JPS6163689A - Pyridine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is lower alkyl; R<2> is H, hydro carbon group which has 0-4 unsaturated bonds and may be substituted with alkoxy, aryloxy, etc., or group of formula II (R<6> is lower alkyl; m is 0-2; n is 2-4); R<3> is group of formula III (R<7> is H, halogen, etc.; the group of formu la IV is hetero-cyclic group containing furan, thiophene, etc.); R<4> is group of formula V (R<8> and R<9> are H, alkyl, etc.);R<5> is lower alkyl], its ester derivative and its salt. EXAMPLE:Methyl 5-diisopropoxyphosphinyl-2,6-dimethyl-4-(2-pyridyl)-1,4-dih-ydro pyridine-3-carboxylate. USE:Vasodilator and hypotensor having high safety. PREPARATION:The objective compound can be prepared e.g. by reacting the compounds of formulas IV-VIII preferably at molar ratios of 1:0.0: (0.0-1):1.5:1.5, optionally in a solvent, preferably at 40-100 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to 1,4-dihydropyridine-3-carboxylic acid ester derivatives and salts thereof useful as pharmaceuticals.

The compound according to the present invention has the following general formula (1)% formula% W! Represents a group.

(11RI represents lower alkyl.

(2) R2 represents one substituent selected from the group consisting of the substituents described in Φ to ■ below.

ΦHydrogen.

■It is branched or unbranched, chained or cyclic, or a state in which a chain and a cyclic are combined, and it has an unsaturated bond of O to 4i1. A hydrocarbon having 1 to 9 carbon atoms, which is substituted with one or more of the substituents listed in (a) to (a) below, or is unsubstituted.

(a) alkoxy group, (b) aryloxy group, (C)
Aralkyloxy group, (d) amino group, (e) alkyl-substituted amino group, (f) alkylthio group [Here, R6 represents a lower alkyl group, m is O-2
, n represents an integer of 2 to 4,] (3) R3 represents general formula (II) - [wherein R? represents hydrogen, halogen, nitro group, alkoxy group, or alkylthio group, and represents a heterocycle including benzofurazan. ] represents.

(4) R4 is represented by the general formula (!13 [wherein R11 and R9 are the same or different and represent hydrogen, an alkyl group, or an alkenyl group, or R8
and R9 combine to form part of a 6M ring. R8 and R9
When bonded to form part of a 6-membered ring, the ring is unsubstituted or substituted with lower alkyl. ]
represents.

(5) RS represents lower alkyl.

(Prior Art) Many 1,4-dihydropyridine derivatives have been known, but among them, 2,6-dimethyl-4-(2-ditophenyl)-1,4-dihydropyridine is particularly known. -3,5-dicarboxylic acid dimethyl ester (
-Ship name: Nifedipine) is used as a compound that has coronary vasodilation and blood pressure lowering effects.

Furthermore, as the 1,4-dihydropyridine derivative having a heterocycle at the 4-position, for example, dazodipine
ine (PY 108-068): 5ando
z AGP, Newmann Japanese Patent Publication No. 54-1038
76, ), Mesudipine:
J, Cardiovasc, Pharmac.
ol,.

5(1), 162 (1983)), and similar compounds are also disclosed in JP-A-57-028082.

Furthermore, Special Publication No. 46-037349. Japanese Patent Publication No. 54-048
796° Japanese Patent Publication No. 54-070284. JP-A-55-03
3497. Japanese Patent Publication No. 55-047657. JP-A-55-0
50021. JP-A-55-064570° JP-A-55-
064571. Japanese Patent Publication No. 55-124761. Unexamined Japanese Patent Publication 1973
-124760. Japanese Patent Publication No. 55-047656. Japanese Patent Application Publication No. 5
6-140989゜Unexamined Japanese Patent Publication No. 57-007468. Japanese Patent Publication No. 57-131763. Japanese Patent Publication No. 57-206659. Japanese Patent Publication No. 58-167569. JP-A-58-201765° JP-A-59-042380. Japanese Patent Publication No. 59-080663.
Japanese Patent Publication No. 59-076083. Similar compounds are also disclosed in publications such as .

On the other hand, in the field of phosphoric acid derivatives represented by general formula (1), the following dihydropyridine derivatives are known.

Von K, l5sleib, R, Wolff u
nt M, Lengies, J.

Prakt, Chemie, 318. 207～
20 (1976).

The report by Summersleib et al. only describes the methods for producing the following two compounds. In reality, these compounds have no antihypertensive effect, as described below.

(Problems to be solved by the invention) Several compounds related to nifedipine are already known, but many of them are unstable to light or
It had many drawbacks, such as short duration of action and serious side effects. The purpose of the present invention is to
The object of the present invention was to create a compound that does not have these drawbacks and that far exceeds the pharmacological action of conventional nifedipine analogues.

(Means for Solving the Problems) The present inventors have discovered that by introducing various heterocycles in place of the phenyl group at the 4-position of the 1,4-dihydropyridine skeleton of nifedipine, A number of derivatives were synthesized by converting one into a linear or cyclic phosphonate group, and their pharmacological effects were investigated.

As a result, it was discovered that the 1,4-dihydropyridine derivative represented by the general formula (1) and its salt compounds have excellent vasodilatory and blood pressure lowering effects, and are also highly safe, and finally the present invention has been achieved. This is what I did.

Further details of the above-mentioned compounds according to the present invention are as follows.

In the compound according to the present invention, examples of R1 include lower alkyl having 1 to 3 carbon atoms, such as methyl, ethyl, and propyl.

In the compound according to the present invention, R2 may be a linear or branched chain hydrocarbon having 1 to 5 carbon atoms, such as methyl, ethyl, topropyl,
Isopropyl, n-butyl, isobutyl, 5ec-butyl, tert-butyl, rhopentyl, isopentyl,
Neopentyl etc. In addition, as R2, carbon number 3 to 5
unsaturated hydrocarbons such as allyl, crotyl, 2-methylallyl, l-methylallyl, 3,3-dimethylallyl, ■-ethyl-2-propenyl, propargyl, l-methyl-2-butenyl, 3-butenyl, 3-methyl -3-
Mention may be made of butenyl, 3-butynyl, prenyl, and the like. Furthermore, as R2, a cyclic hydrocarbon, for example, 3 to 7
Examples of the cycloalkylalkyl group include cycloalkylalkyl groups in which cycloalkyl has 3 to 6 carbon atoms and alkyl has 1 to 3 carbon atoms, such as cyclopropylmethyl,
Examples of alkoxyalkyl groups include cyclobutylmethyl, cyclopentylmethyl, etc., and examples of alkoxyalkyl groups include β-methoxyethyl, β-ethoxyethyl, β- 1-
Examples of the phenylalkenyl group include propoxyethyl, β-isopropoxyethyl, etc.; examples of the phenylalkyl group include those in which the alkyl has 1 to 3 carbon atoms, such as benzyl, phenethyl, etc.; examples of the phenylalkenyl group include fulkenyl having 1 to 3 carbon atoms is 2 to 3, for example, a cinnamyl group.

Furthermore, R2 is an alkylthioalkyl group in which alkylthio has 1 to 5 carbon atoms and alkyl has 2 to 4 carbon atoms, such as 2-methylthioethyl group, 2-ethylthioethyl group, 2-propylthioethyl group, etc. As the dialkylaminoalkyl group, dialkylamino has 1 to 3 carbon atoms and alkyl has 2 to 4 carbon atoms, such as 2-dimethylaminoethyl group, 3-dimethylaminoethyl group, 2-diethylamino Examples include ethyl group.

R2 further includes 2-(N-benzyl-N-methylamino)ethyl, 2-(N-phenethyl-N-methylamino)ethyl, 3-(N-benzyl-N-methylamino)propyl, 4- (N-benzyl-N-methylamino)butyl, etc., and as an aralkyloxyalkyl group, aralkyloxy has 7 carbon atoms.
~9 and the alkyl has 1 to 3 carbon atoms, such as β-benzyloxyethyl, β-phenethyloxyethyl, etc. As the aryloxyalkyl group, the aryloxy has 6 to 1O carbon atoms and the alkyl Number of carbons is 1
-3, substituted or unsubstituted, for example, β-phenoxyethyl group, etc. can be mentioned.

In the compound according to the present invention, examples of the heterocycle contained in R3 include pyridine, furan, thiophene, and benzofurazan. The heterocycle is unsubstituted or substituted with a halogen, a nitro group, an alkoxy group having 1 to 3 carbon atoms, an alkylthio group having 1 to 3 carbon atoms, or the like. More specifically, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 2-pyridyl
Chenyl, 4-benzofurazanyl, 2-methylthio-3
~pyridyl, 5-nitro-2-furyl, 5-nitro-2
- Chenyl, etc. can be mentioned.

In the compound according to the present invention, R4 is represented by general formula (II)
represents a chain or cyclic phosphonate as shown in R7 and R8 of the chain phosphonate include hydrogen, an alkyl group, or an alkenyl group. More specifically, the alkyl group has 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5ec-butyl, tert-butyl, n-pentyl, isopentyl, 5eC -Pentyl, neopentyl, etc. can be mentioned, but particularly preferred is one having a carbon number of 1
~4 alkyl. Preferred examples of the alkenyl group include allyl, crotyl, 2-methylallyl, 1-methylallyl, 1-methyl-2-butenyl, and prenyl having 3 to 5 carbon atoms.
When is a cyclic phosphonate, it is unsubstituted or has 1 carbon number.
Substituted with ~3 alkyl groups. Specifically, for example, 2-oxo-1,3,2-dioxaphosphorinane-2
-yl, 5,5-dimethyl-2-oxo-1,3,2-
Dioxaphosphorinan-2-yl, 4 (R),
6 (R)-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl and the like.

In the compound according to the present invention, R5 is methyl,
Examples include alkyl groups having 1 to 3 carbon atoms such as ethyl and propyl.

In the above, R1. R2
, R3, R4, and Rs, but the present invention is not limited to these examples.

For compounds according to the invention, compounds capable of forming salts include salts with pharmaceutically usable organic or inorganic acids. These acids include, for example, hydrochloric acid,
Examples include hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, alkyl or arylsulfonic acids, fumaric acid, malic acid, maleic acid, succinic acid, citric acid, tartaric acid, oxalic acid, acetic acid, and amino acids such as glycine. be able to.

(See next page below) Although the compound of the present invention has an asymmetric carbon, all optically active forms and mixtures thereof are included within the scope of the present invention.

The racemic compound can be separated if desired, for example, when the compound of the present invention is a base, by the action of an optically active acid, and the optically active base can be obtained from the separated salt. Furthermore, when the compound of the present invention is an acid, an optically active acid can be obtained in the same manner by reacting with an optically active base.

The main method for producing the compound of the present invention represented by general formula (1) will be illustrated.

-CI) Same as above. ) The raw material compounds (VI), (rV) and (V-N) are preferably mixed in a molar ratio in the range of l: o, s: o, s to l: 4:4, more preferably l: 0.9. :0.9~1
: Mix in the range of 1.5:1.5. The reaction can be performed with alcohols such as methanol, ethanol, and isopropanol, aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and carbon tetrachloride, ethers such as tetrahydrofuran and dioxane, acetonitrile, dimethylformamide, etc. The reaction is carried out in the presence or absence of an aprotic solvent or water at room temperature to 150°C, preferably 40 to 100°C.

Separation of the target product from the reaction mixture can be performed by conventional operations such as concentration, extraction, column chromatography, and recrystallization.

Furthermore, as another method, a reaction formula is illustrated below. These production methods can also be carried out using the same molar ratio, reaction solvent, reaction temperature, and separation operation as in Production Method 1.

- [■] The raw material compound [■] is the compound [■] and (
IV) can be easily obtained by dehydration condensation in an organic solvent.

Sarakoko NH2 (In the formula, R4 and R5 are the same as above.) Note that the above-mentioned middle ammonium salts include ammonium acetate, ammonium carbonate, ammonium hydrogen carbonate, and the like.

The bosphonate esters of the general formula (IV) used as starting materials are known from the literature or can be prepared by methods known from the literature. (for example,
^, N., Pudovic and V., P.

Aver'yanoua+ Zhur, 0bsh
ch, Doklady Akad, NaukS
, S, S, R,, 101, 889-92
(1955),) General formula (V) used as starting material
The β-ketocarboxylic acid esters of are known in the literature or can be prepared according to methods known in the literature (for example,
' Umsetzungvon Diketen wi
tAlkoholenSPhenolen unt
Melcap-1anen” in Houben
-Weyl, Methoden der Orga
Nischen Che+sie Vol, ■ 4.2
30 (196B), Y., Oikawa, K.
, Sugano and O.
su, J, Org, Chem.

The enamine esters of the general formula (V-N) used as starting materials are known from the literature or can be prepared according to methods known from the literature. (For example, A
, C. Cope, et al., J. Am.

Che+n, Soc,, 67, 1017 (194
5) See ) General formula (IV-N) used as starting material
The enamine esters can also be produced in the same manner as in the case of general formula (V-N).

The heterocyclic aldehyde of general formula (Vl) used as a starting material can be a commercially available product or can be produced according to a known method.

The heterocyclic methylidene derivative of the general formula [■] used as a starting material can be produced according to a known method (for example, ^, N, Pudoruk+G, E
, Yastrebova and V, 1
．． N1kitina, zh.

0bshch, Khim, 37.510-11 (
1967), R., Wolffunt M., Len.
Gies, J., Prakt, Chemie, +
See ats, 207-20 (1976). ), an example of its production is shown in the reference example below.

The heterocyclic methylidene derivatives of the general formula [■] used as starting materials are known from the literature or can be prepared according to methods known from the literature (for example, G
, Jones, “The Knoevenage
lCondensation ″in Org,
Reactions, Vol. , and has excellent vasodilatory effects such as coronary vasodilation and blood pressure lowering effects, so it is effective against circulatory system diseases such as hypertension, heart failure, arrhythmia, angina, myocardial infarction, cerebrovascular disorders, and peripheral circulation disorders. It can be widely used as a therapeutic agent.

The compound of the present invention has a weaker action on myocardium than the known compounds nifedipine and diltiazem, but on the other hand, it is specifically used on coronary blood vessels, and on the other hand, the onset of action is slower and the action is longer lasting than nifedipine. It has a long-lasting antihypertensive effect. Furthermore, it is stable against light.

Test examples are shown below regarding the effects of representative compounds of the present invention on coronary blood vessels and blood pressure in comparison with the known compound diltiazem.

1. Test method and results <al Coronary vasodilatory effect The effect of intracoronary administration of the compound of the present invention on a constant pressure perfusion specimen of a guinea pig heart isolated according to Langerdorf's method was investigated (Table 1).

In addition, the strength of the coronary vasodilatory action of diltiazem, a known compound, measured by the same method was 10°7.10-6.
The rate of increase in perfusion amount at each dose of 10-5 g/heart was 0, 8.2 B, and %, respectively. As a result, the excellent coronary vasodilatory action of the compound of the present invention is mild.

(Intoxicated antihypertensive effect: The blood pressure of the femoral artery is measured using a pressure-reducing blood pressure rat using a pressure-depleted blood pressure rat under no anesthesia.) The compound of the present invention is
．． After oral administration at doses of 10 and 30 mg/kg, the subsequent changes in blood pressure over time were measured, and the rate of decrease in mean arterial blood pressure (
%) was calculated, and the rate of blood pressure reduction at the time of the maximum drop was shown as the hypotensive effect (Table 2).

The antihypertensive effects of diltiazem, a known compound, measured in the same manner were 0.12, 1, and 28.9% at doses of 3, 10, and 30 mg/kH, respectively.

This clearly demonstrates the excellent antihypertensive effect of the compound of the present invention.

Note that the compound represented by the above formula (IX) (R is hydrogen and 0C
When a similar test was conducted on two of 113), no hypotensive effect was observed in any of them.

C) Acute toxicity The toxicity of the present invention, hardware 1, is weak, with LD5. All values are 400 mg/kg or more when administered orally to rats.

Wow.

When the compound of the present invention is administered as a medicament, it may be administered as such or in a pharmaceutically acceptable non-toxic and inert carrier, preferably in a range of 0.1% to 9.5%, preferably (L5% to 90%).
It is administered to animals, including humans, as a pharmaceutical composition containing %.

(Next page below) 1st Table 93% 28% 35% 2nd Table 23.8% 10.2% 30.9% 412.322.443.6 9 B, 714.332.0 1110.316.446. 1 2035.640.748.2 As carriers, one or more solid, semisolid or liquid diluents, fillers and other formulation auxiliaries are used.

Preferably, the pharmaceutical composition is administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally, intracellularly, locally (transdermally, etc.), or rectally. Of course, it is administered in a dosage form compatible with these administration methods. For example, oral dosage forms are particularly preferred.

Although it is desirable to adjust the dose in consideration of the patient's condition such as age, weight, route of administration, nature and severity of the disease, etc., the amount of the active ingredient of the present invention for adults is usually as follows:
1-1000mg, preferably 2-100mg per day
mg range is common. In some cases, a lower dose than this may be sufficient, and in other cases, a higher dose may be required. When administering a large amount, it is desirable to divide the dose into several times a day.

Oral administration can be carried out in solid or liquid forms, such as powders, powders, tablets, sugar coatings, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets, and other dosage forms. I can do it.

Powders are prepared by comminuting the active substance to a suitable fineness. Powders are prepared by bringing the active substance to a suitable fineness and then mixing it with similarly finely divided pharmaceutical carriers, such as starch, edible carbohydrates such as mannitol, and the like. Flavoring agents, preservatives, dispersing agents, coloring agents, as necessary.
Flavors and other substances may be mixed.

Capsules are manufactured by first filling powdered powders or powders as described above, or granules as described in the section on tablets, into capsule shells such as gelatin capsules. Ru. Mixing lubricants and fluidizing agents, such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol, into the powder,
A filling operation can also be carried out afterwards. Addition of disintegrants or solubilizers, such as carboxymethylcellulose, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, calcium carbonate, sodium carbonate, can improve the effectiveness of the drug when the capsule is ingested. .

In addition, a soft capsule can be prepared by suspending and dispersing the fine powder of this hole in vegetable oil, polyethylene glycol, glycerin, or a surfactant, and wrapping the suspension in a gelatin sheet.

Tablets are manufactured by preparing a powder mixture, granulating or slugging it, adding a disintegrant or blanching agent, and then tableting.

Powder mixtures are prepared by mixing suitably powdered materials with the diluents and bases mentioned above, optionally with binders (e.g. sodium carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc.), f4 decomposition retarders, etc. Agents (such as paraffin), resorbants (such as quaternary salts), and/or adsorbents (such as bentonite, kaolin, dicium phosphate, etc.) may also be used. The powder mixture can first be moistened with a binder such as syrup, starch paste, acacia, cellulose solution or polymeric substance solution and then forced through a sieve to form granules. Instead of granulating the powder in this way, it is also possible to first run it through a tablet press and then crush the resulting imperfectly formed slugs into granules.

The granules thus produced can be prevented from sticking to each other by adding stearic acid, stearate salts, talc, mineral oil, etc. as lubricants. The mixture thus lubricated is then compressed into tablets. Alternatively, the drug may be mixed with a fluid inert carrier and then directly compressed into tablets without going through the granulation or slugging steps as described above. Clear or translucent protective coatings consisting of an occlusive coating of shellac, coatings of sugar or polymeric materials, and overcoatings consisting of wax may also be used.

Other oral dosage forms, such as solutions, syrups, elixirs, etc., can also be made into dosage units, a fixed amount of which contains a fixed amount of the drug. Syrups are prepared by dissolving the compound in a suitable flavored aqueous solution, and elixirs are prepared by using a non-toxic alcoholic carrier.

Suspensions are formulated by dispersing the compound in a non-toxic carrier. Solubilizers and emulsifiers (eg, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavoring agents (eg, peppermint oil, saccharin), and others can also be added as desired.

If desired, dosage unit formulations for oral administration may be microencapsulated. The formulation may also be coated or
By embedding it in polymers, wax, etc., it is possible to prolong the action time and achieve sustained release.

Parenteral administration may be carried out using liquid dosage unit forms, such as solutions or suspensions, intended for subcutaneous, intramuscular or intravenous injection.

These are prepared by suspending or dissolving a quantity of the compound in a non-toxic liquid carrier compatible with the purpose of injection, such as an aqueous or oily vehicle, and then sterilizing the suspension or solution. . Alternatively, a fixed amount of the compound may be placed in a vial, and then the vial and its contents may be sterilized and sealed. Extra vials or carriers may be provided with the powdered or lyophilized active ingredient for melting or mixing immediately prior to administration. Nontoxic salts or salt solutions may be added to make the injection solution isotonic. Furthermore, stabilizers, preservatives, emulsifiers, and the like can also be used in combination.

For rectal administration, the compound may be administered as a low melting point water soluble or insoluble solid such as polyethylene glycol, cocoa butter, higher esters (e.g. myristyl palmitate).
It can be carried out by using suppositories containing mixtures thereof.

In addition to the active ingredient according to the present invention, the preparation of the compound of the present invention may contain (or may be used in combination with) other drugs such as nitrites, β-blockers, diuretic antihypertensive agents, and the like.

(See next page) (Example) The method for producing the raw material compound of the compound of the present invention is listed below as a reference example, and the method of producing the compound of the present invention! ! ! Although examples related to the structure are listed below, the present invention is not limited thereto.

Reference Example 1 Diisopropyl 2-oxopropylphosphonate Log
and 4.82 g of pyridine-2-aldehyde in 10 g of benzene.
Dissolved in 0ml, 0.77g piperidine and 2.7g acetic acid.
Add water, attach a water distillation tube, and heat under reflux for 2 hours.

After cooling, the precipitated crystals are filtered off, and the filtrate is washed with water and then with a 5% aqueous solution of caustic soda. After washing with water, wash with 30% acidic sodium sulfite solution, wash with water and dry with magnesium sulfate. Benzene was distilled off under reduced pressure to obtain 12 g of a brown oil. This was subjected to silica gel column chromatography, eluted with n-hexane:ethyl acetate (4:1), then with the same mixed solvent (1:1), and diisopropyl
6.2 g of 2-oxy7-1-(2-pyridylmethylidene)propanephosphonate are obtained. Recrystallization from n-hexane yields 5.7 g of colorless crystals. m, p, 102
°C0I Rv @ (cm-'): 1690
．． 158 (L 1475t 1385°1300, 1
250. 11?5. 1095. 1040. 10
00 elemental analysis value Calculated value (%) as Cl5H22NO4P C: 57.87 H near, 12 N: 4.
50 Actual value (%) C: 57.40 H near, 23
N 74.50 Example 1 2.5 g of diisopropyl 2-oxy/-1-(2-pyridylmethylidene)propanephosphonate and methyl 3-
Aminocrotonate 0.92g in Impropatool 45
ml and refluxed for 4 hours and 30 minutes. After the reaction, the reaction solution is concentrated under reduced pressure, ether is added to the residue to crystallize it, and the crystals are collected by filtration. After washing the crystals with ether, they were recrystallized from a mixed solvent of ethyl acetate and ether to give colorless crystals of methyl 5-diisopropoxyphosphinyl-2,6-
1.96 g of dimethyl-4-(2-pyridyl)-C4-dihydropyridine-3-carboxylate are obtained.

mp 146-148°C IRν2 (c+m-1): 3280. 322
0. 3100. 1700°1640.1500,1
430, 1250, 1210, 1105, 1090゜1
000.97O NMR (CDC13,6): 1.00 (3H,d)
, 1.03 (3H.

d) , 1.16 (3H, d) , 1
．． 21 (38,d), 2.12 (3H
,d), 2.25 (3H,s),
3.59 (3H, s), 4.20-4.5
5 (2H, m), 5.00 (LH, d), 7.
06-7.17 (IH, m).

7.40 (LH, d), 7.53-7.6
2 (IH, m), 8.46-8.50 (I
Lm), 8.64-8.68 (LH, m) Elemental analysis value C2DH29N20s Calculated value as P (%) C
: 5B, 81 H near, 15 N: 6.85 Actual value (%) C: 58.60 H: 7.26 N:
6.91 Example 2 2.74 g of diisopropyl 2-oxo-1-(2-pyridylmethylidene)propanephosphonate and 2-(N
-benzyl-N-methylamino)ethyl 3-aminocrotone) 2.18 g in 40 ml of isopropanol
and heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluting with n-hexane:ethyl acetate (1:1), ethyl acetate, chloroform:methanol (10:1), and a pale yellow color was obtained. 4.0 g of oil are obtained. This was crystallized from ether and recrystallized from a mixed solvent of ethyl acetate and ether to obtain 2-(N-benzyl-N-methylamino)ethyl 5-diisopropoxyphosphinyl-2, dimethyl-4-. 2.6 g of light brown crystals of (2-pyridyl)-1,4-dihydropyridine-3-carboxylate are obtained. Ill・p・98:~101℃I Rp island (cm'
): 3200. +3070,1690,16
50°1510, 1240.1115.98ONMR(
C[1C13, δ) :tJJ6 ('311.d)
, 1-05 (311d), 1.14 (3
H, d), 1.2i (3Ld), 2. L2
(3H,d), 2.18 (38,s), 2.
25 (3H,s), 2.62 (2)t,t)
.

3.48 C2H,s), 4-15 (2Lt)
, 4.20~4.54 (21(,m), 5.0
0 (IH, d), 7.03~7.12 (1)1
．． s), 7-27 (5H, s), 7.36~
7.54 (2im), 8.22~8.35 (I
H, m), 8.42-8.52 (IH, m) Elemental analysis value Calculated value as C211H4@N3 os P (
%) C: 64.30 H: 7.44 N:
7.75 Actual value (%) C: 64.19 H: 7.
65 N: 7.50 or less Compounds of Examples 3 to 23 were obtained in the same manner as in Example 1.2.

Example 3 Methyl 5-diallyloxyphosphinyl-2,6-dimethyl-4-(2-pyridyl)-1,4-dihydropyridine-3-carboxylate mp 123-124・℃ Elemental analysis value Calculated value as C20H25N 205P (
%) C: 59.40 H: 6.23 N: 6.9
3 Actual value (%)・C: 59・, 31 H: 6.32
N: 6.93 indeed 4 2-(tobenziroot methylamino)ethyl 5-diallyloxyphosphinyl-236-cymethyl-4-(2
-pyridyl)-, 4-dihydropyridine-3-carboxylate dihydrochloride mp 142℃ (decomposition) Elemental analysis value C21HsiN30s P ・2HCI
・Calculated value (%) as 5H20 C: 49.72 H: 6.91
N 76.00 Actual value (%) C: 5 (116H:
6.25 N: 6.19 Example 5 Methyl 5-diisopropoxyphosphinyl-2,6-
Dimethyl-4-(3-pyridyl)-1,4-dihydropyridine-3-carboxylate mp 169-171°C Elemental analysis value C20H29N2 os Calculated value as P (%) C: 58.81 H near, 15 N: 6.
85 Actual value (%”) C: 58.53 H: 7.1
2 N 76.72 Example 6 2-(N-benzyl-N-methylamino)ethyl 5
-diisoproboxyphosphinyl-2,6-dimethyl-4-(3-pyridyl) -1,4-dihydropyridine-
3-carboxylate dihydrochloride mp 164-167℃ Elemental analysis value C29H40N30S P ・2 HCI
・Calculated value (%) as 2H20 C: 53.44 H: 7.13
N: 6.49 actual value (%) C: S3.24 H:
1.39 N: 6.46 Example 7 Methyl 5-diisopropoxyphosphinyl-2,6-
Dimethyl-4-(4-pyridyl)-1,4-dihydropyridine-3-carboxylate mp 15B to 160°C Elemental analysis value C20H29N2 os Calculated value as P (%) C: 58.81 H near, 15 N: 6.
85 Actual value (%) C: 5B, 41 H: 7.33
N: 6.90 Example 8 Methyl 5-diisopropoxyphosphinyl-4-(2
-furyl") -2,6-dimethyl-1,4-dihydropyridine-3-carboxylate mp 149-15
1℃ Elemental analysis value Calculated value (%) as Cl8H2BNO6P C: 57.42 H: 7.10 N:
3.52 Actual value (%') C: 57.24 H:
7.22 N 73.42 Example 9 2-(N-benzyl-N-methylamino)ethyl 5
-diisopropoxyphosphinyl-4-(2-furyl)
-2,6-dimethyl-1,4-dihydropyridine-3-
Carboxylate Light brown oil I R (Neat): 3280.3220.310
0.1690.1642°1495, 13B5.124
0.1215.1105.980 Example 10 Methyl 5-diallyloxyphosphinyl-2,6-dimethyl-4-(2-furyl')-1,4-dihydropyridine-3-carboxylate mp 115-117°C Elemental analysis Value Calculated value (%) as Cl9H24N06P
C: 58.01 H: 6.15 N: 3.56 Actual value (%) C: 51.76 H: 6.28 N
:3.51 Example 11 2-(N-hensyl-N-methylamine)ethyl 5-
Diallyloxyphosphinyl-4-(2-furyl)-2
゜6-Simethyl-1,4-dihydropyridine-3-carboxylate Light brown oil IR (Neat): 32B0.3220.31
00.1690.1640°1495, 1450.13
82.1300.1230.1150.1100゜Example 12 Methyl 5-diisopropoxyphosphinyl-2,6-
Cymethyl-4-(5-nitro-2-furyl)-1,4-
Dihydropyridine-3-carposichelate mp 204
~207°C Elemental analysis value Clst (calculated value as gyN20@P (%) C: 51.58 H: 6.15 N:
6.33 Actual value (%) C: 51.66 H: 6.2
3 N: 6.23 Example 13 2-(N-benzyl-N-methylamino)ethyl 5-
Diisopropoxyphosphinyl-2,6-cymethyl-4
-(5-nitro-2-furyl) -1,4-dihydropyridine-3-carboxylate mp 134-13
6℃ elemental analysis value C2BH38N3 os Calculated value as P (%) C: 5B, 42 H: 6.65 N
: 7.30 Actual value (%) C: 5B, 43 H: 6
．． 65 N Near, 1B Example 14 Methyl 5-diisopropoxyphosphinyl-2,6-
Dimethyl-4-(2-chenyl')-1,4-dihydropyridine-3-carboxylate mp 188-189°C Elemental analysis value C1, H2, NOs PS Calculated value (%) C: 55.19 H: 6 .83N
: 3.39 Actual value (%) C: ss, o7H near, O
IN: a, t.

Example 15 2-(N-benzyl-N-methylamino)ethyl 5-
Diisopropoxyphosphinyl-2,6-dimethyl-
4-(2-chenyl)-1,4-dihydropyridine-
3-carboxylate mp 106-109 °C (Pirate) Elemental analysis value C28H29N20S PS ・C6H3N30? Calculated value (%) C: 52.64 H: 5.46
N: 9.03 actual value (%) C: 52.74 H
: 5.40 N 78.98 Example 16 Methyl 5-diisopropoxyphosphinyl-2,6-
Cymethyl-4-(5-nitro-2-chenyl”)-1
, 4-dihydropyridine-3-carboxylate mp
197-198°C Elemental analysis value C+s H2? N20? Calculated value as PS (%') C: 49.78 H: 5.9
4 N: 6.11 Actual value (%) C: 49.5
1 H: 6.18 N: 6.09 Example 17 2-(N-benzyl-N-methylamino)ethyl 5-
Diisopropoxyphosphinyl-2,6-cymethyl-4
-(5-nitro-2-chenyl) -1,4-dihydropyridine-3-carboxylate mp 102-104°C Elemental analysis value Calculated value as C28H38N307PS (
%) C: ss, te H: 6.61 N: 6.8
9 Actual measurement value (%) C: 55.38 H: 6.62
N: 6.94 Example 18 Methyl 4-(4-benzofurazanyl)-5-diallyloxyphosphinyl-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate mp 160-161°C Elemental analysis value C21H24N3 os Calculated value as P (%) C: 56.63 H: 5.43 N
79.43 Actual value (%) C: 56.70 H: 5
．． 42 N: 9.54 Example 19 2-(N-benzyl-N-methylamino)ethyl 4-
(4-Benzofurazanyl)-5-diallyloxyphosphinyl-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate mp 103-104°C Elemental analysis value Calculated value as C30H35N 406 P (%') C: 62 .28 H: 6.10 N: 9
．． 68 Actual value (%) C: 62.22 H: 6.1
6 N: 9.72 Example 20 Methyl 4-(4-benzofurazanyl)-2,6-dimethyl-5-(2-oxo,-1,3,2-dioxaphosphorinan-2-yl) -1,4 -dihydropyridine-
3-Carboxylate @p 248-250℃ Elemental analysis value Cl8H2ON30SP Calculated value (%)
C: 53.34 H2 4.97 N: 10.3
7 Actual measurement value (%) C: 53.47 H: 5.01
N: 10.22 Example 21 Methyl 5-diallyloxyphosphinyl-2,6-dimethyl-4-(2-methylthio-3-pyridyl') -
1,4-dihydropyridine-3-carboxylate mp
117~llB℃ Elemental analysis value C2u (2yN205 Calculated value as PS (%) C: 55.99 H: 6.04 N 7
6.22 Actual value (%) C: 56.01 H: 6
．． 26 N 76.12 Example 22 2-(N-benzyl-N-methylamino)ethyl 5
-diallyloxyphosphinyl-2,6-cymethyl-4
-(2-Methylthio-3-pyridyl) -1,4-dihydropyridine-3-carboxylate l1l) 104.5-105.5°C Elemental analysis value C5oH3eNs 05 Calculated value as PS (%) C: 61.73 H: 6.56 N:1
．． 20 Actual value (%) C: 62.00 H: 6.89
N: 6.84 Example 23 Methyl 2.6-dimethyl-4-(2-methylthio-3
-pyridyl)-5-(2-oxy-1.3.2-dioxaphosphorinan-2-yl) -1,4-dihydropyridine-3-carboxylene 1-mp106-10
7℃ (decomposition) Elemental analysis value Cl8 H23N20
S P S ・%) as I20

Claims (1)

[Claims] 1,4-dihydropyridine-3-carboxylic acid, its ester derivatives, and salts represented by the following general formula [I] ▲Mathical formula, chemical formula, table, etc.▼[I]. Here, R^1 to R^5 are the following (1) to (5), respectively.
) represents the substituent described in (1) R^1 represents lower alkyl. (2) R^2 represents one substituent selected from the group consisting of the substituents described in [1] to [2] below. [1] Hydrogen. [2] Branched or unbranched, chain or cyclic, or a combination of a chain and a ring, and has 0 to 4 unsaturated bonds. Hydrocarbons having 1 to 9 carbon atoms, which are the following (a) to (f)
Substituted with one or more of the substituents listed in (1) or unsubstituted. (a) alkoxy group, (b) aryloxy group, (c)
Aralkyloxy group, (d) amino group, (e) alkyl-substituted amino group, (f) alkylthio group [3] ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ [Here, R^6 represents a lower alkyl group, m is 0~
An integer of 2, n represents an integer of 2 to 4. ] (3) R^3
is the general formula [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] [In the formula, R^7 represents hydrogen, halogen, nitro group, alkoxy group, or alkylthio group, ▲ Numerical formula, chemical formula, There are tables, etc. ▼ represents a heterocycle including furan, thiophene, pyridine, and benzofurazan. ] represents. (4) R^4 is the general formula [III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [III] [In the formula, R^8 and R^9 are the same or different, hydrogen,
represents an alkyl group or an alkenyl group, or R
^8 and R^9 combine to form part of a 6-membered ring. R^
When 8 and R^9 combine to form a part of a 6-membered ring, the ring is unsubstituted or substituted with lower alkyl. ] represents. (5) R^5 represents lower alkyl.