JPS62195392A - Dihydropyridine-5-phosphonamidic acid compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I {X<1> and X<2> are H, nitro, trifluoromethyl, lower alkyl, (halogen-substituted) lower alkoxy, F or Cl; R<1> and R<2> are H, 1-6C alkyl or R<1> and R<2> together form (substituted) 1,4-butylene; R<3> is 1-10C alkyl or R<3> and R<2> together form (substituted) ethylene, etc.; Y is 1-4C alkyl, group of formula II [R<5> and R<6> are (substituted) 1-4C alkyl] or group of formula III} and its salt. EXAMPLE:5-(Ethoxy-N, N-dimethylamino-phosphinyl)-2,6-dimethyl-4-(3-chlorophe ny-l)--1,4-dihydropyridine-3-carboxylic acid 2-(N-benzyl-N-methylamino)-ethyl ester. USE:A remedy for circulatory diseases. PREPARATION:The compound of formula IV is made to react with the comopund of formula V.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention relates to novel 1,4-dihydropyridine-5-phosphonamic acid derivatives, methods for producing the same, and cardiovascular systems containing these compounds. Concerning system acting drugs.

(Prior Art) It is known that 1.4-dihydropyridines inhibit the contraction of smooth muscle and cardiac muscle through calcium antagonistic action, and therefore can be used to treat coronary diseases, brain diseases, hypertension, and arrhythmia (A , Fleck-enstein
, Annu, Rev., Pharmacol, T.
oxicol, +17+149~166 (1977
)reference). These compounds have a dihydropyridine ring with 3.
It is characterized by having a carboxylic acid ester group at the 5-position, but it has been reported that even if this is replaced with a phosphonic acid ester, it has similar activity (Japanese Unexamined Patent Publication No. 16139-1989).
2). However, only phosphonic acid diesters are specifically shown in -1.

(Problems to be solved by the invention, effects of the compounds of the present invention) The present inventor synthesized a novel 1,4-dihydropyridine-5-phosphonamic acid derivative and tested its pharmacological activity, and found that it has a strong antihypertensive effect. I discovered that. Moreover, it has been discovered that these compounds have clinically useful features, such that their effects are slow when administered orally, and no symptoms of heart palpitations are observed.

(Means for Solving the Problems) The present invention is based on the general formula (1) [wherein XI and means a lower alkoxy group, a fluorine atom, or a chlorine atom that may be substituted; R' and R'' are the same or different from each other and are a hydrogen atom, a straight chain or branched alkyl group having 1 to 6 carbon atoms, or R1 and R2 taken together mean a 1,4-butylene group optionally substituted by a lower alkyl group; R3 is a straight or branched alkyl group having 1 to 10 carbon atoms, or R2 together means an ethylene group or a 1,3-propylene group which may be substituted with a lower alkyl group; Y is a straight or branched alkyl group having 1 to 4 carbon atoms, or Rs and Rh 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 (hereinafter, blank) f-be (in the formula, R' is the above has the same meaning as ).
Compounds represented by and general formula (1) with salt-forming ability
The present invention relates to a pharmacologically acceptable salt of the compound represented by:

The compound represented by general formula (1) may have geometric isomers and optical isomers, but the present invention also includes pharmacologically acceptable salts of these and compounds with salt form properties. include.

The present invention also relates to a composition for clinical trials of circulatory system diseases, which is characterized by containing a pharmacologically acceptable salt of the compound represented by the above general formula (1) or a compound having salt form properties. .

Further, the present invention is based on the general formula (■) (hereinafter, blank space) x I
x Z [where x', x'', R', R'', and R3 are general formula (1)
(7) Same as explanation. ] The compound represented by the general formula (I[) H,N-C=CHC0,Y (I[[)HI [wherein, Y has the same meaning as in the description of the general formula (I)]. ]
The present invention relates to a method for producing a compound represented by the above general formula (1), which is characterized by reacting a compound represented by the formula (1). (Hereinafter, blank space) H [In the formula, X', The compound represented by the above general formula (I) is reacted with the compound represented by the formula (V) (wherein R1 and R2 have the same meanings as explained in the general formula (I)). Regarding the manufacturing method.

This will be explained in more detail below.

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

(Scheme 1) + Hz N C= CHCOz Y (
I ) ■ H3 (III) (Hereinafter, blank space) (Scheme 2) (rV) (V) (In the scheme, xl, xl, R1, R2, R2゜Y
, Z have the same meaning as above. ) (hereinafter, blank space) The raw material compound (n) is a new compound, but it is based on existing technology (for example, D, W, White, J, Am, Chem
, Soc, +92, 7125-7135 (1970)
See. ) can be synthesized by applying. Furthermore, although the starting compound, general formula (IV), is also a new compound, those in which Z is a hydroxyl group can be obtained by hydrolyzing those in which Z is a cyanoethoxy group.

(See Japanese Patent Application No. 59-148979.) Those 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.

Since the compounds of the present invention have the effect of suppressing the contraction of smooth muscle and cardiac muscle, they are useful for treating coronary diseases, brain diseases, and hypertension in humans and mammals.

When the compound of the present invention is used to treat 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 forms suitable for oral administration, e.g. tablets, solutions, powders or capsules; in forms suitable for transdermal administration e.g. ointments or poultices; in forms suitable for inhalation e.g. aerosols or solutions suitable for spraying; Forms suitable for parenteral administration, e.g. sterile aqueous solutions suitable for use as injections;
Alternatively, it can be used in the form of a suppository suitable for use within the anus, vagina, rectum, etc.

The above pharmaceutical or veterinary composition containing the compound of the present invention contains about 0% of the compound of the present invention, based on the weight of the total composition.
．． 1 to 99.5%, preferably about 0.5 to 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 is:
The type and severity of the symptoms to be treated and individual differences (age, gender,
There are differences depending on anger sensitivity, etc. The daily dosage by intravenous administration is 0.00 active ingredient per kg of body weight.
01~lO■, preferably 0, OOO5~lnw. The daily dosage for oral and transdermal administration is similarly 0.001 to 1 active ingredient per kg of body weight.
00■, preferably 0.005 to 10■. Also,
When administered in the form of crude drugs into the vagina, rectum, etc., the daily dosage is 0.00 of the active ingredient per 1 kg of body weight.
It is 1 to 200 square meters, preferably 0.005 to 100 square meters. 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 of adjuvants that can be incorporated into tablets, capsules etc. are binders such as gum tragacanth, gum arabic, corn starch or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch, potato starch, alginic acid, etc., lubricants such as stearic acid. Magnesium, sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint, wintergreen oil or cherry oil. When the usage unit is a capsule, it may contain, in addition to materials of the above-mentioned type, a legal carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the use unit.

For example, 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 are prepared by dissolving the active substance in water for injection, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle such as ethyl oleate. By suspending it, it can be formulated according to conventional pharmaceutical procedures. Buffers, preservatives, antioxidants, etc. can be mixed as necessary.

(Examples, Effects and Effects (Test Examples)) The present invention will be explained in more detail below using Examples and Test Examples. Note that 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)-1,4-dihydropyridine-3-carboxylic acid 2
Synthesis of -(N-benzyl-N-methylamino)-ethyl ester α-acetyl-3-chlorostyrylphosphonamic acid
0-Ethyl-N,N-dimethyl ester-, Og and 3
-Aminocrotonic acid 2-(N-befudyl-N-methylamino)-ethyl ester 1.0g in toluene 20ml
and refluxed for 15 hours. After distilling off toluene under reduced pressure, the residue was subjected to silica gel chromatography (eluent: ethyl acetate/ethanol = 9/1 (v/v), Rf = 0.
5) to obtain the title compound.

Compounds of Examples 2 to 33 were synthesized in the same manner.

Table 1-(1) to (6) shows the structure, yield, properties, and M of the compounds.
The S spectrum data are listed together.

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 (hereinafter, blank) 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 5 ml of methylene chloride, 200 μl of oxalyl chloride was added dropwise at room temperature, and the mixture was stirred for 15 minutes. The reaction vessel was cooled to -30°C. Excess ammonia dissolved in methylene chloride was added dropwise to this, and the reaction temperature was gradually returned to room temperature. The solvent was distilled off under reduced pressure, and an aqueous sodium bicarbonate solution was added to the residue, followed by extraction with methylene chloride. After separating the organic layer and drying it over anhydrous sodium sulfate, the solvent was distilled off and the residue was subjected to silica gel chromatography (
Eluent; ethyl acetate/ethanol = 9/1. v/v,
Rf = 0.5) to obtain the title compound.

Compounds of Examples 35 to 37 were synthesized in the same manner. Table 1
-(71 shows the structure, yield, properties, and MS spectrum data of the compound.

Test Example 1゜(1) Calcium antagonism Suspend a guinea pig removed cecal cord in a 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 for 10 to 20 minutes.
Concentration ID of the test drug required to cause 50% relaxation by adding 0mM to contract, and cumulatively administering the test drug after the tension stabilizes. Find (M) and its inverse logarithm root (pIDs.)
was calculated. The results are listed in Table 2.

(2) Antihypertensive effect The antihypertensive effect of the compound of the present invention was tested using 5) (Spontaneous hypertensive rats) anesthetized with urerethane-α-chloralose. Blood pressure in the femoral artery of each rat was measured invasively.Each compound was mixed with 3% tween 80-
It was dissolved in physiological saline and injected into the femoral artery. Based on the correlation between drug dose and maximum blood pressure reduction rate, the drug required to lower blood pressure by 30%
,. (■/kg) was determined. The results are listed in Table 2.

(Hereinafter, blank spaces) Table 2 Calcium antagonistic effect (p I D so) and antihypertensive effect <E D3°) Hydrochloride of the compound of Example 1 7.4 0.26 Hydrochloride of the compound of Example 13 7.4 1 .4 Compound of Example 17 8.5 0.77 Hydrochloride of the compound of Example 27 8.0 0.17 Formulation example 1゛: Tablet ingredients (1000 tablets) Hydrochloride of the compound of Example 1 5.0 (g) Milk 1! 190
．． 0 Corn starch 75.0 Microcrystalline cellulose 25.0 Methyl cellulose 3.0 Stearin Magnesium 2.0300,0 Measure the amounts of the above ingredients, put them in a V-type mixer, and mix them uniformly. This mixed powder is made into tablets by direct compression. -The weight per tablet is 300 ■.

Formulation Example 2: Capsule ingredients (1000 tablets) Hydrochloride of the compound of Example 1 5 (g) Corn starch 145 Hui crystalline cellulose
145 Stearin Magnesium
5. Measure the amounts of the above ingredients, put them into a type mixer, and mix them uniformly. This mixed powder is filled into hard capsules. The content per 1 capsule is 300 μ.

Formulation Example 3: Syrup component (2% liquid) Hydrochloride of the compound of Example 1 2.0 (g) White sugar 3
0.0 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, water was 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. O(g) Milk P' 8
8.0 Microcrystalline Cellulose 10.0 Methyl Cellulose 1.0100.0 The amounts of the above ingredients were measured, placed in a V-type mixer, and mixed uniformly.

Claims (4)

[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,
means a hydrogen atom, a nitro group, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group optionally substituted with a halogen atom, a fluorine atom, or a chlorine atom; R^1 and R^2 are the same or Unlike hydrogen atoms,
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 taken together are optionally substituted with a lower alkyl group; R ^3 is a linear or branched alkyl group having 1 to 10 carbon atoms, or R^3 and R^2 together are an ethylene group which may be substituted with a lower alkyl group, or 1
, 3-propylene group; Y is a linear or branched alkyl group having 1 to 4 carbon atoms, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^5 and R^6 are the same or different, with 1 to 4 carbon atoms optionally substituted with 1 to 2 phenyl groups
) or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^5 has the same meaning as above). ]
Compounds represented by and general formulas with salt-forming ability (I
) A pharmacologically acceptable salt of the compound represented by (2) 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,
means a hydrogen atom, a nitro group, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group optionally substituted with a halogen atom, a fluorine atom, or a chlorine atom; R^1 and R^2 are the same or Unlike hydrogen atoms,
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 taken together are optionally substituted with a lower alkyl group; R ^3 is a linear or branched alkyl group having 1 to 10 carbon atoms, or R^3 and R^2 together are an ethylene group which may be substituted with a lower alkyl group, or 1
, 3-propylene group; Y is a linear or branched alkyl group having 1 to 4 carbon atoms, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^5 and R^6 are the same or different, with 1 to 4 carbon atoms optionally substituted with 1 to 2 phenyl groups
) or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^5 has the same meaning as above). ]
Compounds represented by and general formulas with salt-forming ability (I
1. A composition for treating circulatory system diseases, comprising a pharmacologically acceptable salt of a compound represented by: (3) 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,
means a hydrogen atom, a nitro group, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group optionally substituted with a halogen atom, a fluorine atom, or a chlorine atom; R^1 and R^2 are the same or Unlike hydrogen atoms,
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 taken together are optionally substituted with a lower alkyl group; R ^3 is a linear or branched alkyl group having 1 to 10 carbon atoms, or R^3 and R^2 together are an ethylene group which may be substituted with a lower alkyl group, or 1
, 3-propylene group; Y is a linear or branched alkyl group having 1 to 4 carbon atoms, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^5 and R^6 are the same or different, with 1 to 4 carbon atoms optionally substituted with 1 to 2 phenyl groups
) or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^5 has the same meaning as above). ]
In the method for producing a compound represented by the general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, X^1, X^2, R^1, R^2, R^ 3 is the same as the explanation for general formula (I). ] Compounds represented by the general formula (III) ▲Mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, Y has the same meaning as explained in the general formula (I).
A manufacturing method characterized by reacting a compound represented by ]. (4) 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,
means a hydrogen atom, a nitro group, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group optionally substituted with a halogen atom, a fluorine atom, or a chlorine atom; R^1 and R^2 are the same or Unlike hydrogen atoms,
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 taken together are optionally substituted with a lower alkyl group; R ^3 is a linear or branched alkyl group having 1 to 10 carbon atoms, or R^3 and R^2 together are an ethylene group which may be substituted with a lower alkyl group, or 1
, 3-propylene group; Y is a linear or branched alkyl group having 1 to 4 carbon atoms, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^5 and R^6 are the same or different, with 1 to 4 carbon atoms optionally substituted with 1 to 2 phenyl groups
) or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^5 has the same meaning as above). ]
In the method for producing a compound represented by the general formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) [In the formula, X^1, X^2, R^3, and Y are the general formula (I) It has the same meaning as in the explanation, and Z means a hydroxyl group or a chlorine atom. ] Compounds represented by the general formula (V) ▲Mathematical formulas, chemical formulas, tables, etc.▼(V) [In the formula, R^1 and R^2 have the same meanings as explained in the general formula (I). A manufacturing method characterized by reacting a compound represented by ].