JPH0447678B2 - - Google Patents

Description

[Detailed description of the invention]

(Field of Industrial Application) The present invention relates to a method for producing a 1,4-dihydropyridine-2-amino-5-phosphonic acid diester having a new type of antihypertensive action due to calcium antagonistic action, and an antihypertensive agent thereof. (Prior Art) It is known that 1,4-dihydropyridines can be used to treat coronary diseases, brain diseases, hypertension, and arrhythmia because they suppress the contraction of smooth muscle and myocardium through calcium antagonistic action (A .
Fleckenstein, Annu.Rev.Pharmacol.Tox−
17, 149-166 (1977)). However, most of the existing drugs or 1,4-dihydropyridines under development have carboxylic acid ester groups substituted at the 3 and 5 positions. Dihydropyridine-5-phosphonate derivatives are described in several documents, but they do not predict the structure of the present invention. That is,
AIRazumov et al.
Dihydropyridine-4-alkyl-5-phosphonate derivatives were synthesized [Zh. Obshch. Khim. 47, 1190-1191]
(1977) and ibid.51, 547-552 (1981)], and
Von K. Issleib et al.
6-dimethyl-4-phenyl-3-ethoxycarbonyl-1,4-dihydropyridine-5-phosphonate and diethyl 2,6-dimethyl-4-
Only two types of 1,2-dihydropyridine-4 (4-methoxyphenyl)-3-ethoxycarbonyl-1,4-dihydropyridine-5-phosphonate
-allyl-5-phosphonate. [J.Prakt, Chem.] Volume 318, 207-220
(1976)], but there is no description in any of the literature that predicts pharmacological activity. Furthermore, Japanese Patent Publication No. 58-26872 describes the cardiac action of 1,4-dihydropyridine-5-phosphonate derivatives, but the specification of this patent application states:
There is no description of an example in which a 1,4-dihydropyridine-5-phosphonate derivative was specifically synthesized or a biological activity test example in which a 1,4-dihydropyridine-5-phosphonate derivative was specifically tested. (Problems to be Solved by the Invention) 1,4-dihydropyridine 3,5-dicarboxylic acid alkyl esters, such as nifedipine, are extremely poorly soluble in water, and when administered orally, are poorly absorbed from the gastrointestinal tract (e.g. , Japanese Patent Publication No. 59-88420
(see issue). (Means and effects for solving the problem) As a result of intensive searches for water-soluble 1,4-dihydropyridi-5-phosphonate derivatives, the present inventors found that a dihydropyridine ring represented by the following general formula () It has been found that a group of compounds with an amino group introduced at the 2-position are highly water-soluble. The amino group introduced at the 2-position can form a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, or sulfuric acid, or an organic acid such as acetic acid, lactic acid, oxalic acid, succinic acid, or tartaric acid. This salt formation resulted in obtaining a dihydropyridine-5-phosphonate derivative that is more easily soluble in water. Further, the amino group of the 2-amino-1,4-dihydropyridine-5-phosphonate derivative represented by the general formula () is easily acylated with various acylating agents. For example, carboxylic acid chloride represented by carboxylic acid halide, carboxylic acid bromide, carbonate ester chloride, etc.; methanesulfonic acid chloride represented by sulfonic acid halide, trifluoromethanesulfonic acid chloride, benzenesulfonic acid chloride, p- Acylated with toluenesulfonic acid chloride or the like, preferably in the presence of a deoxidizing agent, the physical properties of this 2-amino-1,4-dihydropyridine-5-phosphonate derivative, particularly the balance between oil solubility and water solubility can be changed to suitably adjust the drug efficacy physicochemically. Hereinafter, the scope, synthesis method, medicinal efficacy, etc. of the compound of the present invention will be explained step by step. The present invention is based on the general formula () “ ^{In the} formula, Unlike,
Each represents an alkyl group having 1 to 6 carbon atoms or a cyanoethyl group; R ³ is a hydrogen atom or
CO ₂ R ⁵ (R ⁵ means a linear or branched lower alkyl group having 1 to 6 carbon atoms; R ⁴ means a lower alkyl group; Me means a methyl group) This invention relates to compounds represented by the general formula () and pharmacologically acceptable salts of the compound represented by the general formula () with salt-forming ability.
Optical isomers, diastereomers, etc. may exist, and the present invention also includes these isomers and their pharmaceutically acceptable salts having a basic nitrogen. The above pharmacologically acceptable salts are exemplified by the following acid salts. Namely, hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide; sulfonic acids such as sulfuric acid, benzenesulfonic acid or p-toluenesulfonic acid, and the like. The present invention also relates to a method for producing a compound represented by the following general formula (). That is, the general formula () [In the formula, X, R ¹ , and R ² have the same meanings as in the above general formula (). ] and the general formula () [In the formula, R ⁴ has the same meaning as explained in the above general formula (). ] A general formula () characterized by reacting a compound represented by [In the formula, X, R ¹ , R ² , R ⁴ , and Me have the same meanings as described above. ]Relating to a method for producing a compound represented by Compounds represented by general formula () and general formula ()
The reaction with the compound represented by is preferably carried out in an inert solvent. Although the α-acetylstyryl derivative represented by the general formula (), which is a starting material, is a new substance, it can be prepared using known methods (for example, ANPudovik et al., Zh.Obsh-
ch. In addition, the acetamidine derivative represented by the general formula () can be obtained by known methods (for example, SMMcElvain et al. J.
Am.Chem.Soc., 73, 2764 (1951)). The compound represented by the general formula () may be used in the form of a salt such as sulfate, hydrochloride, carbonate, or acetate; in that case, the compound is neutralized by adding an appropriate base to the reaction system. can do. Examples of inert solvents include alcoholic solvents such as methanol, ethanol, propanol, and isopropanol, 1,2-dimethoxyethane,
Ether solvents such as THF, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, nitrile solvents such as acetonitrile and benzonitrile, amide solvents such as DAM, DMF, and N-methylpyrrolidone, and DMSO and sulfolane. It is possible to use sulfoxide solvents and the like. The reaction is carried out between room temperature and 200°C, preferably between 50°C and 200°C.
The reaction is carried out by heating at 120° C. for a sufficient time to allow the reaction to proceed, for example from 30 minutes to 100 hours, preferably from 5 hours to 20 hours. The present invention also relates to a method for producing a compound represented by the following general formula (). That is, (3) General formula () [In the formula, X, R ¹ , R ² , R ⁴ , and Me have the same meanings as described above. ] and the general formula () YCO ₂ R ³ () [wherein, Y means a chlorine atom or a bromine atom,
R ³ has the same meaning as explained in the general formula () above. ], preferably in the presence of a deoxidizing agent. [In the formula, X, R ¹ , R ² , R ³ , R ⁴ , and Me have the same meanings as described above. ] This invention relates to a method for producing a compound represented by: This reaction is carried out in an inert solvent such as benzene, toluene, ether or pyridine in the presence of a deoxidizing agent such as triethylamine, pyridine or ethylmethylpyridine at temperatures ranging from 0°C to 200°C, preferably from 50 to 120°C. It is carried out within the range of. In addition, the compound represented by the general formula () and its pharmaceutically acceptable salts suppress the contraction of smooth muscle and cardiac muscle due to calcium antagonism, as shown in the test examples described below. Useful in treating diseases, brain diseases, and hypertension. When the compound of the present invention is used for the above-mentioned therapeutic purposes, pharmaceutically
or into a pharmaceutical or veterinary composition comprising a veterinary acceptable diluent or carrier. These compositions may be in a form suitable for oral administration, such as a tablet or capsule, in a form suitable for transdermal administration, such as an ointment or poultice, in a form suitable for inhalation, such as an aerosol or solution suitable for spraying, or in a form suitable for parenteral administration. For example, it can be used in the form of a sterile aqueous solution suitable for use as an injection, or in the form of a suppository suitable for use within the anus, vagina, rectum, etc. The above composition containing the compound of the present invention contains about 0.1 to 99.5 of the compound of the present invention based on the weight of the total composition.
%, preferably about 0.5-95%. In addition to the compounds of the invention or compositions containing the compounds of the invention, other pharmaceutically or veterinary active compounds can be included. Additionally, these compositions can contain more than one compound of the invention. The daily dosage of the drug containing the compound of the present invention varies depending on the type and severity of the symptoms to be treated and individual differences (age, sex, sensitivity, etc.). The daily dosage by intravenous administration is 0.0001 to 10 mg, preferably 0.0005 to 1 mg of active ingredient per kg of body weight.
mg. The daily dosage for oral and dermal administration is similar to that of active ingredient per kg of body weight.
It is 0.001-100mg. In addition, when administered in the form of suppositories into the vagina, rectum, etc., the daily dosage is 0.001 to 200 mg of active ingredient per 1 kg of body weight, preferably
It is 0.005-100mg. The content of active ingredient in the inhalant is 0.1-10%, preferably 0.1-2%. These daily dosages can be administered in two or more divided doses per day, if necessary. The above-mentioned composition containing the compound of the present invention can be produced by a conventional method, and can contain conventional excipients. (Examples) The present invention will be explained in more detail below using Examples, Test Examples, and Formulation Examples, but the scope of the present invention is not limited thereto. In addition, in the following structural formula, Me means a methyl group; Et means an ethyl group. Example 1 O-hexyl-O'-cyanoethyl 2-amino-6-methyl-4-(o-trifluoromethyl)
Synthesis of -1,4-dihydropyridine-3-ethoxycarbonyl-5-phosphonate O-hexyl-O'-cyanoethyl α-acetyl-o-trifluoromethylstyryl phosphonate 1.29 g, carboethoxyacetamidine hydrochloride (EtOC(O )CH ₂ C (=NH) (NH ₂ )・HCl)
0.50 g and 0.20 g of sodium ethoxide were dissolved in 20 ml of ethanol and refluxed for 1 hour. After the reaction, the solvent was distilled off under reduced pressure and the residue was subjected to silica gel chromatography and eluted with 10% ethanol-ethyl acetate. Fractions containing the target product were collected and the solvent was distilled off under reduced pressure to obtain the title compound. Compounds of Examples 2 to 7 were obtained in a similar manner. The physical properties are listed in Table 1, and the spectral data are listed in Table 2.

[Table] Table 2. Spectral data example 1 of Examples 1 to 7 MS.m/e (intensity ratio) 181 (31) 324 (100) 325
(52) 398 (16) 470 (15) 543 (5, M ⁺ ) NMR (CDCl ₃ ): δ8.02 (1H, broad s), 7.64 ~
6.97 (4H, m), 6.48 (2H, broad s), 5.63
(1H, d, J = 10Hz). 4.24~3.42 (6H, m),
2.70~2.34 (2H, m), 2.10 (3H, broad s),
1.95-0.46 (14H, m) Example 2 MS, m/e (intensity ratio) 290 (35) 291 (22) 398
(100) 399 (20) 509 (5, M ⁺ ) NMR (CDCl ₃ ): δ8.00 (1H, broad s), 7.44 ~
7.01 (4H, m). 6.50 (2H, broad s), 4, 62
(1H.d, J=11Hz), 4.33-3.40 (6H, m), 2.83
~2.45 (2H, m). 2.22 (3H, broad s), 1.78
~0.64 (14, m) Example 3 MS, m/e (intensity ratio) 181 (23) 255 (100)
291 (31) 398 (76) 508 (8, M _± 1) NMR (CDCl ₃ ): δ7.88 (1H, broad s) 7.58~
7.00 (4H, m), 6.53 (2H, broad s) 5.11
(1H, d, J=10Hz), 4.34~3.65 (6H, m),
2.73-2.35 (2H, m), 2.27 (3H, broad s),
1.87-0.74 (14H, m) Example 4 MS, m/e (intensity ratio) 99 (20) 301 (27) 398
(100) 399 (18) 520 (4, M ⁺ ) NMR (CDCl ₃ ): δ8.00-7.18 (5H, m), 6.39 (2H,
broad s), 4.71 (1H, d, J=11Hz), 4.28~
3.50 (6H, m), 2.76-2.37 (2H, m), 2.23
(3H, broad s). 1.66-0.66 (14H, m) Example 5 MS, m/o (intensity ratio) 302 (28) 317 (100)
422 (20) 439 (13, M ⁺ ) NMR (CDCl ₃ ): δ8.54 (1H, broad s), 8.42 ~
7.40 (4H, m), 6.82 (2H, broad s), 4.96
(1H, d, J=11Hz), 4.54~3.72 (6H, m),
2.45 (3H, broad s), 1.79-1.15 (9H, m) Example 6 MS, m/e (intensity ratio) 317 (70) 324 (82) 325
(100) 389 (73) 462 (21, M ⁺ ) NMR (CDCl ₃ ): δ8.38 (1H, broad s), 7.85 ~
7.16 (4H, m) 6.73 (2H, broad s), 5.37 (1H.
d, J=11Hz) 4.51-3.18 (6H.m), 2.36 (3H,
broad s), 1.68 to 0.85 (9H, m) Example 7 MS, m/e (intensity ratio) 255 (25) 301 (25) 317
(100) 355 (31) 391 (38) 428 (13, M ⁺ ) NMR (CDCl ₃ ): δ8.54 (1H, broad s), 7.70 ~
7.04 (4H, m). 6.77 (2H, broad s), 5.71
(1H, d, J=10Hz), 4.93~3.40 (6H, m),
2.32 (3H, broad s), 1.63-0.92 (9H, m) Example 8 O,O'-diethyl 2-ethoxycarbonylamino-6-methyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3 Synthesis of -ethoxycarbonyl-5-phosphonate O,O'-diethyl 2-amino-6-methyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-ethoxycarbonyl-5-phosphonate (Example 5) Compound) 0.61g, pyridine
0.1 g was dissolved in 20 ml of benzene and refluxed. 5 ml of a benzene solution containing 0.15 g of ethyl chlorocarbonate was added dropwise over 5 minutes, and reflux was continued for 2 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate. Fractions containing the target product were collected and the solvent was distilled off under reduced pressure to obtain the title compound. Compounds of Examples 9 and 10 were obtained in a similar manner. The physical properties of the obtained compound are shown in Table 3, and the spectral data are shown in Table 4.

[Table] Table 4. Spectrum data examples of Examples 8 to 10 8 MS, m/e (intensity ratio) 389 (100) 390 (21)
494 (14) 511 (3, M ⁺ ) NMR (CDCl ₃ ): δ8.30-7.25 (4H, m), 4.84 (1H,
d, J=12Hz), 4.52-3.57 (8H, m), 2.34
(3H, d, J=4Hz), 1.55 to 0.91 (12H, m) Example 9 MS, m/e (intensity ratio) 389 (100) 390 (24)
461 (8) 534 (2, M ⁺ ) NMR (CDCl ₃ ): δ7.80-7.04 (4H, m), 5.40 (1H,
d, J=12Hz), 4.46-3.08 (8H, m), 2.45
(3H, d, J = 4Hz), 1.57 to 0.61 (12H, m) Example 10 MS, m/e (intensity ratio) 389 (100) 390 (18)
417 (14) 500 (2, M ⁺ ) NMR (CDCl ₃ ): δ7.54-6.61 (4H, m), 5.14 (1H,
d, J=11Hz), 4.47-3.22 (8H, m), 2.32
(3H, d, J = 4Hz), 1.59-0.75 (12H, m) <Test example> 2-Amino-1,4-dihydropyridine-5-
Pharmacological effects of phosphonate derivatives. (1) Calcium antagonism Suspend the removed guinea pig's cecal cord in the nutrient solution with a tension of 1 g and wait for it to stabilize. Replace the nutrient solution with a calcium-free high potassium solution;
After 10 to 20 minutes, add 10mM of calcium chloride to cause contraction, and after the tension stabilizes, administer the test drug cumulatively to determine the concentration of test drug required to achieve 50% relaxation.
ID ₅₀ (M) was calculated and its inverse logarithm value (pID ₅₀₎ was calculated. The results are summarized in Table 5. (2) Antihypertensive effect Spontaneous hypertensive rats (SHR) were treated with urethane (600 mg/Kg) - α -Chloralose (60mg/Kg)
Anesthetize by intraperitoneal (ip) administration. The rat is fixed in a dorsal position and a tracheal cannula is inserted. The test drug was dissolved in 3% Tween 80-physiological saline and intravenously injected through the femoral vein. Changes in blood pressure were measured invasively through a cannula inserted into the common carotid artery, and 30%
Drug dose required to lower blood pressure ED ₃₀ (mg/
Kg) was calculated. The results are summarized in Table 5.

[Table] (3) Toxicity test Acute toxicity was investigated when 500 mg/Kg of the hydrochloride salts of the compounds of Examples 2 and 3 were orally administered to ICR male mice (6 weeks old). There were 3 animals in each group, and the progress was observed for one week, and no toxic symptoms were observed. Formulation Example 1 Tablet Ingredients (1000 tablets) Hydrochloride of the compound of Example 1 5.0 (g) Lactose 190.0 Corn starch 75.0 Microcrystalline cellulose 25.0 Methyl cellulose 3.0 Magnesium stearate 2.0 300.0 Weigh the amounts of the above ingredients and place them in a V-type mixer. , mix evenly. This mixed powder is made into tablets by direct compression. The weight of one tablet is 300mg. Formulation example 2: Capsule ingredients (1000 tablets) Hydrochloride of the compound of Example 1 5 (g) Corn starch 145 Microcrystalline cellulose 145 Magnesium stearate 5 300 Weigh the amounts of the above ingredients, put them in a V-type mixer, and mix uniformly. do. This mixed powder is filled into hard capsules. The content per capsule is 300mg. Formulation example 3: Syrup ingredients (2% solution) Hydrochloride of the compound of Example 1 2.0 (g) White sugar 30.0 Glycerin 5.0 Flavoring agent 0.1 96% ethanol 10.0 Methyl p-oxybenzoate 0.03 Distilled water To 100.0 g in total Amount: 60g of white sugar and the hydrochloride of the compound of Example 1
After cooling, a flavor solution dissolved in glycerin and ethanol was added. Water was then added to this mixture to make a total amount of 100.0 g. Formulation Example 4: Powder Hydrochloride of the compound of Example 1 1.0 (g) Lactose 88.0 Microcrystalline cellulose 10.0 Methyl cellulose 1.0 100.0 The above ingredients were weighed, placed in a V-type mixer, and mixed uniformly.

Claims (1)

[Claims] 1 (1) General formula () [ ^{In the} formula, Unlike,
Each represents an alkyl group having 1 to 6 carbon atoms or a cyanoethyl group; R ³ is a hydrogen atom or
CO ₂ R ⁵ (R ⁵ means a linear or branched lower alkyl group having 1 to 6 carbon atoms; R ⁴ means a lower alkyl group; Me means a methyl group)] and pharmacologically acceptable salts of compounds represented by the general formula () with salt-forming ability. (2) General formula () [ ^{In the} formula, Unlike,
Each means an alkyl group having 1 to 6 carbon atoms or a cyanoethyl group. ] and the general formula () [In the formula, R ⁴ means a lower alkyl group. ] A general formula () characterized by reacting a compound represented by [In the formula, X, R ¹ , R ² and R ⁴ have the same meanings as described above; Me means a methyl group. ] A method for producing a compound represented by (3) General formula () [ ^{In the} formula, Unlike,
Each represents an alkyl group having 1 to 6 carbon atoms or a cyanoethyl group; R ⁴ represents a lower alkyl group; Me represents a methyl group. ] and the general formula () YCO ₂ R ³ () [wherein, Y means a chlorine atom or a bromine atom,
R ³ is a hydrogen atom or a compound represented by CO ₂ R ⁵ (R ⁵ means a linear or branched lower alkyl group having 1 to 6 carbon atoms) in the presence of a deoxidizing agent,
General formula () characterized by reaction [In the formula, X, R ¹ , R ² , R ³ , and R ⁴ Me have the same meanings as described above. ] A method for producing a compound represented by (4) General formula () [ ^{In the} formula, Unlike,
Each represents an alkyl group having 1 to 6 carbon atoms or a cyanoethyl group; R ³ is a hydrogen atom or
CO ₂ R ⁵ (R ⁵ means a linear or branched lower alkyl group having 1 to 6 carbon atoms; R ⁴ means a lower alkyl group; Me means a methyl group)] 1. An antihypertensive agent comprising a compound represented by the general formula (2) and a pharmacologically acceptable salt of a compound represented by the general formula () having salt-forming ability.