JPH06500336A - Dihydropyridine compound and method for producing the same - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Dihydropyridine compound and method for producing the same Background of the invention field of invention The present invention relates to novel dihydropyridine derivatives with antihypertensive properties.

Description of related technology In the literature, it has been described as a calcium ion channel blocker, and it has been shown to be a calcium ion channel blocker. Many 2,6-dialkyl-4-aryl-1, 4-dihydropyridine-3,5-dicarboxylate derivatives are known. child A typical example of such derivatives is nifedipine, which is dimethyl 1,4-dihydrogen. Dro-2,6-cymethyl-4-0-nitrophenylpyridine-3,5-dicarbo It is a xylate. Yet another class of 1,4-dihydropyridine derivatives, viz. Nilbazibin is also known, and is characterized by a 1,4- Dihydropyridine has a cyano group at the 2nd position.

Many 1-ants have adrenergic beta receptor blocking properties and also exhibit antihypertensive effects. -roxy-3-amino-propan-2-ol derivatives are also known. professional bra Noronol and atenolol, each 1-(naphtho-1-yloxy) )-3-isopropylaminopropan-2-ol and 1-p-carbamoyl Methylphenoxy-3-isopropylaminopropan-2-ol is the most widely used This is an example of it being used.

These two chemical structures, namely 2,6-dialkyl-4-aryl-1, 4-dihydropyridine-3,5-dicarboxylate and 1-aryloxy- Attempts to combine 3-aminopropan-2-ol have been previously described. , can be found in various literature and patents.

Report by Merck employees (Journal of Medicinal Chemistry) Tory (J, Med, chew,) + 24,628-63L1981) , 3 to the 4-aryl substituent of the 4-aryl-1,4-dihydropyridine derivative An example is described in which an -amino-2-hydroxypropoxy substituent is introduced. rice National Patent No. 4,500,527 also shows that the -CII=N- group causes the 4-aryonyl substitution. Similar compounds with a 3-amino-2-hydroxypropoxy substituent attached to the substituent have been described, and this compound has antihypertensive properties and adrenergic beta receptors. It is claimed to have body blocking properties.

More recently, the 4-aryl-1,4-dihydropyridine derivatives Introducing a 1-aryloxy-3-aminopropan-2-ol moiety to the lyl substituent Structurally similar compounds have been disclosed in European Patent No. 194,751, JP 86-12662, JP 87-149659, JP 87-228060, JP 87-149659, JP 87-228060, JP No. 89-9936, and Japanese Patent Application Laid-open No. 89-151554. However, this All of the compounds described in these patent documents have a l,4-dihydropyridine moiety. 2,6-Dialkyl-4-Ori-, which has a lower alkyl group in the second position of Partial structure of Ru-1,4-dihydropyridine-3,5-dicarboxylate share the characteristics of

We now demonstrate that a new class of compounds has antihypertensive effects. I found it. This group of compounds has a cyacium at the second position of the 1,4-dihydropyridine moiety. A group or a halo (lower) alkyl group is introduced, resulting in a 3-waxy 2-hydro group. The roxypropylamino substituent is a 4-aryl-1,4-dihydropyridine moiety is a compound bonded via an alkylene linking group via a 4-aryl substituent to be.

The present invention is based on the following formula: The present invention provides dihydropyridine represented by: or an acid addition salt thereof. child Here, the enemy represents a cyano or haloalkyl group, and the alkyl group in the group is 1 to 6. carbon atoms. R1 represents an alkyl group having 1 to 6 carbon atoms; , RZ and R3 each independently represent an alkyl group having 1 to 6 carbon atoms; , X and Y are each independently a hydrogen atom, an alkali having 1 to 6 carbon atoms; Represents a kill group, a halogen atom, or a nitro group, and Ar is optionally substituted. and A represents an alkylene group having 1 to 10 carbon atoms. represents a group.

The aryl group Ar is a phenyl or naphthyl group substituted as necessary. is preferred, and the substituents are ortho and to the oxy of the aryloxy group Ar0- Preferably, it is located in the / or para position. Suitable substituents include, for example, 1 to Alkoxy groups having 6, preferably 1 to 4 carbon atoms, halogen atoms, etc. For example, fluorine, chlorine or bromine atoms and 1 to 6, preferably 1 to 4 carbon atoms There are alkyl groups that have elementary atoms. Such substituents include methyl group, methoxy group , or a chlorine atom is particularly preferred. Ar is preferably a substituted phenyl group It is. Specific examples of Ar0- in which Ar is a monosubstituted phenyl group include 2-methoxy Phenoxy, 4-methoxyphenoxy, 2-chlorophenoxy, 4-chlorophene Noxy, 2-methylphenoxy, 2,4.6-trimethylphenoxy, 4-butylene Lomophenoxy and 4-(N-methylsulfonyl)aminophenoxy groups are present. Ru.

In this specification, the term lower alkyl group refers to a straight chain or branched group having 1 to 6 atoms. , preferably a saturated hydrocarbon radical having 1 to 4 carbon atoms. X and The halogen atom represented by / or Y includes, for example, fluorine, chlorine, or odor. An elementary atom is suitable, and the alkyl group represented by X and/or Y is a methyl group. The preferred term C1-C10 alkylene refers to C1-C10 alkylene groups. ~10, preferably 1 to 6, divalent linear or branched paraffinic carbons means a hydrogen residue.

As the acid addition salt of the dihydropyridine derivative of the present invention, for example, salts derived from organic acids, such as hydrochlorides or sulfates, or salts derived from organic acids, and For example, oxalate, lactate, silicate, tartrate, maleate, fumarate, acetate. , salicylate, citrate, benzoate, β-naphthoate, adipate, Methanesulfonate, benzenesulfonate, or P-toluenesulfonic acid Examples include salt.

The dihydropyridine derivative of the present invention is useful in the production of chemically similar compounds. can be produced by using any chemical method known to be useful. I can do it.

One of the preferred methods for producing the dihydropyridine compound of the present invention is the following formula: (in the formula -ill, R2, R1, A, X, and Y have the above meanings) The amine represented and the following formula: (In the formula, ^r represents an optionally substituted aryl group, and L represents an appropriate leaving group. (reactive functional group), such as methanesulfonyloxy, benzenesulfonyloxy p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy, p -represents a nitrobenzenesulfonyloxy, chloro, bromo, or iodo group. This is the process of reacting with the epoxide or alcohol derivative represented by .

A second preferred method for producing the dihydropyridine compound of the present invention is represented by the following formula: (In the formula) il, R', R2, R3, A, , X, and Y have the above meanings. and Z is a suitable leaving group (reactive functional group), such as methanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzene Sulfonyloxy, chloro, bromo, (Ar in the formula is phenyl as described above) Alternatively, it is a step of reacting with an amine represented by (representing a naphthyl group).

The dihydropyridine compound of the present invention has the following formula: (wherein R is the inventive compound as defined above) represents the remainder of the molecule of the compound, and Ar is a phenyl or naphthyl group. The aminoketone represented by It can also be produced by reduction using an alcoholic solution of alcohol.

When - is a cyano group, the dihydropyridine of the present invention has the following formula: (wherein R represents the remainder of the molecule of the compound of the invention as defined above) Acetic acid can be removed from the expressed acetate oxime by heating, for example in acetic anhydride. It can also be manufactured by

Separation and isolation of the dihydropyridine reaction products of the invention from the reaction mixture, if and purification using methods commonly used for this type of purpose, e.g. using suitable solvents. This can be done by extraction, chromatography, precipitation, recrystallization, etc. .

The dihydropyridine of the present invention includes an asymmetric carbon at the 4th position of the 1,4-dihydropyridine nucleus. Elementary atoms and asymmetric carbon atom of 3-aryloxy-2-hydroxypropylamino moiety Since there are children, there are at least two sets of optical isomers, and therefore the present invention Dihydropyridine can exist as each optical isomer or as a mixture of them. Sometimes they exist as compounds. into each optical isomer of a racemic mixture of optical isomers The resolution is carried out by the usual methods used for racemic resolution, e.g. diastereomer salts. chemically with common optically active acids (such as tartaric acid or camphor sulfonic acid). This can be done by dividing into.

The compounds of the present invention and their pharmaceutically acceptable salts exhibit potent and long-lasting vasodilation. It has tonic and antihypertensive activity and is effective in cardiovascular disorders and hypertension. For example, in the therapeutic treatment of coronary artery insufficiency, angina or myocardial infarction, and hypertension. It is useful.

Such excellent pharmacological activity of the compound of the present invention is due to W, R', R2, R3, A , X, Y groups, as well as a substituent of the phenyl ring at the 4th position of the dihydropyridine nucleus. It is thought that the structure is characterized by the substitution pattern. More details To explain, the enemy groups are cyano, trifluoromethyl, difluoromethyl, Monofluoromethyl, 2,2.2-)lifluoroethyl, trichloromethyl, Consisting of dichloromethyl, monochloromethyl, 2,2.2-)dichloroethyl preferably selected from cyanide and trifluoromethyl; Ru. R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Can be selected from the group consisting of amyl, isoamyl, hexyl, isohexyl, Preferably methyl, ethyl, propyl, isopropyl, butyl or iso Butyl. R2 and R3 groups are each independently methyl, ethyl, propylene isopropyl, butyl, isobutyl, amyl, isoamyl, hexyl, iso can be selected from the group consisting of hexyl, preferably methyl and ethyl, respectively. , propyl, isopropyl, butyl, isobutyl. The group of A is methi Ren, ethylene, propylene, trimethylene, tetramethylene, pentamethylene , hexamethylene, heptamethylene, octamethylene. and preferably tetramethylene. The groups X and Y each independently represent water. Preferably selected from the group consisting of elementary atoms, nitro groups, chlorine atoms, and fluorine atoms. . Preferred substitution pattern with substituents on the phenyl ring at position 4 of the dihydropyridine nucleus The horns are 1, 2, 3.5-11, 2.4.5-11, 2°3-11, 2.4-1 1, 2.5-11, 2.6-11, 3.4-11, 3.5-11, 2-11, 3 -1 and 1.4-.

For therapeutic purposes, the dihydropyridine compounds of the invention may be administered in daily doses. 0.1-500 mg, preferably 1-250 mg can be administered.

The IFI composition of the present invention contains a dihydropyridine compound or contains its pharmaceutically acceptable salts at a dosage of about 0 per dosage unit for oral and parenteral use. ．． 01a+g to about 500mg, preferably about 0.1mg to about 25Qmg contains.

Those skilled in the art will appreciate that the amount of active ingredient in a dosage unit form is determined by the activity of the ingredient as well as the amount administered. It will be understood that this is determined by taking into account the size of the human body being used. active formation The ingredients are usually in solid form, such as tablets, granules, powders, capsules, troches, and lozenges. Di, or herbal medicine, or FA? I liquid or solution form, such as silombe, It can be incorporated into injections, emulsions, lemonades, etc. Pharmaceutical carrier or As diluents, non-toxic, pharmaceutically acceptable substances in solid or liquid form may be used. I can stay. Examples of solid or liquid carriers or diluents include lactose, Magnesium stearate, white clay, sea Iw, corn starch, talc, star Phosphoric acid, gelatin, agar, pectin, acacia, peanut oil, olive oil, acacia Rui contains commonly used substances such as sesame oil, cocoa butter, and ethylene glycol. be. The carrier or diluent may also include release-retarding substances, such as monostearic acid. Glyceryl, glyceryl distearate, wax, etc. may also be used.

For the purpose of demonstrating the usefulness of the compounds of the present invention, pharmacological tests of representative compounds are described below. Show the results.

1) Blood pressure lowering effect Passed exam 1L ■ Three Wistar rats were used per group. Each animal has a blood pressure pulse were counted periodically.

The test compound was administered through a catheter inserted into the femoral vein at least 2 hours after surgery. It was administered intravenously throughout the day.

Sample soybeans Dihydropyridine A (product of Example 1.2) 2) Ca channel binding test Inferno 1 Vascular tissue was frozen at -80°C.

Frozen tissues were soaked in buffer (0.25M C.O., 10mM MOPS, pH 7.4). ) and thaw it in a polytron (kinematic) in the same buffer. The mixture was homogenized using a squid (Kinematica). Gauze the homogenate After filtering, the filtered homogenate was filtered using a Teflon glass homogenizer. Homogenized using The homogenate was centrifuged (1,000g x 10 minutes). ). The supernatant was centrifuged twice (10,000g x 10 minutes). Centrifuge the supernatant again (100,000g x 60 minutes) to obtain pellets. Transfer the pellet again to the buffer ( 5011M Tris-HCl, pH 7.4>. Coarsely mix this suspension. This was called the rosome membrane fraction. The resulting suspension was stored at -80°C until use.

(b) A-frozen crude microsomes to i′ of 3HPN200410 I unzipped the image. [3H] PN20O-110 (0,1HM) in a 50μ2 film With the preparation, the final volume was 200u1. Close and incubate at 37°C for 90 minutes. I bet. At the end of the incubation period, aspirate the reaction mixture using the wand. It was quickly filtered through a Whatman GF/C glass filter. Next, The filter was washed with 3H1 buffer (50 m Tris-HCl, pH 7,4). Washed twice. In 6d clear sol I (C1ear-sol [), Baraca Packard's Synnarration Counter (Packard TRI) Radioactivity was counted using -CARB4530).

Wipe up plan! Dihydropyridine A base 101 fruit (3) Binding with β receptors 1 hiro (a) Amount of l″1 mylosome SD rats were killed by decapitation. The heart was removed and buffer solution (0,25 sig sugar, Using Polytron (Kinematica) in 10mM MOPS, pH 7,4) and homogenized. Homogenate using a Teflon glass homogenizer and homogenized. Centrifuge the homogenate (1,000g x 10 minutes) , the tissue mass was removed, and the supernatant was centrifuged twice (10,000 g x 10 minutes). Up The supernatant was centrifuged again (100,000 g x 60 minutes) to obtain a pellet. Pe resuspended in buffer solution (50n+M Tris-HCl, pH 7.4), This suspension was called the crude microsomal membrane fraction. The resulting suspension is kept for 18 hours until use. Stored at 0°C.

(b) 3H-dihyroalprenol (Ill(A) to i) The crude microsomal membrane fraction was thawed and -['H]DHA (1HM) was added to 50 Incubate for 30 min at 25°C with a final volume of 200 μ2 with 2 μ2 of membrane preparation. Incubated. At the end of the incubation period, the reaction mixture is aspirated It was quickly filtered through a Wandman GF/C glass filter. 3M1 filter buffer (50ml 1M Tris-HCl, p17.4) five times.

A scintillation counter (Pa Radioactivity was counted using ckard TRI-CARB4530).

Baifengokamikinship Dihydropyridine A 101 results 1-"L-Gai The present invention will be explained in more detail with reference to the following examples; The examples are not intended to be limiting.

Example 1 5-isopropyl 3-methyl 4-(2-(4-bromobutoxy)-5-di trophenyl]-2-cyano-6-methyl-1,4-dihydropyridine-3,5 -dicarboxylate (3,5 g) and 2-hydroxy-3-phenoxypropro Pyridine (0.5d) was added to a solution of pyramine (3.7g) in acetonitrile (65m). ) and the mixture was heated and stirred under reflux for 4 hours. The reaction mixture was placed under reduced pressure. a Shrunk. The residue was subjected to silica gel column chromatography and chloroform -After elution with methanol 96/4 (v/v), 3.6g of solid was obtained by concentration. It was done.

Furthermore, by recrystallizing from ethanol, 5-isopropyl 3-methyl 2-cyano-4-C2-(4-(2-hydroxy-3-phenoxypropylamine) (butoxy)-5-nitrophenyl]-6-methyl-1,4-dihydropyridi 3,5-dicarboxylate (2,3 g) was obtained as a yellow crystalline solid.

:mp142-151'C; IR(KBr)2234.1699.1589.1514.1468.1384 ．． 1373.1340゜1274, 1184.109B, 755.691c m-';'HNMR (CDCIs-TMS) 610.25 (brs, L H), 8.19 and 8.18 (2d, IH).

8, 10 and 8.09 (2dd, 1B), 7.30 (dd, 2H ), 6.98 (dd, LH), 6.91 (dA 21), 6 ．． 8 7 and 6.86 (2d, IH), 5.22 (s IH), 4.90 an d 4.90 (2dd, LH), 4.34-4.23 (j+LH), 3.91 -4.10 (s+, 4H), 3.69 (s, 3H), 2.55-2.98 (m, 4) 1), 2.32 and 2, 29 (2s, 3H), 2.10-1. 60 (+w, 411), 2.10-1.60 (br, 2H), 1 ．． 27. P. 26.1.01 and 1.00 (4d, 61 (); mass spectrometry, m/e (FD) 623 ( M”+H).

Example 2 5-isopropyl 3-methyl 4-(2-(4-aminobutoxy)-5-di trophenyl)-2-cyano-6-methyl-1,4-dihydropyridine-3,5 - dicarboxylate (69911g) in methanol (40at) solution with 1,2 - heating the mixture with epoxy-3-phenoxypropane (247 g); The mixture was stirred under reflux for 40 hours. The reaction mixture was transferred under reduced pressure to m! ＠T、T、Silver the residue Subjected to Kagel column chromatography, chloroform-methanol 96/4 After elution (v/v), 210 mg of solid was obtained by concentration. Furthermore, Eta By recrystallizing from alcohol, 5-isopropyl 3-methyl 2-cyano -4-[2-+4-(2-hydroxy-3-phenoxypropylamino)buto xy)-5-nitrophenyl]-6-methyl-1,4-dihydropyridine-3, 5-dicarpoxyle) (190 mg) was obtained as a yellow crystalline solid. the Spectroscopic data were consistent with those obtained in Example 1.

Example 3 By the method of Example 1, 5-isopropyl 3-methyl 4-(2-(4-bropropyl) Mobutoxy)-3,5-dichlorophenyl)-2-cyano-6-methyl-1,4 -dihydropyridine-3,5-dicarpoxylate) (317 mg) and 2-hydro 5-isopropyl from roxy-3-phenoxypropylamine (390ng) 3-methyl 2-cyano-4-[2-+4- (2-hydroxy-3-phenoxy cipro and ruamino)butoxyl-3,5-dichlorophenyl]-6-methyl-1 , 4-dihydropyridine-3,5-dicarboxylate (190 mg) Obtained as a foamy solid.

mp52-60’C; IR(KBr)2236.1703.1588.1511.1454.1385 ．． 1274.1174゜1095,755.692cn+-';')I -NMI'l (CDCI s-TMS) δ7.30-7.24 (n, 2H) , 7.17 and 7.16 (2s, 1) 1), U ．． 97 (dd, 1) 1), 6.91-6.89 (m, 2H), 6.71 (s, 1 )1), 5.903 and 5.088 (2s, LH), 4.93 (hpt, IH), 4.32-4.23 axis, LH), 3.86-4.08 (shape, 4H), 3 ．． 71 (s, 3H), 3.05-2.78 (m, 4H), 2.33 and 2 ．． 32 (2s, 3) 1), 2.60-1.72 (m, 4H), 2.60-1.7 2 (br　s, 2H), 1.066.1.072, 1.079 and 1.0 84 (4d, 6H); Mass spectrometry, m/e (FD) 646 (M'+H) Example 4 By the method of Example 1, 3,5-dimethyl 4-+2-(4-bromobutoxy) c)-5-nitrophenyl)-2-cyano-6-methyl-1,4-dihydropyri Zin-3,5-dicarboxylate (400 mg) and 2-hydroxy-3-phene 3,5-dimethyl 2-cyano-4- from noxypropylamine (474 mg) [2-(4-(2-hydroxy-3-phenoquinepropylamino)phytoxy) -5-nitrophenyl]-6-methyl-1,4-dihydropyridine-3,5-di The carboxylate (301 mg) was obtained as a yellow crystalline solid.

mp142-153°C; IR(KBr)2236, 1704.1589, 1513, 1466.1385 ．． 1339, 1272° 1187, 1099. 754. 692 can- ';'HNMR (CDCh-TMS) δ10.70-9.90 (br, 18 ), 8.19 (d, 1) I), 8.10 and 8.09 (2dd, IH), 7 ．． 30 (dd, 2H), 6.99 (dd, IH), 6.91 (d, 2) 1), 6 ．． 87 and 6.86 (2d, LH), 5.25 (s 1B) , 4.31-4.22 (s, 1[(), 4.10-3.91 (m, 4fi), 3.69(s, 3 H), 3.60 and 3.59 (2s, 3H), 2.97-2.78 (n+ , 4H), 2.33 and 2.29 (2s, 3) 1), 2.05-1.55 (m, 4) 1), 2.05-1.55 (br, 2) 1); mass spectrometry, m/e ( FD) 595 (M”+) I) Example 5 By the method of Example 2, 5-isopropyl 3-methyl 4-(2-(4-amino) Knotoxy)-5-nitrophenyl)-2-cyano-6-methyl-1,4-dihy Dropyridine-3,5-dicarboxylate (400 mg) and 1,2-epoxy -3-(naphth-1-yloxy)propane (170+sg) to 5-isopropane Pill 3-methyl 2-cyano-4-(2-[4-(2-hydroxy-3-(na) phth-1-yloxy)pro and ruamino)butoxyco5-nitrophenyl]- 6-Methyl-1,4-dihydropyridine-3,5-dicarboxylate (138 mg) was obtained as a yellow foamy solid.

5-isopropyl 3-methyl 2-cyano-4-C2-[4-(2-hydroxy C-3-(naphth-1-yloxy)propylamino)butoxy]-5-nitro phenyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylene Maleic acid (21 mg) was added to a solution of salt (123+ mg) in ethanol (l mL). was added and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. Chlorophore the residue. The organic layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate, and the filtrate was When concentrated, 2-cyano-4-(2-[4-(2-hydroxy-3-(naphtho-1) -yloxy)propylamino)ptoxyco-5-nitrophenyl]-6-methy 5-isopropyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3 - The maleate salt of methyl ester (130 mg) was obtained as a pale yellow crystalline solid. It was done.

mp94.5-105.0°C; IR (Br) 3408.3086.2980.2237.1702.1623 ．． 1581.1512°1467, 1386.1341.1302.1270. 1241.1216.1100c1';'HNMR(CDC13-T?lS ) δ9.08(br　s, LH), 8.18(br　d, J=8.0Hz, I H), 8°12 (d, J=2.8Hz, LH), 8.03 (dd, J=9.0 and 2.8Hz, IB), 7.76(d, J=7.6Hz.

IJI), 7.47-7, 38 (m, 3H), 7.35-7.23 (m, IH), 6.72 (d, J=8.4HzA 18), 6 ．． 68 ( dj-7,5Hz, IH), 6.31 (s, 2H), 5.17 (s IH), 4 ．． 87 (hpt, LH), 4.64 (br　s, 1)1), 4.19-4.10 (m, 2H), 3.92 (br　s, IH), 3.61 and 3.60 (2 s, 38), 3.43-3.25 (m, 4H), 2.293 and 2.29 0 (2s, 3) 1), 2.26-1.50 (m, 8H), 1.25 (d, J=6 ゜2Hz, 3H), 0.98 (d, J=6.2Hz, 3M): Mass spectrometry, m/e (FD) 673 (M”+1) Example 6 Dimethyl 2-trifluoromethyl-4-(2-(4-(2-hydroxy-3- phenoxypropylamino)butoxy)-5-nitrophenyl]-6-methyl- Method for producing 1,4-dihydropyridine-3,5-dicarboxylate Dimethyl 4-+2-(4-bromobutoxy)-5-nitrophenyl)-2 -trifluoromethyl-6-methyl-1,4-dihydropyridine-3,5-dica Ruboxylate (0.20g, 0.36sIlol) and 2-hydroxy-3- Phenoxypropylamine (0.30g, 1.80mmol) in acetonitrile The reaction solution obtained by refluxing the solution (5 m) for 2 hours was poured into saturated aqueous sodium bicarbonate solution, and chloroform ( 5idX3). Combine the extracts, wash with saline, and add anhydrous sulfuric acid solution. Dehydrated with thorium. The filtrate was concentrated under reduced pressure, and the residue was filtered into a silica gel column. Chromatography and chloroform-methanol 10/1 (ν/v) After elution, concentration yields dimethyl 2-trifluoromethyl-4-(2-(4-( 2-Hydroxy-3-phenoxypropylamino)butoxy)-5-nitrophe ]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained as a yellow foamy solid (0.20 g).

IR(KBr)3350.2950.1700.1515.1497.1341 ．． 753.693cm-';'HNMR (CDC13-TAS) δ8.09 (dd, IH), 8.07-8.09 (s+, IH), 7.29 (t, 2H), 6.97 (t, LH), 6.90 (d, LH), 6. 88 (d, IH), 5.37 (s, IH), 4.14-S. 12 (m , LH) , 4.08-4.06 (a+, 2H), 4.00-3.96 (s+ , 2H), 3.63 (s, 3H), 3.59@(s, 3H) , 2.90- 2.79 (m, 4H), 2.40 (s, 3H), 1.90-1.71 (m, 4H ); Mass spectrometry, +i/e (FD) 63B (M”+H) Example 7 5-isopropyl 3-methyl 2-trifluoromethyl-4-(2-(4-( 2-Hydroxy-3-phenoxypropylamino)butoxy)-5-nitrophe ]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate 5-isopropyl 3-methyl 4-[2-(4 -bromobutoxy)-5-nitrophenyl)-2-)IJfluoromethyl-6- Methyl-1,4-dihydropyridine-3,5-dicarboxylate (0,65g , 1.10 mmol) and 2-hydroxy-3-phenoxypropylamine (0 , 93g, 5.60sIlol) to 5-isopropyl 3-methyl 2-t Lifluoromethyl-4-(2-+4-(2-hydroxy-3-phenoxypropylene) ropylamino)butoxy)-5-nitrophenyl]-6-methyl-1,4-dihy Dropyridine-3,5-dicarboxylate as a yellow foamy solid (0,63 g) Obtained by doing.

IRO [Br) 3350.2980.2949.172B, 1699.158 9.1514.1497゜1340, 1269.1228.1177, 1145 ．． 1082.754.692 cm-';'HN gate R (CDC13-T gate 5) 68.17-8.08 (m, 2H), 7.29 (t, 2H), 6.97 (t, I H).

6.91 (d, 2H), 6.87 (d, 18), 5.32 (s, 18), 4.91-4.86 (■, LH), 4.13|4.08 (m , LH), 4.08-4.02 (m, 2)1), 4.00-3. 95 (m, 28), 3.62 (s, 3H), @2.89-2.7 5 (n+.

4H), 2.38 (s, 3H), 1.91-1.86 (m, 2H), 1.72 -1.68 (s, 2H), 1.23 (d, 3) 1), 0°97 (d, 3H); Mass spectrometry, w/e (FD) 666 (M”+H) Example 8 5-isopropyl 3-ethyl 2-trifluoromethyl-4-C2-[4-( 2-Hydroxy-3-phenoxypropylamine)butoxy)-5-nitrophe Nyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate -Process for producing hydrochloride.

5-isopropyl 3-ethyl 4-(2-(4-bromobutoxy)-5-di trophenyl]-2-trifluoromethyl-6-methyl-1,4-dihydropyri Zine-3,5-dicarboxylate (0,30 g.

0.50++nol) and 2-hydroxy-3-phenoxypropylamine (0° A solution of 42g, 2.50+u+ol) in a7tonitrile (5m) was refluxed for 2 hours. .

The reaction solution was poured into saturated aqueous sodium bicarbonate solution and extracted with chloroform (5aiX3). extract liquid Both were washed with brine and then dehydrated with anhydrous sodium sulfate. Reduce pressure of filtrate The residue was subjected to silica gel column chromatography and purified with chloroform. After elution with methanol 10/1 (v/v), concentrate and 5-isopropyl. 3-ethyl 2-trifluoromethyl-4-(2-(4-(2-hydroxy-3 -phenoxypropylamino)butoxy)-5-nitrophenyl]-6-methyl = 1,4-dihydropyridine-3,5-dicarboxylate in yellow oil (0, 28g).

5-isopropyl 3-ethyl 2-trifluoromethyl-4-(2-(4-( 2-Hydroxy-3-phenoxypropylamino)butoxy)-5-nitrophe ]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate) (0.25g, 0.36+*mol) in methanol (3m) solution with 2N chloride A hydrogen methanol solution (2d) was added, and the mixture was stirred at room temperature for 1 hour. Reduce methanol When distilled off under pressure, 5-isopropyl 3-ethyl 2-trifluoromethyl-4 -(2-(4-(2-hydroxy-3-phenoxypropylamino)butoxy) -5-nitrophenyl]-6-methyl-1,4-dihydropyridine-3,5-di The carboxylate-hydrochloride salt was obtained as a yellow foamy solid (0.26 g).

IR (Br) 3354.29B1.1700.1590.1514.1498 ．． 1341.1274°1234, 1201.1177, 1146.1080. 754.693 cm-1;'HN gate R (CDC13-TMS) 68.06- 8.03 (m, 28), 7.23-7.21 (Rin, 211), 6.94 (t, IB), 6.85 (d, 2H), 6.81 (d, 01), 5.33 (s, 1) 1), 4.88 (p, IH) @, 4.61 (b s, 01) , 4.09-3.96 (+w, 68), 3.37-3.23 (m, 4H), 2.41 (s, 3H), 2.20-P. 95 (m, 4H).

1.19 (d, 3B), 1.11 (t, 3B), 0.98 (d, 38); Mass Analysis, m/e (FD) 680 (M”+H) Example 9 Dimethyl 4-(3,5-dichloro-2-(4-(2-hydroxy-3-pheno xypropylamino)butoxy)phenyl]-6-methyl-2-trifluorome Process for producing thyl-1,4-dihydropyridine-3,5-dicarboxylate By the method of Example 6, dimethyl 4-(3,5-dichloro-2-(4-bromo) butoxy)phenyl]-6-methyl-2-trifluoromethyl-1,4-dihyde Lopyridine-3,5-dicarboxylate (0.74g) and 2-hydroxy- 3-phenoxypropylamine (1,08g) to dimethyl 4-[2-+4 -(2-hydroxy-3-phenoxypropylamino)butoxy)-5-nito Lophenyl]-6-methyl-2-trifluoromethyl-1,4-dihydropyridi -3,5-dicarboxylate was obtained as a yellow foamy solid (0,43 Jl). It was.

rR(KBr)3338.2951.1709.1563.145L 1435 ．． 1286.1043.899, 802.667 cm -'; 'HNMR (CDCh-TMS) 67.26 (t, 2) 1), 7.23 (d, II), 6.99 (bs, LH), 6.95 (t, 18), 6.88 ( d, 2H), 5.24 (s, IH), 4.37 (br s, I H), 4.02-3D99 (m, 4H), 3 ．． 67 (s, 3H), 3.61 (s, 38), 3.16-3.0 2 (a+, 4) 1), 2.43 (S, 3H), Q. 00-1.90 (n.

4H); If1 analysis, m/e (FD) 661 (M” book 1) Example 10 3-ethyl 5-methyl 4- C2-+4- (2-hydroxy-]-]6- Methyl-2-trifluoromethyl 1,4-dihydropyridine-3,5-dicarbo Production of xylate By the method of Example 6, 3-ethyl 5-methyl 4-(2- (4-bromobutoxy)-5-nitrophenyl)-6-methyl-2-trifluoro lomethyl-1,4-dihydropyridine-3,5-dicarboxylate (0,50 g) (!=2-hydroxy-3-phenoxypropylamine (0.45g) 3-ethyl 5-methyl 4-C2-(4-(2-hydroxy-3-pheno xypropylamine)butoxy)-5-nitrophenyl]-6-methyl-2-t Lifluoromethyl-1,4-dihydropyridine-3,5-dicarboxylate Obtained as a yellow foamy solid (0.43 g).

IR(KBr)3332.2948.1?22.1708.1589.1514 ．． 1496.1341゜1017, 753.692 cm-';'HNMR( CDC13-TMS) δ8.09 (dd, 1) 1), 8.08 (s, LH), 7 ．． 28 (t, 2H), 6.96 (t, 18), 6.90 (d, 2H) , 6.87 (d, LH), 5.36 (s, IH), 4.13-3 ．． 95 (P1, 7H), 3.57 (s, 3H), 2.88 (ddd, LH), 2.81 (dd, LH), 2.77 (t, 2H), 2.38 (sA 3H), 1 ．． 89-1 ．． 68 (w, 48), 1.16 (t, 3H); mass spectrometry, m/e (FD) 65 2(M”+1) Example 11 By the method of Example 1, 5-ethyl 3-methyl 4-(2-(2-bromoe Toxy)-5-nitrophenyl)-2-cyano-6=methyl-1,4-dihydro Pyridine-3,5-dicarboxylate (405 mg) and 2-hydroxy-3- From phenoxypropylamine (548 mg) to 5-ethyl 3-methyl 2-methyl Ano-4-(2-(2-(2-hydroxy-3-phenoxypropylamino)ethyl) Toxy)-5-nitrophenyl]-6-methyl-1,4-dihydropyridine-3 ,5-dicarboxylate (86 mg) was obtained as a yellow crystalline solid.

5p 191-193°C (recrystallized from methylene chloride); +1? (KBr)2 226.1697.1644.1624.1599.1588.1506.13 44゜1275, 1045.826.755 co+-';')I NMR (CDCh-TMS) δ8.30 (br s, 1) 1), 8.175 (d, J =2.7Hz, LH), 8.106(dd, J=9.0 and 2.9Hz, It(), 7.30 (br t, J=7.3) 1x, 2H), 6.99 (br t, J=1.4Hz, IH), 6.94-6.90 (m, 3H), 5.34a nd 5.29 (2s, IH), 4.40-4.16 (m, 3) 1), 4.09 -3.93 (m, 411), 3.70 (s, 3H), 3.26-2.87 (m, 4H), 2.35 and 2.34 (2s, 3) 1), 1.201 and 1.198 (2t, J=8.0 and 8.0Hz, 31(); mass spectrometry, m/e (FD) 580 (M”+H) Example 12 By the method of Example 1, 3,5-dimethyl 4- + 2- (2-bromoethoxy c)-5-nitrophenyl)-2-cyano-6-methyl-1,4-dihydropyri Zine-3,5-dicarboxylate (423 mg) and 2-hydroxy-3-phenylene 3,5-dimethyl 2-cyano-4 from noxypropylamine (440I1g) -[2-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy) -5-nitrophenyl]-6-methyl-1,4-dihydropyridine-3,5-di The carboxylate (96 ISg) was obtained as a yellow crystalline solid.

mp160-163”C (recrystallized from methylene chloride); IR (KBr) 22 38.1705.1652.1632.1598.15B7.1509.149 L1432, 1344.1301.1275.1217.1120.825.7 63cm-';')l NMR (CDCh-TMS) δ8.17(t, J -3,0Hz, LH), 8.10 (dd, J=9.0 and 2.7Hz, L H), 7.33-7.23 (m, 2H), 7.02-6.90C11,48), 5.35 and 5.34 (2s, LH), 4.42-3.94 (m, 5H) , 3.71 and 3.61 (2s, 3H), 3.25-2.88 (11,4 H), 2.35 and 2.34 (2s, 3H); Mass spectrometry, s/e (FD) 567 (M”+22 Example 13 5-ethyl 3-methyl 4-C2-(4-(2-hydroxy-3-)Futsuki dipropylamino)butoxy)-5-nitrophenyl]-6-methyl-2-tri Preparation of fluoromethyl-1,4-dihydropyridine-3,5-dicarboxylate By the method of Method Example 6, 5-ethyl 3-methyl 4-(2-(4-bromo butoxy)-5-nitrophenyl)-6-m+2-trifluoromethyl-1 , 4-dihydropyridine-3,5-dicarboxylate (0,25 g) and Droxy-3-phenoxypropylamine (0.22g) to 5-ethyl 3- Methyl 4-(2-+4-(2-hydroxy-3-phenoxypropylamide) (butoxy)-5-nitrophenyl]-6-methyl-2-trifluoromethyl -1,4-dihydropyridine-3,5-dicarboxylate is a yellow foamy solid ( 0°25g).

IR(KBr)3328.2950.1700.1514.1496.1340 ．． 1268.1175゜1082, 753.692 cm-';'HNMR( CDC1z-TMS) 68.09 (dd, 18), 8.08 (s, LH), 7 ．． 29 (t, 2H), 6.97 (t, IH), 6.91 (d, 2H) , 6.88 (d, 18), 5.36 (s, 1B), 4.1 3-3.9T (m, 78), 3.63 (s, 3) 1), 2.89 (ddd, LH), 2.82 (dd, LH) , 2.78 (t, 2H), 2.39 (s, 38), @1.90-1 ．． 67 (Waku, 4H), 1.15 (t, 3H); Mass spectrometry, m/e (FD) 6 52 (M”+1).

Example 14 3-ethyl 5-isopropyl 4-(s-(4-(2-hydroxy-3- enoxypropylamino)butoxy)-2-nitrophenyl]-6-methyl-2 -trifluoromethyl-1,4-dihydropyridine-3,5-dicarboxylate 3-ethyl 5-isopropyl 4-[5-( 4-bromobutoxy)-2-nitrophenyl]-6-methyl-2-trifluoro Methyl-1,4-dihydropyridine-3,5-dicarboxylate (0,40g ) and 2-hydroxy-3-phenoxypropylamine (0.45 g) to Chil 5-isopropyl 4-(5-+4-(2-hydroxy-3-phenoxy propylamino)butoxy)-2-nitrophenyl]-6-methyl-2-trif fluoromethyl-1,4-dihydropyridine-3,5-dicarboxylate is yellow Obtained as a foamy solid (0.39 g).

IR (Br) 3341.2981.2939.172B, 1702.160 0.1518.1345°1283, 1079.754.691 cm-'; 'HNMR (CDC13-TMS) δ7.91 (d, LH), 7.27 (t, 2H), 6.98 (d, LH), 6.96 (t, LH), 6.91 (d , 2H), 6.75 (dd, LH), 6.37 (s, LH) , 5.92 (s, Lg), 4.88 (p, LH ), 4.18-3.95 (i+, 7H), 2.89-2.68 (m , 4H), 2.40 (s, 3H), 1.88|1.66 (m, 4H) , 1.20 (t, 3H), 1.14 (d, 3H), 0.88 (a, 3H ); Mass spectrometry, m/e (FD) 680 (M''+1).

Example 15 3-ethyl 5-isopropyl 4-(2-(4-(2-hydroxy-3-ph) phenoxypropylamino)ethoxy)-5-nitrophenyl-6-methyl-2 -trifluoromethyl-1,4-dihydropyridine-3,5-dicarboxylate 3-ethyl 5-isopropyl 4-[2-( 4-bromoethoxy)-5-nitrophenyl]-6-methyl-2-trifluoro Methyl-1,4-dihydropyridine-3,5-dicarboxylate (0,30g ) and 2-hydroxy-3-phenoxypropylamine (0.35 g) to Chil 5-isopropyl 4-(2-(4-(2-hydroxy-3-phenoxy pro-(amino)ethoxy)-5-nitrophenyl-6-methyl-2-trif fluoromethyl-1,4-dihydropyridine-3,5-dicarboxylate is yellow Obtained as a foamy solid (0.20 g).

IR(KBr)3328.29B1.2937.1702.1589.1514 ．． 1497.1340°1269, 1228.10B2.753.692cs- 'HNMR (CDC13-TMS) 68.11 (s, 18), 8.10 (dd, 1[+), 7.27 (t, 2H), 6.96 (t, LH), 6. 92 (d, 2H), 6.90-6.88 (m, IH), 6.6 7 (s, IH), 5.4R (s, IH), 4.89 (p+ LH), 4.25-3.88 (w, 78), 3.21-2.85 (L 4H), 2.40 (s, 3H), 1.20 (d, 3H), 1.14 (t, 3H) , 0.98 (d, 3H); mass spectrometry, m/e (FD) 652 (M''+1).

Example 16 By the method of Example 1, 3,5-dimethyl 4-(2-(6-bromohexyl) xy)-5-nitrophenyl)-2-cyano-6-methyl-1,4-dihydropi Lysine-3,5-dicarboxylate (425 mg) and 2-hydroxy-3-phthalate 3゜5-dimethyl 2-cyano- from phenoxypropylamine (463+mg) 4-(2-(6-(2-hydroxy-3-phenoxypropylamino)hexylo xy)-5-nitrophenyl]-6-methyl-1,4-dihydropyridine-3, The 5-dicarboxylate (35011 g) was obtained as a yellow foamy solid.

IR(KBr)2236.1708.1682.1644.1624.1588 ．． 1514.1341°1270, 1245.1217.754 cm-'; 'HNMR (CDCh-TMS) δ8.16-8.14 (n+, LH), 8. 08 (dd, J=9.1 and 2.8Hz, IH), 7.32-7. 22 (+1.2H), 6.99-6.82 (m, 4H), 5.2 9 (s, LH) A 4.22-3.90 (m , 5H), 3.68 (s, 3H), 3.58 (s, 3H), 2.97-2.68 (m, 4H), 2.34 and 2.33 (2s.

3H), 1.93-1.45 (s, 8H); Mass spectrometry, m/e (FD) 622 (M”).

Example 17 Diethyl 4-(2-(4-(2-hydroxy-3-phenoxypropylamino) )butoxy)-5-nitrophenyl-6-methyl=2-trifluoromethyl- Method for producing 1,4-dihydropyridine-3,5-dicarboxylate By the method of Example 6, diethyl 4-C2-(4-bromobutoxy)-5- [nitrophenyl]-6-methyl-2-trifluoromethyl-1,4-dihydropi Lysine-3,5-dicarboxylate (0,50g) and 2-hydroxy-3-phthalate Diethyl 4-C2-+4-( 2-Hydroxy-3-phenoxypropylamino)butoxy)-5-nitrophe Nyl2-6-methyl-2-trifluoromethyl-1,4-dihydropyridine-3 ,5-dicarboxylate was obtained as a yellow foamy solid (0.45 g).

IR(KBr)3343.2981.2937.170. , 1589.1514 ．． 1497.1340°1274, 753.691 cm-';'H! tMR (CDCh-TMS) δ8.12-8.08 (m, 2H), 7.29 (t, 2 H), 6.97(t,1)1).

6.91 (d, 2H), 6.87 (d, 18), 5.35 (s, 1) 1), 4.11-3.95 (s, 9) 1), Q. 88(ddd, LH ), 2.82 (ddd, IH), 2.77 (t, 2H), 2.38 (s, 38) , 1.88-1.69 (Ugu, 4H), 1.15 (t.

6H); Mass spectrometry, m/e (FD) 680 (M''+1).

Example 18 By the method of Example 1, 3,5-dimethyl 4-(2-(4-bromobutoxy) )-5-nitrophenyl)-2-cyano-6-nityl-1,4-dihydropyridi 3,5-dicarboxylate (367 mg) and 2-hydroxy-3-pheno Xypropylamine (302+sg) 3,5-dimethyl 2-cyano-6- Nithyl-4-(2-(4-(2-hydroxy-3-phenoxypropylamine) butoxy)-5-nitrophenyl)-1,4-dihydropyridine-3,5-dica Ruboxylate (240 mg) was obtained as a yellow crystalline solid.

sp 158-162°C (recrystallized from ethanol): IR (KBr) 223 6.1704.1586.1510.1432.1335.1268.1214 ゜1180, 1096.750.691　C11-';'HNMR(CDCl2 -TMS) 68.19 and 8.18 (d, J=2.7Hz, IH), 8 ．． 08 (dd, J=9.1 and 2.7Hz, IH), 7.28 (t, J= 7.5Hz, 2H), 6.97 (t, J=7.3Hz, LH), 6.90 (d, J=8.0Hz, 2H), 6.86 (d, J=9.2H2, LH) , 5.26 (s, LH), 4.33-S. 25 (m, LH) , 4.08-3.92 (m, 4) 1), 3.68 (s, 3H), 3.61 an d 3.60 (2s, 3H), 3.15 and 3°06 (2dd, J=7. 5, 13.1 and 7.4, 13.0Hz, LH), 2.97-2.77 ( s, 4H), 2.36 and 2.25 (2dd, J=7.4, 12.9a nd 7.4.13.1Hz, LH), 1.97-1.68 (+w, 48), 1 ．． 25 and 1.19 (2t, J=7.0 and 7.4Hz, 3H) ; Mass spectrometry, */e (FD) 609 (M+÷1).

Example 19 By the method of Example 1, 5-isopropyl 3-methyl 4-(2-(4-bropropyl) Mobutoxy)-5-nitrophenyl)-2-cyano-6-methyl-1,4-dihy Dropyridine-3,5-dicarboxylate (514-g) and 2-hydroxy -3-(2-methoxyphenoxy)propylamine (567 mg) to 5-iso Propyl 3-methyl 2-cyano-4-(2-[4-+2-hydroxy-3- (2-methoxyphenoxy)pro-ruamino)butoxy]-5-nitrophenyl ]-6-Methyl-1,4-dihydropyridine-3,5-dicarboxylate (3 71 mg) as a yellow crystalline solid.

■ p 73-79°C (recrystallized from ethanol-water); IR (KBr) 22 34.1700.11590.1471.13B6.1372.1341.12 73°1180.1096 cm-'; 'HNMR (CDCl2-TMS) 68.20-8.07 (Zeng, 2H) +7 ．． 02-6.80 (m, 5H), 5.22 (s, LH), 4.90 and 4 ．． 89 (2hept, J=6.2 and 6.2Hz, 1)1), 4.31- 4.24 (m, 18), 4.13-3.72 (-, 4M), 3.86 (s, 3H), 3.68 (s, 3H), 2.97-2.79 (+* , @4H), 2.33 and 2.30 (2s, 3H), 1.97-1.70 (m, 4H), 1.28 , 1.27, 1.01 and 1.00 (4d, J=6.3, 6.3, 6.2 and 6.3Hz, 6)1); Mass spectrometry, m/e (FD) 653 (M”+ 1).

Example 20 3-ethyl 5-isopropyl 4-(2-+4-(2-hydroxy-3- (2-methoxyphenoxy)propylamino)butoxy)-5-nitrophenyl ]-6-methyl-2-trifluoromethyl-1,4-dihydropyridine-3,5 -Production method of dicarboxylate By the method of Example 6, 3-ethyl 5-isopropropylene Pill 4-[2-(4-bromobutoxy)-5-nitrophenyl]-6-methyl -2-trifluoromethyl-1,4-dihydropyridine-3,5-dicarboxy (0,30 g) and 2-hydroxy-3-(2-methoxyphenoxy)pro 3-ethyl 5-isopropyl 4-(2-( 4-(2-hydroxy-3-(2-methoxyphenoxy)propylamino)buto xy)-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1,4 -dihydropyridine-3,5-dicarboxylate is a yellow foamy solid (0,29 g) was obtained.

IR(XBr)3342.2980.2939.1698.1590.1506 ．． 1340.1274゜1223, 1178.1078.1023.748c +w-';'HNMR (CDCb-TMS) δ8.10-8.07 (fog, 2H ), 7.16 (bs, LH), 7.00-6.86 (m, 5) 1), 5.32 (s, 1) 1), 4.88 (p, 1) 1), 4.29 (br　s,　IH)　　4.11-S. 00 axis, 61(), 3° 84 (s, 3H), 3.84-2.92 (m, 4H), 2.39 (s, 3) 1), 1.99-1.84 (a+, 4g), 1.22 (d, 3 H), 1.13 (t, 3B), 0.97 (d, 3H); mass spectrometry, m/e (F D) 710 (M”+1).

Example 21 By the method of Example 1, 5-isopropyl 3-methyl 4-(2-(5-bropropyl) mopentyloxy)-5-nitrophenyl)-2-cyano-6-methyl-1,4- dihydropyridine-3,5-dicarboxylene) (0.35g) and 2-hydro 5-isopropyl from xy-3-phenoxypropylamine (0.35g) 3 -Methyl 2-cyano-4-[2-+5-(2-hydroxy-3-phenoxy propylamino)pentyloxy)-5-nitrophenyl]-6-methyl-1,4 - Dihydropyridine-3,5-dicarboxylate (0,35 g) as a yellow foam. Obtained as a solid.

IR(KBr)2236.1700.1652.1645.1634.1589 ．． 1515.1496°1340, 1302.1270.1215.1096. 755c+s-';')l NMR (CDC13-TMS) 68.18(d , J=2.8) 1z, 111), 8.09(dd, J=9.0 and 2.9 Hz, LH), 7.32-7.23 (m, 2H), 7.02-6.87 (m, 4 H), 5.22 (s, LH), 4.95-4.87 (+s, 1) 1), 4.34-4.25 (m, LH), 4.10-4.03 (m, 2H ), 3.99 (d, i=5.6Hz, LH), 3 ．． 89 (t, J=7.1Hz, LH), 3.70 and 3.68 (2s, 3 H), 3.11-2.68 (m, 4H), 2.37 and 2.31 (2s, 3 H), 1.984.58 (m, 6H), 1.28, 1.27, 1.03 and 1.00 (4d.

J=5.8, 5.8, 6.2 and 6.2Hz, 6H); mass spectrometry, m/ e(FD)637(M”+1).

Example 22 By the method of Example 1, 5-isopropyl 3-methyl 4-(2-(4-bromo butoxy)-5-chlorophenyl)-2-cyano-6-methyl-1,4-dihyde Lopyridine-3,5-dicarboxylate (429B) and 2-hydroxy-3- 5-isopropyl 3-methyl from phenoxypropylamine (341 mg) 2-cyano-4-[5-chloro-2-+4-(2-hydroxy-3-phenoxylene) cypropylamino)butoxy)phenyl]-6-methyl-1,4-dihydropyly Dine-3,5-dicarboxylate (280 mg) was obtained as a yellow powder.

IR(KBr)2236.1698.1682.1520.1496.1464 ．． 1243.1213゜1100, 1095.801.755 cm-';' HNMR (CDC13-TMS) δ7.30 (br t, J=7.7Hz, 2 B), 7.22 (t, J=2.5Hz, LH), 7.11 and 7.09 ( 2t, J=2.5 and 2.5Hz, LH), 7.00-6.90 axis, 2 11), 6.70 (br d, J=8.5Hz, LH), 5.04 (s, 18), 4.93-4.89 (m, 18), 4.3P- 4.24 (m, t.

), 4.07-3.85 (m, 4H), 3.70 (s, 3H), 3.00-2. 75 (m, 4H), 2.31 and 2.27 (2s, 3H), 1.86-1 ．． 75 (m, 48), 1.27, 1.26, 1.09 and 1.08 (4d , J=6.1, 6.2, 6.6 and 6.5Hz, 6H); Mass spectrometry, m/e (FD) 612 (gate"+1).

Example 23 By the method of Example 2, 5-isopropyl 3-methyl 4-(2-(4-amino) Knotoxy)-5-nitrophenyl)-2-cyano-6-methyl-1,4-dihy Dropyridine-3,5-dicarboxylate (1,80 g) and 3-(2-chloro phenoxy')-1,2-epoxypropane (0,49 g) to 5-isopropy 3-methyl 4-1:5-[4-(3-(2-chlorophenoxy)-2- hydroxypropylamino)butoxy]-5-nitrophenyl]-2-cyano- 6-Methyl-1,4-dihydropyridine-3,5-dicarboxylate (0,3 8 g) of a yellow foamy solid.

IR(KBr)2236.1699.1644.1599.1516.1514 ．． 1488.1340°1272, 1214.1096.752 c++-' ;’HNMR (CDC1z-TMS) δ8.19-8.16 axis, L1(), 8 ．． 12-8.07 (w, LH), 7.37-7.34 (m, 1B), 7.22 ( t, J=7.8Hz, 1)I), 6.96-6.84(-,3H), 5.22( s, 1) 1), 4.93-4.87 (s, LH), 4.38-4.32 (m, L H), 4.16-3.96 (m, 4H), 3.684 and 3.678 (2 s, 3H), 3.07-2.82 (m, 4H), 2.32 and 2.29 ( 2s, 38), 1.95-1.74 (s, 2H).

1.28, 1.27, 1.02 and 1.00 (4d, J=6.2, 6.2 , 6.2 and 6.2Hz, 6H); Mass spectrometry, s+/e (FD) 657 (M”+1).

Example 24 3-ethyl 5-isobutyl 4-(2-(4-(2-hydroxy-3-phenylene) noxypro and ruamino)butoxy)-5-nitrophenyl]-6-methyl-2- Trifluoromethyl-1,4-dihydropyridine-3,5-dicarboxylate 3-ethyl 5-isobutyl 4-(2-(4- Bromobutoxy)-5-nitrophenyl]-6-methyl-2-trifluoromethyl (1,4-dihydropyridine-3,5-dicarboxylene) (0,47g) and 2-hydroxy-3-phenoxybrobylamine (0.42 g) to 3-ethyl 5-isobutyl 4-(2-+4-(2-hydroxy-3-phenoxypyl) ropylamino)butoxy)-5-nitrophenyl]-6-methyl-2-triflu Olomethyl-1,4-dihydropyridine-3,5-dicarboxylate is a yellow Obtained as a foamy solid (0.44 g).

IR (Br) 3352.2960.1727.1703.1589.1514 ．． 1498.1341°1273, 1228.1175.1080.1015. 753.692 cm-';'HNMR (CDCh-TMS) 68.08 ( dd, 18), 8.05 (dd, LH), 7.26 (t, 2+1), 6.96 ( t, IH), 6.88 (d, 2) 1), 6.85 (d, 1B), 6.70 (s, LH), 5.38 (s, LH) @, 4.39 (bs.

LH), 4.11-3.99 (■, 6H), 3.12-3.02 (m, 28), 2.43 (s, 3H), 1.96-P. 90 (m, 4 H), 1.84-1.81 (s, LH), 1.16 (t, 38) , 0.84 (d, 3H), 0.78 (d, 38)@; Mass spectrometry, s/e (FD) 694 (M''+1).

Example 25 3-ethyl 5-propyl 4-(2-(4-(2-hydroxy-3-pheno (xypropylamino)butoxy)-5-nitrophenyl]-6-methyl-2-to of lifluoromethyl-1,4-dihydropyridine-3,5-dicarboxylate By the method of Production Example 6, 3-ethyl 5-propyl 4-[2-(4-butyl) lomobutoxy)-5-nitrophenyl]-6-methyl-2-trifluoromethyl -1,4-dihydropyridine-3,5-dicarboxylate (0,35g) and 2 -Hydroxy-3-phenoxypropylamine (0.38g) to 3-ethyl 5-propyl 4-(2-(4-(2-hydroxy-3-phenoxyprotyl) amino)butoxy)-5-nitrophenyl]-6-methyl-2-trifluorome Chil-1,4-cyhydropyridine-3,5-dicarboxylate forms a yellow foamy solid. (0.30 g).

IR(KBr)3342.2940.1724.1703.1514.1497 ．． 1340.1274°1228, 1176, 1081. 753cm- ';'HNMR (CDC1i-TMS) δ8.10-8.06 (+++, 2 H), 7.27 (t, 2) 1), 6.97 (t, IH).

6.89 (d, 2H), 6.86 (d, IH), 6.74 (s, LH), 5.37 (s, 1B), 4.34 ibr s, LH ), 4゜ 10-3.91 (m+8H), 3.10-2.97 (w, 4H), 2.4 1 (s, 31), 1.97-1.84 (m, 4H), 1D5 8-1.50 (s, 2H), 1.15 (t, 3B), 0.81 (t, 3H); quality Quantitative analysis, −/e (FD) 680 (M”+1).

Example 26 By the method of Example 2, 5-isopropyl 3-methyl 4-(2-(4-amino) Knotoxy)-5-nitrophenyl)-2-cyano-6-methyl-1,4-dihy Dropyridine-3,5-dicarboxylate (1250 mg) and 1,2-epoxy C-3-(2-methylphenoxy)propane (304mg) to 5-isopropylene 3-methyl 2-cyano-4-(2-[4-(2-hydroxy-3-(2- methylphenoxy)propylamino)butoxy]-5-nitrophenyl]-6- Methyl-1,4-dihydropyridine-3,5-dicarboxylate (230 mg ) was obtained as a yellow foamy solid.

IR(KBr)2236.1701.1644.1590.1514.1496 ．． 1399.1271゜1215, 1097. 7532cm-';'H NMR (CDCl2-TMS) δ8.20-8.18 (m, IH), 8.12 -8.07 (m, LH), 7.17-7.13 axis, 2H), 6.92 and 6.79 (m, 3H), 5.22 (s, LH), 4.94-4.86 (m, 1H ), 4.36-4.29 (m, 1) 1), 4.09-3.93 (+m, 4H), 3.69 and 3.68 (2g, 3H), 3.04-2.80 (m, 4H) , 2.33 and 2.30 (2s, 3H), 2.25-2.23 (2s, 3H) 11), 1.95-1.73 (s, 4H).

1.28, 1.27, 1.02 and 1.01 (4d, J=6.2, 6. 1.6.1 and 6.2Hz, 6H); Mass spectrometry, m/e (FD) 6 37 (M”+1).

Example 27 By the method of Example 2, 5-isopropyl 3-methyl 4-(2-(4-7 mi) Knotoxy)-5-nitrophenyl)-2-cyano-6-methyl-1,4-dihy Dropyridine-3,5-dicarboxylate (125 g) and 1,2-epoxy -3-(2,4,6-) IJ methylphenoxy)propane (356nAg) 5-isopropyl 3-methyl 2-cyano-4-(2-[4-(2-hydro xy-3-(2,4,6-methylphenoquine)propylamino)butylene shi]-5-nitrophenyl]-6-methyl-1,4-dihydropyridine-3,5 -dicarboxylate (160 mg) was obtained as a yellow foamy solid.

IR(KBr)2236.1700.1646.1636.1590.1518 ．． 1340.1270゜1214, 1095.735 cm-';'HNMR (CDCh-TMS) 610.30 (br　s, LH), 8. L8(d, J= 2.9Hz, 1) 1), 8.08 (dd, J=9.2 and 2.9Hz, 1 )1), 6.87-6.80 (+s, 3B), 5.22 (s, IH), 4.95 -4.86 (m, IH), 4.38-4.29 (m, L) I), 4.10-3.98 (m, 21 (), 3.85-3.63 (Incense A 2 B), 3.68 and 3.67 (2s, 3) 1), 3.09-2.87 (+w, 4H), 2. 36 and 2.33 (2s, 3H), 2.25-2゜18 (m, 9H), 1 ．． 98-1.78 (m, 4) 1), 1.28, 1.27, 1.01 and 1 ．． 00 (4d, J=6.2, 6°2.6.2 and 6.2Hz, 6)1); Mass spectrometry 9 m/e (FD) 665 (M”+1).

Example 28 By the method of Example 1, 5-isopropyl 3-methyl 4-(lupoxylate (2,28 g) and 2-hydroxy-3-phenoxypropylamine (2,50 g) ) to 5-isopropyl 3-methyl 2-cyano-4-[:2-(4-(2 -hydroxy-3-phenoxypropylamino)butoxy)-5-methyl-3- Nitrophenyl]-6-methyl-1,4-dihydropyridine-3,5-dicarbo The xylate (0.93 g) was obtained as a yellow foamy solid.

IR(KBr)2236.1699.1600.1530.1526.1498 ．． 1222.1095.755cm-'; 'HNMR (CDC13-TMS) δ7.47 (d, J=1.4Hz, LH) , 7.32-7.25 (+++, 3H), 6.96 (br　t, J=7.2Hz , LH), 6.90 (br d, J=7.9Hz, 2H), 5.203 an d 5.195 (2s, LH), 4.93 (hept, J=6.2H z, 18), 4.33-4.24 (s, 18), 4.06-3 ．． X5 axis, 2H), 3 ．． 80-3.74 (m, 2H), 3.709 and 3.706 (2s, 3H ), 3.06-2.77 (m, 41 (), 2.32 (s, 3H), 2.31 a nd 2.17 (2s, 3H), 1.98-1.68 (a+, 4H), 1.23 (br　d, J=6.3Hz.

3H), 1.062 and 1.060 (2d, J=6.3 and 6.3 Hz, 3H); Mass spectrometry, m/e (FD) 637 (M''+1).

Example 29 By the method of Example 1, 5-isopropyl 3-methyl 4-(2-(3-bropropyl) mopropoxy)-5-nitrophenyl)-2-cyano-6-methyl-1,4-di Hydropyridine-3,5-dicarboxylene) (280 mg) and 2-hydroxy C-3-phenoxypropylamine (224 mg) to 5-isopropyl 3- Methyl 2-cyano-4-[2-(3-(2-hydroxy-3-phenoxypro pyramino)propoxy)-5-nitrophenyl]-6-methyl-1,4-dihy Dropyridine-3,5-dicarboxylate (120 mg) as a yellow foamy solid I got it.

TR(KBr)3466, 3232.3089.2981.2929.2240 ．． 1735.1713°1702, 1520. 150B, 1342. 12 74. 1213. 1099. 825. 756.　692cm-'; 'HNMR (CDCh-TMS) 68.15 and 8.14 (2d, LH ), 8.08 and 8.06 (2dd, LH), 7.27 and 7.25 (2dd, 2H), 6.97-6.83 (m, 4H), 5.20 (sr Lg), 4.87-4 ．． 83 (m, 1) 1), 4.34-4.32 (m, 18), 4.04-3.93 (m, 4H), 3.68 and 3.67 (2s, 3H), 3.0-2.7 ( m, 4H), 2.26 and 2.21 (2g, 3H), 2.18-2.00 (m, 3H), 1.23.1.22.0.97 and 0.94 (4d, 6H ) Mass spectrometry, m/e (FD) 609 (M''+1).

Example 30 By the method of Example 1, 5-isopropyl 3-methyl 4-(2-(4-bropropyl) Mobutoxy)-4,6-dichlorophenyl)-2-cyano-6-methyl-1,4 -dihydropyridine-3,5-dicarboxylate (0,38g) and 2-hydro xy-3-phenoxypropylamine (0.34g) to 5-isopropyl 3 -Methyl 2-cyano-4-[4,6-dichloro-2-+4-(2-hydroxy C-3-phenoxypropylamino)butoxy)phenyl]-6-methyl-1. 4-dihydropyridine-3,5-dicarboxylate (0.20 g) as a yellow foam. Obtained as a solid.

IR (Br) 2235.1696.1578.1522.1454.1302 ．． 1246.1213°1096,755 C11-'; 'HN gate R (CDC1ff to T gate 5) 67.31-7.23 (11,2H), 6.99-6.86 (scratch, 4H), 6.72 (dd, J=8.1 and 1. 8Hz, LH), 5.70 and 5.69 (2s, LH), 5.03-4. 95 (m, LH), 4.33-4.22 (m, IH), 4.05-3.82 (m , 4B), 3.680 and 3.676 (2s, 3H), 2.93-2.7 2 (m, 48), 2.24 and 2.23 (2s, 3H), 1.90-1. 68 (m, 4H), 1.24, 1.23, 1.03 and 1.01 (4d, J=6.2, 6.2, 6.3 and 6.3Hz, 6H): Mass spectrometry, m/ e(FD)645(M”).

Example 31 By the method of Example 1, 5-isopropyl 3-methyl 4-(2-(4-bropropyl) Mobutoxy)-5-nitrophenyl)-2-cyano, -6-methyl-1,4- Dihydropyridine-3,5-dicarboxylate (400IIg) and 2-hydro xy-3-(4-methoxyphenoxy)propylamine (44b+g) to 5- Isopropyl 3-methyl 2-cyano-4-(2-[4-+2-hydroxy- 3-(4-methoxyphenoxy)propylamino)butoxy]-5-nitrophe ]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (183 mg) was obtained as a yellow powder.

mp　81-84℃　; IR(KBr)2235.1699.1590.1510.1341.1302 ．． 1273.1216゜1097+824C@l-'; 'HNMR (CDC13-TMS) δ10.02 (brs, 18), 8.1 8 (d, J-2, 7Hz, LH), 8.09 (br d, J=9.1Hz, IH), 6.88-6.79 (m, 5H), 5.22 (s, I H), 4.94-4D86 (m, 1) 1) , 4.34-4.27 (s, IH), 4.07-3.87 (m, 4H), 3.7 6 (s, 3H), 3.68 and 3.67 (2s, 3H), 3.03-2. 84 (m, 4H), 2.34 and 2.31 (2s, 3H), 1.95-1 ．． 75 (m, 4H), 1゜28.1.27, 1.01 and 1.00 (4d , J=6.0, 6.0, 6.0 and 6.0Hz, 6H); mass spectrometry, m /e(FD)653(M”+1).

Example 32 By the method of Example 1, 5-isopropyl 3-methyl 4-(2-(4-bropropyl) Mobutoxy)-5-nitrophenyl)-2-cyano-6-methyl-1,4-dihy Dropyridine-3,5-dicarboxylene) (490 mg) and 3-(4-dicarboxylene) 5-isopropylene (lophenoxy)-2-hydroxypropylamine (553 mg) Lopyl 3-methyl 4-[2-[4-(3-(4-chlorophenoxy)-2- hydroxypropylamino)butoxy]-5-nitrophenyl]-2-cyano- 6-Methyl-1,4-dihydropyridine-3,5-dicarboxylate (388 -g) was obtained as a yellow powder.

mp　96-99°C; IR(KBr)2234.1693.1516.1514.1493.1338 ．． 1301.1275゜1213, 1099.824 crs-';'HNM R (CDCl2-TMS) δ8.19-8.16 (s, LH), 8.12-8 ．． 08 (sr, LH), 7.26-7.22 (m, 2H), 6.88- 6.82 (m, 3H), 5.22 (s, IH), 4.93-4. 87 Crs, kH), 4.33-4° 27 (++, 18), 4.07-3.88 (m, 4H), 3.69 and 3 ．． 68 (2s, 3H), 3.01-2.80 (m, 4H), 2.32 and 2.30 (2s, 3H), 1.95-1.74 (s, 4H), 1.28, 1.2 7, 1.02 and 1゜0H4d, J=6.1, 6.2, 6.1 and 6.2 Hz, 68); mass spectrometry, s+/e (FD) 657 (M''+1).

Example 33 Diethyl 4-(2-+4-(2-hydroxy-3-(2-methoxyphenol) xy)pro and ruamino)butoxy)-5-nitrophenyl]-6-methyl-2- Trifluoromethyl-1,4-dihydropyridine-3,5-dicarboxylate By the method of Production Example 6, diethyl 4-(2-(4-bromobutoxy) -5-nitrophenyl]-6-methyl-2-trifluoromethyl-1,4-dihydryl Dropyridine-3,5-dicarboxylate (0,50 g) and 2-hydroxy- 3-(2-methoxyphenoxy)propylamine (0.51g) to diethyl 4-(2-(4-(2-hydroxy-3-(2-methoxyphenoxy)propyl (ruamino)butoxy)-5-nitrophenyl]-6-methyl-2-trifluoro Methyl-1,4-dihydropyridine-3,5-dicarboxylate is a yellow foam. Obtained as a solid (0.46 g).

IR(KBr)3315.2939.1702.1629.1591.1506 ．． 1455.1368゜1340, 1278.1095.744 cm -' 'HNMR (CDC13-TMS) δ8.10 (s, IH), 8.07 (d d, LH), 6.99-6.86 (m, 51), 5.33 (s, LH) , 4.19-4.18 (m, LH), 4.08-3.97 (@, 8H), 3.85 (Sword A 3H), 2.93- 2.81 (s, 4H), 2.38 (s, 31), 1.19-1. 86 (11,2H), 1.75-1.72 (11,2g), 1.16 -1 ．． 13 (jou, 6H); Mass spectrometry, */e (FD) 695 (M''+1).

Example 34 By the method of Example 1, (+)-5-isopropyl 3-methyl 4-(2-( 4-bromobutoxy)-5-nitrophenyl)-2-cyano-6-methyl-1, 4-dihydropyridine-3,5-dicarboxylate (13,99g) and (-) -2-Hydroxy-3-phenoxyprobylamine (13,03g) (+) -5-isopropyl 3-methyl 2-cyano-4-(2-(4-(2-hydro xy-3-phenoxypro and ruamino)butoxy)-5-nitrophenyl]-6 -Methyl-1,4-dihydropyridine-3,5-dicarboxylate (7°40 g) was obtained as a yellow crystalline solid.

mp 105-107°C (regeneration from acetonitrile-diisopropyl ether) crystalline matter); (a)”o +118 @ (co, 8. methanol); IR (KBr) 224 5.1698.15B9.1472.13B4.1341.1275.1096 ．． 756 + 691 cta-'; 'HNMR (CDCh-TMS) 610.03 (br　s, 1B), 8.18 (d, J=2-7Hz, LH), 8.09 (dd, J=9.1 and 2.7 Hz, 11), 7.29 (t, J=7.9Hz, 2H), 6.98 (t, J=7 ．． 2Hz, 18), 6.91 (d, J-8, 3Hz, 2H), 6. 86 (d, J-9, 3H2, IH), 5.22 (s, 1) 1) A 4.90 (hept , J=6.2Hz, 1B), 4.37-4.27 (s, IH), 4.10-3.91 (m, 4H), 3.68 (sword@, 3H), 3.06 -2.84 (m, 4B), 2.34 (s, 3H), 1.99-1.72 (m, 4 H), 1.27 and 1.01 (2d, J=6゜1 and 6.2Hz, 6H); Example 35 By the method of Example 2, (+)-5-isopropyl 3-methyl 4-(2-( 4-aminobutoxy)-5-nitrophenyl)-2-cyano-6-methyl-1, 4-dihydropyridine-3,5-dicarboxylene) (8,65g) and (+) -1,2-epoxy-3-phenoxypropane (1,65g) to (+)-5- Isopropyl 3-methyl 2-cyano-4~(2-+4-(2-hydroxy -3-phenoxypro and ruamino)butoxy)-5-nitrophenyl]-6-mer Chil-1°4-dihydropyridine-3,5-dicarboxylate (2,73g) was obtained as a yellow crystalline solid.

1ρ103-105°C (recrystallized from ethanol-hexane); [α]” n+123' (co, 8. methanol); Example 36 By the method of Example 1, 5-ethyl 3-methyl 4-(2-(4-bromobutylene) Toxy)-5-nitrophenyl)-2-cyano-6-methyl-1,4-dihydro Pyridine-3,5-dicarboxylate (776 mg) and 2-hydroxy-3- 5-ethyl 3-methyl 2-methyl from phenoxypropylamine (635 mg) Ano-4-(2-(4-(2-hydroxy-3-phenoxypropylamino)bu) Toxy)-5-nitrophenyl]-6-methyl-1,4-dihydropyridine-3 ,5-dicarboxylate (540s+g) was obtained as a yellow powder.

mp　136-138°C; 'HNMR (CDC13-TMS) δ8.20-8.07 (Il12H), 7 ．． 31-7.27 (m, 2H) + 7.00-6.84 (s + 4) 1), 5.25 (s, IN), 4.34-4.25 (m, IF+), 4. l5-3.91 (incense A 6H), 3.69 an d 3.68 (2g+3H), 3-01-2.78 (m, 4H), 2.33a nd 2.30 (2s, 3H), 1.95-1.71 (s+, 4B), 1.23 -1.17 (m, 3H); Mass spectrometry, m/e (FD) 609 (M''+1).

Example 37 By the method of Example 6, 3,5-diethyl 4-[2-(4-bromobutoxy) )-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1,4-di Hydropyridine-3,5-dicarboxylate (0,75g) and 2-hydroxy -3-(4-(N-methylsulfonyl-N-tetrahydropyran-2-yl) 3.5-diethyl 4- from aminophenoxy)propylamine (1,34g) C2-[4-[2-hydroxy-3-(4-(N-methylsulfonyl-N~ tetrahydropyranyl)aminophenoxy)pro and ruamino]butoxy]-5- [nitrophenyl]-6-methyl-2-trifluoromethyl-1,4-dihydropi Lysine-3,5-dicarboxylate was obtained as a yellow foamy solid (0,87 g). It was done. The foamy solid (0,87 g) and P-)luenesulfonic acid HzO (0, 70g) (7) The methanol solution (20af) was refluxed for 2 hours. Bring the reaction solution to saturation It was poured into soda water and extracted with chloroform (tsdX 3). Combine the extract and After washing with saline, it was dehydrated with anhydrous sodium sulfate. The filtrate was evaporated under reduced pressure. 1, the residue was subjected to silica gel column chromatography, and chloroform- After elution with methanol 10/1 (v/v), 4 condensation yields 3.5-diethyl. 4-C2-[4-[2-hydroxy-3-(4-(N-methylsulfonyl) aminophenoxy)propylamino]butoxy]-5-nitrophenyl]-6~ Methyl-2-trifluoromethyl-1,4-dihydropyridine-3,5-dical The boxylate was obtained as a yellow foamy solid (0.54 g).

IR (Br) 2983.2934.1702.1628.1609.1590 ．． 1510.1468°1368, 1340.1275.1152.1098. 752 cm-';'HNMR (CDCh-TMS) δ8.10-8.07 (m, 2H), 7.16 (d, 2H), 6.92-6.75 (m, 4H), 5.35 (s, LH), 4.24-4.15 (m, 1) 1), 4.10-3.93 (m, 8H), R. 02-2.85 (m.

4H), 2.95 (s, 3H), 2.39 (s, 3H), 1.95-1.73 ( m, 4) 1), 1.15 (t, 6H); mass spectrometry, Il/e (FD) 759 ( M”+1).

Example 38 By the method of Example 37, 5-isopropyl 3-methyl 4-[2-(4-butyl) lomobutoxy)-5-nitrophenyl]-2-cyano-6-methyl-1,4-di Hydropyridine-3,5-dicarboxylate (0,82g) and 2-hydroxy -3-(4-(N-methylsulfonyl-N-tetrahydropyran-2-yl) 5-isopropyl 3- from aminophenoxy)propylamine (1,44g) Methyl 4-[2-[4-[2-hydroxy-3-(4-(N-methylsulfo) nitrophenyl)aminophenoxy)propylamino]butoxy]-5-nitrophenyl] -2-cyano-6-methyl-1,4-dihydropyridine-3゜5-dicarboxy The rate was obtained as a yellow foamy solid (0.71 g).

IR(KBr)2236.1699.1590.1512.1340.1268 ．． 1152.1096cm-'; 'HNMR (CDC13-TMS) δ8.20-8.07 (11,2M), 7. 22-7.14 (m, 2H), 6.92-6.80 (11,3H), 5. 22 (s, LH), 4.33-4.27 (m, IH), 4. 11-3.88 axis, 4g), 3.68and 3, 67 (2s, 3H), 3.02-2.76 (m, 7H), 2.33 and 2.31 (2s, 3H), 1. X7-1.66 ( +w, 4 H), 1.29-0.97 (m, 6H); Mass spectrometry, s/e (FD) 7 16 (M”+1).

international search report international search report Continuation of front page (72) Inventor Takeshi Hamaya Ibaraki-based Tsukuba City Sengen 1-14-14-403 (72) Inventor 1) Yang Part 2-13-28-402 Yoguchi, Tsuchiura City, Ibaraki Prefecture (72) Inventor Masakazu Press conference 1-5-11- Sumiyoshi Yamate, Higashinada Ward, Kobe City, Hyogo Prefecture

Claims (8)

[Claims] 1. A dihydropyridine compound represented by the following formula or an acid addition salt thereof. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (W in the formula is a cyano or haloalkyl group in which the alkyl group has 1 to 6 carbon atoms) represents a group having an elementary atom, R1 represents an alkyl group having 1 to 6 carbon atoms; , R2 and R3 are each independently an alkyl group having 1 to 6 carbon atoms; represents, and X and Y each independently have a hydrogen atom and 1 to 6 carbon atoms. Represents an alkyl group, halogen atom or nitro group, Ar is optionally substituted represents an aryl group having 1 to 10 carbon atoms, and A represents an alkylene group having 1 to 10 carbon atoms. represent ) 2. When X and/or Y are halogen atoms, the halogen atoms are fluorine The dihydropyridine according to claim 1, which is a chlorine or bromine atom. compounds or their acid addition salts. 3. Claim 1A, wherein the acid addition salt is a hydrochloride or a sulfate. or the dihydropyridine compound described in 2. or an acid addition salt thereof. 4. The above acid addition salts include oxalate, lactate, succinate, tartrate, maleate, and malate, acetate, salicylate, citrate, benzoate, β-naphthoic acid, Adibate, methanesulfonate, benzenesulfonate, or p-tolu The dihydropipropylene according to claim 1 or 2, which is an ensulfonate. Lysine compounds or their acid addition salts. 5. The following formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (W, R1, R2, R3, A, X, and Y in the formula have the meanings defined in claim 1. ) and the following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Ar in the formula has the meaning defined in claim 1. and L represents a suitable leaving group (reactive functional group). 2. The dihydrocarbon according to claim 1, wherein the dihydrocarbon is reacted with an alcohol derivative. A method for producing a pyridine compound or an acid addition salt thereof. 6. The following formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (W, R1, R2, R3, A, X, and Y in the formula have the meanings defined in claim 1. and Z represents a suitable leaving group (reactive functional group)) The following formula: ▲Mathematical formula, chemical formula, table, etc.▼ (Ar in the formula has the meaning defined in claim 1) The dihydropyridine compound or its acid according to claim 1, characterized in that Method for producing addition salts. 7. The leaving group (reactive functional group) is methanesulfonyloxy, benzenesulfonyl oxy, p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy , p-nitrobenzenesulfonyloxy, chloro, bromo, or iodo group 7. A method according to claim 5 or 6, characterized in that: 8. When W is a haloalkyl group, the haloalkyl group is a trifluoromethyl group. The dihydropyridine compound according to any one of claims 1 to 7, characterized in that , or its acid addition salts.