JPH0453870B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a method for producing 1,4-dihydropyridine-5-phosphonic acid diamide, which has 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 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. Regarding dihydropyridine-5-phosphonate derivatives, JP-A-59-161392 describes dihydropyridine-5-phosphonic acid diesters, but no examples of dihydropyridine-5-phosphonic acid diamides have been found. (Effects of the compounds of the present invention) The present inventor converted hostonic acid diester at position 5 into a completely new phosphonic acid diamide and tested its pharmacological activity. As a result, toxicity was reduced while maintaining strong calcium antagonistic and antihypertensive effects. I found out what I can do. The present invention is based on the general formula () (In the formula, X ¹ and X ² are the same or different from each other and mean a hydrogen atom, a nitro group, a halogen atom, or a trifluoromethyl group, and Y is a lower alkyl group having 1 to 4 carbon atoms,

【formula】

[Formula], R ¹ and R ² are the same or different and represent an alkyl group having 1 to 4 carbon atoms, R ³ and R ⁴ are R ¹ ,
It has the same meaning as R ² or refers to an ethylene group or propylene group that is unsubstituted or substituted with an alkyl group having 1 to 4 carbon atoms when bonded to each other. ) and pharmacologically acceptable salts of the compound represented by the general formula () with salt-forming properties. Geometric isomers and optically active forms of the compound represented by the general formula () may exist, and the present invention also includes pharmaceutically acceptable salts of these and of compounds capable of forming salts. The present invention also relates to an antihypertensive agent characterized by containing a pharmaceutically acceptable salt of a compound represented by the above general formula () or a compound capable of forming a salt thereof. The present invention also provides a compound represented by the general formula (), which is characterized by reacting a compound represented by the general formula () with a compound represented by the general formula () as shown in Scheme 3 below. The present invention relates to a method for producing the compounds shown. A step-by-step explanation will be given below. The compound of the present invention is synthesized according to the flow of Scheme 1. (X ₁ , X ₂ , R ¹ , R ² , R ³ , R ⁴ in Scheme-1,
and Y have the same meaning as in the general formula (). ) Although some of the raw material compounds, acetonylphosphonic acid diamide, are new, they were all synthesized by applying existing technology. (For example, (1)VSAbramov et al., Khim.Org.
soedin.Fosfora，Akad.Nauk SSSR.Otd.
OBshch.Tekh.Khim., 1967, 119-29, (2)T.
Mukaiyama et al., Bull.Chem.Soc.Japan, 39~
241–219 (1966)). That is, as shown in Scheme-2, it was synthesized from the reaction of a phosphorodiamidous acid derivative [a] and iodoacetone. (R ¹ , R ² , R ³ and R ⁴ in Scheme-2 have the same meaning as explained in general formula ().) Examples of R ¹ and R ² include methyl group, ethyl group, and propyl group. , isopropyl group, butyl group, isobutyl group, sec-butyl group, amyl group, hexyl group, and the like. Examples of R ³ and R ⁴ are, in addition to those listed for R ¹ and R ² , when combined together -CH ₂ -CH ₂ -,

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

Examples include [Formula]. The reaction shown in Steam 3 below in Scheme 1 will be explained in more detail. (X ¹ , X ² , Y, R ¹ , R ² , R ³ and R ⁴ in Scheme-3 have the same meaning as in the general formula ()). General formula () characterized by reacting a compound represented by general formula () with a compound represented by general formula () in an inert solvent as shown by
It also relates to the manufacturing method. The starting compound () can be obtained by the reaction of acetonylphosphonic acid diamide and benzaldehydes by applying known techniques, and the starting compound () can be easily obtained by the reaction of the corresponding carbonyl compound with ammonia. It will be done. The raw material compound () may be produced in the reaction system by mixing the corresponding carbonyl compound and ammonia,
It does not necessarily have 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 penzene, 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 20 hours to 50 hours. As mentioned above, the compounds of the present invention suppress the contraction of smooth muscle and cardiac muscle through calcium antagonistic action, and therefore are useful for the treatment of 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 0.0001-100mg. 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, Test Examples, Formulation 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. Example 1 N,N,N',N'-tetraethyl-3-(2-
Synthesis of (N-benzyl-N-methylamino)-ethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-5-phosphonic acid diamide N,N,N' , N'-tetraethyl-α-acetyl-(3-nitrostyryl)-phosphonic acid diamide
1.1 g of 2-aminocrotonic acid and 0.9 g of 2-(N-benzyl-N-methylamino)ethyl ester were dissolved in 20 ml of toluene and refluxed for 130 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate, Rf value 0.6).
The title compound was obtained. Compounds of Examples 2 to 14 were obtained in the same manner. The physical properties of the obtained compound are shown in Table 1, and the spectral data are shown in Table 2.

【table】

【table】

【table】

【table】

[Table] Formulation example 1 Tablets Ingredients (1000 tablets) Hydrochloride of the compound of Example 1 5.0g Lactose 190.0 Cornstarch 75.0 Microcrystalline cellulose 25.0 Methyl cellulose 3.0 Magnesium stearate 2.0 300.0 Weigh the amounts of the above ingredients and mix them in a V-type mixer. and 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) Hydrochloride of the compound of Example 1 5g Corn starch 145 Microcrystalline cellulose 145 Magnesium stearate 5 300 Measure out 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% solution) Hydrochloride of the compound of Example 1 2.0g White sugar 30.0 Glycerin 5.0 Flavoring agent 0.1 96% ethanol 10.0 Methyl p-oxybenzoate 0.03 Distilled water Amount to make the total amount 100.0g 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 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 1.0g Lactose 88.0 Microcrystalline Cellulose 10.0 Methylcellulose 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, X ¹ and X ² are the same or different and are a hydrogen atom, a nitro group, a halogen atom,
means a trifluoromethyl group; Y is a lower ^alkyl group having 1 to ⁴ carbon atoms; R ³ and R ⁴ have the same meaning as R ¹ R ² or are bonded to each other and represent an ethylene group that is unsubstituted or substituted with an alkyl group having 1 to 4 carbon atoms; means a propylene group. ) and pharmacologically acceptable salts of the compound represented by the general formula () with salt-forming ability. 2 General formula () (In the formula, X ¹ and X ² are the same or different from each other and mean a hydrogen atom, a nitro group, a halogen atom, or a trifluoromethyl group; Y is a lower alkyl group having 1 to 4 carbon atoms; [Formula ] [Formula] means; R ¹ and R ² are the same or different from each other and represent an alkyl group having 1 to 4 carbon atoms; R ³ and R ⁴ are R ¹ ,
It has the same meaning as R ² or is bonded to each other, and means an ethylene group or propylene group which is unsubstituted or substituted with an alkyl group having 1 to 4 carbon atoms. 1. A vasodilator comprising a compound represented by formula () or a pharmacologically acceptable salt of a compound represented by general formula () having salt-forming ability. 3 General formula () (In the formula, X ¹ and ^{X 2} are the same or different from each other and mean a hydrogen atom, a nitro group, ^a halogen atom, or a trifluoromethyl group; 1 to 4 alkyl group; R ³ and R ⁴ have the same meaning as R ¹ and R ² or are bonded to each other and are unsubstituted or substituted with an alkyl group having 1 to 4 carbon atoms. (means an ethylene group or a propylene group). (In the formula, Y is a lower alkyl group having 1 to 4 carbon atoms,
[Formula] means [Formula]. ) A general formula () characterized by reacting a compound represented by (In the formula, R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ² and Y have the same meanings as in the general formulas () and () above.).