JPH0160467B2 - - Google Patents

Description

[Detailed description of the invention]

Industrial Application Field The present invention relates to 1,4-dihydropyridine-3,5-
The present invention relates to a method for producing a dicarboxylic acid diester derivative or an acid addition salt thereof. More specifically, the present invention aims to provide novel 1,4 compounds that have excellent pharmacological effects such as hypotensive effect and vasodilatory effect and have a long duration of action.
-Dihydropyridine-3,5-dicarboxylic acid diester derivative or an acid addition salt thereof. Conventional technology Conventionally, the formula 4-(o-nitrophenyl)-2, represented by
6-dimethyl-1,4-dihydropyridine-3,
5-dicarboxylic acid dimethyl ester (hereinafter abbreviated as nifedipine) is known. Nifedipine is a compound that has excellent pharmacological effects such as hypotensive action, but it has the disadvantage that its duration is short. Many nifedipine derivatives have been studied with the aim of obtaining compounds that have pharmacological effects such as long-lasting blood pressure lowering effects. For example, Tokkosho
Publication No. 56-6417 describes the 3rd or 5th position of nifedipine.
4- position converted to aminoalkyl ester
(m-nitrophenyl)-2,6-dimethyl-1,
4-dihydropyridine-3,5-dicarboxylic acid,
-3-Methyl ester-5-β-(N-benzyl-N-methylamino)ethyl ester hydrochloride (hereinafter abbreviated as nicardipine) has been reported. Further, JP-A-55-9083 reports a nifedipine derivative in which the 2'-nitrophenyl group at the 4-position of nifedipine is converted to a 2',3'-dihalogen-substituted phenyl group. Among these nifedipine derivatives, especially felodipine (4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5- Ethyl ester) is known to be excellent (Stig-Lennart Bostro¨m
et al., Nature, Vol. 292, p. 777 (1981)) ₆ However, although these compounds have excellent pharmacological effects, their sustained action is not fully satisfactory. Furthermore, in the document Arzneim.Forsch.29, 226 (1979), the 2'-nitrophenyl group at the 4-position of nifedipine is 2'-nitro-4'-methoxyphenyl group, 2'-
Nifedipine derivatives converted to disubstituted phenyl groups such as nitro-4'-chlorphenyl groups have been described, and these nifedipine derivatives are said to have the same or weaker coronary vasodilatory effect than nifedipine. It has been reported. OBJECT OF THE INVENTION The present inventors have discovered that nifedipine derivatives 1,
As a result of detailed studies on the structure and activity of 4-dihydropyridine-3,5-dicarboxylic acid diester derivatives, we found that the phenyl group at the 4-position of nifedipine was
1,4-dihydropyridine-converted into a 2',5'-disubstituted phenyl group and further converted the 3- or 5-position methyl ester group into an aminoalkyl ester group.
The present invention was achieved by discovering that 3,5-dicarboxylic acid diester derivatives have a strong pharmacological effect such as a blood pressure lowering effect, and that the duration of the pharmacological effect is extremely long. Therefore, the object of the present invention is to produce a novel 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative or an acid addition salt thereof, which has excellent pharmacological effects such as hypotensive effect and has a long duration. It is about providing law. Structure and Effects of the Invention The novel 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative provided by the present invention has the following formula [] [In the formula, R ¹ is a methyl group, R ² is a substituted or unsubstituted benzyl group, R ³ is a methyl group, A is a linear or branched alkylene group having 1 to 6 carbon atoms, X is a nitro group, and Y is a Represents a fluorine atom. ] It is expressed as . The 1,4-dihydropyridine-
The 3,5-dicarboxylic acid diester derivative has a 2',5'-disubstituted phenyl group etc. at the 4-position and an aminoalkyl ester group at the 5-position, and has been specifically described in the literature. This is a new compound that has not been disclosed in the literature, and has pharmacological effects such as long-lasting blood pressure lowering effects. In the above formula [], R ² is a substituted or unsubstituted benzyl group. Substituents for benzyl groups include, for example, halogen atoms such as fluorine atoms and chlorine atoms; lower alkoxy groups such as methoxy, ethoxy, and propoxy groups; lower alkyl groups such as methyl, ethyl, and propyl groups; trifluoromethyl, trichloromethyl Examples include halogenated lower alkyl groups such as. R ² is preferably a benzyl group. A is a linear or branched alkylene group having 1 to 6 carbon atoms, such as linear alkylene groups such as methylene, ethylene, trimethylene, tetramethylene, and pentamethylene; 2,2-dimethyltrimethylene, 1,1- Examples include branched alkylene groups such as dimethyltrimethylene. A is ethylene,
2,2-dimethyltrimethylene is preferred. 1,4-dihydropyridine-3,5- of the present invention
Dicarboxylic acid diester derivatives may be acid addition salts, such as inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid; acetic acid, propionic acid, citric acid, succinic acid, tartaric acid, maleic acid, etc. Organic carboxylic acids such as acids; methanesulfonic acid,
Examples include organic sulfonic acids such as ethanesulfonic acid, benzenesulfonic acid, and P-toluenesulfonic acid. 1,4-dihydropyridine-3,5- of the present invention
Preferred examples of dicarboxylic acid diester derivatives are as follows. (110) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2-(N-benzyl -N-methylamino)ethyl] ester, (114) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester -5-[3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl]ester, (132) 4-(2'-fluoro-5'-nitrophenyl)-2,6-dimethyl-1 ,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2-(N-4-methoxyphenylmethyl-N-methylamino)ethyl] ester, (134) 2,6-dimethyl- 4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2-(N-4-fluorophenylmethyl-N-methyl (amino)ethyl] ester, (136) 4-(2'-fluoro-5'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[ 3-[N-(4-trifluoromethylphenyl)methyl-N-methylamino]-
2,2-dimethylpropyl] ester, (138) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester 5-[2-[N-(2′,6′-dichlorophenyl)methyl-N-methylamino]ethyl]ester, (146) 4-(2′-fluoro-5′-nitrophenyl)-2,6 -dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[3-(N-benzyl-N-methylamino)propyl] ester, (148) 2,6-dimethyl-4 -(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[4-(N-benzyl-N-methylamino)butyl] ester, (150) 4-(2'-Fluoro-5'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2-(N-benzyl -N-methylamino)-1,1-dimethylethyl] ester, (152) 4-(2'-fluoro-5'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarvone Acid-3-methyl ester-5-[3-(N-benzyl-N-methylamino)-3,3-dimethylpropyl] ester, (154) 2,6-dimethyl-4-(2'-fluoro-5 '-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[4-(N-benzyl-N-methylamino)-2,2-dimethylbutyl] ester, (156 ) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[4-[N-methyl-N -(4-trifluoromethylphenyl)methyl]butyl]ester, (158) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarbonate Acid-3-methyl ester-5-[4-(N-4-methoxyphenylmethyl-N-methylamino)-2,2-dimethylbutyl] ester, 1,4-dihydropyridine-3,5- of the present invention
The dicarboxylic acid diester derivative has the following formula [] [In the formula, X and Y are the same as defined above. ] Aldehyde compound represented by and the following formula [] [In the formula, A, R ² and R ³ are the same as defined above. ] Acetoacetate compound represented by and the following formula [] [In the formula, R ¹ is the same as defined above. ] It is produced by reacting with a 3-aminocrotonic acid ester compound represented by the following, and subjecting it to a salt-forming reaction if necessary. To obtain the aldehyde compound of the above formula [],
The following formula [] [In the formula, X and Y are the same as defined above, and R ⁴ represents methyl or hydroxymethyl. ] can be easily produced by oxidizing it in the presence of a known oxidizing agent. As an oxidizing agent, chromium,
Examples include oxidizing agents containing elements such as silver and selenium. The acetoacetate compound of the above formula [] and the 3-aminocrotonic acid ester compound of the above formula [] can be easily produced by known methods [M. Iwanami et al., Chem.Pharm.Bull.27 Vol. 1426
(1979)]. When reacting the above aldehyde compounds, acetoacetate compounds, and 3-aminocrotonic acid ester compounds, they may be reacted without a solvent or with lower alcohols such as ethanol, propanol, isopropanol, n-butanol, and t-butanol. ; 30 to 180°C, preferably 50 to 150°C in an organic solvent such as a halogenated hydrocarbon such as chloroform, dichloroethane, or trichloroethane; or an aromatic compound such as benzene or pyridine.
The heating reaction is usually carried out for 2 to 24 hours. The aldehyde compound, acetoacetate compound, and 3-aminocrotonic acid ester compound can be used in amounts of 0.8 to 1.5 and 0.8 to 1.5 equivalents, respectively, per equivalent of the aldehyde compound. 1,4-dihydropyridine-3,5- of the present invention
Dicarboxylic acid diester derivatives can also be converted into corresponding acid addition salts by treatment with an acid by a reaction known per se. 1,4-dihydropyridine-3,5- of the present invention
Dicarboxylic acid diester derivatives have pharmacological effects such as excellent blood pressure lowering effects and long-lasting effects, such as improving angina pectoris, cerebral blood flow, and circulation disorders.
It is effective as a therapeutic agent for cardiovascular diseases such as hypertension and ischemic heart disease. Furthermore, since the compound of the present invention is easily soluble in water, it can be used as an injection, and on the other hand, when administered orally, it is well absorbed and has high bioavailability. 1,4-dihydropyridine-3,5- of the present invention
Dicarboxylic acid diester derivatives are administered orally or parenterally, such as subcutaneously, intramuscularly, intravenously, transdermally, or rectally. The dosage form for oral administration is
Examples include tablets, pills, granules, powders, suspensions, capsules, etc. To form tablets, excipients such as lactose, starch, crystalline cellulose; carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, etc. It can be molded by a conventional method using a binder; a disintegrant such as sodium alginate, sodium hydrogen carbonate, or sodium lauryl sulfate. Pills, powders, and granules can also be formed using the above-mentioned excipients and the like in a conventional manner. Solutions and suspensions are formed by conventional methods using, for example, glycerin esters such as tricaprylin and triacetin, and alcohols such as ethanol. Capsules are formed by filling granules, powders, liquids, etc. into capsules made of gelatin or the like. Dosage forms for subcutaneous, intramuscular, and intravenous administration include injections in the form of aqueous or nonaqueous solutions, suspensions, and the like. As the non-aqueous solutions and suspensions, propylene glycol, polyethylene glycol, olive oil, ethyl oleate, etc. are used, and preservatives, stabilizers, etc. are added to these as necessary. The injection agent is sterilized by filtration through a bacteria retention filter, addition of a sterilizing agent, etc. as appropriate. Examples of dosage forms for transdermal administration include ointments and creams; ointments use fatty oils such as castor oil and olive oil; vaseline and the like; creams use fatty oils; diethylene glycol and sorbitan monofatty acid ester. It is molded by a conventional method using an emulsifier such as. For rectal administration, conventional suppositories such as gelatin soft capsules are used. 1,4-dihydropyridine-3,5- of the present invention
The dosage of the dicarboxylic acid diester derivative varies depending on the patient's age, sex, degree of disease, dosage form, etc., but is usually 0.01 to 10 mg/Kg/day, preferably
It is 0.05-5 mg/Kg/day. The present invention will be explained in more detail below with reference to Examples. Reference example 1 Put 20ml of acetic anhydride into a 200ml three-necked flask,
Ice cold. To this, 3.0 g (19.4 mmol) of 2-fluoro-5 nitrotoluene was added dropwise, and 5 ml of concentrated sulfuric acid was added dropwise little by little. While keeping the temperature below 10°,
A solution (20 ml) of acetic anhydride containing 6.0 g (57.0 mmol) of chromic anhydride was added dropwise over about 1 hour. 2 more
Stirred for hours (~5°). The post-reaction solution was poured into 150 ml of ice water and extracted with CH ₂ Cl ₂ . CH ₂ Cl ₂ phase,
After washing with water and drying with Na ₂ SO ₄ , the solvent was distilled off, and 4.23 g (15.6 mmol, 80%) of 2-fluoro-5-nitrobenzylidene diacetate was obtained as a pale yellow liquid.
Obtained. Physical property values: - IR Vcm ^-1 max (neat): 3090, 1754, 1528, 1488,
1348, 1190, 1092, 1056, 1046, 996, NMR δppm ( _CDCl3 ): 8.48-8.13 (m.2H),
7.88 (S.1H), 7.28 (dd, 1H, J=9Hz), 2.13
(S.6H) 4.02g of the above diacetate derivative,
(14.8 mmol) were added with 25 ml of dioxane, 10 ml of H ₂ O, and 1 ml of concentrated sulfuric acid, and the mixture was heated under reflux for 30 minutes. After evaporating the medium under reduced pressure and concentrating, water was added and CH ₂ Cl ₂
Extracted with. The CH ₂ Cl ₂ phase was washed with water, dried with Na ₂ SO ₄ , the solvent was distilled off, and the obtained yellow-orange liquid was purified by silica gel column chromatography.
1.96 g (11.6 mmol 1.78%) of 2-fluoro-5-nitrobenzaldehyde was obtained as pale yellow crystals. Physical property value: ÷− mP59−60゜IRV cm ⁻¹ max (KBv): 1690, 1618, 1524,
1348, 1252 cm ^-1 NMR δppm (CDCl ₃ ): 10.20 (S.1H), 8.77−
8.32 (m.2H), 7.42 (dd, 1H, J=9Hz) Reference example 2 2,2-dimethyl-3-(N-benzyl-N-
2.07 g of (methylamino)propyl alcohol was dissolved in 1 ml of benzene and heated to 70°C. 1.0 g of diketene was slowly added dropwise to this mixed solution. After stirring for 1.5 hours, the solvent was distilled off, the residue was subjected to silica gel chromatography, and the hexane-ethyl acetate elution fraction was concentrated to obtain the desired acetoacetic acid-[2,2-dimethyl-3-(N-) benzyl-N-methylamino)
2.8 g of [propyl]ester (oil) was obtained. Substance value NMR (CDCl ₃ ) δppm: 7.35 (S.5H), 3.95
(S.2H) 3.57 (S.2H), 3.38 (S.2H), 2.28
(S.2H), 2.18 (S.3H), 2.15 (S.3H), 0.89
(S.6H) Other acetoacetate compounds can also be obtained in the same manner. Example 1 2-fluoro-5-nitrobenzaldehyde
168mg (1.00mmol) of acetoacetic acid-3-(N-
Benzyl-N-methylamino)-2,2-dimethylpropyl ester 290 mg (0.99 mmol), methyl 3-aminocrotonate (1/5 mg (1.00 mmol)
and 1 ml of isopropanol were added, and the mixture was heated under reflux for 10 hours. After distilling off the solvent, the residue was subjected to silica gel column chromatography (n-Hexane: ACOEt
= 2:1 elution), 4-(2'-fluoro-5'-nitrophenyl)-2,6-dimethyl-
184 mg (0.34 mmol, 34% ) obtained. IR Vcm ^-1 max (CHCl ₃ ): 3450, 2950, 1686,
1616, 1466, 1346, 1308, 1118, 1100 NMR δppm ( _CDCl3 ): 8.23−7.76 (m.2H),
7.16 (S.5H), 6.94 (dd, 1H, J=9Hz), 6.60
(brs.1H), 5.28 (S.1H), 3.84 (S.2H), 3.56
(S.3H), 3.39 (S.2H), 2.30 (S.3H), 2.26
(S.5H), 2.05 (S.3H), 0.86 (S.6H) Hydrochloride mp209−212゜IR Vcm ^-1 max (KBv): 3450, 2970, 1684, 1522,
1344, 1210, 1114, 1090, 1014 Example 2 2-fluoro-5-nitrobenzaldehyde
330 mg, methyl 3-aminocrotonate 126 mg, acetoacetic acid-2-(N-benzyl-N-methylamino)ethyl ester 253 mg, isopropanol 1
After heating under reflux for 12 hours, the solvent was distilled off.
The residue was subjected to silica gel chromatography to obtain the desired 2,6-dimethyl-4-(2'-fluoro-
5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2-(N-benzyl-N-methylamino)ethyl] ester was obtained. Physical property value IR Vcm ^-1 max (CHCl ₃ ): 3450, 1692, 1618,
1468, 1348, 1306, 1120, 1104 NMR δppm ( _CDCl3 ): 8.26-7.72 (m.2H),
7.12 (S.5H), 6.87 (t.1H, J=9Hz), 6.37
(S.1H), 5.23 (S.1H), 4.06 (t.2H, J=6Hz),
3.53 (S.3H), 3.40 (S.2H), 2.55 (t.2HJ=6Hz)
2, 26 (S.6H), 2.12 (S.3H) Hydrochloride IR Vcm ^-1 max (KBv): 3450, 1685, 1520, 1345 Example 3 Measurement of blood pressure lowering effect By intravenous infusion under anesthesia, 1 and 4 of the present invention
The effects of -dihydropyridine-3,5-dicarboxylic acid diester derivatives on blood pressure and heart rate in rats were investigated. That is, a male Wistar rat weighing approximately 250 g was used, and this rat was treated with 500 mg/Kg of urethane and a
- Chloralose 100mg/Kg was administered intraperitoneally, and the patient was anesthetized and fixed. The test compound was dissolved in a small amount of ethanol, then diluted with physiological saline to a final concentration of 5% ethanol or less, and then intravenously administered to rats via a catheter inserted into the femoral vein. Injected. Blood pressure was measured with a pressure transducer through a catheter inserted into the common carotid artery of the rat, and heart rate was measured from the blood pressure waveform. The effect of the test compound on blood pressure was determined by calculating the mean blood pressure by 20% of the mean blood pressure value before administration of the test compound.
Expressed as decreasing dose of test compound (ED ₂₀ μg/Kg). The effect on heart rate was expressed as the dose of the test compound that increased the heart rate by 10% (ED ₁₀ μg/Kg) compared to the heart rate before administration. In addition, in order to measure the duration of the antihypertensive activity of the test compound, the time required for the degree of blood pressure reduction to be halved (T
1/2) was measured. These results are shown in Table 1.

[Table] Example 4 Tablets were manufactured according to the following formulation. Compound of Example 1 20g Polyvinylpyrrolidone 300g (molecular weight 40,000-50,000) Ethanol 1.5 Calcium carboxymethylcellulose 190g Magnesium stearate 10g The above ingredients were mixed and stirred and then compressed to produce tablets containing 20mg of the active ingredient per tablet. Example 5 Capsules were manufactured according to the following formulation. Compound of Example 2 10g Lactose 148g Avicel 100g Magnesium stearate 2g The above ingredients were mixed and stirred and filled into hard capsules by a conventional method to produce capsules containing 10mg of the main drug. Example 6 Blood pressure lowering effect of oral administration A male Wistar rat (weighing about 250 g) that had been fasted for 16 hours or more was fixed in a Bollman cage after a catheter was inserted into the femoral artery under ether anesthesia. After more than 1 hour had passed since the animals became narcotized, the test compound was forcibly administered using an oral probe. The test compound was prepared by dissolving it in water. The femoral artery pressure was measured over time, and the values calculated using the following formula: Change in mean blood pressure (mmHg)=Mean blood pressure after administration (mmHg) - Mean blood pressure before administration (mmHg) are shown in Table 2.

【table】

Claims (1)

[Claims] 1. The following formula [] [In the formula, X represents a nitro group and Y represents a fluorine atom. ] and the following formula [] [In the formula, A represents a linear or branched alkylene group having 1 to 6 carbon atoms, R ² represents a substituted or unsubstituted benzyl group, and R ³ represents a methyl group. ] Acetoacetate compound represented by and the following formula [] [In the formula, R ¹ represents a methyl group. ] The following formula [ ], which is characterized by reacting with a 3-aminocrotonic acid ester compound represented by [ ] and subjecting it to a halogenetic reaction as necessary. [In the formula, R ¹ , R ² , R ³ , A, X, and Y are the same as defined above. ] 1,4-dihydropyridine-3,5 represented by
-Production method of dicarboxylic acid diester derivative or its acid addition salt. 2. 1,4-dihydropyridine- according to claim 1, wherein in the above formula [], A is an ethylene group or a 2,2-dimethyltrimethylene group.
A method for producing a 3,5-dicarboxylic acid diester derivative or an acid addition salt thereof.