JPH02180867A - Dihydropyridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I {n is 1-18; R<1> is alkyl, cycloalkyl or alkoxyalkyl; R<2> is H, halogen, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, alkylthio, etc.; R<3> is group of formula IV [X is O, H, (alkyl-substituted) N; Y is carbon cyclic or hetrocyclic aromatic group or H} or an acid-added salt thereof. EXAMPLE:Methyl 2-{3-[4-(3-methylphenylamino)pyridyl]sulfonylureyl} ethyl 1,4- dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate. USE:A medicine. Low toxic and useful as a remedy for hypertensives, ischemic heart diseases, heat and peripheral circulatory diseases, etc. PREPARATION:For example, a compound of formula III is reacted with a compound of formula II preferably in the presence of an acid catalyst or dehydrating agent in a solvent to provide the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel dihydropyridine derivatives which are used as medicines and the like.

[Prior art]

Dihydropyridine F of the present invention! For example, nifedipine, nicardipine, etc. are known as compounds similar to the body. Although these compounds are known to be useful as antihypertensive agents, peripheral and cerebral vasodilators, and coronary artery treatment agents (angina pectoris), it is hoped that dihydropyridine derivatives with even better effects will emerge. There is.

[Problem to be solved by the invention]

An object of the present invention is to provide dihydropyridine derivatives and acid addition salts thereof that have even better pharmacological activity.

[Means to solve the problem]

The present invention has excellent calcium antagonism (Ca-Anta
gonist), antihypertensive action, platelet aggregation inhibitory action, phosphogesterase inhibitory action, etc., such as coronary vasodilators, cerebral blood flow increasing agents, antihypertensive agents, thrombosis prevention or treatment agents, phosphogesterase inhibitors, etc. General formula (+) useful as a medicine [wherein n is an integer of 1 to 18, R1 is alkyl, cycloalkyl or alkoxyalkyl]
is a hydrogen atom, halogen, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, halogenated alkyl, halogenated alkoxy, alkylthio, alkylsulfonyl, alkoxyoxygen, hydrogen or alkyl RW
A nitrogen which may be substituted, Y represents a carbocyclic aromatic group, a heterocyclic aromatic group, or hydrogen, and the carbocyclic group and the heterocyclic group are aryl, aralkyl, carboxyl, amino, arylamino. , aryloxy, sulfamoyl, -5o! NHCONHR' (here, R4 represents alkyl) (however, it may be substituted with 2 to 3 of these substituents), a group represented by -A-Y (here, A is -NIISOON HCON HS (herein, Z represents halogen or halogenated alkyl)] (hereinafter referred to as compound N)
)) and its acid addition ■I■ salts.

Compound (1) of the present invention has a unique structure compared to conventionally known dihydropyridine compounds, and has unique activity due to the specificity of this structure. . In other words, the compound N) of the present invention and its acid addition salts have high W& organ and tissue selectivity, especially in vasodilatory action, and their acute toxicity (extremely low toxicity).
A major feature is that it is extremely safe.

Furthermore, in addition to the blood pressure lowering effect, the compound (1) also has a diuretic effect, and dihydropyridine C, which is commonly used for the treatment of hypertension or congestive heart failure,
It is considered to be superior to a-Antagonist. Compound (1) can also be used as a diuretic.

In the above formula, the alkyl group represented by R1 may be branched or linear, and is particularly preferably an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec- Examples include butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., with C and -4 alkyls being preferred, and lower cycloalkyl (
Cs-), for example cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl.

Regarding R1, as cycloalkyl, lower (C-to)
Cycloalkyl is preferred, such as cyclopropyl,
Examples include cyclobutyl, cyclopentyl, and cyclohexyl.

Regarding R1, the alkoxyalkyl preferably has a total number of carbon atoms of 3 to 7, such as methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2
-methoxy-1-methylethyl, 2-ethoxy-1-methylethyl and the like.

The substituent represented by Rt may be substituted at any position on the phenyl ring in -substituent (1), but in particular, it may be substituted at 2 or/and 3 at the bonding position with the dihydropyridine ring.
It is preferable that the

The halogen in Rz, halogenated alkyl, and halogenated alkoxy include fluorine, chlorine, bromine, and iodine atoms, with fluorine or chlorine being particularly preferred. Chain or branched alkyls are preferred, and those in which some of the hydrogens are halogenated ((CFi)
)xCHCHg-5CFzCHt-, etc.), and all hydrogens may be halogenated (trifluoromethyl, etc.).

As the alkyl halide, 2-fluoroethyl, 2.
2.2-) Lifluoroethyl, fluoromethyl, 3.
3.3-1-lifluoropropyl and the like are exemplified.

The alkoxy in the halogenated alkoxy is preferably an alkoxy having 1 to 4 carbon atoms, and some or all of the hydrogen may be halogenated. Examples include fluoromethoxy, trifluoromethoxy, hexafluoro-2
-propoxy, 2.2.2-) trifluoroethoxy, and the like.

As the alkyl and cycloalkyl for R8, those exemplified for R1 are preferable.

The alkylsulfonyl, alkylsulfinyl, and alkyl in alkylthio in R1 are preferably those having 1 to 6 carbon atoms as exemplified in R1. For example, examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc., examples of alkylsulfinyl include methylsulfinyl, ethylsulfinyl, propylsulfinyl, etc., and examples of alkylthio include methylthio, ethylthio, propylthio, isopropylthio, etc.

Examples of alkoxy in R2 include straight or branched alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

The alkoxy in the alkoxycarbonyl in R2 is preferably an alkoxy having 1 to 4 carbon atoms, and examples of the alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl.

As the hydrogen represented by X or the alkyl in nitrogen which may be substituted with alkyl, those having 1 to 6 carbon atoms as exemplified for R1 are suitable.

Regarding Y, phenyl is preferred as the carbocyclic aromatic group. The heterocyclic group is preferably a 5- to 7-membered ring containing one or more nitrogen atoms, sulfur atoms or oxygen atoms as a petro atom, especially a 6-membered ring, preferably pyridyl; as 2-pyridyl, 3
-pyridyl and 4-pyridyl.

Aryl as a substituent in y, or aryl in aralkyl, oryloxy and arylamino, is an aromatic ring having 6 to 10 carbon atoms, such as phenyl,
Examples include naphthyl. Examples of alkyl in aralkyl include those having 1 to 6 carbon atoms as exemplified for R1, such as benzyl, α-phenylethyl, β-phenylethyl, and γ-phenylpropyl.

Regarding Y, -3o, alkyl as R4 in NHCONHR' has 1 to 6 carbon atoms as exemplified for R1.
Examples include ethyl and isopropyl.

Examples of the optionally substituted alkyl in Y include those having 1 to 6 carbon atoms as exemplified for R1.

Examples of the halogen in Z and the halogen in the alkyl halide include fluorine, chlorine, bromine, and iodine atoms. Also, the alkyl in the alkyl halide is R1
Examples include those with 1 to 6 carbon atoms, and those in which some of the hydrogens are halogenated ((Ch)z(:HCHi
-1CF3CH! -, etc.), or one in which all hydrogens are halogenated (trifluoromethyl, etc.).

The dihydropyridine derivative (1) can be produced by reacting any part constituting the dihydropyridine derivative (1) with the remaining components by a method known per se. For example, dihydropyridine derivative (1) is produced as follows.

Production method 1 CI) (In the formula, R1, R1, R3 and n are the same as above) In the reaction of compound (III) and (II), conditions for a normal esterification reaction can be employed.

Further, the reaction is preferably carried out in the presence of an acid catalyst or a dehydrating agent.

Catalysts used in this reaction include hydrogen chloride, concentrated sulfuric acid,
Examples include inorganic acids such as phosphoric acid, and organic acids such as para-toluenesulfonic acid and trifluoroacetic acid. Examples of the dehydrating agent include dicyclocarposiimide, N,N-carbonyldiimidazole, -alkyl-2-halogenopyridinium halide, and thionyl chloride. The amount of catalyst may be the amount used in normal esterification reactions, and is not particularly limited.

As a reaction solvent, ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform,
Examples include halogenated hydrocarbons such as carbon tetrachloride, and solvents used in normal esterification reactions such as pyridine. The molar ratio of compounds (m) and (II) in this reaction is not particularly limited, but (■) is used in an equivalent amount of 1 to 6 times, preferably 1 to 2 times the amount of (II). The reaction temperature varies depending on the reaction conditions used. For example, when thionyl chloride is used, the reaction proceeds quickly in the range of 0 to 50°C, and preferably 0°C to around room temperature.

The above intermediate compound (n) is synthesized by the following methods (a) to (C).

The compound is produced, for example, as follows.

(a-1) (In the reaction formula, n and R4 have the same meanings as above) Step (2) is a step of converting the carboxyl of compound (1) into a hydroxyl group. This step is usually carried out by using ethyl chlorocarbonate and triethylamine to form a mixed acid anhydride, and then reducing the mixture in the presence of a solvent such as tetrahydrofuran.

Step (2) is a step of introducing a protecting group into compound (2), and the introduction of a 6-silyl group, preferably a silyl group, is carried out by a method known per se.

Step (1) is a step of converting the nitro group in compound (3) into an amino group, and is carried out by a method known per se, such as reduction. In the reduction, catalytic reduction using palladium as a catalyst is suitable.

Step (2) is a step in which compound (4) and compound (5) are reacted. The reaction is carried out using an appropriate solvent at lOO℃~2
This is done by heating to 00°C.

Step (2) is a step in which compound (6) and compound (7) represented by R, -NGO are reacted.

The reaction is carried out at room temperature by dissolving in a suitable solvent and stirring.

Step (2) is a step of removing the protecting group from compound (8) and converting it into intermediate compound (II-1), and deprotecting is carried out by a method known per se depending on each protecting group. For example, removal of the silyl group is carried out with, for example, tetrabutylammonium fluoride.

(a-2) [In the reaction formula, R1 is R, CH! HN- represents an amino group substituted with alkyl as a substituent of a carbocyclic aromatic group for Y; Rh represents an alkyl group (preferably having 1 carbon number);
-4 alkyl), n has the same meaning as above] Step (1) is a step of aminating compound (9) using aqueous ammonia or the like to lead to compound (10) having a sulfamoyl group. This step is carried out by reacting with aqueous ammonia at 0°C to room temperature.

Step (1) is a step in which compound (10) and P-hydroxyalkyl-phenol (11) are reacted to obtain compound (12). The process is carried out in the presence of a basic compound such as sodium hydrogen carbonate, using an appropriate solvent, and at room temperature to 100°C.
This is done by heating to ℃.

Step (1) is a step of converting free carboxylic acid into an alkali ester, and this step is carried out using an appropriate esterifying agent. The esterification agent used is
For example, azomethine is exemplified, with which a methyl ester can be obtained.

Step (1) is a step of converting the nitro group in compound (13) into an amino group, and is carried out by a method known per se, such as reduction. In the reduction, catalytic reduction using palladium-carbon as a catalyst is suitable.

Step (1) is a step in which an alkanoyl group is induced into the amino group of compound (14) to obtain compound (16).

1 The step is carried out by reacting the compound (14) with the compound (15) represented by LCOOH or a reactive derivative thereof. Examples of the reactive derivative include those known per se such as acid chloride. . The reaction is carried out under conditions known per se, for example in the presence of a base such as pyridine in a solvent such as tetrahydrofuran.

Step (2) is a reduction and deesterification step.

In this step, in order to perform a reduction reaction, compound (16) is reacted with borohydride in the presence of diethyl ether, or sodium borohydride is reacted with the compound (16) in the presence of an acid catalyst.
Compound (17) can be obtained by working in diglyme. The reduction reaction is carried out by mixing an acid catalyst such as boron fluoride and sodium hydride in an appropriate ratio in an appropriate solvent and stirring the mixture.

Step (1) is a deesterification step, in which compound (17) is reacted with an alkali such as sodium hydroxide to obtain compound (II-2) having a free carboxylic acid.

(b) Among compound (1), a compound in which R3 is -AY is produced, for example, as follows.

[In the reaction formula, Re is alkyl (preferably carbon number 1-6
(alkyl of
). This step is the same as reaction step a-1■.

Step (1) is a reaction step for inducing an ethoxycarbonyl group in compound (19). The reaction consists of a two-step process, in which compound (19) and sodium hydride are reacted in tetrahydrofuran at room temperature, and then ethoxycarbonyl chloride is reacted at room temperature.

Step (2) is a step in which compound (20) is reacted with hydroxyalkylamine compound (21) to obtain compound (If-3). This step is carried out by refluxing in toluene or xylene solvent.

(Left below) Step (2) is a step in which a chlorosulfonyl group is introduced into p-chlorobenzoic acid to obtain compound (22), in which chlorosulfonic acid is reacted with heating at 100°C to 150°C.

(2) Step is to induce a nitro group to compound (22) to form compound (22).
9). The process is carried out under conditions known per se using nitric acid and sulfuric acid as nitration agents.

Step (2) is a step in which compound (9) and amine compound (21) are reacted to obtain compound (23) having a sulfamoyl group. This step uses an appropriate solvent and is carried out at -80°C.
- Performed by adding amine compound at room temperature.

Step (2) is a step of obtaining compound (24) from compound (23). The step is (1) 3,4-dihydrolff-2H
A step of protecting hydroxyl using pyran or toluenesulfonic acid (the reaction proceeds by stirring at room temperature using an appropriate solvent), (2) a step of deriving a phenoxy group (the reaction conditions are step a- (Same as 2■)
, (3) Step of inducing free carboxylic acid into ester (reaction conditions are the same as Step a-2■), and (4)
It consists of a step of deprotection using methanol and toluenesulfonic acid (the reaction proceeds by stirring at room temperature using an appropriate solvent).

Step (2) is a step of reducing the nitro group of compound (24) to an amino group, and this step is the same as step a-2 (2),
Compound (25) can be obtained.

Step (2) is a step in which an alkanoyl group is induced into the amino group of compound (25) to obtain compound (26).

This step is carried out under the same reaction conditions as in step a-2 (2).

Step (2) is a reduction step of compound (26), and is a reduction step of compound (26).
Compound (27) is obtained by reacting 6) with borohydride in the presence of diethyl ether or with sodium borohydride in diglyme in the presence of an acid catalyst.
can be obtained. The reaction conditions for this step are step a-2.
This is the same as ■.

Step (2) is a step of de-esterifying, and this step is carried out under the same reaction conditions as steps a to 20.

(b-3) 29) can be obtained.

Step (2) is a step of introducing hydroxyalkyl to the amino group of compound (29). This step gives compound (29) 2-
Hydroxyfuran is reduced and alkylated in the presence of sodium borocyanide.

(c) In compound (1), R3 is 2. Step (2) is a step in which compound (10) and phenol are reacted to obtain compound (2B). The process is step a-2
It is carried out under the same conditions as 0.

Step (2) is a step of reducing the nitro group of compound (28) to an amino group, using the same method as step a-20 (catalytic reduction with palladium-carbon in a basic aqueous solution of an appropriate concentration) or hydroxylation. A compound (in the formula, Z has the same meaning as above) is produced by a method of reacting lithium in the presence of water, for example, as follows.

(c-1) (In the reaction formula, 2 has the same meaning as above) Step (2) is a step of introducing a chlorosulfonyl group into m-substituted aniline compound (30) to obtain compound (31),
Compound (31) can be obtained by reacting under the same conditions as in Step b-2 (2).

Step (2) is a step in which compound (31) is aminated using aqueous ammonia or the like to yield compound (32) having a sulfamoyl group. The process is step a-2
carried out under similar conditions.

Step (2) is a step in which compound (32) and compound (33) are reacted to form a thiadiazoline ring compound (34). The process is carried out in a suitable solvent in the presence of an acid catalyst at room temperature to
Proceed by stirring at 100°C.

Step (2) is a step to introduce a hydroxyl group, and the reaction is carried out by adding compound (34) and a reducing agent such as boron hydride, followed by adding sodium hydroxide, followed by aqueous hydrogen peroxide, and stirring at room temperature. By proceeding, a compound (■-6) having a hydroxyl group at the terminal carbon of the carbon chain can be obtained.

(c-2) (In the reaction formula, 2 has the same meaning as above) ■Step is to add 2.5 to the compound (32) produced in step c-1.
- This is a step of reacting dihydroxydioxane in the presence of an acid catalyst to obtain compound (U-7).

(c-3) μ (In the reaction formula, 2 has the same meaning as above) Step (2) is a step in which compound (32) and compound (35) are reacted to form a thiadiazole ring compound (n-8). This step is carried out under the same conditions as step c-1 (2).

Manufacturing method 2 (IV) (V) (Vl
)m Dihydropyridine derivative (1) The reaction of compounds (IV), (V) and (Vl) is usually carried out at a temperature of 20°C to about 160″C1, preferably about 0°C to about 13°C.
The reaction is carried out at 0°C, and the solvent used may be any solvent as long as it is inert to the reaction, including alkanols such as methanol, ethanol, propatool, isopropanol, butanol, and 5ec-butanol, ethyl ether, Preferred examples include ethers such as dioxane, tetrahydrofuran, ethylene glycol monomethyl ether, and ethylene glycol dimethyl ether, acetic acid, and pyridine, such as N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile. The amounts of compounds (IV), (V) and (Vl) used are:
This is carried out by using 1 to 1.5 moles of each of the other two compounds to 1 mole of one of the three compounds. It usually takes 1 to 30 RM to complete the reaction.

Compound (Vr), which is a raw material compound, is produced as follows.

(n) CHsCOCFItCOORs
(Vll) [In the formula, R3 is lower alkyl (usually 1 carbon number
-4), and all other symbols have the same meanings as above] That is, it is produced by reacting intermediate compound (It) with diketene or compound (■). The reaction between intermediate compound (II) and diketene is carried out by heating the mixture in the absence of a solvent or in a solvent inert to the reaction, usually at about 40 to about 130"C, or in a solvent inert to the reaction. The reaction can be carried out in a suitable solvent (e.g., ethyl ether, tetrahydrofuran, dimethoxyethane, etc.) at about -20°C to about 40°C in the presence of a catalyst such as valadimethylaminopyridine. The reaction with compound (II) is carried out in the presence of a base such as sodium methoxide, sodium ethoxide, potassium butoxide, sodium hydride, sodium amide, sodium metal, etc.
Approximately 0°C to approximately 100°C in an inert solvent or without solvent
It will be held in

Since compound (1) has a basic group, it can also be converted into an acid addition salt by known means. Such salts are not particularly limited as long as they are pharmacologically acceptable, such as salts with inorganic acids (hydrochlorides, hydrobromides, phosphates,
sulfates, etc.), salts with organic acids (acetates, succinates, maleates, fumarates, malates, tartrates), etc.

The novel compound (1) or its acid addition salt thus produced can be collected at any purity by appropriately using known separation and purification means, such as concentration, extraction, chromatography, reprecipitation, recrystallization, etc. .

[Action/Effect]

The compound (1) of the present invention and its acid addition salts have extremely low toxicity, and are highly effective against mammals (e.g. mice, rats, rabbits, dogs, etc.).
Strong and long-lasting hypotensive effect in cats and humans
It has peripheral vasodilating effect, coronary artery dilating effect, cerebral vasodilating effect, etc., and is effective for hypertension, ischemic heart disease (angina pectoris, myocardial infarction, etc.), cerebral and peripheral circulatory disorders (cerebral infarction, cerebral infarction, etc.) in humans. It is currently used as a preventive and therapeutic drug for circulatory system diseases such as hyperactive cerebral ischemia.

When compound (1) and its acid addition salts are used as the above pharmaceuticals, they are mixed with appropriate pharmacologically acceptable additives (e.g., carriers, excipients, diluents, etc.) and other pharmaceutically necessary ingredients. It can be made into pharmaceutical compositions such as powders, granules, tablets, capsules, and injections, and can be administered orally or parenterally. Compound (f) and its acid addition salt are incorporated into the above formulation in effective amounts. The dosage varies depending on the route of administration, symptoms, and patient's weight or age, but for example, when orally administered to adult hypertensive patients, the dosage is 0.05 to 20 μ/kg body weight/day, particularly 0.05 to 20 μ/kg body weight/day.
It is desirable to administer 1 to 4 cm/kg body weight/day in one to several divided doses per day.

〔Example〕

The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.

In addition, each raw material compound used in the following examples is manufactured by the method shown by the following reaction formula, respectively.

(Left below) (Starting compound of Example 7) 6-C7) Hexa/Jk----1→CHO(CI
10H (Starting compound of Example 8) Example 1 Methyl 2- (3-(4-(3-methylphenylamino)pyridyl)sulfonyluleyl)ethyl 1.4-
Dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate 511■ (1,54+*mo
l) 1,4-dihydro-5-methoxycarbonyl-2
゜6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid was added, dimethylformamide (DMF) (2-1) and chloroform (41) were added to the reaction flask, and the reaction flask was placed in a water bath, and the reaction mixture was heated to 183 mm while stirring well. (1,5
After 0 dropwise addition of 4 m++*ol) of thionyl chloride was completed, the mixture was stirred and reacted for 2 hours.

To the resulting reaction solution was added 540IIg (1,
54 smol) of 3-(2-hydroxyethyl)ureylsulfonyl-4-(3-methylphenylamino)pyridine was added dropwise with good stirring under water cooling.

After dropping, the reaction mixture was stirred for 1 hour, and an aqueous sodium bicarbonate solution (260 μ/25 ml) was added to the resulting reaction solution, which was extracted with chloroform (50+1×5). dry,
Filtered. After concentrating the filtrate with an evaporator, it was recrystallized from dichloromethane-methanol to give 6301 g of methyl 2-(3-(4-(3-methylphenylamino)pyridyl)sulfonylureyl)ethyl as a pale yellow powder.
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate was obtained (yield 62%).

I RvBG CI+-': 2500~36
00 (m).

! 680. 1640. 16 Summer 5 (s, c=
0).

H-NMR (DMSO-d,) δ: 8.99 (IH,
s.

-NH2OH-), 8.62 (IHLs), 8.2
(III, d), 7.8-8.0 (2H, m)
, 7.59 (IH, d), 7.47 (IH.

t), 7.30 (IH, L), 6.95~
7.10 (4)1. m).

6.68 (IH, s, broad), 5.73
(LH, d.

J-1,5Hz), 4.93 (IH,s), 3.
92 (211, L).

3.51 (3L s), 3.21 (21,t),
2.31 (3H.

s), 2.26. 2.20 C6H, both
s).

Example 2 Methyl 2-(3-(4-(3-isopropyluleylsulfonylpyridyl)amino)phenyl)ethyl 1
．． 4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate 51.31 g (1,54 mol) of 1,4-dihydro- Take 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid and add 2 liters of dry DMF.
and dry dichloromethane were added and shaken well to make a homogeneous solution. Place the flask in a water bath and add 184 g (122, l,
1.34 mmol) of thionyl chloride was added dropwise. After the completion of the dropwise addition, the reaction solution obtained by stirring and reacting for 3 hours was added with 2
460 mg of 4-(
3-(2-hydroxyethyl)phenylamino)-3
-Isopropylureylsulfonylpyridine was added with stirring under water cooling, and the mixture was stirred and reacted for about 1 hour.To the reaction solution, a sodium hydrogen carbonate aqueous solution (200 mg/40 m
l ) was added and extracted with dichloromethane (6 (1+
The 1×4)-dichloromethane layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated using an evaporator. The resulting residue (14 g) was subjected to silica gel column chromatography (dichloromethane/methanol 8.5:1.
5) and purified by preparative HPLC (005, 10% water-methanol) to give 250 μm of pale yellow powder methyl 2-
(3-(4-(3-isopropyluleylsulfonylpyridyl)amino)phenyl)ethyl 1,4-dihydro-2□ 6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-carboxylate was obtained. (yield 40%).

I Rv 2B am-': 3330 (br,
m)+1690, 1640 (s, c=o).

H-NMR (DMSO-di) δ: 9.03 (LH,
s).

8.62 (IH, s), 8.11 (IH, d,
J=6Hz), 7.91~7.99 (2H, Mongolia)
, 7.46-7.49 (2H,s), 7.
31 (IH, t, J=7.8Hz), 7.11 (
IH,s), 7.10 (IH.

d, J-7,8Hz), 7.00 (IH, d
, J=7.8Hz), 4.93(Ill,
s), 4.24 (2Fl, t, J-6,
51(z), 3.63 (III.

steel), 3.52 (3B, s), 2.2
7. 2.22 (6H, both s)+1.0
1. 0.98 (611, both s).

Example 3 4-(3-carboxy-6-phenoxy-5-sulfamoylanilino)butyl methyl l.

2101 g (0,63+s+5ol) of 1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate
-(3-nitrophenyl)pyridine-3-carboxylic acid was dissolved in DMF (0,4 ml) and dichloromethane (1,8 ml).
) in a mixed solvent of 0.05 m while cooling in a water bath.
Thionyl chloride (0.69 m+wol) of 1 was added dropwise with stirring. After 1.5 hours, 4-(3-hydroxy-6-phenoxy-5-sulfamoylanilino)butylated alcohol (24og, o, e 3wolinol) in DMF
The solution (2 ml) was added dropwise and the reaction was stirred for 3 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol:chloroform-1:3) and preparative HPLC (ODS-10i methanol-20.1% hydrochloric acid-
70:30) to give 75μ of pale yellow powder 4-(
3-Carboxy-6-phenoxy-5-sulfamoylanilino)butyl methyl 1,4-dihydro-2,6
-Simethyl-4-(3-nitrophenyl)pyridine-3
5-dicarboxylate was obtained.

I Rv i! 'x cm-': 3500~230
0. 1690 (cm0).

1530 (NOx), 1490. 1440 (
Sow).

1350 (sow), 1220 (sow)
H-NMR(^cetone-d h)δ: 1.4
~1.6 (4H.

br), 2.34 (6H,s), 3.17
(2H, br), 3.60 (3H, s), 3
．． 94 (28,br), 4.63 (LH,br
).

5.10 (IH,s), 6.47 (2H,s
) + 6.91 (28, d.

J-7,94Hz), 7.02 (IH,t, J
-7,24Hz)+7.28(2H,tt J=8H
z), 7.46 (IH, t, J-7,88Hz
).

7.58 (IL d, J-1, 82Hz), 7.
70 (IL d.

J-7, 68Hz), 7.92 (IH, d,
J=1.86H2), 7.98(1■, d,
J-6,54Hz), 8.10 (2H,s
).

Example 4 4-(2-Butylamino-4-carboxy-6-sulfamoylphenoxy)phenethylmethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-di Carboxylate In the same manner as in Examples 1 to 3, the acid chloride of 1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4°-(3-nitrophenyl)pyridine-3-carboxylic acid and 3- n-Butylamino-4-[4-(2-hydroxyethyl)phenoxy]-5-sulfupmoylbenzoic acid was condensed to form 4-(2-butylamino-4-carboxy-6-sulfamoyl) in a yield of 54%. phenoxy) phenethyl methyl 1,4-dihydro-2,6-dimethyl-4-
(3-nitrophenyl)pyridine-3,5-dicarboxylate (pale yellow powder) was obtained.

IRν! iB CI-': 3350 (br
, m), 1690 (s, c-0)+135
0 (s), 1220 (s).

HNMR (CDCffii) δ: 0.74 (
3H,t.

J-17, 3H2) 1 1.69 (2H15ext
et, J-7-64Hz)+1.35 (28,q
unitL, J-7, 52Hz), 2.20 (
38,s)+2.25 (3H,s), 2.80
(21,t, J-6,34Hz).

3.04 (2H, t, J-6, 86Hz),
3.58 (311, s).

3.6~4.3 (2H, br), 4.1~4.4
(2H, m).

4.92 (IH,s), 5.18 (21,s)
, 5.91 (18,s).

6.79 (2)1. d, J-8,5Hz)
, 7.04 (2)1. d.

J-8,6Hz), 7.27 (Ill, t
, J-7,6Hz), 7.43(IH,d,
J-7,8Hz), 7.52 (LH,d,
J=1.5Hz).

7.89-7.92 (311, ws, ^r).

Example 5 2-(3-butylamino-5-carboxy-2-phenoxybenzenesulfonamido)ethylmethyl 1.4-
Dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate 1,4-dihydro-5-methoxycarbonyl-2,6-dicarboxylate in the same manner as in Examples 1 to 3. Acid chloride of 4-(3-nitrophenyl)pyridine-3-carboxylic acid and 3
-n-butylamino-5-N-(2-hydroxyethyl)sulfamoyl-4-phenoxybenzoic acid,
2-(3-butylamino-5-carboxy-2-phenoxybenzenesulfonamido)ethyl methyl 1,4-dihydro-2,6-simethyl-4-(3
-nitrophenyl)pyridine-3,5-dicarboxylate (pale yellow powder) was obtained.

I Rv2HC1-': 3350 (br, m)
+1680 (s, c-0)+1480, 1340.
1210°H-NMR (CDC/!3) δ: 0.80
(311, t.

J=7.22Hz), 1.14 (2H,5ext,
J-7, 72H2).

1.41 (211, qint, J=6.8Hz>,
2.33 (3)1. s).

2.35 (3H, s), 3.09 (2L L,
J-6, 86Hz).

3.21 (2H,br), 3.64 (3H,s)
, 4.04 (2H.

br), 5.08 (2H, br, s), 6.1
1 (IH, s).

6.87 (2H, d, J-7,88+1z),
7.07 (IH, t.

J=7.2H2), 7.29 (2H,t,
J=8Hz), 7.34 (Ill.

L, J=88Z), 7.61 (Ill,
s), 7.63 (18, d.

J-6,5Hz), 7.95 (IH,d,
J-7,1Hz), 7.96(1)1. d,
J-1,7Hz), 8.07 (IH,d,
J-1, 71h).

Example 6 Rhochloro-3,4-dihydro-1,1-dioxide-
7-Sulfamoyl-2H-1,2,4-benzothiadiazin-3-ylmethyl methyl 1,4-dihydro-2
,6-dimethyl-4-(3nitrophenyl)pyridine-
3,5-dicarboxylate Similarly to Examples 1-3, l,4-dihydro-5
-methoxycarbonyl-2,6-dimethyl-4- (3
-nitrophenyl)pyridine-3-carboxylic acid acid chloride and 6-chloro-3-(2-hydroxymethyl)-3,
4-dihydro-2H-1.

2.4-benzothiadiazine-7-sulfonamide 1
．． 1-dioxide was condensed to form 6-chloro- in a yield of 54%.
3,4-dihydro-1,1-dioxide-7-sulfamoyl-28-1,2,4-benzothiadiazine-3-
yl methyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-
Dicarboxylate (pale yellow powder) was obtained.

I Rv HB C1l+-': 3350
(br+ mL 1690 (s+c-0)
+1600, 1520.1480.1350.1220
゜1180゜H-NMR (DMSO, CDCl5) δ: 9.
0B (IH,s).

7.8~8.2 (5H), 1.6~1.8 (IH
, br), 7.3-7.6 (3H, br), 6.
98 (IH, d, J=9.2Hz).

4.8-5.2 (2H, br), 4.0-4.
5 (2H, m).

3.56 (3H, s), 2.32 (6H, s).

Example 7 6-(6-chloro-3,4-dihydro-1,1=dioxide-7-sulfamoyl-2H-1°2.4-benzothiadiazin-3-yl)hexyl methyl 1.4-
Dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3゜5-dicarboxylate 1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4- Acid chloride of (3-nitrophenyl)pyridine-3-carboxylic acid and 6-chloro-3-(6-hydroxyhexyl)-3,4-dihydro-2H-1゜2.4-benzothiadiazine-7 -Sulfonamide-1,1-dioxide was condensed, yield 85
% of 6-(6-chloro-3,4-dihydro-1,l-dioxide-7-sulfamoyl-2H-1,2°4-benzothiadiazin-3-yl)hexylmethyl 1.4
-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate (pale yellow powder) was obtained.

I Rv HB cyi-': 3700-3000
．． 1680 (Go)+1600.1520 (NOx
), 1480 (NOri +1340 (50ri, 122
011170 (501)H-NMR (^cetone
-d a) δ: 1.2 to 1.7 (88°m),
1.92 (2H,q, J-7,9Hz), 2.
35 (3H,'s).

2.38 (3H,s), 3.61 (3H,s)+
4.0-4.1 (2H, s), 4.96 (i
ll, t), 5.13 (IH, s).

6.61 (3H,br), 7.03 (IH,s)
, 7.08 (iH,s).

7.51 (IH, t, J-7,9Hz), 7.7
2 (IH, d.

J-7,7tlz), 8.01 (IH,d, J-
8.0Hz), 8.07(IH,s), 8.13
(IH,s), 8.17 (IH,s).

Example 8 10-(6-chloro-3,4-dihydro-1゜1-dioxide-7-sulfamoyl-2H-1゜2.4-benzothiadiazin-3-yl)decanyl methyl 1.4
-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3゜5-dicarboxylate 1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl- Acid chloride of 4-(3-nitrophenyl)pyridine-3-carboxylic acid and 6-
Chlor-3-(10-hydroxydecanyl)-3,4-
Dihydro-2H-1゜2.4-benzothiadiazine-7
-Sulfonamide 1,1-dioxide was condensed to yield 1O-(6-chloro-3,4-dihydro-1
゜1-dioxide-7-sulfamoyl-28-1゜2
．． 4-Benzothiadiazin-3-yl)decanyl methyl 1,4-dihydro-2,6-cymethyl-4-(3-
Nitrophenyl)pyridine-3°5-dicarboxylate (pale yellow powder) was obtained.

I Rv aeG as-': 370 (1 to 300
0 (@), 1680 (5, C=0) 11600,
1520 (Now), 1480 (No.

1340 (Sot), 1220.1170 (SO
□).

H-NMR (Acetone-d δ: 1
．． 2-1.5 (12H.

br), 1.34 (4H, br), 1.94 (
21 (, q, J-8, 1Hz).

2.35 (311,s), 2.38 (3H,s)
, 3.61 (3H, s) 3.9~4.1 (2H,
s+)+ 4.97 (IH, t, J-6, 1Hz)
+5.14 (11,s), 6.66 (3H,br
), 7.04 (IH,s).

7.14 (IH,s), 7.52 (IH,t,
J=7.9H2).

7.73 (IH, d, J-8, 2H2), 8.0
2 (III, dJ-8, 2112), 8.14
(2)1), 8.16 (II, s).

Claims (1)

[Claims] General formula ▲ Numerical formulas, chemical formulas, tables, etc.
^2 is a hydrogen atom, halogen, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, halogenated alkyl, halogenated alkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl, cyano, or nitro, and R^3 is a mathematical formula, chemical formula, table, etc. There is a group represented by ▼ (where, Cyclic and heterocyclic groups include aryl, aralkyl, carboxyl, amino, arylamino, aryloxy, sulfamoyl, -SO_2
may be substituted with 2 to 3 substituents selected from NHCONHR^4 (where R^4 represents alkyl) (however, these groups may be optionally substituted with alkyl); -A-Y group (where A is -NHS
O_2-, -NHCONHSO_2- or -NH-
and Y has the same meaning as above) or ▲ a group represented by ▼ (where Z represents halogen or halogenated alkyl)] or a dihydropyridine derivative represented by Acid addition salts.