JPS59137461A - 1,4-dihydropyridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound of diastereomers of 2,6-dimethyl-4-(3-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid-3-(1-benzyl-3-piperidyl)ester-5-methyl ester shown by the formula I , whose hydrochloride has 196-202 deg.C melting point. USE:A drug for circulatory organs such as hypotensor, vasodilator, etc. PROCESS:For example, a compound shown by the formula II is reacted with a halogenating reagent such as SOCl, etc. at -70-100 deg.C to give an acid halide, which is reacted with a compound shown by the formula III to give diastereomers shown by the formula I , this reaction solution is subjected to common operation such as extraction, concentration, column chromatography, etc., a HCl gas or HCl solution obtained by dissolving it in a proper solvent is added to the solution to give a hydrochloride. The solvent is optionally removed, it is subjected to fractional crystallization with a proper single or mixed solvent, to crystallize a compound having 196-202 deg.C melting point.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to IMI to 1,4-dihydropyridine derivatives. Furthermore, in detail, in the second invention, the melting point of the hydrochloride is 196 to
202'C 2,6-dimethyl-4-(3-nitrophenyl)-1,/I-dihydropyricin-3,5-
Dicarboxylic acid ~l-(1-hensyl-3-piperidyl)
This invention relates to ester-5-methyl ester and its salt.

This compound has antihypertensive effects, coronary vasodilatory effects, peripheral vasodilatory effects, etc., and is a useful compound as a circulatory organ drug such as an antihypertensive agent and a vasodilator.

The present invention will be explained in detail below.

This compound number Jj (2,6-dimethyl-4-(3-nitrophenyl)-", 4-dihydropyridine-3,5-dicarboxylic acid-3-<t-hensyl-3-bipeIJsil ) Of the diastereomers of Eslar-5-notyl-ester, it is a compound (referred to as the α-form) whose hydrochloride has a melting point of 196-202"C. Also, the melting point of its hydrochloride is 2:) 6-24
The compound at 2°C is combined with the beta form.

Next, the manufacturing process of this compound will be illustrated.

Listing↓ 1 [Diastereomer (α-form, β-form)] Compound represented by formula 11 (hereinafter referred to as compound ■).

Further, the compounds represented by Formula 1 tn-xr are also referred to as Compounds m to Compounds XI. ) and compound (2) are esterified by 1. For example, (a) A method in which compound (2) is made into an acid halide using a halogenating reagent and then reacted with compound (1). This is carried out using well-known methods such as the method of reacting compound (1) with compound (2) in the presence of a weak halogenating reagent (e.g., thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride). Particularly advantageous is a method in which the compound (1) is converted into an acid halide using a compound (2), such as phosphorus (tooled phosphorus, etc.), and then reacted with the compound (2).

Furthermore, regarding the method using a halokenizing reagent in (a),
I will explain in detail.

This method is not shown in a reaction formula.1 For example, when Valoken is chlorine, it is represented by the following formula.

II IV ■ C diastereomers (α-form, β-form)] Reactions include dichloromethane, chloroform, carbon tetrachloride, chlorenated hydrocarbons such as 1J-rubenrene, etc.

・＼Aromatic hydrocarbons such as toluene, tetrahydrofuran, ethers such as dioxane, acetate, etc.
-Ryl,N,N-dimethylformamide.

Presence of aprotic polar solvents such as methyl phospholinoctriamide, amines such as pyridine, triethylamine, etc.1. or carried out in the absence, especially "1,
The reaction is carried out using thionyl monide as a halogenating reagent, in the presence of N,N-dimethylformamide or hexamethylphosphorinoctriamide, and using the above-mentioned solvents alone or in combination.

The molar ratio of carboxylic acid and thionyl chloride is 1.0:0.8~
1. 〇22.0 range, preferably 1.01.9 to 1:
The ratio is 0:1.2.

Thionyl chloride and N,N-methylformamide.

Alternatively, the molar ratio of hexamethylphosphoric triamide is 1:1 to 1:100, preferably 1:5 to 1:50.

The reaction is carried out at -70'C to 100'C, preferably -20°C.
It is carried out at a temperature of ~50°C.

Then, the obtained compound IV (does not need to be isolated)
By reacting υ with compound I, diastereomers (α-form and β-form) represented by formula I can be obtained.

As the solvent, the solvent used in producing Compound IV from Compound 11 is used.

The reaction is carried out at a molar ratio of compound (1) and compound (2) of 1.0:0.8.
~1.0:2.0 or more preferably 1.0;0.9~1.0
= 1.2 at d10 degrees from -70°C to 100°C, preferably from -20°C to 50°C.

1 Fire II V ■ ■ [Diastereomers (α, β)] (in iu, Y
represents a halogen atom. ) Compound V+, which is used as a starting raw stone in this manufacturing method.

When Ken is chlorine, it can be expressed by the quadratic reaction formula.

1 ■ The pill ratio of compound ■ and vl is 1.0・0.5~1.0:
4.0 range, preferably 1.0:0.9-1.0:
It is 2.0.

Reactions include alcohols such as isopropanol and isobutanol, aromatic substances such as henzene and toluene, hydrocarbons, and hydrocarbons such as fform, carbon tetrachloride, and chlorobenzene.
:I lean hydrocarbon @5. triethylamine in the presence or absence of polymers such as tetrahydrofuran, dioxane, dimethoxyethane, aprotic polar solvents such as acetonitrile, N,N-dimethyl sulamide, etc.;

The reaction is carried out with or without addition of an organic base such as n'-butylamine or pyridine, or an inorganic base such as sodium hydroxide, potassium hydroxide or potassium carbonate.

The reaction temperature is room temperature to 200'C, preferably 30 to 150'C.
It is ℃.

Manufacturing method 3 1---□□□----□□1μ--□□A-1CM,
Iwa++ami ct al,, Chem, Ph
arm, Bull, 27°1426 (+979
) 3 self-posted and 4p = Shita method]■
■ I [diastereomer (α form, β form)] (in the formula, R,
and when one of R2 is a methyl group, the other represents a henzylpiperine group. ) The molar ratio of compounds ■ and ■ is 1
．． 0:0.8 to 1.0:4.0, preferably 1.
The range is from 0:0.9 to 1.0:1.5.

Reactions include alcohols such as methanol, ethanol, and impropatol, aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and carbon tetrachloride, and tetrahydrofuran.

Ethers such as diochitane and ditoxyethane.

In the presence or absence of an aprotic polar solvent such as acetolyl, or water, etc., the temperature is from room temperature to 150°C, preferably from 30 to 100°C.
Performed at °C.

Manufacturing method 4 CM. 1wc1n; uni et al. , Chem
．． Pharm. Bull. , 27.

1426 (ID79)] Vll IX
■ [Diastereomer (α-form, β-form)] (in the formula, R+
and R2 have the same meanings as above. ) Ammonium salts used in place of ammonia. Ammonium acetate and ammonium carbonate are most suitable.

Compound ■, IX. The molar ratio of I3 and ammonia (or ammonium salt) is 1.0:0.8:0.8
~180;4,0:4.0 range, target is 1.0
: 0.9 : 0.9~1.0 : 1.5 : 1
．． The range is 5.

Reactions include alcohols such as methanol, ethanol, and isopropanol, aromatic hydrocarbons such as henzene and toluene, chloroform, and carbon tetrachloride.

From room temperature to room temperature in the presence or absence of halokenated hydrocarbons such as chlorobenzene, ethers such as tetrahydrofuran, cyoxane, and cyclohexane, aprobiotic polar solvents such as acetonitrile thilbormamide, or water. The temperature is 150°C, preferably 30 to 100°C.

Manufacturing method 5 (11.llcrbert Fox et.al.,
J. Org. Chem. , j6.

+259 (1951)? j: )X XI N1(2 c++3c = coco., R2 --□□
□□ー□ーー→■ ■ [Stereomer (α-form, β-form)] (In the formula, R
+ and R2 have the same meanings as above. ) Compounds X, XI
The molar ratio of and ■ is 1.0:0.8:0. 8-1.
0; 4.0: Range of 4.0, preferably 1, 0
: 0.9 : 0.9~1.0 : 1.5 :
It is in the range of 1.5.

Reactions include alcohols such as methanol, ethanol and isopropanol, aromatic carbons such as benzene and luene, hydrogens such as chloroform and carbon tetrachloride, and tetrahydrofuran.

Ethers such as nmexane, nmexane, and xyethane.

Presence of an aprotic polar solvent such as att/toutryl, N,N-dimethylbormamide, or water] or in the presence of a ladle at room temperature to 150°C, preferably 30 to 100°C.
Performed at °C.

Compounds (1) to (3) and (1) to (XI) used as starting materials in the method of the present invention are known compounds or can be obtained by methods known per se.

Sentence 1 expansion is shown below.

Compound II: T, Shibanuma et al.
,, Chem, PI+arm.

Bull, 28.2809 (+980) Compound III: J, 11. Biel ct al,, J
,Org,Chem,, 26°409(i (196
+) Compound VT: G. Jones, “Tl+e kno
evenagel condensation"Org
, Reaction, 15.204 (1967)
Compound ■ S, 8 Glickmann at al.
, 1. 8m, CI+amSoc,, 67, 101
7 (+945) 'Compound IX, XI
: A, B, Bocse, Ind, End, Ch
cm,, 32°+6 (1940) Compound Vl;

The reaction solutions according to the above production methods 1 to 5 each contain diastereomers of IyI. r of hydrochloride, ■: Point 1
96-202°C Te certain compound (α form) and 23b-24
There is a compound (β form) at 2°C. These are Thin Layer I7 Tokurafui (TLC tentative, Merck Company Art 117)
98;Developing solvent, chlormecne:acetic acid 1,000/l/:
11J ethyl 7min-50: 50: IV/
A compound that is distinguished by V) and exhibits a low Rf value is the α-form. To isolate the desired α-form from a mixture of α-form and β-form, the following procedure is performed, for example.

Extract and concentrate the reaction solution 1 After normal operations such as column chromatography, add hydrogen chloride gas or a hydrogen chloride/S solution dissolved in an appropriate solvent to form a hydrochloride, (Production method I
If the halogen of the halogenating reagent is chlorine, then formula 2
Since the diastereomer represented by 2 is produced as a hydrochloride, this operation is not necessarily necessary depending on the isolation method. ) After removing the solvent if necessary, 'A! From a suitable single or mixed refrigerant '73'>jllA'+ζ
When the product is purified, the α-isomer crystallizes and the β-isomer remains in the solution.

Suitable single or mixed solvents for fractionated R111 products include:

-tNitanol, Rishil [+Porrem, Ethanol-
Examples include acetone, l:I l:l pol J2-acetone, chloroform-ether, l:I l:I porum-ethyl acetate, and the like.

+1& is a fJL mixed solvent of ethanol-acetone 5 chloroporm-acetone.

i+: :Ir, Compound V which is the starting material *4 in ili'l method 2.

As in the case of the diastereomers represented by formula 1, the α' form is a diastereomer with respect to each other (preparation 1) When the noastereomer ① is produced according to procedure 2.

There are two forms: a compound that forms the α form) and a β' form (a compound that forms the β form when the di)' stereomer ① is produced according to Production Method 2). Therefore, if only the α' form of the starting compound (2) is separated and used, the diastereomer l obtained by production method 2 is α
Since it is only the body, the above-mentioned α body and β body are included! No need for step III, just 2 extractions and concentration.

The α-isomer of diastereomer (■) can be obtained by conventional operations such as column chromatography and crystallization.

Salts of this compound include inorganic acid salts such as dihydrochloride, hydrobromide phosphate, sulfate, oxalate,! l: Anotriacids such as acid salts, fumarates, maleates, and malates can be used.

Next, the effect of this compound on blood pressure below the knee will be explained.

Test Method QL J'l rk Large (3-15 kg) nails were treated by intravenous administration of 30 ny/kg of pentobalchtal sodium. A cannula was inserted into the sixth stage J artery, and a constant +111 pressure was recorded on the Voriclave using a pressure cadence juicer (Nihon Kohden).

The results are shown in Table 1.

Table 1 1 □ 1--: 1 body +---- □ β body--- 1 4 As shown in Table 1, the α body exhibits a clear hypotensive effect from 1 minute after administration, and after 90 minutes or more. It lasted.

In a 6-type experiment, 11 people (9 to 18 kg) were subjected to thiobental sodium anesthesia and their renal arteries were constricted to create R-type hypertension. Changes in blood pressure during non-anesthesia-■-2 were determined in a sand dish manner through a polyethylene cannula (fixed to the back of the neck) inserted from the left carotid artery into the descending artery.

A suspension in 0.3% carboxymethyl cellulose was administered orally at a dose of 0.5 ml per kg of body f111 using a dupe for oral administration.

The results are shown in Table 2.

The compounds of the present invention are considered in consideration of their pharmacological actions.

It can be used in various pharmaceutical forms for administration purposes, particularly in oral dosage forms such as tablets and powders.

In the case of tablets, each tablet contains 5 to 30% (w/
w) Just include it. Other ingredients (carriers) include commonly used excipients and disintegrants.

Li1 lubricants, binders, coating agents, etc. are used.

Excipients include butyl sugar and milk IJ, disintegrants include Nbun, carboxymethyl cellulose, etc., and d1Y lubricants include stearic acid magnesium.6. Talc, etc. Binding agents include chemical syrup, borihinyl alcohol, seratin, hydroquinopropylcellulose, etc.
As a coating agent, a dispersant and a plasticizer are used as a dispersant.Methyl cellulose is used as a dispersant. Ethyl cellulose etc.
Glycerin, polyethylene glycol, etc. are used as the plasticizer.

Crystalline cellulose is also used as having disintegration, binding and excipient properties.

In the case of a powder, the compound of the present invention may be contained in an amount of 1 to 20% (W/W). As carriers, excipients such as glucose and lactose, binders such as hydroquinepropyl cellulose, etc. are used. The LDso of the compound of the present invention (α form) when administered orally to male rats is 127 mg/kg. The recommended dosage range is 1 to 100+■ per day for adults (approximately 60 kg).

Examples and reference examples are shown below.

Example 1゜2.6-cymethyl-4. -(3-nitrophenyl)-1
,4-dihydropyridine-3,5-7carphonic acid monomethyl ester (10.00 g) was mixed with dichloromethane and N,N
- Mixed solvent of tumedelbolamide (4:1 v/v
) Suspended in 70 ml of thionyl chloride 2.4.
Add 3 ml. After stirring under water cooling for 1 hour, 6.33 g of ■-Hensyl-3-hydroquine piperidine was added, and the mixture was further stirred under water cooling. After reacting for 2.5 hours, the reaction solution was diluted with 100% water.
ml and then with 100 ml of brine, and the dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then, add 100 ml of acetone and 8 ml of ethanol to the concentrated solution.
ml of yellow 2, (J-7 methyl-, 1-(3
-nitrophenyl)-1,4-dihydroUlpyridine~3
, 5-dicarboxylic acid = 3-(1--\sonol-3-piperidyl) ester-5-menal esral hydrochloride (α form) (11). Melting point 11] 7-198°C (
ethanol). This compound '1 River, C,, L (Merck & Co., Art) 1798 iDevelopment ltanol 1ink'-1 methane+ffi!:@ethyltriethylamine.

In addition, 5.21 g of β-isomer was obtained from the 1'NJ liquid of products 3 and 11.

1+ili point 2 (39-240°C (ethanol-methanol) LA' substance (!l: (ll'L is shown below).

2<(old(r.cm-'): 1680.
1525. 1345N M 12 (I
IMSO--δ): 1.3-2
．． 2 (411. broad).

2. Visit Hi11. s), 2.7-
3.4 (41L broad').

3, 57 (311.s), 4.40 (211.s).
s), 4.98 (Iff. s).

,'+. 20 (Ill. Inroad), 7
．． 3-8.2 (9+1.m).

9, 17 (IIl. uroad) Elemental content Jnoi 11°f (C,, I-132 CβN3 0G
):C 71N Actual AIll(+!'+(%)62.16 6,01
7.76ill calculation) 1zuL (%) 6
2.04 5.96 7.75 Example 2゜11 (α' form) 2.6 with a melting point of 236-238°C obtained in Example 1 above
-Simethyl-4-(3-diI.lophenyl)-1,4-
Dihydropyridine-3,5-dicarboxylic acid-3-methyl-5-(3-piperidyl) ester hydrochloride (α' form) 1
．． 35 g of hensyl chloride, 0.52 g of hensyl chloride, and 62 g of 1-ethylamine O were stirred under reflux for 24 hours in 20 ml of THF, poured into 50 ml of water, and extracted twice with 30 ml of ethyl acetate. Combine the ethyl acetate layers and add 1 part of 4N hydrochloric acid.
After stirring vigorously for 1 hour, the ethyl acetate layer was washed with 20 ml of brine and then with 10 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Add a mixed solvent of chloroporum and acetone (1:9v/v) to this concentrate.
When 10 ml of 2.6-dimethyl-4-(3-dilophenyl)-L4-dihydropyridine-3,5-dicarboxylic acid-3-(1-benzyl-
1.22 g of 3-piperidyl) ester-5-methyl ester hydrochloride (α form) is obtained. Melting point 197-198°
C (ethanol). ']'' of the compound obtained in this example
L, C, IR, and NMR were consistent with those of the α form obtained in Example 1.

Example 3゜3-21・口＼Methyl dilideneacetoacetate 2.49
g and 2.74 g of 3-7 minocrotonic acid-1-benzyl-3-piperidyl ester in 10 ml of methanol.
After stirring under reflux for 0 hours, the reaction solution was concentrated under reduced pressure, and the target compound (
Separate the fraction containing α-isomer).

After concentrating the fraction containing this target compound, 40% chloroform
ml, add 10 ml of 4N hydrochloric acid, and stir vigorously for 1 hour. Thereafter, the chloroform layer is washed twice with 20 ml of water, dried over anhydrous sodium sulfate, and concentrated again. Add 3 ml of ethanol and 2 ml of acetone to this concentrate.
When 7ml of mixed solvent was added and stirred, a yellow 2,6-
Dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3°5-dicarboxylic acid-3-(1-hensyl-3-piperidyl) ester-5-methyl ester Jha salt (α form) 1. 61 g is obtained. Melting point 19
7-198°C (ethanol). TLC, JR, and NMR of the compound obtained in this example were consistent with those of the α-isomer obtained in Example 1.

Example 4゜+N! 4.98 g of methyl 3-nitrohenlideneacetoacetate and 6 of acetoacetic acid-1-pencyl-3-piperityl ester
, 05 g and 29% ammonia water 1.7[i.g.
After stirring under reflux for 12 hours in ml of methanol, the two reaction solutions were treated in the same manner as in Example 3 to obtain 2,6-Shimejiru-4-(
3-nitrophenyl)-1,4-dihydropyridine-3
,5-dicarboxylic acid-3-(1-benzyl-3-piperidinyl) ester-5-methyl ester hydrochloride (α form)
Obtain 3.02g. Melting point: 196.5-198°C (ethanol). In this example, (TLC, IR of the compound shown)
, NMR was consistent with that of the α form obtained in Example 1.

Example 5 2.53 g of Minoclo I-medyl phosphate and acetoacetic acid.
1-Hentru 3-piperidyl ester 5.5.0 g
After stirring at reflux in 10 ml of 'r II F for 19 hours.

The reaction solution was compressed by overpressure and subjected to chromatographic column chromatography (18 eluate, chloroporum: acetone-9:
1 v/v) to separate the fraction containing the target compound. Then, after concentrating the fraction containing the target compound.

Dissolve in acetone 7 [1 ml, add hydrogen chloride saturated ether to make p] 11. When ether is further added to this, 2.10 g of yellow crystals are obtained. Melting point 176
~178°C0 This was mixed with acetone-ethanol (9:1v
/v) to form 2,6-dinothyru-4-(3
~2l-lophenyl)-1,4-dihydropyridine-3
,5-dicarboxylic 11-3-(1-hensyl-3-piperinor)-5-methyl ester hydrochloride (α form) 0.9
3g is obtained. Melting point: 197-198.5°C0 T1. of the compound obtained in this example. C, Il, and NMR were consistent with those of the α form obtained in Example 1.

Senior Example 1゜1 2.6~Tmethyl-4-(3-nitrophenyl)-1,
3.31 g of 4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester was added to 23 ml of a mixed solvent of dichloromethane and N,N-dimethylpolamide (4:IV/v).
32 g of thionyl chloride was added while cooling with water.

After stirring for 1 hour under water cooling, 1.51 g of 3-hydroxypiperidine hydrochloride was added.

Roughly stir in water for 1 hour and 20 minutes. After the reaction is complete.

Dissolve in 50 ml of chloroborum and wash with 40 ml of water.

Add 40ml of 1N thorium hydroxide to the solution and stir vigorously. Take the L + Roborum layer, wash it twice with 20 ml of water, and then concentrate the L + Roborum layer. The concentration 11
When K was dissolved in 20 ml of acetone, 2 ml of concentrated hydrochloric acid was added, and the mixture was stirred under water cooling, 2.6-dimethyl-4-(3-
2) Lophenyl)-1,4-dihydropyridine-3,
2.07 g of 5-dicarboxylic acid-3-methyl-5-(3-piperinor) ester hydrochloride (α' form) is 111
It will be done.

Melting point: 2a 6-238°C IR (Nujol, cut-'): 1695
．． 1530.135ONM12 (IIMsO-d6.δ
): 1.4-2.1 (411, broad), 2.32
(311,s), 2.35 (311,s)
, 2.7-3.3 (411, broad),
3.56 (3,50,311), 4.7-5.2
(Ill, L+roacl), 5.05 (I
H,s), 7.4-8.1 (411m),
9.33 (IIl, s) Elemental analysis value (C,,H,
, N30 et al. HC6) CHN Actual value (%) 55.73 5.74 9.42 Calculated value (%) 55.81 5.80 9.30 Also. From the above crystal mother liquor, 2,[;-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate-3-methyl-5-(3
-piperinor) ester hydrochloride (β' form) 1.27 g is obtained.

Patent Applicant (102) Kyowa Hakko Kogyo Co., Ltd. Procedural Amendment March 22, 1981 Mr. Commissioner of the Japan Patent Office 1. Indication of Case 1988 Patent Application No. 11719 2. Title of Invention 1.4-Dihydropyridine fatty conductor 3. Relationship with the person making the amendment Patent applicant postal code 100 Address 6-1 Otemachi-chome, Chiyoda-ku, Tokyo Name
(102) Wedge 5 of the Detailed Description of the Invention in the Specification of Kyowa Hakko Kogyo Co., Ltd., content of amendment V NH3 (or ammonium salt)" is corrected.

(2) Same book, page 9, manufacturing method 5 XJ Correct.

(3) Add the following sentence between the bottom two lines and the first line of page 13 of the same book.

"The drug was dissolved in polyethylene glycol 400 and administered through the brachial vein at a dose of 0.1-kg per body weight IK9." Edit to ``Up''.

(5) Corrected in Reference Example 10, page 23 of the same book.

Claims (1)

[Claims] 2,6-methyl-4-(3-nitrophenyl)-1,Il,-dihydropyridine-3,5-dicarboxylic acid-3-(1-hensyl-3-piperidyl) whose hydrochloride has a melting point of 196 to 202°C. Ester-5-methyl ester and its salts.