-5H-1-pyrindin-2-yl] piperazin-1-yl]] ethyl-2-imidazolidinone. USE:An antihypertensive agent. PREPARATION:A compound shown by formula V is made to react with a compound shown by formula VI (X is eliminable atom or eliminable group) optionally in a solvent such as toluene preferably in the presence of a base (e.g. sodium carbonate) at 40-200 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to new and useful pyridine compounds having antihypertensive action.

Purpose of the present invention The present invention provides 4-phenyl-2-
(4-Substituted-1-piperazinyl)pyridine derivatives are provided.

Structure and effects of the invention According to the invention - Sailor (I) means, R2, R3 and R5 are the same or different hydrogen atoms.

means a halogen atom, a lower alkyl group or a lower alkoxy group, R4 means a hydrogen atom or a lower alkyl group, A and B
are the same or different and mean a hydrogen atom or a lower alkyl group, or may be taken together as adjacent R8, R6 and R7 are the same or different and mean a hydrogen atom or a lower alkyl group, Alternatively, they may be taken together to form a lower alkylene group, n means 2 or 3, and m means an integer from 3 to 9. ) A pyridine compound and its salts are provided.

The salts of the compound represented by formula (I) are preferably physiologically acceptable salts, such as inorganic acid salts such as hydrochloride, hydrogen iodide, sulfate, phosphate, and citrate. , maleate, fumarate, tartrate, benzoate, lactate, methanesulfonate, and other organic acid salts. Since the compound of formula (I) and its salts may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the compounds of the present invention.

When the compound represented by formula (1) has an asymmetric carbon atom, at least two types of stereoisomers may exist. These stereoisomers, mixtures and racemates thereof are included in the compounds of the present invention.

Terms used in this specification will be explained below.

"Lower" means 1 to 6 carbon atoms, unless otherwise specified.
means. The lower alkyl group or lower alkyl moiety may be linear or branched. Examples of the "lower alkyl group" include methyl and ethyl.

Propyl 1 Examples include isopropyl and butyl.

Examples of "halogen atoms" include fluorine, chlorine, and bromine.

One example is iodine. As a "lower alkoxy group",
For example, methoxy, ethoxy, propoxy.

Examples include isopropoxy and butoxy. Examples of the "lower alkylene group" include methylene diethylene and the like.

Among the compounds of the present invention, in formula (I), R2 is a fluorine atom, a methyl group or a methoxy group at the 4-position, R3 is a hydrogen atom or a fluorine atom at the 2-position, and A
and B are both methyl groups, or - together -
(CH2)m (m means an integer from 3 to 6)
and its physiologically acceptable salts.

Particularly suitable compounds include, for example, the following compounds and their physiologically acceptable salts.

1- (2-(4-C4-(4-fluorophenyl)-
6,7-sihydro-5H-1-pyrindin-2-yl]
piperazin-1-yl]]ethyl-2-imidazolidinone]-(2-(4-[:4- (4-fluorophenyl)
-5,6,7,8-tetrahydroquinoline-2-ylcopiperazin-1-yl]]ethyl-2-imidazolidinone 1-C2-(4-(4-(4-methylphenyl)-6
,7-dihuman'0-5H-1-pyrindin-2-yl)
piperazin-1-yl]]ethyl-2-imidazolidinone 1-(2-(4-(2,3-dimethyl-4-(4-fluorophenyl)pyridin-6-yl)piperazine-1
-yl]]ethyl-2-imidazolidinone 3- (2-(4-(4-(4-fluorophenyl)-
6,7-sihydro-5H-1-pyrindin-2-yl]
piperazin-1-yl]]ethyl-2,4 (IH,
3H)-quinazolinedione 3- (2-(4-(2,3
-dimethyl-4-(4-fluorophenyl)pyridine-
6-yl]piperazin-1-yl]]ethyl-2,4(
IH.

3H)-quinazolinedione Compounds of formula (I) are, for example, compounds of general formula (II) (wherein R
2, R2, A and B have the same meanings as above. ) and a compound represented by the general formula (I[) It can be produced by reacting with a compound represented by:

The leaving atom or leaving group represented by Examples are chlorine and bromine.

Examples include halogen atoms such as iodine, lower alkylsulfonyl groups such as methanesulfonyl, lower alkylsulfonyloxy groups such as methanesulfonyloxy, and arylsulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy.

The reaction between the compound of formula (I[) and the compound of formula (III) is carried out without a solvent or in a suitable solvent under normal pressure or increased pressure. A specific example of the solvent is toluene.

Aromatic hydrocarbons such as xylene, ketones such as methyl ethyl ketone, methyl isobutyl ketone, ethers such as dioxane, diglyme, alcohols such as ethanol, isopropyl alcohol, butanol, N, N-dimethylformamide, dimethyl Examples include sulfoxide. This reaction is preferably carried out in the presence of a base, and specific examples of the base include sodium carbonate,
Alkali carbonates such as potassium carbonate, sodium bicarbonate.

Examples include alkali bicarbonates such as potassium bicarbonate and tertiary amines such as triethylamine, although an excess amount of the compound of formula (II) may also serve as the compound.

In addition, when using a compound in which X is chlorine or bromine in formula (I[), the reaction proceeds smoothly by adding an alkali metal iodide such as sodium iodide or potassium iodide. Reaction temperature is usually 40-200°C
It is.

Compounds of formula (I[) and compounds of general formula (I
V) (In the formula, R6 means the same as shown above.) It can also be produced by reacting with a compound represented by V).

The reaction between the compound of formula (II) and the compound of formula (IV) is
The reaction is carried out without a solvent or in a suitable solvent under normal pressure or increased pressure. A specific example of the solvent is toluene.

Examples include aromatic hydrocarbons such as xylene, ketones such as methyl ethyl ketone and methyl isobutyl ketone, ethers such as dioxane and diglyme, N, N-dimethylformamide, and dimethyl sulfoxide. The reaction temperature is usually 40-200°C.

The compound of formula (I) is isolated and purified by conventional methods. The compound of formula (I) thus obtained can be converted into a salt by treatment with various acids according to conventional methods.

Starting compound (II) can be produced, for example, by a method similar to Reference Examples 1, 12, 24, and 30 or a method similar thereto. The starting compound (I[) is, for example, J.

Med, Chem, 6.669 (1963) or J, Chem, Soc.

3546 (1960), and the starting compound (IV) is prepared, for example, by J.
, 3551 (1960).

The results of pharmacological tests on the substitute compounds of the present invention are shown below, and the pharmacological action of the compounds of the present invention is explained.

Test Example: For antihypertensive effects experiments on spontaneously hypertensive rats (SHR), 18- to 26-week-old male SHR (Kaimoto-Aoki strain), self-bred at Dainippon Pharmaceutical Co., Ltd. Research Institute, were used.
For information on how to establish this strain, see Jap, C1rcu1
．． J., 27.282 (1963)] was used. Weeks et al.'s method (Proc, S
oc.

Exp, Biol, Med, 104.646
(1960)), an arterial cannula (polyethylene tube manufactured by Natsume Seisakusho Co., Ltd., 5P31:1) was implanted into the abdominal aorta of rats. The other end of the cannula was exposed and fixed under the skin of the back of the neck. After 1 to 4 days, the cannula was connected to a pressure transducer (Nihon Kohden, MP-4T type), and the awake blood pressure was measured by the direct method.

On the day of the experiment, blood pressure was measured for 1 hour before administration of the test compound, and then the test compound suspended in 0.5% tragacanth aqueous solution was orally administered (3, Omj/kg) L, thereafter 7
Blood pressure was measured continuously over time.

Table 1 shows the blood pressure before administration of the test compound, the time at which the maximum hypotensive effect is shown (peak time), and the blood pressure changes at the peak time and 7 hours after administration. The degree of hypotensive effect at 7 hours appears to be a good measure to assess the duration of action of the test compound. Note that the blood pressure change is displayed using the average blood pressure calculated from the systolic blood pressure and the diastolic blood pressure.

(Margin below) table Antihypertensive effect 30 minutes Example) Compound! Taste it (question below).

+5 (-9) (blank below) As is clear from the results of the above pharmacological tests, the compound of formula (1) and its physiologically acceptable salts have excellent antihypertensive effects and are also weakly toxic. For example, it can be used as an antihypertensive drug for the prevention and treatment of various types of hypertension.

The compound of formula (1) and its salts may be administered via oral, parenteral or rectal administration, and oral administration is preferred. The dosage varies depending on the type of compound, administration method, patient's symptoms, age, etc., and is usually 0.
1 to 100 μ/kg/day. The compound of formula (I) or a salt thereof is usually administered in the form of a preparation prepared by mixing it with a pharmaceutical carrier.

As the pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the compound of formula (T) or its salt is used. Specifically, for example, lactose, glucose, mannitol, cyclodextrin, starch, white sugar, crystalline cellulose, gelatin, gum arabic, hydroxypropylcellulose, hydroxypropylmethylcellulose, light anhydrous silicic acid.

Magnesium stearate, talc, tragacanth.

Titanium oxide, sorbitan fatty acid ester, vegetable oil.

Examples include water. Dosage forms include tablets, capsules,
Examples include granules, powders, syrups, suspensions, injections, and halves. These formulations are prepared according to conventional methods.

These formulations may also contain other therapeutically valuable ingredients.

In order to explain the present invention more specifically, reference examples and examples are given below, but the present invention is not limited to these examples. Compounds can be identified using elemental analysis, mass spectra, IR spectra, UV spectra, NM
This was carried out using R spectrum and the like. Furthermore, in the tables of Reference Examples and Examples, the following abbreviations are used to simplify the description.

A: Ethanol AC Niacetonitrile CF: Chloroform DMF: N,N-dimethylformamide HX: Hexane IA: Isopropyl alcohol M: Methanol MC/Methylene chloride PE: Petroleum ether T: Toluene W: Water Reference example 1 4-(4-fluoro phenyl)-5,6,7°8.9.
10-hexahydrocycloocta[b]pyridine-2(
Preparation of LH)-one 5 g of 4-fluorobenzoylacetonitrile.

A mixture of 4.6 g of cyclooctanone and 25 g of polyphosphoric acid is stirred at 120° C. for 2 hours. Pour the cold liquid and reaction liquid into ice water, add diethyl ether, and stir.
Collect the precipitate by filtration. Recrystallization from isopropyl alcohol yields 5 g of the desired product.

Melting point: 235-238°C Reference Examples 2-11 Using the corresponding raw material compounds, the compounds in Table 2 are obtained by reacting and treating in the same manner as in Reference Example 1.

Table 2 p.

Reference example 12 2-tllO-4-(4-fluorophenyl)-5
, production of 6,7,8-tetrahydroquinoline = 4-(4
A mixture of 18.7 g of -5,6,7°8-tetrahydro-2(IH)-quinolinone and 29 g of phenylphosphonic dichloride was stirred at 170°C for 1 hour. The cold solution and reaction solution are dissolved in 200 rIL of chloroform, added dropwise to stirring ice water over about 30 minutes, and made basic by gradually adding concentrated aqueous ammonia. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from isopropyl alcohol-petroleum ether to obtain 15.1 g of the desired product. Melting point 111-112°
C Reference Examples 13 to 22 Using the corresponding raw material compounds, the reaction was carried out in the same manner as in Reference Example 12.
Processing gives the compounds in Table 3.

(Space below) Table B/"-fcr Reference Example 23 Production of 2-chloro-4-(4-methylphenyl)-6゜7-sihydro-5H-1-pyrindine: 4~Methylbenzoylacetonitrile and cyclopentanone 4-(4-methylphenyl')-1,5,6°7-tetrahydro-2H-1-pyrindin-2-one was obtained by the same reaction and treatment as in Reference Example 1, and then in Reference Example 12. React and process in the same manner and recrystallize from ethanol to obtain the desired product.

Melting point 71-72°C Reference example 24 4-(4-fluorophenyl)-2-(4-benzyl-
Production of 1-piperazinyl)-5,6,7,8-tetrahydroquinoline: 2-1-4-(4-fluorophenyl)-5,6,
A mixture of 2 g of 7,8-tetrahydroquinoline, 1.27 g of potassium iodide and 4.04 g of N-benzylpiperazine is heated to 170° C. for 6 hours. The cold solution and reaction solution are diluted with chloroform, washed with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography, and the portion eluted with chloroform was concentrated to obtain 2.8 g of the desired product. This is treated with an ethanol solution of maleic acid, and then recrystallized from methanol to obtain the target simalate salt.

Melting point 174-175°C Reference Examples 25-29 Using the corresponding raw material compounds, react in the same manner as in Reference Example 24.
Processing gives the compounds in Table 4.

(Margins below) Table (Margins below) Reference example 30 Production of 4-(4-fluorophenyl)-2-(1-piperazinyl)-5,6,7,8-tetrahydroquinoline: 4-(4-fluorophenyl) -2-(4-benzyl-
2.8 g of 5,6,7,8-tetrahydroquinoline (1-piperazinyl) was dissolved in 50 g of methylene chloride, 1.0 g of α-chloroethyl chloroformate was added, the mixture was heated under reflux for 2 hours, and then concentrated under reduced pressure. Methanol 50-
and heated under reflux for 2 hours. Concentrate the reaction solution under reduced pressure,
The residue is dissolved in 5% hydrochloric acid and washed with chloroform. The aqueous layer is made basic with potassium carbonate, extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated.

The residue was subjected to column chromatography using alumina, and the portion eluted with chloroform-methanol (100:2) was concentrated to obtain 2.1 g of the desired product. This is treated with an ethanol solution of maleic acid, and then recrystallized from ethanol to obtain the target product, simalate salt 1/4 hydrate.

Melting point 143-145°C Reference example 31 4-(4-chlorophenyl)-2-(1-piperazinyl)-6,7,8,9-tetrahydro-5H-cyclohebuta(b) Production of pyridine 2-chloro- Using 4-(4-chlorophenyl)-5゜6.7.8-tetrahydro-5H-cyclohebuta[b]pyrindine, the reaction and treatment were carried out in the same manner as in Reference Example 24 to obtain 4-(4-chlorophenyl)-2- (4
-benzyl-1-piperazinyl) -5,6,7゜8-
Tetrahydro-5H-cyclohebuta(b)pyridine was obtained, and then reacted and treated in the same manner as in Reference Example 30, and recrystallized from methanol-ethanol to obtain the target maleate salt.
A quarter hydrate is obtained.

Melting point 176-178°C Reference Examples 32-36 Using the corresponding raw material compounds, react in the same manner as in Reference Example 30.
Processing gives the compounds in Table 5.

Table 5 p+ (blank below) Example 1 1- (2-(4-C4-(4-fluorophenyl)-
Preparation of 6,7-sihydro5H-1-pyrindin-2-ylcopiperazin-1-yl]ethyl-2-imidazolidinone: 4-(4-fluorophenyl)-2-(1-piperazinyl)-6 , 2 g of 7-sihydro-5H-1-pyrindine,
Anhydrous potassium carbonate 4.1g, potassium iodide 0.1
g+ A mixture of 1.75 g of 1-(2-chloroethyl)-2-imidazolidinone and 35 g of methyl isobutyl ketone is heated under reflux for 7 hours. Add 100 rIL of chloroform to the cold solution and reaction solution, and wash with water.

The organic layer is dried over anhydrous sodium sulfate and then concentrated, the residue is subjected to silica gel column chromatography, and the portion eluted with chloroform-methanol (100:3) is recrystallized from acetonitrile to obtain 2.07 g of the desired product. . Melting point: 171-173°C Examples 2-9 Using the corresponding starting compounds, the compounds shown in Table 6 were obtained by reacting and treating in the same manner as in Example 1.

R2 /゛<mi, \-'~゛~R3 A~'''ri, O B/1.:~N''N NCH2C) 12N''''min・Q Examples 10-14 The corresponding 2-chloropyridine compound Reference example 24
．． Reactions and treatments were carried out in the same manner as in Reference Example 30 and Example 1 to obtain the compounds shown in Table 7.

(Hereafter the margin) (hereinafter ↑゛margin) Example 15 3- (2-(4-(4-(4-fluorophenyl)-
5,6,7,8,9,10-hexahydrocycloocta(b)pyridin-2-ylcopiperazin-1-yl]
Preparation of ethyl-2,4(LH,3H)-quinacyridinedione: 4-(4-fluorophenyl)-2-(1-piperazinyl)-5,6,7,8,9,10-hexahydrocyclo Octa(b) pyridine 2g and 2゜3-dihydro-5H
-Oxazolo(2,3-b)quinazolin-5-one1.
Stir 2 g of the mixture at 130° C. for 1.5 hours. Chloroform is added to the cold liquid and the reaction liquid and dissolved by heating, and then the insoluble matter is filtered off.

The filtrate is cooled, and the precipitated crystals are collected by filtration and recrystallized from chloroform to obtain 2.26 g of a quarter hydrate of the target product.

Melting point 250-252°C Example 16 3-C2-[:4-(4-(4-fluorophenyl)-6,7-sihydro5H-1-pyrindin-2-ylcopiperazin-1-yl]]ethyl −2,4(IH,
Production of 3H)-quinazolinedione: Using 4-(4-fluorophenyl)-2-(1-piperazinyl)-6,7-sihydro-5H-1-pyrindine, reaction and treatment were carried out in the same manner as in Example 15, and chloroform - Recrystallize from methanol to obtain the desired product. Melting point 222~
224°C Example 17 3- (2-(4-(4-(4-fluorophenyl')
-5,6,7,8-tetrahydroquinoline-2-ylcopiperazin-1-yl]]ethyl-2°4 (IH,
Preparation of 3H)-quinazolinedione: 4-(4-fluorophenyl)-2-(1-piperazinyl)-5,6,7,
Using 8-tetrahydroquinoline, the reaction and treatment were carried out in the same manner as in Example 15, and the product was recrystallized from chloroform-methanol to obtain a quarter hydrate of the desired product. Melting point 144-146
°C Example 18 3-(2-(4-C2,3-dimethyl-4-(4-fluorophenyl)pyridin-6-yl)piperazine-1
-yl]]ethyl-2,4(IH.

3H)-Production of quinazolinedione Using 6-chloro-2,3-dimethyl-4-(4-fluorophenyl)pyridine, react and treat in the same manner as in Reference Example 24, Reference Example 30, and Example 15. , Recrystallize from tetraroform-methanol to obtain the desired product. Melting point 210
~212°C Patent applicant Dainippon Pharmaceutical Co., Ltd.

Claims (1)

[Claims] General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 is a group: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ , R_2, R_3 and R_5 are the same or different and mean a hydrogen atom, halogen atom, lower alkyl group or lower alkoxy group, R_4 means a hydrogen atom or a lower alkyl group, A and B are the same or different and mean a hydrogen atom or a lower alkyl group, or may be taken together with adjacent carbon atoms to form a ring: ▲ Numerical formula, chemical formula, table, etc. ▼, and R_6 and R_7 are the same or different and may be hydrogen atoms or means an alkyl group, or may be taken together to form a lower alkylene group, n means 2 or 3, m means an integer from 3 to 9); The salts.