JPH0321552B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to certain dihydropyridines, particularly certain 1,4-dihydropyridines having a hydroxy- or oxo-substituted heterocyclic residue in the side chain attached to the 2-position, which are useful as antiischemic and antihypertensive agents. Regarding. The invention also relates to pharmaceutical formulations containing these compounds. The compounds of the present invention can reduce the movement of calcium into cells and thus delay or prevent cardiac spasms that are thought to be caused by intracellular calcium accumulation in ischemic conditions. Excessive calcium influx in ischemic conditions can have a variety of additional untoward effects, which may further exacerbate the ischemic myocardial condition. These include decreased efficiency in oxygen utilization for ATP production, activation of fatty acid oxidation by mitochondria, and potential promotion of cell necrosis.
The compounds are therefore useful in the treatment or prevention of various cardiac conditions, such as angina pectoris, cardiac arrhythmias, heart attacks, and cardiac hypertrophy. The compounds also have vasodilatory activity since they can block calcium influx into the cells of vascular tissue and are therefore useful as antihypertensive agents and also for the treatment of coronary artery spasm. European Patent Application No. 60674 describes and claims several dihydropyridine antiischemic and antihypertensive drugs in which the 2-position of the dihydropyridine ring is substituted with a specific N,N-disubstituted-aminoalkoxymethyl group. ing. Our earlier pending European Patent Application No. 100189 contains two
A series of compounds substituted with aromatic heterocyclylalkoxymethyl groups have been described and claimed. We have now found another dihydropyridine compound with valuable therapeutic properties in which the substituent in the 2-position carries a hydroxy- or oxo-substituted heterocyclic group. According to the invention, the following formula: Provided are novel 1,4-dihydropyridine derivatives and pharmaceutically acceptable salts thereof; in the above formula R represents an aryl or heteroaryl group, and R ¹ and R ² are each independently a carbon atom Numbers 1-4
represents an alkyl group or a 2-methoxyethyl group; represents a membered nitrogen-containing heterocyclic ring, and the heterocyclic ring or another fused heterocyclic ring optionally further comprises one or more C1-C4 alkyl groups, phenyl groups, CN,
N(R ³ ) ₂ , (CH ₂ ) _n CO ₂ R ³ or (CH ₂ ) _n CON
(R ³ ) ₂ , in which case each R ³ independently represents H or an alkyl group having 1 to 4 carbon atoms, or two R ³ are substituted with the nitrogen atom to which they are bonded. Together, they represent pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(alkyl having 1 to 4 carbon atoms)-piperazinyl group, m represents 0 or 1, and Y represents -( _CH2 ) _o- , -CH ₂ CH (CH ₃ ) - or -
_CH2C ( _CH3 ) _2- , n represents 1 to 3 when X is bonded to Y via a ring carbon atom, and 2 or 2 when X is bonded to Y via a ring nitrogen atom. Represents 3. Pharmaceutically acceptable acid addition salts of compounds of formula are those formed from acids that form non-toxic acid addition salts, such as hydrochlorides, bromates, sulfates or bisulfates, phosphates, etc. salts or acidic phosphates, acetates, citrates, fumarates, gluconates, lactates, maleates, succinates and tartrates. For compounds with acidic substituents, salts can also be formed with bases, such as sodium, potassium and ammonium salts. The "aryl group" used in the definition of R in this specification includes unsubstituted phenyl group, nitro, halogen atom, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, hydroxy, trifluoromethyl and Includes phenyl groups substituted with one or two substituents each independently selected from cyano groups. "Aryl group" also means 1-
and 2-naphthyl groups. The "heteroaryl group" used in the definition of R herein means an optionally substituted aromatic heterocyclic ring, such as benzofuranyl group; benzothienyl group; optionally methyl, methylthio, cyano or pyridine group substituted with a halogen atom; quinoline group; benzoxazolyl group; benzothiazolyl group; furyl group; pyrimidinyl group; thiazolyl group; 2,1,3-benzoxadiazol-4-yl group; 2,1 ,3-
and a thienyl group optionally monosubstituted with a halogen atom or an alkyl group having 1 to 4 carbon atoms. 5- or 6-membered nitrogen atom-containing heterocyclic ring X
may contain 1 to 3 nitrogen atoms in the ring,
May be saturated or unsaturated. As will be understood by those skilled in the art, a hydroxy- or oxo-substituted heterocyclic ring can be keto-enol tautomeric, with the group existing as a free hydroxy group in the tautomeric enol form. , or as an oxo group in the keto form. Which particular isomer is present under normal circumstances can be easily determined by suitable physical means such as, for example, infrared spectroscopy. A compound may also exist as a mixture of two forms. However, the present invention includes both possible forms of the compound, and in the description and examples herein, references to the hydroxy or keto form of the compound include all possible tautomeric forms. and is not intended to indicate which is the predominant tautomeric form of the compound. The ring must be present (i.e., n represents 2 or 3). Examples of suitable heterocyclic rings include 2-,4- and 5-imidazolones, 3-pyrazolones, pyrroline-2,5-dione, imidazolidine-2,4-
dione, 2-pyridone, 3-piperazinone, 4-
Pyrimidone, pyrimidine-2,4-dione, 5-
Hydroxy-(1H)-1,2,3-triazole and 1-oxo-1,3-dihydropyrrolo[2,3b]pyridine. Heterocyclic ring X may further contain substituents. Preferred substituents are amino, lower alkyl, especially methyl, carbamoyl and CN groups. Therefore, certain preferred examples of X are 1
-(2-amino-4-imidazolone), 1-(imidazolidine-2,4-dione), 1-(4-amino-2-imidazolone), 2-(1-oxo-1,3
-dihydropyrrolo[2,3b]pyridine), 6-
(2-amino-4-pyrimidone) and 6-(2,
3-dimethyl-4-pyrimidone). "Halogen atom" means fluorine, chlorine, bromine and iodine. Alkyl and alkoxy groups having 3 or more carbon atoms may be straight chain or branched. Compounds with asymmetric centers may exist as one or more pairs of enantiomers, and the present invention includes separated d and l optically active isomers as well as mixtures thereof. Preferred groups for R are 2-chlorophenyl and 2,3-dichlorophenyl groups. R ¹ and
^R2 is preferably _CH3 or _C2H5 , especially ^R1 _{is CH3}
and R ² is preferably C ₂ H ₅ . Y is
When X is bonded to Y via a ring nitrogen atom, it is preferable to represent -(CH ₂ ) ₂ -, and when X is bonded to Y via a ring carbon atom, -
_CH2- is preferred. Particularly preferred compounds of the invention are therefore: 2-amino-1-{2-<[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxy carbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy>ethyl}-4
-imidazolone; 1-{2-〈[4-(2,3-dichlorophenyl)
-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine-
2-yl]methoxy>ethyl}-imidazolidine-2,4-dione; 4-amino-1-{2-[[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl -6-methyl-1,4-dihydropyridin-2-yl]methoxy>ethyl}-2
-imidazolone; 2-{2-〈[4-(2,3-dichlorophenyl)
-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine-
2-yl]methoxy>ethyl}-1-oxo-1,
3-dihydropyrrolo[2,3-b]pyridine; 6-{(4-(2,3-dichlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-
6-Methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-2,3-dimethyl-4-
pyrimidone; and 2-amino-6-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl} -4-pyrimidone. The latter compounds are preferred as they have particularly advantageous properties. The compounds of the present invention are prepared by several different methods according to the present invention. (a) One method is to prepare the compound of the formula by Hantzsch synthesis according to the following reaction mechanism: (wherein R, ^R1 , ^R2 , Heat at reflux in an alkanol such as ethanol for about 15 minutes, then add aminocrotonate (). Instead of this,
Aminoclonate (), Ketoester ()
and the aldehyde may be heated together in a solvent. Preferably, the solution is neutralized by adding a small amount of a lower alkanoic acid, such as acetic acid. The resulting solution is heated at 60-130°C, preferably under reflux, until the reaction is substantially complete, generally for 24 hours or less. The product of formula is then isolated and purified in conventional manner, for example by partitioning, recrystallization or chromatography. Ketoesters () are known compounds or can be prepared using prior art methods such as Troostwijk and
Kellogg.JCSChem.Comm.1977, p932 or in the same manner as European Patent Application No.
Manufactured using the method described in No. 60674. Similarly, amino-clonates () and aldehydes are known compounds or can be prepared by known methods according to the prior art. (b) As an alternative method of haunchi synthesis, the compound represented by the formula is prepared by the following reaction; Crotonate () is generally prepared in situ by reacting the corresponding ketoester () with ammonium acetate in a suitable organic solvent such as a C1-C4 alkanol such as ethanol by refluxing for up to 1 hour. Ru. The crotonate () is then reacted with the compound (), generally by heating in a solvent at a temperature of 60-130°C for up to about 5 hours. The product () is then isolated and purified by conventional methods as described above. The starting material () is also a known compound, or
Alternatively, it can be produced by a known method according to prior literature (see Can. J. Chem., 1967, 45, 1001). Although all compounds of the present invention are prepared by the methods described in (a) or (b) above, in many cases certain compounds may be more conveniently prepared starting from preformed dihydropyridine. Such methods are within the knowledge and skill of those skilled in the art and will vary depending on the nature of the heterocyclic ring X desired. Although the following methods are illustrative of some methods of making compounds of formulas containing specific heterocyclic rings, alternative variations will be readily apparent to those skilled in the art. (c) In another method, a compound of the formula in which X is 4-pyrimidone or 3-pyrazolone is a compound of the formula: (wherein R, R ¹ , R ² and Y are as defined above, and R ⁴ represents a lower alkyl group having 1 to 4 carbon atoms.) : (In the formula, R ⁵ represents N(R ³ ) ₂ , an alkyl group having 1 to 4 carbon atoms, or a phenyl group, and R ³ is as defined above.) It is produced by obtaining a compound in which X represents a 2-substituted-4-pyrimidone group; or by reacting with hydrazine to obtain a compound in which X in the formula represents a 3-pyrazolone group. Reaction of a compound of the formula with guanidine (R ⁵ in formula a represents NH ₂ ) gives the corresponding compound of the formula in which X represents 2-amino-4-pyrimidon-6-yl. .
Similarly, reaction with acetamidine (R ⁵ in formula a represents CH ₃ ) gives compounds of the corresponding formula in which X is 2-methyl-4-pyrimidon-6-yl. In each case, the reaction is carried out using reactants dissolved in an organic solvent such as ethanol in the presence of an organic base. After several days at room temperature, the reaction is nearly complete and the product is then isolated in conventional manner using conventional extraction, washing and evaporation techniques and, if necessary, purified by recrystallization or chromatography. Further, a compound of the formula in which X represents a 5-(3-pyrazolone) group can also be obtained by carrying out a reaction using hydrazine hydrate by a conventional method. Another variation of this method can also be used to prepare certain compounds of the formula where X is a bicyclic system containing a pyrimidone ring. For example, when a compound of the formula is reacted with 2-aminoimidazolium sulfate, a compound of the formula is obtained, where X represents a 7-(5-hydroxyimidazo[1,2-a]pyrimidine) group. Similarly, by reaction with 2-iminopiperidine,
A compound is obtained in which X represents a 4-oxo-tetrahydropyrido[1,2-a]pyrimidine group. Of course, the final products can also be subjected to simple conversion reactions to introduce substituents or to modify them according to conventional and well-known procedures. For example, by carrying out methylation using iodomethane in the presence of a base, a compound of the formula in which X is 2-amino-4-pyrimide can be converted to a compound in which X is 2-amino-3-methyl-4-
Corresponding compounds that are pyrimidone can be prepared. Similarly, treating a compound of the formula where X is 2-methyl-4-pyrimidone with iodomethane gives the corresponding compound where X is 2,3-dimethyl-4-pyrimide. It will be done. The ketoester starting material has the formula:
Prepared from the corresponding (1,4-dihydropyridin-2-yl)methoxyalkanoic acid by conventional procedures. Thus, one route we have used is to react the imidazolide derivative of the acid with the sodium salt prepared from 2,2-dimethyl-1,3-dioxane-4,6-dione and sodium hydride. . Ring opening of the product is achieved by heating in a lower alkanol to yield the desired ketoester. Amidine and guanidine represented by formula a are known compounds. (d) In another method, a compound in which X represents a 1-(2-amino-4-imidazolone) group is a compound of the following formula: (wherein R, R ¹ , R ² , R ⁴ and Y are as defined above) and ammonia. The reaction is readily carried out by adding the compound of formula to a saturated solution of methanolic ammonia. After several hours at room temperature, the solvent is evaporated to yield the desired product. The starting material of the formula is the corresponding 2-
[(N-alkoxycarbonylmethyl)amino]
It is obtained by reacting alkoxymethyl-1,4-dihydropyridine with cyanogen bromide in chloroform at room temperature for several hours. (e) In another method, X in the formula is a 1-(imidazolidine-2,4-dione) group or
-amino-2-imidazolone) group and 3-
Or, the compound representing a group optionally substituted with a lower alkyl group at the 5-position is represented by the following formula: (In the formula, R, R ¹ , R ² and Y represent those defined above, R ⁶ each independently represents H or an alkyl group having 1 to 4 carbon atoms, and Q
represents a CO ₂ (alkyl having 1 to 4 carbon atoms) group or CN. ) and a base. Base-catalyzed ring-closure reactions occur readily;
For example, adding sodium hydride to a suspension of a compound of formula in a lower alkanol at room temperature
This is conveniently done by stirring for 2 hours. The solvent is removed and the product is purified according to conventional methods. Each R ⁶ in the formula represents a hydrogen atom,
When a compound of the formula in which Q represents CO ₂ C ₂ H ₅ is reacted with a base, a compound of the formula in which X represents imidazolidine-2,4-dione-1-yl is obtained. Similarly, each R ⁶ in Eq.
By the reaction of a compound in which represents a hydrogen atom and Q represents CN, a compound of the formula in which X represents 4-amino-2-imidazolon-1-yl is obtained. Urea starting materials of the formula in which Q represents a CO ₂ (alkyl containing 1 to 4 carbon atoms) group are described in pending European patent application no.
As described in No. 843014523, the corresponding 2-
[(N-alkoxycarbonylmethyl)amino]
It is obtained by reacting alkoxymethyl)-dihydropyridine with an isocyanate. Compounds of the formula in which Q represents CN can be obtained by reacting the corresponding 2-[(N-cyanomethyl)amino]alkoxymethyl-1,4-dihydropyridine with an isocyanate. (f) In the formula, X is 1-(5-amino-2-imidazolone) or 1-(imidazolidine-2,5-
Compounds of formula (d) representing a dione) group are
Similar to the method described in and (e), but with: (In the formula, R, R ¹ , R ² , Q and Y are as defined above.) It is produced using a compound represented by the formula as a starting material. When Q represents a CO ₂ (alkyl having 1 to 4 carbon atoms) group, cyclization of the compound of the formula in methanolic ammonia with stirring at room temperature for several hours, generally overnight, results in the formation of a compound of the formula A product is obtained in which X is imidazolidin-2,5-dion-1-yl. Alternatively, when Q is CN, cyclization can be carried out using sodium methoxide in methanol at room temperature for about 1 hour,
is a 1-(5-amino-2-imidazolone) group. The starting compound of the formula is the corresponding 2
-(aminoalkoxymethyl)-1,4-dihydropyridine is reacted with carbonyldiimidazole followed by aminoacetonitrile to obtain a compound of formula where Q is CN, or alkoxycarbonylmethylisocyanate Q in the formula is CO ₂
It is produced by obtaining a compound represented by (alkyl having 1 to 4 carbon atoms) group. (g) A compound represented by the formula in which X is a 2-methyl-5-imidazolone group can be prepared by converting the corresponding 2-(aminoalkoxymethyl)-1,4-dihydropyridine according to the following reaction formula. Obtained by reaction with ethyl N-(ethoxycarbonylmethyl)acetimidate: The reaction occurs at room temperature and is conveniently carried out by stirring a solution of the reactants in a lower alkanol solvent such as ethanol for several hours. (h) A compound represented by the formula in which X is 4-ethoxycarbonyl-5-hydroxy-(1H)-1,2,3-triazole group has the following formula: (wherein R, R ¹ , R ² and Y are as defined above)
-Azidoalkoxymethyl-1,4-dihydropyridine by reacting with diethylmalonate in the presence of a base. The reaction is
This is conveniently carried out by heating the reaction in a lower alkanolic solvent with the addition of sodium hydride. The reaction is generally completed under reflux.
24 hours is enough. The product is isolated and purified according to conventional methods. Azide starting material of formula XI and formula X
Amines of the formula are described in European Patent Application Publication No. 89167. (i) A compound of the formula in which X represents a 2-(1-oxo-1,3-dihydropyrrolo[2,3-b]pyridine) group is the corresponding 2-(aminoalkoxymethyl)-1, It is obtained by reacting 4-dihydropyridine () with 2-bromomethyl-3-ethoxycarbonylpyridine in an inert organic solvent such as acetonitrile in the presence of an acid scavenger such as potassium carbonate. It takes 1 to 2 days under reflux to complete the reaction.
The product is then isolated and purified using conventional methods. (j) Compounds of the formula in which X is a 1-(5-cyano-3-methylpyrimidine-2,4-dione) cold group are the corresponding 2-(aminoalkoxymethyl)-1,4-dihydropyridine () in the presence of trace amounts of base in a lower alkanol solvent, 2-cyano-N-ethoxycarbonyl-2
-Ethoxymethylene-N-methylacetamide. Generally, refluxing in methanol for 2 to 3 hours is sufficient. (k) where X is 1-(dihydro-pyrrole-2,
Compounds of the formula representing the group 2-(aminoalkoxymethyl)-1,4-
It is obtained by reacting dihydropyridine () with maleic anhydride in an inert organic solvent such as acetonitrile under reflux for 1 to 2 hours. The ability of compounds to inhibit calcium movement into cells is demonstrated by the ability of these compounds to reduce the response of isolated heart tissue to elevated calcium ion concentrations in vitro. This test is performed by fixating a spirally cut piece of rat aorta on one side and on the other connected to a force transducer. The tissue is immersed in a bath of saline containing potassium ions at a concentration of 45 mM and no calcium. Add calcium chloride to the bath with a pipette to obtain a final calcium ion concentration of 2mM. The change in tension caused by the resulting tissue contraction is recorded. The bath is emptied and replaced with fresh saline and the test repeated 45 minutes later with each test compound present in the saline. Record the concentration of compound required to reduce the reaction by 50%. The antihypertensive activity of the compounds is also evaluated by measuring the blood pressure reduction after oral administration in spontaneously hypertensive rats or renally hypertensive dogs. For administration to humans in treating or preventing heart conditions and high blood pressure, the oral dosage of the compound is 2 to 2 per day per average adult patient (70 Kg).
It would be in the 100mg range. Thus, for a typical adult patient, an individual tablet or capsule will generally contain from 1 to 10 mg of active compound in a pharmaceutically acceptable excipient or carrier. Doses for intravenous administration will generally range from 1 to 10 mg per dose as required. For actual use, the physician will determine the actual amount that will be optimal for the individual patient. This will vary depending on the age, weight and response of the patient. The above dosages are exemplary of average cases; there are, of course, individual instances where higher or lower dosage ranges may be beneficial and are within the scope of the invention. For human use, compounds of formula () may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier chosen with regard to the intended route of administration and standard formulation practices. Dew. For example, they may be in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules, alone or mixed with excipients, or containing flavorings or colorants. It can be administered orally in the form of an elixir or suspension. These can be administered parenterally, e.g. intravenously,
Administration can also be intramuscular or subcutaneous. For parenteral administration they are best used in the form of sterile aqueous solutions, which may contain other substances, such as sufficient salts or glucose to make the solution isotonic. Accordingly, in another aspect, the invention provides a pharmaceutical composition comprising a compound of formula () or a pharmaceutically acceptable addition salt thereof, and a pharmaceutically acceptable diluent or carrier. The present invention also encompasses compounds of formula (), or pharmaceutically acceptable addition salts thereof, for use in humans for the treatment of cardiovascular conditions, including the prevention or treatment of heart conditions, or as antihypertensive agents. The following examples illustrate the invention. Example 1 2-amino-6-{[4-(2-chlorophenyl)
-3-Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-4-pyrimidone Guanidine hydrochloride (0.20
g), ethyl 4-{[4-(2-chlorophenyl)-
3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine-2
-yl]methoxy}acetoacetate (0.99g)
and 1,5-diazabicyclo[4.3.0]non-
A solution of 5-ene (0.30 g) is stirred at room temperature for 5 days and then evaporated. The residue is dissolved in chloroform, washed with 2M hydrochloric acid, 10% aqueous sodium carbonate and water, dried over MgSO ₄ and evaporated. Recrystallization of the solid residue from ethyl acetate gives the title compound (0.23 g): mp185-187
℃. Actual values: C, 56.08; H, 5.14; N, 11.33.
Theoretical value of C ₂₃ H ₂₅ ClN ₄ O ₆ : C, 56.50; H, 5.15;
N, 11.46%. Example 2 2-amino-6-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl} -4
-pyrimidone Ethyl 4-{[4-(2,
3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,
A solution containing 4-dihydropyridin-2-yl]methoxy}acetoacetate (0.74 g), 1,5-diazabicyclo[4.3.0]non-5-ene (0.25 g) and guanidine hydrochloride (0.14 g) was stirred for 5.5 hours. Heat to reflux then evaporate. The residue is dissolved in chloroform and the solution is washed successively with water, 10% aqueous sodium carbonate and water, dried over anhydrous magnesium sulfate and evaporated. Triturate the residue in ethyl acetate, collect the resulting precipitate, and wash thoroughly with diethyl ether. It was then recrystallized from ethyl acetate/ethanol and dried to give the title compound (0.20
g) is obtained: mp222-225°C. Actual value; C,
52.10; H, 4.56; N, 10.54. Theoretical values _{for C23H24Cl2N4O6} : C, 52.78 _{; H} , 4.62; _N , 10.70%. Examples 3-12 The following compounds are suitable 4-
(1,4-dihydropyridin-2-ylmethoxy)
It is obtained by the method (c) described in Example 1 or 2, in which acetoacetate is reacted with a suitable amidine or guanidine of formula a.

【table】

[Table] Example 12 2-amino-6-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl] methoxymethyl}-3
-Methyl-4-pyrimidone 2-Amino-6-{[4-(2,3-dichlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-
6-Methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-4-pyrimidone (0.52
g), iodomethane (0.14 g) and potassium carbonate (0.14 g) are stirred at room temperature for 4 days and then evaporated. The residue was partitioned between chloroform and water, the organic phase was washed twice with water,
Dry over anhydrous magnesium sulfate and evaporate. Crystallization of the residue from ethyl acetate gives the title compound (0.23 g): mp 202-205°C. Actual values: C, 53.42; H, 4.87; N, 10.49.
Theoretical value of C ₂₄ H ₂₆ Cl ₂ N ₄ O ₆ : C, 53.64; H, 4.88;
N, 10.43%. Example 13 By the method described in Example 12, 6-{[4-(2,3-dichlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-
When using 6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-2-methyl-4-pyrimidone, 6-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl- 5-Methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-2,3
-dimethyl-4-pyrimidone is obtained. Product melting point: 153-158℃. Actual value: C, 55.66; H,
5.09; N, 7.97. Theoretical value of C ₂₅ H ₂₇ Cl ₂ N ₃ O ₆ : C,
55.98; H, 5.07; N, 7.83%. Example 14 7-{[4-(2,3-dichlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine-2
-yl]methoxymethyl}-5-hydroxyimidazo[1,2-a]pyrimidine 2-aminoimidazolium sulfate (0.52 g), ethyl 4-{[4-
(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-
1,4-dihydropyridin-2-yl]methoxy}acetoacetate (1.50 g) and 1,5-
Diazabicyclo[4.3.0]non-5-ene (1.06
The mixture of g) is heated under reflux for 3.5 hours and then evaporated. The residue is partitioned between chloroform and water, the organic phase is washed three times with water, dried over anhydrous magnesium sulphate and evaporated. The residue was chromatographed on silica gel (3 g),
Purify by eluting with chloroform and 0-1% methanol by volume. Collecting the appropriate fractions, evaporating them and crystallizing the residue from ethyl acetate gives the title compound (0.28 g): mp187-188
℃. Measured values: C, 5.4.48; H, 4.64; N, 10.42.
Theoretical value of C ₂₅ H ₂₄ Cl ₂ N ₄ O ₆ : C, 54.85; H, 4.42;
N, 10.24%. Example 15 The following compound is obtained by the method described in Example 14 using 2-iminopiperidine as starting material.

[Table] Example 16 5-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-
Methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-3-pyrazolone in ethanol (20 ml).
Chlorophenyl)-3-ethoxycarbonyl-5
A solution in which -methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetoacetate (0.50 g) and pidrazine hydrate (0.50 g) were dissolved was kept at room temperature for 4 days,
Then evaporate. Pour the residue into silica gel (1.0g)
Purify by chromatography using dichloromethane and 0-5% methanol by volume. Collecting the appropriate fractions, evaporating them and crystallizing the residue from ethyl acetate gives the title compound (0.18 g); mp 207°C. Actual values: C, 57.11; H, 5.15; N, 9.19.
Theoretical value of C ₂₂ H ₂₄ ClN ₃ O ₆ : C, 57.20; H, 5.24;
N, 9.10%. Example 17 2-amino-1-<2-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5
-methoxycarbonyl-6-methyl-1,4-
dihydropyridin-2-yl]methoxy}ethyl>-4-imidazolone 2- in saturated methanolic ammonia (10 ml)
{2-[(N-cyano-N-ethoxycarbonylmethyl)amino]ethoxymethyl}-4-(2,3-
dichlorophenyl)-3-ethoxycarbonyl-
5-methoxycarbonyl-6-methyl-1,4-
A solution of dihydropyridine (0.70 g) is stirred at room temperature for 16 hours and then evaporated. Recrystallization of the solid residue from ethanol gives the title compound (0.46 g) in hemihydrate form. mp134-138℃.
Actual value: C, 51.83; N, 5.27; N, 10.02.
Theoretical value of C ₂₃ H ₂₆ Cl ₂ N ₄ O ₆ −0.5H ₂ O: C, 51.68;
H, 5.06; N, 10.48%. Example 18 Following the method of Example 17, starting material was 4-(2-chlorophenyl)-2-{2-(N-cyano-N-ethoxycarbonylmethyl)amino]ethoxymethyl}-3-ethoxycarbonyl. -5-
Using methoxycarbonyl-6-methyl-1,4-dihydropyridine, 2-amino-1-<2-
{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-
1,4-dihydropyridin-2-yl]methoxy}-ethyl>-4-imidazolone is obtained. The product exhibits characteristics of the hemihydrate form: mp110-113
℃. Actual values: C, 55.45; H, 5.56; N, 11.20.
Theoretical value of C ₂₃ H ₂₇ ClN ₄ O ₆ −0.5H ₂ O; C, 55.20;
H, 5.60; N, 11.20%. Example 19 1-〈2-{[4-(2-chlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine-2
-yl]methoxy}ethyl>imidazolidine-
2,5-dione methanol (1 ml) and 880 ammonia water (2 ml)
ml) in 1-〈2-{[4-(2-chlorophenyl)
-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine-
A solution of 2-yl]methoxy}ethyl-3-(ethoxycarbonylmethyl)urea (1.08 g) is stirred at room temperature for 16 hours and then evaporated. The residue is purified by chromatography on silica (2.5 g) eluting with chloroform and 0-4% V/V methanol. Collection of appropriate fractions, evaporation and recrystallization of the solid residue from a mixture of ethyl acetate and acetone yielded the title compound (0.20 g).
Obtained: mp140℃. Actual value: C, 56.17;
H, 5.64; N, 8.45. Theoretical _{value of C23H26ClN3O7 :}
C, 56.15; H, 5,38; N, 8.54%. Example 20 1-〈2-{[4-(2-chlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine-2
-yl]methoxy}ethyl>imidazolidine-
2,4-dione 1-〈2-{[4-(2-
Chlorophenyl)-3-ethoxycarbonyl-5
-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}ethyl>
Sodium hydride (60 mg; 80% dispersion in oil) is added to a suspension of -1-(methoxycarbonylmethyl)urea (0.52 g), and the mixture is stirred at room temperature for 1 hour. evaporate the reaction mixture;
The residue is partitioned between ethyl acetate and water. The organic phase is dried with _MgSO4 , evaporated and the residue is triturated in diethyl ether. The resulting solid is collected, washed with diethyl ether and dried to give the title compound (0.41 g): mp 105-107°C (decomposition).
Actual values: C, 56.20; H, 5.50; N, 8.36.
Theoretical value of C ₂₃ H ₂₆ ClN ₃ O ₇ : C, 56.16; H, 5.33;
N, 8.54%. Examples 21-27 The following compounds are obtained by the method of Example 20 using appropriate starting materials of the formula and have the morphological characteristics shown in the table.

【table】

[Table] Example 28 1-〈2-{[4-(2-chlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine-2
-yl]methoxy}ethyl>-2-methyl-5
-Imidazolone 2-(2-aminoethoxy)methyl-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (1.02 g) and ethyl N-(ethoxycarbonylmethyl) in ethanol (20 ml) The acetimidate (0.43 g) solution is stirred at room temperature for 16 hours and then evaporated. The residue was chromatographed on silica (10 g) and dichloromethane and 0-5%
Purify by eluting with V/V methanol. The appropriate fractions are collected and evaporated to give the title compound (0.07g): mp 167-169°C. Actual values: C, 58.30; H, 5.79; N, 8.55.
Theoretical value of C ₂₄ H ₂₈ ClN ₃ O ₆ : C, 58.83; H, 5.72;
N, 8.58%. Example 29 1-〈2-{[4-(2-chlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine-2
-yl]methoxy}ethyl>-2-pyridone A solution of 1-(2-hydroxyethyl)-2-pyridone (6.15 g) in tetrahydrofuran (30 ml) was dissolved in sodium hydride (3.0 g; (80% dispersion in oil) is added to the suspension over 45 minutes. The mixture was stirred at room temperature for 1 hour, a solution of ethyl 4-chloroacetoacetate (8.23 g) in tetrahydrofuran (20 ml) was added dropwise over 3 hours, and then stirred at room temperature for 16 hours. The reaction mixture is treated with ethanol (10 ml), poured into concentrated hydrochloric acid (10 ml) and extracted with ethyl acetate. The ethyl acetate extract was dried with _MgSO4 and evaporated to give a brown oil of ethyl 4-[2-(2-
Pyridon-1-yl)ethoxy]acetoacetate is obtained, which is 75% pure according to NMR. A solution of this crude product (5.4 g) and ammonium acetate (1.50 g) in ethanol (20 ml) was heated to 50°C for 30 minutes, and methyl 2-(2-chlorobenzylidene) acetoacetate (3.57 g) was dissolved in ethanol (20 ml). )
and heat the mixture under reflux for 3 hours. The reaction mixture was evaporated, the residue was dissolved in toluene,
Wash with 2M hydrochloric acid, dry with _MgSO4 and evaporate.
The residue was chromatographed on silica (50 g) and chromatographed with petroleum ether (bp 40-60°C) for 70-
Purify by eluting with 100% V/V dichloromethane.
The appropriate fractions are collected and evaporated to give the title compound (0.15g): mp 114-115°C.
Actual values: C, 61.66; H, 5.55; N, 5.75.
Theoretical value of C ₂₅ H ₂₇ ClN ₂ O ₆ : C, 61.37; H, 5.65;
N, 5.70%. Examples 30 and 31 The following compounds are obtained by the method of Example 29 using appropriate starting materials of the formula and which exhibit the morphological characteristics shown in the table.

【table】

[Table] Example 32 1-〈2-{[4-(2-chlorophenyl)-3-
Ethoxycarbonyl-5-memethoxycarbonyl-6-methyl-1,4-dihydropyridine-
2-yl]methoxy}ethyl>-4-ethoxycarbonyl-5-hydroxy-(1H)-1,2,
3-triazole 2-(2-azidoethoxy)methyl-4-(2-chlorophenyl)-3- in ethanol (80 ml)
Ethoxycarbonyl-5-methoxycarbonyl-
6-Methyl-1,4-dihydropyridine (2.17
g), diethyl malonate (4.00 g) and sodium hydride (0.75 g; 80% dispersion in oil) is heated under reflux for 16 hours and then evaporated.
The residue was partitioned between 0.1M hydrochloric acid and ethyl acetate,
The organic phase is washed with water, dried over Na ₂ SO ₄ and evaporated. The residue is triturated in ether and the resulting solid is collected and purified by chromatography on silica (30 g) eluting with dichloromethane and 0-5% V/V methanol. The appropriate fractions are collected and evaporated to give the title compound (0.89g): mp 121-124°C. Actual value: C, 55.01;
H, 5.49; N, 10.07. _{Theoretical value of C25H29ClN4O8} :
C, 54.69; H, 5.32; N, 10.21%. Example 33 2-〈2-{[4-(2,3-dichlorophenyl)
-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}ethyl>-1-oxo-1,3-dihydropyrrolo[2,3-b]pyridine acetonitrile ( 2-(2-aminoethoxy)methyl-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.50 g) in 30 ml); A mixture of 2-bromomethyl-3-ethoxycarbonylpyridine (0.31 g) and potassium carbonate (0.56 g) is heated under reflux for 41 hours, filtered and evaporated. The residue is silica (10
Purify by chromatography using g), eluting with dichloromethane and 0-5% V/V methanol. Collect and evaporate appropriate fractions,
Triturate the residue in ether. The resulting solid is collected, washed with ether and dried to give the title compound (0.22g): mp 147-149°C. Actual values: C, 57.96; H, 5.07; N, 7.47.
Theoretical value of C ₂₇ H ₂₇ Cl ₂ N ₃ O ₆ : C, 57.86; H, 4.86;
N, 7.50%. Example 34 5-cyano-1-<2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}ethyl> -3
-Methylpyrimidine-2,4-dione Methanol containing 1 drop of triethylamine (2
ml), 2-(2-aminoethoxy)methyl-
4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-
1,4-dihydropyridine (0.82g) and 2-
A solution in which cyano-N-ethoxycarbonyl-2-ethoxymethylene-N-methylacetamide (0.5 g) was dissolved was heated under reflux for 2 hours, and toluene (5 g) was dissolved in toluene (5 g).
ml) and evaporate. The residue is silica (5
Purify by chromatography using g) and eluting with toluene and 0-100% V/V chloroform. Collect appropriate fractions and evaporate them,
The residue is crystallized from a mixture of ethyl acetate and diethyl ether. The resulting solid is collected and recrystallized from a mixture of acetone and diisopropyl ether to yield the title compound (0.25 g): mp155~
156℃. Actual value: C, 57.46: H, 5.09; N,
10.13. Theoretical value of C ₂₆ H ₂₇ ClN ₄ O ₇ : C, 57.50; H,
5.03; N, 10.32%. Example 35 1-〈2-{[4-(2-chlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine-2
-yl]methoxy}ethyl>maleimide 2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)- in acetonitrile (2 ml)
A solution containing 3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.82 g) and maleic anhydride (0.25 g) was heated under reflux for 50 minutes, and acetic anhydride (1 ml) was added.
Process with. This is heated at reflux for a further 1 hour, diluted with methanol (2 ml), heated at reflux for a further 20 minutes and evaporated. The residue is partitioned between ethyl acetate and 10% aqueous sodium carbonate solution, the organic phase is dried over Na ₂ CO ₃ and evaporated. The residue was chromatographed on silica (3 g) and chromatographed with toluene and 0-100%
Purify by eluting with V/V chloroform. The appropriate fractions are collected and evaporated and the residue is triturated in diethyl ether. The resulting solid is collected and recrystallized from a mixture of acetone and diisopropyl ether to give the title compound (0.18 g): m.
p.140-141℃. Actual value: C, 58.77; H, 5.16;
N, 5.85. Theoretical value of C ₂₄ H ₂₅ ClN ₂ O ₇ : C, 58.95;
H, 5.15; N, 5.73%. Example 36 The following ingredients are blended into tablets: mg/tablet of the product of any of the examples 10 dicalcium phosphate 120 magnesium stearate 1.8 sodium lauryl sulfate 0.2 Ingredients are thoroughly mixed, compressed, and granulated. and compressed again to form tablets of desired size. Example 37 The following ingredients are formulated into capsules: mg/capsule of the product of any of the examples 10 Corn starch 127 Cellulose (microcrystalline) 127 Magnesium stearate 5.4 Sodium lauryl sulfate 0.6 Mix each ingredient thoroughly. The ingredients are then filled into hard gelatin capsules of appropriate size. Production example 1 Ethyl 4-{[4-(2-chlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine-2
-yl]methoxy}acetoacetate 2-{[4-
(-chlorophenyl)-3-ethoxycarbonyl-
5-methoxycarbonyl-6-methyl-1,4-
A solution containing dihydropyridin-2-yl]methoxy}acetic acid (4.24 g) was treated with ice-cooling together with carbonyldiimidazole (1.70 g), and the mixture was stirred at 0° C. for 2.25 hours. A solution of the sodium salt of 2,2-dimethyl-1,3-dioxane-4,6-dione in dimethylformamide [2,2-dimethyl-1,3-dioxane-4,6-dione sodium salt dissolved in dimethylformamide (30 ml)]
-Produced by stirring a mixture of dimethyl-1,3-dioxane-4,6-dione (1.44 g) and sodium hydrogen (0.30 g; 80% dispersion in oil) while cooling on ice for 30 minutes. ] over a period of 10 minutes, the mixture is stirred at room temperature for 16 hours and then evaporated. The residue was dissolved in dichloromethane, washed twice with 1M hydrochloric acid and water, dried over _MgSO4 ,
Evaporate. The residual oil (6 g) is dissolved in ethanol (50 ml) and the solution is heated to reflux for 6 hours and evaporated. The residue was dissolved in diethyl ether, washed twice with 10% aqueous sodium carbonate and once with saturated aqueous sodium chloride, dried over _MgSO4 ,
Evaporate. The residue was chromatographed on silica (30 g) and 5-15% V/V with hexane.
Purify by eluting with ethyl acetate. The appropriate fractions are collected and evaporated and the residue is crystallized from ethanol to give the title compound (1.5 g):
mp88~89℃. Actual value: C, 58.18; H, 5.78;
N, 2.85. Theoretical value of C ₂₄ H ₂₈ ClNO ₅ : C, 58.36;
H, 5.71; N, 2.84%. Production example 2 Ethyl 4-{[4-(2,3-dichlorophenyl)
-3-Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetoacetate Carbonyldiimidazole (5.20 g) and 2-{[4-( 2,3
-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4
A solution of -dihydropyridin-2-yl]methoxy}acetic acid (14.00 g) was stirred at room temperature under a nitrogen atmosphere for 2 hours, and then pyridine (2.40 g) and 2,2-
Add over 8 minutes to a solution in which dimethyl-1,3-dioxane-4,6-dione (4.56 g) is dissolved. The mixture was stirred at room temperature for 2.5 h, then cooled with water and iced.
Wash sequentially with 2.5M hydrochloric acid, saturated brine,
Dry over anhydrous magnesium sulfate and evaporate. The residue is dissolved in ethanol (200ml) and the solution heated to reflux for 2.75 hours to evaporate. Triturate the residue in diethyl ether, collect the resulting solid,
Washing with diethyl ether and drying gives the title compound (9.0 g): mp 99-102°C. Production Examples 3 to 6 The following compounds are produced from appropriate 2-(dihydropyridin-2-ylmethoxy)acetic acid by the methods of Production Examples 1 and 2.

[Table] Production Example 7 2-{2-[(N-cyano-N-ethoxycarbonylmethyl)amino]ethoxymethyl}-4-
(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-
1,4-dihydropyridine 4-(2-chlorophenyl)-3 in chloroform (10 ml) containing sodium bicarbonate (0.3 g)
-ethoxycarbonyl-2-{2-[(N-ethoxycarbonylmethyl)amino]ethoxymethyl}
-5-methoxycarbonyl-6-methyl-1,4
-Cyanogen bromide (0.35 g) is added to a stirred solution in which dihydropyridine (1.25 g) is dissolved. The mixture is stirred at room temperature for 20 hours and then evaporated. The residue is triturated in diethyl ether and the resulting solid is collected, washed with diethyl ether and dried to give the hemihydrate title compound (0.81 g). mp132
~134℃. Actual value: C, 56.96; H, 5.66; N,
7.94. Theoretical value of C ₂₅ H ₃₀ ClN ₃ O ₇・0.5H ₂ O: C,
56.76; H, 5.86; N, 7.94%. Production Example 8 4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-2-{2-[(N-
ethoxycarbonylmethyl)amino]ethoxymethyl}-5-methoxycarbonyl-6-methyl-
By the method of Production Example 7 using 1,4-dihydropyridine, 2-{2-[(N-cyano-N-ethoxycarbonylmethyl)amino]ethoxymethyl}-
4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine is obtained. The product is obtained in hemihydrate form: mp 148-150 °C. Actual measurements: C, 53.08; H, 5.04; N, 7.46.
Theoretical value of C ₂₅ H ₂₉ Cl ₂ N ₃ O ₇・0.5H ₂ O: C, 53.28;
H, 5.33; N, 7.46%. Production example 9 1-〈2-{[4-(2-chlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-
6-Methyl-1,4-dihydropyridin-2-yl]methoxy}ethyl>-3-(cyanomethyl)urea 4-(2-chlorophenyl)-3-ethoxycarbonyl-2-{2-[N-(1-imidazolyl) carbonyl)amino]ethoxymethyl}-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.98 g), aminoacetonitrile hydrochloride (0.30 g) and N-methylmorpholine (0.44 g)
The solution is stirred for 20 hours at room temperature and then evaporated. The residue is purified by chromatography on silica (10 g5, eluting with dichloromethane and 0-5% v/v methanol. Appropriate fractions are collected and evaporated, and the solid residue is recrystallized from ethanol to give a hemihydrate The title compound in compound form (0.50
g) is obtained: mp 145-147°C. Actual value: C,
55.34; H, 5.84; N, 11.33. C ₂₃ H ₂₇ ClN ₄ O ₆・
Theoretical value of 0.5H ₂ O: C, 55.25; H, 5.60N, 11.21
%. Production example 10 4-(2-chlorophenyl)-3-ethoxycarbonyl-2-{2-[N-(1-imidazolylcarbonyl)amino]ethoxymethyl}-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine 2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (20.4 g), carbonyl dihydropyridine (20.4 g) in tetrahydrofuran (500 ml). Imidazole (8.9
A solution of g) and N-methylmorpholine (20 ml) is stirred for 2 hours at room temperature and then evaporated. Partition the residue between ethyl acetate and water;
The organic phase is washed with water, dried over Na ₂ SO ₄ and evaporated. The solid residue is washed with diethyl ether and dried to give the title compound (16.6 g): mp149
~151℃. Actual value: C, 57.35; H, 5.54; N,
1.122. Theoretical value of C ₂₄ H ₂₇ ClN ₄ O ₆ : C, 57.54; H,
5.43; N, 11.18%. Production example 11 1-〈2-{[4-(2-chlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine-2
-yl]methoxy}ethyl>-1-(cyanomethyl)urea 2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)- in acetonitrile (40 ml)
A mixture of 3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (4.08 g), chloroacetonitrile (1.20 g) and potassium carbonate (1.20 g) was added to 16
Heat at reflux for an hour and then evaporate. The residue is triturated in diethyl ether and the resulting solid is dried and purified by chromatography on silica (40 g) eluting with dichloromethane and 0-5% v/v methanol. When appropriate fractions are collected and evaporated, 4-(2-chlorophenyl)-
2-[2-(N-cyanomethyl)amino. ethoxy]methyl-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine crude product (2.0 g) is obtained. Water (15
ml) and the above product (1.0 ml) in dioxane (15 ml).
Acetic acid (0.5 g) is added to a solution of g) and potassium cyanate (0.35 g), the mixture is stirred for 16 hours at room temperature and then evaporated. The residue is partitioned between ethyl acetate and water, the organic phase is dried over Na ₂ SO ₄ and evaporated. The residue was chromatographed on silica (10 g) and chromatographed with dichloromethane from 0 to 5
Purify by eluting with %v/v methanol. Collection and evaporation of appropriate fractions gives the title compound (53 mg): mp 190-191°C. Actual value:
C, 56.34; H, 5.80; N, 10.99. _{C25H27ClN4O6 _ _ _}
Theoretical values: C, 56.27; H, 5.50; N, 11.42%. Production example 12 2-(2-aminoethoxy)methyl-4-(2,
3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,
Production Example 11 using 4-dihydropyridine as a starting material
1-〈2-{[4-(2,3-
dichlorophenyl)-3-ethoxycarbonyl-
5-methoxycarbonyl-6-methyl-1,4-
Dihydropyridin-2-yl]methoxy}ethyl>-1-(cyanomethyl)urea is produced. The product is foam-like. Rf (silica; chloroform, methanol, ammonium hydroxide; 80:20:
1) 0.7.

Claims (1)

[Claims] Primary formula: (In the formula, R represents an aryl or heteroaryl group, and R ¹ and R ² each independently have 1 to 4 carbon atoms.
represents an alkyl group or a 2-methoxyethyl group; represents a membered nitrogen-containing heterocyclic ring, and the heterocyclic ring or another fused heterocyclic ring optionally further comprises one or more C1-C4 alkyl groups, phenyl groups, CN,
N(R ³ ) ₂ , (CH ₂ ) _n CO ₂ R ³ or (CH ₂ ) _n CON
(R ³ ) ₂ , in which case each R ³ independently represents H or an alkyl group having 1 to 4 carbon atoms, or two R ³ are substituted with the nitrogen atom to which they are bonded. Together, they represent pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(alkyl having 1 to 4 carbon atoms)-piperazinyl group, m represents 0 or 1, and Y represents -( _CH2 ) _o- , -CH ₂ CH (CH ₃ ) - or -
_CH2C ( _CH3 ) _2- , n represents 1 to 3 when X is bonded to Y via a ring carbon atom, and 2 or 2 when X is bonded to Y via a ring nitrogen atom. Represents 3. ) A 1,4-dihydropyridine compound represented by: and a pharmaceutically acceptable salt thereof. 2 In the formula, R represents an aryl group, and the aryl group is unsubstituted or nitro, halogen atom, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, hydroxy, trifluoromethyl, and cyano group. a phenyl group substituted with 1 or 2 substituents, each independently selected, or 1
- or 2-naphthyl group; or R
represents a heteroaryl group, and the heteroaryl group is a benzofuranyl group; a benzothienyl group; a pyridyl group optionally optionally substituted with a methyl, methylthio, cyano or halogen atom; a quinolyl group; a benzoxazolyl group; a benzothiazolyl group Furyl group; Pyrimidinyl group; Thiazolyl group, 2,1,3-benzoxadiazol-4-yl group; 2,1,3-benzothiazole-
Claim 1 representing a 4-yl group or a thienyl group optionally monosubstituted by a halogen atom or an alkyl having 1 to 4 carbon atoms.
Compounds described in Section. 3 In the formula, R is a 2-chlorophenyl group or 2,
A compound according to claim 2, which represents a 3-dichlorophenyl group. 4 In the formula, -2,4-dione, 5-hydroxy-
(1H)-1,2,3-triazole or 1-oxo-1,3-dihydropyrrolo[2,3b]pyridine, any of these groups optionally amino, lower alkyl, carbamoyl or CN
Claims 1 to 10 which may be substituted with a group
A compound according to any one of item 3. 5 In the formula, X is 1-(2-amino-4-imidazolone), 1-(imidazolidine-2,4-dione),
1-(4-amino-2-imidazolone), 2-(1
-oxo-1,3-dihydropyrrolo[2,3b]
pyridine), 6-(2-amino-4-pyrimidone)
or 6-(23-dimethyl-4pyrimidone). Claim 1, wherein R ¹ is CH ₃ and R ² is C ₂ H ₅ . The compound according to any one of claims 1 to 5. 7 The compound according to any one of claims 1 to 6, wherein Y in the formula is -(CH ₂ ) _o and n is 1 or 2. The compound according to item 1. 8 2-amino-1-{2-<[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-
Methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy〉ethyl}-
4-imidazolone; 1-{2-<[4-(2,3-dichlorophenyl)
-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine-
2-yl]methoxy>ethyl}-imidazolidine-2,4-dione;4-amino-1-{2-<[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy>ethyl}-2
-Imidazolone;2-{2-<4-(2,3-dichlorophenyl)-
3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine-2
-yl]methoxy>ethyl}-1-oxo-1,
3-dihydropyrrolo[2,3-b]pyridine; 6-{[4-(2,3-dichlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-
6-Methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-2,3-dimethyl-4-
pyrimidone; or 2-amino-6-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl} -4-pyrimidone; The compound according to claim 1, which is -4-pyrimidone;