JPH0460478B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a new type of 1,4-dihydropyridine-5-phosphonic acid diester having antihypertensive action due to calcium antagonistic action, a method for producing the same, 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 due to their calcium antagonistic effects ( A.
Fleckenstein.Annu.Rev.Pharmacol.Toxicol.
17, 149-166 (1977)). However, existing drugs or 1,4-dihydropyridines under development are
Most of the positions are substituted with carboxylic acid ester groups. 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 [Zn.Obshch.Khim. 47, 1190-1191]
(1977) and ibid.51, 547-552 (1981)], and
Von. K. Issleib et al.
2,6-dimethyl-4-phenyl-3-ethoxycarbonyl-1,4-dihydropyridine-5-phosphonate and diethyl 2,6-dimethyl-
There are only two types of 1,2-dihydropyridine-4-allyl-5-phosphonates: 4-(4-methoxyphenyl)-3-ethoxycarbonyl-1,4-dihydropyridine-5-phosphonate. [J. Prakt, Chem.] Vol. 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, effects of the compounds of the present invention) The present inventors have discovered that 1,4-dihydropyridine-5-
We discovered that introducing a heteroatom into the alkyl chain of the phosphonate moiety of a phosphonate significantly increases its activity. Furthermore, these compounds have longer-lasting effects than existing 1,4-dihydropyridine derivatives,
The present invention was completed based on the discovery that it has an extremely useful feature therapeutically in that it hardly causes heart palpitations. (Means for solving the problems) The compound of the present invention has the general formula () ^“ In the formula, X means a hydrogen atom, a nitro group, a trifluoromethyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; R ⁴ ) [R ³ ,
R ⁴ are the same or different from each other, respectively,
It means a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, or an aralkyl group. ]; R ¹ represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms; R ² represents a straight-chain or branched alkyl group having 1 to 16 carbon atoms;
a straight-chain or branched alkyl group, a straight-chain or branched 2-lower alkoxyethyl group having 1 to 6 carbon atoms or -CH ₂ CH ₂ N(R ⁵ )(R ⁶ ) [R ⁵ ,
R ⁶ has the same meaning as R ³ and R ⁴ described above, and is the same or different from each other. ); n means an integer from 2 to 6. '' and pharmacologically acceptable salts of compounds represented by the general formula () with salt-forming ability. Note that the compound represented by the general formula () has optical isomers, diastereomers, etc., and the present invention is directed to pharmacologically acceptable compounds of these isomers and compounds capable of forming salts of these isomers. It also includes salts that are The present invention also relates to a method for producing the compound of the present invention represented by the general formula (). That is, the general formula () [In the formula, X, Y, R ¹ and n have the same meanings as in the above general formula (). ] Phosphonate derivatives represented by the general formula () [In the formula, R ² has the same meaning as explained in the above general formula (). A dihydropyridine-5-phosphonate derivative represented by the general formula () can be obtained by reacting the compound represented by the above in an inert solvent. The starting compound represented by the general formula () can be obtained from the reaction of a β-ketophosphonate derivative and an aldehyde by applying known techniques, and the starting compound represented by the general formula () can be obtained from the reaction of a β-ketophosphonate derivative with an aldehyde. Easily obtained by reacting a compound with ammonia. The starting compound () may be produced within the reaction system by mixing the corresponding carbonyl compound and ammonia, and does not necessarily need to be isolated. Inert solvents include alcohol solvents such as methanol, ethanol, propanol, and isopropanol, ether solvents such as 1,2-dimethoxyethane and THF, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, acetonitrile, and benzene. Nitrile solvents such as nitrile,
In addition to amide solvents such as DAM, DMF, and N-methylpyrrolidone, sulfoxide solvents such as DMSO and sulfolane, and ester solvents such as ethyl acetate and butyrolactone, pyridine can also be used. The reaction is carried out between room temperature and 200°C, preferably between 60 and 140°C.
C. for 1 hour to 100 hours, preferably 5 hours to 20 hours. As mentioned above, the compound of the present invention has the effect of suppressing the contraction of smooth muscle and cardiac muscle through calcium antagonism, and is therefore useful for treating coronary diseases, brain diseases, and hypertension in mammals. 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 (Examples, Test Examples, Formulation Examples)) The present invention will be explained in more detail below using Examples, but the scope of the present invention is not limited thereto. Example 1 O-cyanoethyl-O'-methyl 3
-methoxycarbonyl-1,4-dihydro-
2,6-dimethyl-4-(2-chlorophenyl)
-Synthesis of pyridine-5-phosphonate O-cyanoethyl-O'-methyl α-acetyl-(o-chlorostyryl)-phosphonate 4.47
0.69 g of methyl 3-aminocrotonate was dissolved in 10 ml of toluene and refluxed for 5.5 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column 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. Yield 1.45g (yield 76%), yellow semisolid MS, m/e (intensity ratio) 260(10)313(100)424(4,
M ⁺ ) NMR (CDCl ₃ ): 7.5-6.8 (4H, m), 6.1 (1H,
broads), 5.1 ((1H, d, J=10Hz), 4.3-3.6
(2H, m), 3.6 (3/2H, d, J=12Hz), 3.5
(3H, s), 3.1 (3/2H, d, J=12Hz), 2.6
(1H, t, 7Hz), 2.3 (7H, m) Examples 2 to 8 Corresponding O-cyanoethyl-
Compounds of Examples 2 to 8 were obtained in the same manner as in Example 1 using O'-alkyl α-acetyl-((substituted styryl)--phosphonate. Example 2 O-cyanoethyl-O'-ethyl 3
-methoxycarbonyl-1,4-dihydro-
2,6-dimethyl-4-(3-nitrophenyl)
Synthesis yield of -pyridine-5-phosphonate 81%, yellow needles mp 168-170°C MS, m/e (intensity ratio) 327 (100) 432 (12, M ⁺ ) NMR (CDCl ₃ ): δ8. 2~6.7 (5H, m), 4.8 (1H,
d, J=10Hz), 4.2-3.3 (4H, m), 3.6 (3H,
s), 2.8-2.0 (8H, m), 1.4-0.9 ((3H, m) Example 3 O-cyanoethyl-O'-ethyl 3
-methoxycarbonyl-1,4-dihydro-
2,6-dimethyl-4-(2-chlorophenyl)
-Pyridine-5-phosphonate yield 76%, yellow semisolid MS, m/e (intensity ratio) 275 (15) 327 (100) 403
(5) 438 (3, M ⁺ ) NMR (CDCl ₃ ): δ7.7-6.8 (4H, m), 6.5 (1H,
broad), 5.2 (1H, d, J = 10Hz), 4.4-3.5
(4H, m), 3.6 (3H, s), 2.8~2.2 (8H, m),
1.6-0.9 (3H, m)) Example 4 O-cyanoethyl-O'-hexyl
3-methoxycarbonyl-1,4-dihydro-
2,6-dimethyl-4-(3-nitrophenyl)
-Pyridine-5-phosphonate yield 64%, yellow crystals mp 153-155℃ MS, m/e (intensity ratio) 383 (100) 488 (20) 505
(5, M ⁺ ) NMR (CDCl ₃ ): δ8.3-7.2 (4H, m), 6.5 (1H,
broad), 4.9 (1H, d, J = 10Hz), 4.1 to 3.4
(4H, m), 3.6 (3H, s), 2.7~2.5 (8H, m),
1.9-0.4 (11H, m) Example 5 O-cyanoethyl-O'-hexyl
3-methoxycarbonyl-1,4-dihydro-
2,6-dimethyl-4-(2-trifluoromethylphenyl)-pyridine-5-phosphonate yield 78%, yellow semisolid MS, m/e (intensity ratio) 383 (100) 466 (10) 528 ( 2,
M ⁺ ) NMR (CDCl ₃ ): δ7.8-7.2 (4H, m), 6.3 (1H,
broad), 5.3 (1H, d, J = 10Hz), 4.3-3.5
(4H, m), 3.6 (3H, s) 2.9~2.1 (8H, m),
1.9-0.6 (11H, m) Example 6 O-cyanoethyl-O'-hexyl
3-methoxycarbonyl-1,4-dihydro-
2,6-dimethyl-4-(3-chlorophenyl)
-Pyridine-5-phosphonate yield 91%, colorless needles mp 110-120°C MS, m/e (intensity ratio) 383 (100) 494 (2, M ⁺ ) NMR (CDCl ₃ ): 7.7-7.0 (4H , m), 6.9 (1H,
broad), 4.7 (1H, d, J = 10Hz), 4.2-3.5
(4H, m), 3.6 (3H, s) 2.8~2.1 (8H, m),
1.9-0.6 (11H, m) Example 7 O-cyanoethyl-O'-hexyl
3-methoxycarbonyl-1,4-dihydro-
2,6-dimethyl-4-(2-chlorophenyl)
-Pyridine-5-phosphonate yield 66%, yellow oil MS, m/e (intensity ratio) 383 (100) 459 (10) 494 (2,
M ⁺ ) NMR (CDCl ₃ ): δ7.5-6.8 (4H, m), 6.3 (1H,
broad), 5.1 (1H, d, J = 10Hz), 4.4-3.4
(4H, m), 3.6 (3H, s), 2.9~2.1 (8H, m),
1.9-0.6 (11H, m) Example 8 O-cyanoethyl-O'-cetyl 3
-methoxycarbonyl-1,4-dihydro-
2,6-dimethyl-4-(2-chlorophenyl)
-Pyridine-5-phosphonate yield 69%, yellow oil MS, m/e (intensity ratio) 523 (100) 599 (7) 634 (2,
M ⁺ ) NMR (CDCl ₃ ): δ7.5-6.7 (5H, m), 5.1 (1H,
d, J=10Hz), 4.3-3.1 (4H, m), 3.6 (3H,
s), 2.9-2.0 (8H, m), 2.0-0.6 (31H, m) Example 9 O-cyanoethyl-O'-ethyl 3
-(β-(N-benzyl-N-methylamino)ethoxycarbonyl)-1,4-dihydro-2,
Synthesis of 6-dimethyl-4-(3-nitrophenyl)-pyridine-5-phosphonate O-cyanoethyl-O'-ethyl α-acetyl-(3-nitrostyryl)-phosphonate 1 g,
3-Aminocrotonic acid β-(N-benzyl-N-
0.74 g of methylamino)ethyl was dissolved in 5 ml of toluene and refluxed for 10 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. Fractions containing the target product were collected and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from ethyl acetate to obtain pale yellow needles. Yield 0.89% (yield 55%) mp 116-117℃ MS, m/e (intensity ratio) 134 (80) 147 (100) 404 (5) NMR (CDCl ₃ ): δ8.2-7.2 (4H, m ), 7.2 (5H,
s), 6.6 to 6.4 (1H), 4.9 (1H, d, J = 10Hz),
4.3~3.6 (6H, m), 3.5 (2H, s), 2.8~2.1
(10H, m), 2.2 (3H, s), 1.4-1.0 (3H, m) Examples 10-11 Corresponding O-cyanoethyl-O'-hexyl
Compounds of Examples 10 and 11 were obtained in the same manner as in Example 9 using α-acetyl-(substituted styryl)-phosphonate. Example 10 O-cyanoethyl-O'-hexyl
3-(β-(N-benzyl-N-methylamino)
ethoxycarbonyl)-1,4-dihydro-2,
6-Dimethyl-4-(3-nitrophenyl)-pyridine-5-phosphonate Yield 29%, yellow oil MS, m/e (intensity ratio) 144 (90) 147 (100) 404 (2) NMR (CDCl ₃ ): δ8.3~7.0 (10H, m), 4.9 (1H,
d, J=10Hz), 4.4-3.4 (6H, m), 3.5 (2H,
s), 2.9~2.1 (10H, m), 2.2 (3H, s), 1.8~
0.6 (11H, m) Example 11 O-cyanoethyl-O'-hexyl
3-(β-(N-benzyl-N-methylamino)
ethoxycarbonyl)-1,4-dihydro-2,
6-Dimethyl-4-(2-chlorophenyl)-pyridine-5-phosphonate Yield 56%, yellow oil MS, m/e (intensity ratio) 144 (75) 147 (100) 369
(15) NMR (CDCl ₃ ): δ7.8-7.0 (9H, m), 6.3 (1H,
broad), 5.2 (1H, d, J = 10Hz), 4.5 to 3.5
(6H, m), 3.5 (2H, s) 2.9~2.1 (10H, m),
2.2 (3H, s), 1.8-0.6 (11H, m) Example 12 O-β-N-benzyl-N-methyl-
Synthesis of amino)ethyl-O'-methyl 3-methoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-phenyl-pyridine-5-phosphonate O-β-(N-benzyl-N-methyl-amino )
Ethyl-O'-methyl α-acetylstyrylphosphonate 1.0g, methyl 3-aminocrotonate
0.4 g was dissolved in 20 ml of toluene and refluxed for 10 hours.
The solvent was distilled off under reduced pressure, and the residue was subjected to alumina column chromatography. Low polar substances were eluted with 30% hexane-ethyl acetate to 100% ethyl acetate, and then the target product was eluted with 10% ethanol-ethyl acetate. was eluted. Fractions containing the target compound were collected and the solvent was distilled off under reduced pressure to obtain 0.65 g of the title compound. Compounds of Examples 13 to 23 were obtained in the same manner. The yield and physical properties are shown in Table 1, and the spectral data are shown in Table 2.

【table】

[Table] Example 32 O-β-(N,N-diethylamino)
Ethyl-O'-methyl 3-methoxycarbonyl-1,4-dihydro-2,6-dimethyl-4
Synthesis of -(3-nitrophenyl)-pyridine-5-phosphonate O-β-(N,N-diethylamino)ethyl-
Synthesis of O'-methyl α-acetyl-(3-nitrostyryl)-phosphonate O-β-(N,N-diethylamino)ethyl-
O′-methyl acetonylphosphonate 1.5g, m
- 1.1g of nitrobenzaldehyde and 20ml of benzene
A catalytic amount of piperidine was added and the mixture was refluxed for 6 hours. After changing the solvent to 20 ml of toluene,
-0.9 g of methyl aminocrotonate was added and the mixture was refluxed for 12 hours. The reaction solution was subjected to alumina column chromatography, low polar substances were eluted with ethyl acetate, and then the target substance was eluted with 10% ethanol-ethyl acetate. The yield, physical properties and spectral data are shown in Tables 3 and 4. Compounds of Examples 33 to 37 were obtained in the same manner. The yield and physical properties are shown in Table 3, and the spectral data are shown in Table 4.

【table】

【table】

[Table] Test Example 1 Pharmacological action of dihydropyridine-5-phosphonate (1) Calcium antagonistic action A guinea pig removed cecal cord is suspended in a nutrient solution with a tension of 1 g, and wait until it stabilizes. Replace the nutrient solution with a calcium-free high potassium solution;
After 10 to 20 minutes, 10mM of calcium chloride is added to induce contraction, and after the tension has stabilized, the test drug is administered cumulatively to determine the dose required to induce 50% relaxation (ID ₅₀ :
The unit M) was determined, and its inverse logarithm value (PID ₅₀ ) was calculated. The results are shown in Table 5. (2) Antihypertensive effect The compound was orally administered to spontaneously hypertensive rats (SHR), and blood pressure was measured non-invasively from the tail artery. The results are summarized in Table 5.

【table】

[Table] Test Example 2 Acute toxicity of dihydropyridine-5-phosphonate Using a group of 5 ddy mice (4 weeks old), the LD ₅₀ was determined by the Richfield-Welcoxon method from the mortality rate 7 days after intraperitoneal administration. was calculated. The results are listed in Table 6.

【table】

[Table] Formulation example 1: Tablet ingredients (1000 tablets) Compound of Example 11 5.0 (g) Lactose 190.0 Corn starch 75.0 Microcrystalline cellulose 25.0 Methyl cellulose 3.0 Magnesium stearate 2.0 300 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 each tablet is 300mg. Formulation example 2: Capsule ingredients (1000 tablets) Compound of Example 11 5 (g) Corn starch 145 Microcrystalline cellulose 145 Magnesium stearate 5 300 Measure the amounts of the above ingredients, put them in a V-type mixer, and mix uniformly. This mixed powder is filled into hard capsules. The content per capsule is 300mg. Formulation example 3: Syrup ingredients (2% liquid) Compound of Example 25 2.0 (g) White sugar 30.0 Glycerin 5.0 Flavoring agent 0.1 96% ethanol 10.0 Ethyl P-oxybenzoate 0.03 Distilled water Amount to make the total amount 100.0 g White sugar and After dissolving the active substance in 60 g of warm water, after cooling, a flavoring 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 Compound of Example 11 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 General formula () “In ^the formula, ⁴ ) [R ³ ,
R ⁴ are the same or different from each other, respectively,
It means a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, or an aralkyl group. ] means ;R ¹
means a straight-chain or branched alkyl group having 1 to 16 carbon atoms; R ² is a straight-chain or branched alkyl group having 1 to 6 carbon atoms;
a straight-chain or branched ^{alkyl group, a straight-chain or branched 2-lower alkoxyethyl group having 1 to 6 carbon atoms or -CH2CH2N(R5)(R6} _{) (} ^{R5 ,}
R ⁶ has the same meaning as R ³ and R ⁴ described above, and is the same or different from each other. ]; n means an integer from 2 to 6. '' and pharmacologically acceptable salts of compounds represented by the general formula () with salt-forming ability. 2 General formula () “In ^the formula, ⁴ ) [R ³ ,
R ⁴ are the same or different from each other, respectively,
It means a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, or an aralkyl group. ] means ;R ¹
means a straight-chain or branched alkyl group having 1 to 16 carbon atoms; R ² is a straight-chain or branched alkyl group having 1 to 6 carbon atoms;
a straight-chain or branched ^{alkyl group, a straight-chain or branched 2-lower alkoxyethyl group having 1 to 6 carbon atoms or -CH2CH2N(R5)(R6} _{) (} ^{R5 ,}
R ⁶ has the same meaning as R ³ and R ⁴ described above, and is the same or different from each other. ]; n means an integer from 2 to 6. An antihypertensive agent characterized by containing a compound represented by the formula () and a pharmacologically acceptable salt of the compound represented by the general formula () having salt-forming ability. 3 General formula () [In ^the formula, ⁴ ) [R ³ ,
R ⁴ are the same or different from each other, respectively,
It means a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, or an aralkyl group. ] means ;R ¹
represents a straight-chain or branched alkyl group having 1 to 16 carbon atoms; n represents an integer from 2 to 6; ] Phosphonate derivatives represented by the general formula () [In the formula, R ² is a straight chain or branched alkyl group having 1 to 6 carbon atoms,
Straight-chain or branched 2-lower alkoxyethyl group or -CH ₂ CH ₂ N (R ⁵ ) (R ⁶ ) (R ⁵ and R ⁶ are the same or different, and each has a hydrogen atom and a carbon number 1 to 6 lower alkyl groups or aralkyl groups.] General formula () characterized by reacting a compound represented by “In ^the formula, ⁴ ) [R ³ ,
R ⁴ are the same or different from each other, respectively,
It means a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, or an aralkyl group. ] means ;R ¹
means a straight-chain or branched alkyl group having 1 to 16 carbon atoms; R ² is a straight-chain or branched alkyl group having 1 to 6 carbon atoms;
a straight-chain or branched ^{alkyl group, a straight-chain or branched 2-lower alkoxyethyl group having 1 to 6 carbon atoms or -CH2CH2N(R5)(R6} _{) (} ^{R5 ,}
R ⁶ has the same meaning as R ³ and R ⁴ described above, and is the same or different from each other. ]; n means an integer from 2 to 6. A method of synthesizing a compound represented by ``.