JPH0615553B2 - Dihydropyridine-5-phosphonamidic acids - Google Patents

Description

The present invention relates to a novel 1,4-dihydropyridine-5-phosphonamidic acid derivative, a method for producing the same, and a circulatory vessel containing these compounds. System drugs.

(Prior Art) 1,4-dihydropyridines are known to be useful for the treatment of coronary diseases, cerebral diseases, hypertension and arrhythmias because they suppress the contraction of smooth muscle and myocardium by calcium antagonism. .Fleck-enstein, Annu.Rev.Pharma
col. Toxicol., 17, 149-166 (1977)). These compounds are characterized in that they have a carboxylic acid ester group at the 3,5 position of the dihydropyridine ring, but it has been reported that even if these compounds are replaced with phosphonic acid esters, they have similar activity (JP-A-59). 161392). However, only the phosphonic acid diester is specifically shown in this.

(Problems to be Solved by the Invention, Action of the Compound of the Present Invention) The present inventor synthesized a novel 1,4-dihydropyridine-5-phosphonamidic acid derivative and tested its pharmacological activity, and found that it has a strong antihypertensive action. I found a thing. Moreover, it has been discovered that these compounds have clinically useful features that, when orally administered, they exhibit a gradual action and no palpitations are observed.

(Means for Solving the Problems) The present invention has the general formula (I) [Wherein, X ¹ and X ² are the same or different from each other and represent a hydrogen atom, a nitro group, a trifluoromethyl group, a lower alkyl group, or a chlorine atom; and R ¹ and R ² are the same or different from each other and are hydrogen. An atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a 1,4-butylene group in which R ¹ and R ² together may be substituted with a lower alkyl group; R ³ represents a linear or branched alkyl group having 1 to 10 carbon atoms, or an ethylene group or 1,3-propylene group in which R ³ and R ² together may be substituted with a lower alkyl group. Y is a linear or branched alkyl group having 1 to 4 carbon atoms, (In the formulas, R ⁵ and R ⁶ are the same or different and mean an alkyl group having 1 to 4 carbon atoms which may be substituted with 1 to 2 phenyl groups), or (Wherein R ⁵ has the same meaning as above). ] And a compound of the general formula (I) capable of forming a salt
Relates to a pharmacologically acceptable salt of the compound represented by

The compound represented by the general formula (I) may have geometrical isomers and optical isomers, but the present invention also includes pharmacologically acceptable salts of these compounds and salt-formable compounds thereof. Include.

The present invention also relates to a composition for clinical trials of cardiovascular disease, which comprises a pharmacologically acceptable salt of the compound represented by the general formula (I) or a compound capable of forming a salt thereof. .

The present invention also has the general formula (II) [In the formula, X ¹ , X ² , R ¹ , R ² , and R ³ are those represented by the general formula (I).
Is the same as the explanation. ] To the compound represented by the general formula (III) [In the formula, Y has the same meaning as described for the general formula (I). ]
The present invention relates to a process for producing a compound represented by the above general formula (I), which comprises reacting a compound represented by

The present invention also has the general formula (IV) [In the formula, X ¹ , X ² , R ³ and Y have the same meanings as described in the general formula (I), and Z means a hydroxyl group or a chlorine atom. ] To the compound represented by the general formula (V) (In the formula, R ¹ and R ² have the same meanings as described in the general formula (I).) A method for producing the compound represented by the general formula (I), which comprises reacting the compound represented by the general formula (I). .

The details will be described below.

The compound of the present invention represented by the general formula (I) is synthesized by the method of scheme 1 or 2 below.

(Scheme 1) (Scheme 2) (In the scheme, X ¹ , X ² , R ¹ , R ² , R ³ , Y, Z
Has the same meaning as above. Although the raw material compound (II) is a new compound, it can be produced by existing techniques (for example, DWWhite, J. Am. Chem. Soc., 92, 7125-7135 (1
970). ) Is applied to synthesize. Further, the general formula (IV) which is a raw material compound is also a novel compound, but a compound in which Z is a hydroxyl group can be obtained by hydrolyzing a compound in which Z is a cyanoethoxy group.

(See Japanese Patent Application No. 59-148979) Also, a compound in which Z is a chlorine atom can be obtained by treating a compound in which Z is a hydroxyl group with a chlorinating agent such as oxalyl chloride.

INDUSTRIAL APPLICABILITY The compound of the present invention has an action of suppressing the contraction of smooth muscle and myocardium, and thus is useful for treating coronary diseases, brain diseases and hypertension of humans and mammals.

When the compound of the present invention is used for treating the above-mentioned diseases, it is formed into a pharmaceutical or veterinary composition comprising the compound of the present invention and a pharmaceutically acceptable diluent or carrier.

These compositions may be in the form suitable for oral administration such as tablets, solutions, powders or capsules, suitable for transdermal administration such as ointments or poultices, suitable for inhalation such as aerosols or solutions suitable for spraying, It can be used in the form suitable for parenteral administration, for example, as a sterile aqueous solution suitable for use as an injection or as a suppository suitable for use in the anus or vagina, the rectum and the like.

The above-mentioned pharmaceutical or veterinary composition containing a compound of the present invention contains about 0.
It contains 1-99.5%, preferably about 0.5-95%.

Other pharmaceutically or veterinary active compounds can be included in addition to the compounds of the present invention or compositions containing the compounds of the present invention. In addition, these compositions may contain a plurality of compounds of the present invention.

The daily dosage of the drug containing the compound of the present invention is
Type and degree of symptoms to be treated and individual differences (age, sex,
Sensitivity etc.) The daily dose by intravenous administration is 0.0001 active ingredient / kg body weight.
-10 mg, preferably 0.0005 to 1 mg. The daily dosage by oral and transdermal administration is likewise 0.001-100 mg, preferably 0.005-10 mg, of active ingredient per kg of body weight. When administered in the form of a suppository in the vagina, rectum, etc., the daily dose is similarly 0.001 to 200 mg of active ingredient per kg of body weight,
It is preferably 0.005 to 100 mg. The content of the active ingredient in the inhalant is 0.1 to 10%, preferably 0.1 to 2%. These daily dosages can be divided into two or more doses per day, if necessary.

The above composition containing the compound of the present invention can be produced by a conventional method, and a conventional excipient can be added thereto.

Examples of adjuvants that can be mixed in tablets, capsules, etc. are binders such as tragacanth, acacia, corn starch or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch, potato starch, alginic acid, lubricants such as stearic acid. Magnesium, sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry oil and the like. When the unit used is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials can be present as coatings or to modify the physical form of the unit used. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.

Sterile compositions for injection may be prepared by dissolving the active substance in water for injection, naturally occurring vegetable oils such as sesame oil, coconut oil, peanut oil, cottonseed oil or the like, or synthetic fat vehicles such as ethyl oleate or the like. By suspending, it can be formulated by usual pharmaceutical operations. If necessary, a buffering agent, a preservative, an antioxidant and the like can be mixed.

(Examples, Actions and Effects (Test Examples)) Hereinafter, the present invention will be described more specifically with reference to Examples and Test Examples. The present invention is not limited to these.

Example 1 (Synthesis Method A) 5- (Ethoxy-N, N-dimethylamino-phosphinyl) -2.6-dimethyl-4- (3-chlorophenyl)-
Synthesis of 1,4-dihydropyridine-3-carboxylic acid 2- (N-benzyl-N-methylamino) -ethyl ester α-Acetyl-3-chlorostyrylphosphonamidic acid 0
-Ethyl-N, N-dimethyl ester 1.0 g and 3-aminocrotonic acid 2- (N-benzyl-N-methylamino)-
1.0 g of ethyl ester was dissolved in 20 ml of toluene and refluxed for 15 hours. After distilling off the toluene under reduced pressure, the residue was subjected to silica gel chromatography (insoluble liquid; ethyl acetate / ethanol = 9/1 (v / v), Rf = 0.5) to obtain the title compound.

Similarly, the compounds of Examples 2-33 were synthesized. Table 1-
The structures, yields, properties, and MS spectrum data of the compounds are collectively described in (1) to (6).

Example 34 (Synthesis Method B) 5- (n-hexyloxy-amino-phosphinyl) -2.
6-Dimethyl-4- (3-chlorophenyl) -1,4-dihydropyridine-3-carboxylic acid 2- (N-benzyl-N
-Methylamino) -ethyl ester synthesis 5- (n-hexyloxy-hydroxy-phosphinyl)
-2.6-Dimethyl-4- (3-chlorophenyl) -1,4-
Dihydropyridine-3-carboxylic acid 2- (N-benzyl-N-methylamino) -ethyl ester (1.0 g) was dissolved in methylene chloride (5 ml) to give oxalyl chloride (200 μm).
1 was added dropwise at room temperature and stirred for 15 minutes. -30 ℃ the reaction vessel
Cooled to. To this, excess ammonia dissolved in methylene chloride was added dropwise, and the reaction temperature was gradually returned to room temperature. The solvent was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was separated, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was chromatographed on silica gel (eluent: ethyl acetate /
Ethanol = 9/1, v / v, Rf = 0.5) to give the title compound.

Similarly, the compounds of Examples 35 to 37 were synthesized. Table 1
The structure, yield, properties, and MS spectrum data of the compound are collectively described in-(7).

Test Example 1. (1) Calcium antagonism The guinea pig excised caecal cord is hung in the nutrient solution with a tension of 1 g and waits for stabilization. Replace the nutrient solution with a calcium-free high potassium solution, and after 10 to 20 minutes, calcium chloride 1
Added 0mM to contract, tension is the test drug was administered cumulatively from stable, the antilog roots determine the concentration ID ₅₀ (M) of the test drug required to relax 50% (pID ₅₀ ) Was calculated. The results are shown in Table 2.

(2) Antihypertensive effect The antihypertensive effect of the compound of the present invention was tested using SHR (spontaneously hypertensive rat) anesthetized with ureretan-α-chloralose. In this test, 3 to 5 SHRs were grouped into one group, and blood pressure in the femoral artery of each rat was measured invasively. Each compound was dissolved in 3% tween 80-physiological saline and injected into the femoral artery. The dose ED ₃₀ (mg / kg) required to reduce the blood pressure by 30% was determined from the correlation between the dose and the maximum blood pressure reduction rate. The results are shown in Table 2.

Formulation Example 1: Tablet Component (1000 tablets) Hydrochloride of the compound of Example 1 5.0 (g) Lactose 190.0 Corn starch 75.0 Microcrystalline cellulose 25.0 Methylcellulose 3.0 Magnesium stearate 2.0 300. 0 Weigh the above components, put in a V-type mixer, and mix evenly. This mixed powder is directly compressed into tablets. The weight per tablet is 300 mg.

Formulation Example 2: Capsule component (1000 tablets) Hydrochloride of the compound of Example 1 5 (g) Corn starch 145 Microcrystalline cellulose 145 Magnesium stearate 5 300 Weigh the above components, put in a V-type mixer and mix evenly. To do. A hard capsule is filled with this mixed powder. The content per capsule is 300 mg.

Formulation Example 3: Syrup component (2% liquid) Hydrochloride of the compound of Example 1 2.0 (g) Sucrose 30.0 Glycerin 5.0 Flavoring agent 0.1 96% Ethanol 10.0 p-Oxybenzoic acid Methyl 0.03 Distilled water Amount to make the total amount 100.0 g After dissolving sucrose and the hydrochloride of the compound of Example 1 in 60 g of warm water, after cooling, a flavoring agent solution dissolved in glycerin and ethanol was added. Then, water was added to this mixture to make a total amount of 100.0 g.

Formulation Example 4: Powders Hydrochloride salt of the compound of Example 1 1.0 (g) Lactose 88.0 Microcrystalline cellulose 10.0 Methylcellulose 1.0 100.0 Weigh the above components and put into a V-type mixer and homogenize Mixed in.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location C07F 9/6558 7537-4H 9/6584 7537-4H

Claims (4)

[Claims] 1. A general formula (I) [In the formula, X ¹ and X ² are the same or different from each other and represent a hydrogen atom, a nitro group, a trifluoromethyl group, a lower alkyl group or a chlorine atom; R ¹ and R ² are the same or different from each other; R ³ represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms, or 1,4-butylene group in which R ¹ and R ² together may be substituted with a lower alkyl group; R ³ Is a linear or branched alkyl group having 1 to 10 carbon atoms, or an ethylene group in which R ³ and R ² together may be substituted with a lower alkyl group, or 1,3-
Means a propylene group; Y is a linear or branched alkyl group having 1 to 4 carbon atoms, (In the formula, R ⁵ and R ⁶ are the same or different and each represents an alkyl group having 1 to 4 carbon atoms which may be substituted with 1 to 2 phenyl groups), or (Wherein R ⁵ has the same meaning as above). ] And a compound of the general formula (I) capable of forming a salt
A pharmaceutically acceptable salt of the compound represented by: 2. General formula (I) [In the formula, X ¹ and X ² are the same or different from each other and represent a hydrogen atom, a nitro group, a trifluoromethyl group, a lower alkyl group or a chlorine atom; R ¹ and R ² are the same or different from each other; R ³ represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms, or 1,4-butylene group in which R ¹ and R ² together may be substituted with a lower alkyl group; R ³ Is a linear or branched alkyl group having 1 to 10 carbon atoms, or an ethylene group in which R ³ and R ² together may be substituted with a lower alkyl group, or 1,3-
Means a propylene group; Y is a linear or branched alkyl group having 1 to 4 carbon atoms, (In the formula, R ⁵ and R ⁶ are the same or different and each represents an alkyl group having 1 to 4 carbon atoms which may be substituted with 1 to 2 phenyl groups), or (Wherein R ⁵ has the same meaning as above). ] And a compound of the general formula (I) capable of forming a salt
A composition for treating cardiovascular disease, which comprises a pharmacologically acceptable salt of the compound represented by: 3. General formula (I) [In the formula, X ¹ and X ² are the same or different from each other and represent a hydrogen atom, a nitro group, a trifluoromethyl group, a lower alkyl group or a chlorine atom; R ¹ and R ² are the same or different from each other; R ³ represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms, or 1,4-butylene group in which R ¹ and R ² together may be substituted by a lower alkyl group; R ³ Is a linear or branched alkyl group having 1 to 10 carbon atoms, or an ethylene group in which R ³ and R ² together may be substituted with a lower alkyl group, or 1,3-
Means a propylene group; Y is a linear or branched alkyl group having 1 to 4 carbon atoms, (In the formula, R ⁵ and R ⁶ are the same or different and each represents an alkyl group having 1 to 4 carbon atoms which may be substituted with 1 to 2 phenyl groups), or (Wherein R ⁵ has the same meaning as above). ] In the method for producing the compound represented by the general formula (II) [In the formula, X ¹ , X ² , R ¹ , R ² , and R ³ are those represented by the general formula (I).
Is the same as the explanation. ] To the compound represented by the general formula (III) [In the formula, Y has the same meaning as described for the general formula (I). ]
A production method comprising reacting a compound represented by: 4. The general formula (I) [In the formula, X ¹ and X ² are the same or different from each other and represent a hydrogen atom, a nitro group, a trifluoromethyl group, a lower alkyl group or a chlorine atom; R ¹ and R ² are the same or different from each other; R ³ represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms, or 1,4-butylene group in which R ¹ and R ² together may be substituted with a lower alkyl group; R ³ Is a linear or branched alkyl group having 1 to 10 carbon atoms, or an ethylene group in which R ³ and R ² together may be substituted with a lower alkyl group, or 1,3-
Means a propylene group; Y is a linear or branched alkyl group having 1 to 4 carbon atoms, (In the formula, R ⁵ and R ⁶ are the same or different and each represents an alkyl group having 1 to 4 carbon atoms which may be substituted with 1 to 2 phenyl groups), or (Wherein R ⁵ has the same meaning as above). ] In the method for producing the compound represented by the general formula (IV) [In the formula, X ¹ , X ² , R ³ and Y have the same meanings as described in the general formula (I), and Z means a hydroxyl group or a chlorine atom. ] To the compound represented by the general formula (V) [In the formula, R ¹ and R ² have the same meanings as described for the general formula (I). ] The manufacturing method characterized by reacting the compound shown by these.