JPH01275591A - Dihydropyridine-5-phosphonic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [X<1> and X<2> are H, NO2, Cl or CF3; Y is (1-3C alkyl-substituted) 1,2-ethylene or 1,3-propylene; A1-A3 are (1-3C alkyl-substituted) 0-8C alkylene or alkenylene; Z1 and Z2 are (substituted) cyclopentylene, cyclohexylene or phenylene; n is 0 or 1]. EXAMPLE:2-(4-Phenylphenyl)ethyl 5-(2,2-dimethylpropylenedioxyphosphinyl)-2,6- dimethyl-4-(3--nitrophenyl)-1,4-dihydropyridine-3-carboxylate. USE:A remedy for circulatory diseases, such as mammalian angina pectoris, cerebral blood circulation disorder or hypertension, having oral antihypertensive action. PREPARATION:A cyclic ester of acetonitrilephosphonic acid expressed by formula II is reacted with benzaldehydes expressed by formula III to afford a compound expressed by formula IV, which is then reacted with a compound expressed by formula V.

Description

[Detailed Description of the Invention] (Field of Industrial Application) The present invention has an oral antihypertensive effect and is effective against cardiovascular diseases such as angina pectoris, cerebral blood circulation disorders, and hypertension in humans and mammals. The present invention relates to dihydropyridine-5-phosphonic acid cyclic ester-3-carboxylic acid esters useful for the treatment of.

The present invention also relates to a pharmaceutical composition containing the above compound.

(Prior Art) Japanese Patent Publication No. 62-169746, European Patent Publication No. 0141222 (hereinafter referred to as Document a) and No. 0159040 (hereinafter referred to as Document A) disclose dihydropyridine-5-phosphones similar to the compounds of the present invention. There is a description of acid cyclic ester-3-carboxylic acid esters.

(Problem to be solved by the invention) Oral antihypertensive activity is higher than that of the compounds described in documents a and b above, the duration of action is longer, and the heart palpitation is weaker,
Dihydropyridine-5-phosphonic acid cyclic ester-3-carboxylic acid esters with different chemical structural features were explored.

As a result, it was discovered that the compounds of the present invention are expected to satisfy these conditions in addition to the above.

(Means for Solving the Problems) The compound of the present invention has the form (1) [wherein, Xl and Xl are the same or different from each other and represent hydrogen, N(h, chlorine or CFi; C1~C
1. which may be optionally substituted by alkyl of 3;
means 2-ethylene or 1,3-propylene; Az, Az, A3 means 00-C6 alkylene or alkenylene optionally substituted by 01-C1 alkyl; Z, , Z, means C3 -C4 alkyl, 01-C4 alkoxy, cyclopentylene, cyclohexylene or phenylene optionally substituted by fluorine or chlorine; n means 0 or l. ] It is a compound shown by.

Furthermore, although the compound represented by the formula (1) has one or more asymmetric carbon atoms, the present invention includes all of these optical isomers.

The compound of the present invention is synthesized according to Scheme 1 below.

(Hereinafter in the margins) [Scheme 1] (a) Ni1□ The raw material compound (If) can be obtained from the reaction of the acetonylphosphonic acid cyclic ester (a) and benzaldehydes by applying known techniques. Compound(
III) can be easily obtained by reacting the corresponding carbonyl compound with ammonia. The raw material compound (III) may be produced in the reaction system by mixing the corresponding carbonyl compound and ammonia, and does not necessarily need to be molded.

Inert solvents include alcoholic solvents such as methanol, ethanol, propatool, and isoproptool; 1.2
- Ether solvents such as dimethoxyethane and THF,
Aromatic hydrocarbon solvents such as benzene, toluene, and xylene, nitrile solvents such as acetonitrile and hendonitrile, amide solvents such as DAM, DMF, and N-methylpyrrolidone, sulfoxide solvents such as ISO and sulfolane, and acetic acid. In addition to ester solvents such as ethyl and butyrolactone, pyridine and the like can also be used.

The reaction is carried out between room temperature and 200'C, preferably between 60 and 1
This is carried out by heating at 40°C for 1 hour to 100 hours, preferably 5 hours to 20 hours.

The compound of the present invention exhibits an oral antihypertensive effect as shown in the test example of the effect of the invention below, and therefore, vasodilation causes circulatory system diseases such as angina pectoris, cerebral blood circulation disorders, and hypertension in mammals. It is useful in the treatment of.

When the compound of the present invention is used for the above-mentioned therapeutic purposes, it is formed into a pharmaceutical or veterinary composition comprising this type of dihydropyridine and a pharmaceutically or veterinarily acceptable diluent or carrier. be done.

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 compositions containing the compounds of the invention contain about 0.1 to 99.5%, preferably about 0.5 to 95%, of the compounds by weight of the total composition.

In addition to the compounds of the present invention or compositions containing the compounds of the present invention, other pharmaceutically or veterinary active compounds may 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, irritability, etc.). The daily dosage for intravenous administration is from 0.0001 to 1 kg of active ingredient per kg of body weight.
IO+ng, preferably 0.0005-1'mg. The dosage per 10 for oral and transdermal administration is similarly 0.001 to 10 per kg of body weight of active ingredient.
It is at 0. In addition, when administering in the form of crude drugs into the vagina, rectum, etc., the daily dosage is 0 active ingredients per 1 kg of body weight.
．． 001-200mg, preferably O,OO5-100
mg. The active ingredient content of the inhaler is 0.1 to 10 stars.
% is preferably 0.1 to 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, Test Examples, Formulation Examples) The present invention will be explained in more detail below using Examples, Formulation Examples, and Test Examples, but the scope of the present invention is not limited thereto. In addition, it means the phenyl group of ph in the following structural formula.

Test Example 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 shown in Table 1.

Table 1 Antihypertensive effect (Note) Structural formula of nicardipine (see next page) Example 1 5-(2,2-dimethylpropylenedioxyphosphinyl)-2,6-dimethyl-4-(3-nitrophenyl)
-1,4-dihydropyridine-3-carboxylic acid 2-
(4-Phenylphenyl)ethyl ester 2.2-dimethylpropylene α-(m-nitrobenzylidene)-acetonylphosphonate 4.38g (12
, 9 mmole) in 21 mfl of toluene,
Heat and dissolve. This is added to 3-aminocrotonic acid 2-(4
-phenylphenyl)ethyl ester 3.63 g (
A solution consisting of 12.9 mmole) and 10 d of toluene was added dropwise over 30 minutes under azeotropic dehydration conditions, and the mixture was further heated for 4 hours. After cooling, the precipitated crystals were collected by filtration to obtain the title compound as a toluene solvate (6.7 g, yield 75%). This was purified by silica gel column chromatography (ethyl acetate Rf value 0.5).

Pale yellow crystals mp 105-106°C Example 2 5-(2,2-dimethylpropylenedioxyphosphinyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3- Carvone M3-
<2.5-dimethoxyphenyl)propyl ester 2.2-dimethylpropylene α-(m-nitrobenzylidene)-acetonylphosphonate 6.79g (20
,0mmole) to toluene 33d! Dissolve and heat to dissolve. This was added to 3-aminocrotonic acid 3- (2,
5-dimethoxyphenyl)propyl ester 5.58
A solution consisting of 16d g (20,0 mmole) of toluene was added dropwise under azeotropic dehydration conditions over 30 minutes, and the mixture was further heated for 4 hours. After cooling, the precipitated crystals were collected by filtration to obtain the title compound as a toluene solvate (11.17 g, yield 81%). This was purified by silica gel column chromatography (ethyl acetate Rf value 0.5).

Pale yellow crystals mp75-77°C Example 3 5-(2,2-dimethylpropylenedioxyphosphinyl)-2,6-dimethyl-4-(3-nitrophenyl)
-1,4-dihydropyridine-3-carboxylic acid 4-
Cyclohexylbutyl ester 2.2-dimethylpropylene α-(m-nitrobenzylidene)-a7tonyl phosphonate) 1. Og (2,95 mmole),
3-aminocrotonic acid 4-cyclohexylbutyl ester 740mg (3.10mmole), toluene L
The solution consisting of Oml was heated overnight under azeotropic dehydration conditions. After distilling off the solvent under slight pressure, the residue was subjected to silica gel column chromatography (ethyl acetate/ethanol = 15/1.V
/V, Rf value 0.6) to give the title compound yellow crystals ('
1.5 g, yield 91%).

mp 112-113°C Example 4 5-(2,2-dimethylpropylenedioxyphosphinyl)-2,6-dimethyl-4-(3-nitrophenyl)
-1,4-dihydropyridine-3-carvone 12-(
4-phenylcyclohexyl)ethyl ester 2,2-dimethylpropylene α-(m-nitrobenzylidene)-acetonylphosphonate 678g (2,0
mmole), 3-aminocrotonic acid 2-(4-
Phenylcyclohexyl)ethyl ester 574mg
(2.0 mmole) and 5 ml of toluene was heated under azeotropic dehydration conditions for 15 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/methanol = 9/LV/V, Rf value 0.
65) to obtain the title compound as yellow crystals (1.21 g, yield 100%).

mp 105-106°C Example 5 5-(2',2-dimethylpropylenedioxyphosphinyl)-2,6-dimethyl-4-(2,3-dichlorophenyl)-L4-dihydropyridine-3=carboxylic acid
2-(4-phenylcyclohexylidene)ethyl ester 2,2-dimethylpropylene α-(2,3-dichlorobenzylidene)-acetonylphosphonate 728mg
(2,0 mmole), 3-aminocrotonic acid 2-
(4-phenylcyclohexylidene) ethyl ester 0.57 g (2.0 mmole), toluene 5
ml solution was heated under azeotropic dehydration conditions for 10 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/methanol = 9/1.V/
V, Rf value 0.65) to convert the title compound into colorless crystals (
0.58 g, yield 46%).

mp83-87°C Example 6 5-(2,2-dimethylpropylenedioxyphosphinyl)-2,6-simethyl-4-(3-nitrophenyl)
-1,4-dihydropyridine-3-carvone M2
-(4-Phenylcyclohexylidene)ethyl ester 2.2-dimethylpropylene α-(m-nitrobenzylidene)-acetonylphosphonate 678mg (2,
0 mmole ), 3-aminocrotonic acid 2-(4
-1 phenylcyclohexylidene) ethyl ester 0.
57 g (2,0 mmole), toluene 3 ma
The solution consisting of 1 was heated under azeotropic dehydration conditions for 10 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/methanol-9/1.V/V
, Rf value 0.65) to give the title compound yellow crystals (1,
04g, yield 86%).

mp 102-105°C Example 7 5-(2,2-dimethylpropylenedioxyphosphinyl)-2,6-dimethyl-4-(3-dil.lophenyl)-1,4-dihydropyridine-3-carvone acid
5-phenyl-3-pentenyl ester 2,2-dimethylpropylene α-(m-nitrobenzylidene)-acetonylphosphonate 1.0 g (2,95 mmole
), 750 μm (3,06 mmole) of 3-aminocrotonic acid 5-phenyl-3-pentenyl ester, and 10 In1 toluene was heated overnight under azeotropic dehydration conditions. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/ethanol = I5/
I, V/V.

Rf value 0.6) to give the title compound as yellow crystals (1.4 g
, yield 84%).

mp 129-129.5°C Example 8 5-(2,2-dimethylpropylenedioxyphosphinyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carvone acid 3
-(4-isopropylphenyl)propyl ester 2,2-dimethylpropylene α-(m-nitrobenzylidene)-acetonylphosphonate 1.0 g (2,95
mmole), 3-aminocrotonic acid 3-(11
A solution consisting of 10 ml of -isopropylphenyl)propyl ester, I.luene was heated overnight under azeotropic dehydration conditions. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/era) - L = 15
/ 1. V/V, Rf (I!!0.6) to obtain the title compound as yellow crystals (1.4 g, yield 82%).

mp 101-102°C Formulation Example 1: Tablet ingredients (1000 tablets) Compound of Example 1 5.0 (g) Lactose 19.0
, 0 Corn starch 75.0 Microcrystalline cellulose 25.0 Methyl cellulose 3.0 Magnesium stearate 2.0300.0 Measure out the amounts of the above ingredients, put them in a type mixer, and mix them uniformly. This mixed powder is made into tablets by direct compression. - Weight per tablet is 300 mg.

Formulation example 2: Capsule ingredients (1000 tablets) Compound of Example 1 5.0 (g) Corn starch 145.0 Microcrystalline cellulose 145.0 Magnesium stearate 5.0300.0 Weigh the amounts of the above ingredients, and mix them using a ■-type mixer. and mix evenly. This mixed powder is filled into hard capsules. The content per capsule is 300 mg.

Formulation Example 3: Syrup ingredient (2% liquid) Compound of Example 1 2.0 (g) White sugar
30.0 Glycerin 5.0 Flavoring agent 0.1 96% Ethanol 10. Op-methyl oxybenzoate 0.03 distilled water
Amount to make total amount 100.0 g White sugar and the hydrochloride salt of the compound of Example 1 were dissolved in 60 g of warm water, and after cooling, a flavoring agent solution dissolved in glycerin and ethanol was added. Then add water to this mixture and make it all
I set it to og.

Formulation Example 4: Powder Compound of Example 1 1.0 (g) Lactose 88
．． 0 Microcrystalline cellulose 10.0 Methyl cellulose 1.0100.0 The above ingredients (2) were weighed and placed in a (2) type mixer and mixed uniformly.

\ Patent applicant: Nissan Chemical Industries, Ltd.

Claims (9)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, X^1 and X^2 are the same or different from each other,
means hydrogen, NO_2, chlorine or CF_3; Y is C
means 1,2-ethylene or 1,3-propylene which may be optionally substituted with alkyl of C_1 to C_3; A_1, A_2, A_3 are C_0 to C_0 which may be optionally substituted with alkyl of C_1 to C_3; C_8 means alkylene or alkenylene; Z_1 and Z_2 are C_1 to C_4 alkyl, C_1 to
means cyclopentylene, cyclohexylene or phenylene optionally substituted by alkoxy, fluorine or chlorine at C_4; n means 0 or 1; ] A compound represented by. (2) Is the pair of X^1 and X^2 hydrogen and NO_2?
The compound according to claim (1), wherein both are chlorine. (3) The compound according to claim (1) or (2), wherein Y is -CH_2C(CH_3)_2CH_2-. (4) The compound according to claim (1), (2) or (3), wherein Z_1 and Z_2 are cyclohexylene or phenylene simultaneously or differently. (5) The compound according to claim (1), (2), (3) or (4), wherein A_1 is a C_2 to C_6 linear alkylene or alkenylene. (6) Claims (1), (2), (
3), (4) or (5). (7) When n=0, the total number of carbon atoms in the alkylene main chains of A_1 and A_3 is 4 to 8.
2), (3) or (4). (8) A claim in which when n=1, the total number of carbon atoms in the main chain of alkylene of A_1, A_2, and A_3 is 0 to 4 (
1), (2), (3) or (4). (9) Claims (1), (2), (3), (4), (5)
, (6), (7) or (8).