JPS60226876A - 1,4-dihydropyridine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 and R2 are H, halogen, trihalomethyl or nitro; R3 is lower alkyl or group of formula II (B is 7-16C alkylene); A is C or N]. EXAMPLE:2,6-Demethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarbo xylic acid 3-methyl ester 5-[8-(1-imidarzolyl)octyl] ester. USE:A drug having vasodilating, blood flow increasing, thrombocyte coagulation inhibiting, and thromboxane-A2 formation inhibiting activities, and useful as a vasodilator, hypotensor, an antithrombotic agent, an antiarteriosclerotic agent, etc. The coronary blood flow can be increased and keeps the high level for a long period by the administration of the compound. PREPARATION:The compound of formula I can be prepared e.g. by reacting the compound of formula III (Y is active group) with imidazole or its alkali metal salt in an inert solvent at room temperature -80 deg.C for several -24hr while stirring.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 1,4-dihydropyridine derivatives, more specifically, the following general formula (1) (wherein R1 and R7 are the same or different, a hydrogen atom, an atom or a nitrogen atom, and B represents a straight chain or branched alkylene group having 7 to 16 carbon atoms.

related.

Compound (1) of the present invention has vasodilating effect, blood flow increasing effect, platelet aggregation inhibiting effect, and thromboxane A.

It is a compound that has a production inhibiting effect and is useful as a pharmaceutical agent such as a vasodilator, antihypertensive agent, antithrombotic agent, and antiarteriosclerotic agent.

In the compounds of the present invention, the chain length of the alkylene group represented by rBJ in formula (1) is particularly important, and compounds in which B is an alkylene group having 7 to 16 carbon atoms have a very strong effect on increasing blood flow. It was found that it has a long-lasting effect.

The compound (1) of the present invention is, for example, a compound represented by the general formula (l[)R1 (wherein, Y represents an active group, and R,, R,, R,, A and B are the same as the radicals) It is produced by reacting imidazole or an alkali metal salt thereof.

The raw material (If) has, for example, the general formula (1), (wherein R+
, k, Ra and A are the same as above) or its active esters or active amides, and the general formula (JT), HO-B-OR4(ff) (wherein R4 is a hydrogen atom or a protected It is produced by carrying out an esterification reaction with an alcohol represented by the following group) and activating the resulting product.

In addition, the compound (1) of the present invention can be prepared by another method, namely (1
) can also be produced by reacting a compound represented by the general formula σ), (wherein B is the same as above).

The reaction of the compound of formula (II) with imidazole or its salt can be carried out using tetrahydrofuran, dioxane, N.

This is done by stirring in an inert solvent such as N-dimethylformamide or dimethyl sulfoxide at room temperature to 80°C for several hours to 24 hours.
The reaction with the compound of formula f) or (V) is carried out in the above-mentioned inert solvent in the presence or absence of a base by stirring at room temperature for several hours. As a base, 1,8-diazabicyclo(5,4,0)-7-undecene (DBU
), imidazole sodium salt, etc. are used. In the formula (If), the active group represented by Y is a sulfonic acid chloride such as mesyl chloride, tosyl chloride, benzenesulfonyl chloride, or 7-hydrogen acid such as hydrochloric acid or hydrobromic acid at the terminal hydroxyl group. Examples include those obtained by reaction.

In addition, in formula (■), the protecting group represented by R4 is:
Examples include trityl group, tetrahydropyranyl group, t-butyl-dimethylsilyl group, methoxymethyl group, etc., and these can be easily removed by hydrolysis with an acid such as hydrochloric acid or acetic acid. .

The compound of formula (1) thus obtained can be converted into an inorganic or organic acid salt such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, acetic acid, citric acid, maleic acid, tartaric acid, etc. according to a conventional method. can lead.

The pharmacological effects of representative compounds of the present invention are as follows.

Using an adult dog that had been anesthetized by intravenously administering 30 rng/pendoparbital and 9, the compound of the present invention (0,
9 (dissolved in IN hydrochloric acid) at 100 μP/g was administered intravenously over 30 seconds, and the coronary blood flow was measured by attaching an electromagnetic blood flow meter probe to the patient's left rotation. The results are shown in Figure 1 (compound of Example 1).
, FIG. 2 (compound of Example 9) and FIG. 3 (Example 11)
Compound).

As is clear from Figures 1 to 3, administration of the compound of the present invention significantly increases the coronary blood flow, and this continues for a long time.

When using the compound (1) of the present invention as a medicine, it is formulated into tablets, capsules, granules, powders, injections, etc. using appropriate excipients, carriers, diluents, etc., and administered orally or Can be administered parenterally.

Next, an example will be given and explained.

Example 1 2.6-dimethyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(8-(1-imidazolyl)octyl) ester: 3-methoxycarbonyl-1-methoxymethyl-2,6
-Simethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 1.0? N,N'-carbonyldiimidazole 5 in tetrahydrofuran solution
Add 93Fn9 and stir at room temperature for 1.5 hours under a nitrogen stream. Add to this 1.8-octanediol 1.5? and 1) Add BUo, 45g and stir for further 5 hours. Add dilute hydrochloric acid to the reaction solution, extract with chloroform, separate the chloroform layer, wash with water, and dry. The residue obtained by distilling off the solvent was purified using silica gel column chromatography to give 1-methoyacymethyl-2,6-dimethyl-4-(3
-nitrophenyl)-1,4-dihydropyricin-3,
s-dicarboxylic acid 3-methyl ester 5-(8-hydroxyoctyl) ester 1.07? (Yield 80 cm) is obtained.

Obtained compound 1.07? was dissolved in methylene chloride, 1.5 mJ of triethylamine and 0.0 mJ of mesyl chloride.
After adding 661114 while stirring with water cooling, the mixture is stirred at room temperature for 2.5 hours. Water is added to the reaction solution, extracted with chloroform, and the chloroform layer is separated, washed with water, and dried. The residue obtained by distilling off the solvent was purified using silica gel column chromatography to obtain 1-methoxymethyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine- as a pale yellow oil. 3,5-dicarboxylic acid 3-methyl ester 5-(8-mesylo-Φdioctyl) ester 1.12 P (yield: 91 h) is obtained.

50 Sodium hydride 163N9ON, N-dimethylformamide 7.54% imidazole 231
and stir at room temperature until hydrogen evolution has stopped.

This imidazole solution was mixed with the previously obtained mesyloxy derivative 1.12? at room temperature under a nitrogen stream. (7) Add to the N,N-dimethylformamide solution and stir for 12 hours. After the reaction is complete, water is added, extracted with chloroform, and the chloroform layer is separated, washed with water, and dried. The residue obtained by evaporating the solvent was purified using 7 silica gel column chromatography to produce 1-methoxymethyl-2 as a pale yellow oil.
,6-dimethyl-4-(3-nitrophenyl)-1,4
-Dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-[8-(1-imidazolyl)octyl]ester 5ssq (yield: 78 cm) are obtained.

A solution of the obtained compound in tetrahydrofuran was added with concentrated hydrochloric acid 1.
Add 3rILl and stir at room temperature for 2 hours. Then, potassium carbonate is added, concentrated under reduced pressure, and extracted with chloroform.

After washing the chloroform layer with water and drying, the solvent was distilled off and the resulting residue was purified using silica gel column chromatography to give 2,6-dimethyl-4-(3- Nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid 3
-Methyl ester 5-(8-(1-imidazolyl)octyl)ester 54oIn9 (yield 70%) is obtained.

IR value: 200 3330 (broad), 3180.3070.29
30.2850°1690, 1525.1510.13
45.1210.1115゜09O NMR value; δCDC4゜1.10-1.82 (12H,m, -(CH2)6
)2.36 (6kl, s, -CH5X2
)3.65 (3H,s, -COOCHs)356 Example 2 2.6-dimethyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(7-(1-imidazolyl)-1-
Methylheptyl] ester: 3-methoxycarbonyl-
To a solution of 308% 1-methoxymethyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid in N,N-di,methylformamide was added N,N'-dihydropyridine-5-carboxylic acid. Add 229 η of imidazole, and add 349 η of concentrated 8-dolytyloxyoctan-2-ol, which was stirred at room temperature for 1 hour under a nitrogen stream.

A solution obtained by adding imidazole 6 fuda to a suspension of 39 m9 of sodium 50 thihydride in N,N-dimethylformamide 2d was added dropwise to the above reaction solution at -20°C under a nitrogen stream, and the mixture was stirred at room temperature for 16. Stirred for 5 hours.

After adding a saturated aqueous ammonium chloride solution to the reaction solution, extraction was performed with ethyl acetate, and the ethyl acetate layer was separated. After washing with water and drying, the solvent was distilled off and the resulting residue was purified using silica gel column chromatography to produce 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine as a pale yellow oil. -3,5-dicarboxylic acid 3-methyl ester 5-(1-methyl-7-dolytyloxyheptyl) ester 386# (yield 63%) is obtained.

Obtained trityl form 230 da of tetrahydrofuran 25
5 d of concentrated hydrochloric acid was added to the d solution, and the mixture was stirred at 35° C. for 2 hours.

Neutralize by adding saturated aqueous sodium hydrogen carbonate solution, and extract with ethyl acetate. After separating the ethyl acetate layer, washing with water and drying,
The residue obtained by distilling off the solvent was purified using silica gel column chromatography to give 2.6-dimethyl-4-(3-nitrophenyl)-1 as a pale yellow oil.
゜4-Dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(7-hydroxy-1-methylheptyl) ester 142+Q (quantitative) is obtained.

To the obtained methylene chloride solution of Compound 115■, 1.5 rrLl of triethylamine and 0.5 d of mesyl chloride were added at 0° C. under a nitrogen stream, and the mixture was stirred for 30 minutes.

Water was added to the reaction solution, stirred at room temperature for 5 minutes, and then extracted with ethyl acetate. After separating the ethyl acetate layer, washing with water and drying,
The residue obtained by distilling off the solvent was purified using silica gel column chromatography to give 2,6-dimethyl-4-(3-nitrophenyl)-1 as a pale yellow oil.
,4-dihydropyridine-3,5-dicarboxylic acid 3-
Methyl ester 130 mg (yield: 97 cm) of 5-(7-medyloxy-1-methylheptyl) ester is obtained.Add 63 ml of 50% sodium hydride to 63 ml of N,N-dimethylformamide, and add imidazole 116 #19 to the sml suspension. The solution obtained by adding is added to the rJ + N-dimethylformamide solution of 106 da mesyloxy compounds at room temperature under a nitrogen stream, and stirred for 6 hours.

After the reaction is complete, saturated ammonium chloride aqueous solution is added, and the mixture is extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water, dried, and the solvent was distilled off. The resulting residue was purified using silica gel column chromatography to obtain 2,6-dimethyl-4-(2,6-dimethyl-4-( 3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 66 rng (yield 66%) of 5-(7-(1-imidazolyl)-1-methylhebutyl) ester is obtained. .

IR value: C brain 3 sub-1 ax 3430, 3290 (broad), 3170 (br
oad), 2930°1685, 1525.1465.
1350.1120.11l100N value: δCDCn
.

2.34.2.35.2.36.2.38 (6H, sX
4. - C mountain x 2) 3.63, 3.66 (1,4)I
, 1.6 H,sX 2, -COOC! 13) 3.8
8.3.92 (2H, tX2. J-7H1, -CH
tN,')C)Is' 4.75-5.00 (IH, m, -CH-) MS value:
rrVz 510(M), 509,508,492,478,4
62°88 Example 3 2.6-dimethyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3,5-dicarboxylic acid bis(
s-(i-imidazolyl)octyl]ester = 2,6-dimethyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester 600 mg, 1.8-octanediol 5.0
7514 and anhydrous potassium carbonate at 130℃
Stir for 17 hours. The reaction mixture was dissolved in an ethyl acetate-benzene mixture, washed with water, and dried. The residue obtained by distilling off the solvent was purified using silica gel column chromatography to give 2°6-dimethyl-4-(3-nitrophenyl) as pale yellow crystals with a melting point of 128-130°C.
483 d of -1.4-dihydropyridine-3,5-dicarboxylic acid bis(8-hydroxyoctyl) ester (yield: 48.5 d) was obtained.

To a solution of 250 drops of the obtained compound in 1 d of anhydrous pyridine, 120 da of mesyl chloride was added dropwise under water cooling, and the mixture was stirred for 75 minutes. Water was added to the reaction solution, stirred for 20 minutes, and then extracted with ethyl acetate. The ethyl acetate layer was added in portions, washed with saturated brine, dried, and the solvent was distilled off. The resulting residue was purified using silica gel column chromatography to give a melting point of 10.
2,6-dimethyl-4=(3-nitrophenyl)-1,4-dihi)' CI as pale yellow crystals at 3-106°C.
? '9 Zine-3,5-dicarboxylic acid bis(8-mesyloxyoctyl) ester 274# (Yield: $90.1
h) is obtained.

Thereafter, when imidazole was reacted in the same manner as in Example 2, pale yellow crystals with a melting point of 116 to 117.5°C were obtained.2.
6-Simethyl-4-(3-nitrophenyl)-1,4-
Dihydropyridine-3,5-dicarboxylic acid bis(8-
(1-Imidazolyl)octyl]ester 215~ (yield 81.3%) is obtained.

IH value,, KBr Crn-1 ax 3260.3170, 3070, 2923, 1692,
1635°1520.1347,1270,1200,
1090. 710゜63 NMR value: δCDC,63 1,1-2,0(24kI, m, -(CH2)a-
X2)2.32 (6r1.s, CHs, -C
H5) 3.8-4.2 (8H, m, -COOCH,
X2. -C1i! N\X2) The following compounds were produced in the same manner as in Examples 1 to 3.

Example 4 2.6-dimethyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(7-(1-imidazolyl)heptyl) ester Melting point: 136-137.5°C Properties: Pale yellow crystal IR value: Shiseisei m-' 3300 (broad), 3170.3050.29
30.2850°1695, 1525.1515.13
45.1270.1205°1115, 1010 9ON value: δCDC-es 1.10-1.81 (10H, m, (CHy)s-)
2.36.2.37 (6H,s, -CH1x2)
3.65 (3H,s, -COOCkls)3J
3 B -4-12 (4H1m, Co0C1jt-1-
〇H4N\)MS value: rrv'z 496 (M+), 495.494.479.478
．． 448°374.342 Example 5 2.6-dimethyl-4-(3-nitrophenyl)-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(12-(1-imidazolyl)dodecyl) ester: Melting point: 113-117°C Properties: Pale yellow crystal IR value: νPengchi(?FFl-' 3290(broad), 3170.3060.29
20.2840°1690.1520,1505,13
45,1205,1115°095 NMI (value: δCDCA3 1.17-1.87 (20H,m, -(CHy)to
-)2.36.2.38(6H,s, -Chi, X
2) 3.65 (3H,S, -COOCHs)
3.90-4.14 (4H, m, -COOC equivalent-, -
C5tN () MS value = rrVz 566 (M”), 565, 564, 549, 548, 4
44 Example 6 2.6-dimethyl-4-(3-nitrophenyl)-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(16-(1-imidazolyl)hexadodecyl) ester: Melting point: 97-99°C Properties: Pale yellow crystal IR value, KBrcWl-t ax 3350 ( broad), 3186.3050.29
00.2850°1695, 1525.1505.13
45.1210.1115°095 NMR value: δCDC type.

1.10-1.84(28H,m,-(Cdt)+4-
) 2.37 (6H, s, -C mountain x 2) 3.64
(31(,s,-COOCHL)3.88-4-10
(4H, rr+, C00C:Ht-1-CH, N C
) MS value: rrv'z 622 (M ), 621, 620, 605, 604, 5
00 Example 7 2.6-dimethyl-4-(2-nitrophenyl)-1,
4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-(8-(1-imidazolyl)octyl ester; Properties: Yellow viscous oil IR value; ν Liquid film cm ”” aX 3300.3171,3080 ,2923,1690,
1641°1530.1207,1110,1090,
1020,750°62 NMR value: δCDC-es 0.8-1.9 (15H,m, -(Cjjt)a
-, -CHtCdans)2.30 (6H,s, -Ci
(,X2)3.7-4.2 (6H,m,-COOCt
(tcHl, -COOCH2CH2.

Note Example 8 2.6-dimethyl-4-(2-pyridyl)-1°4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(8-(1-imidazolyl)octyl ester) Properties: Pale yellow IR value of viscous oil: Shiso Todoro - Heavy 3260, 3177, 3070.2926.1690.
1642°1500, 1430.1304.1210.
1114.1090°1017, 750.662 NMR value: δC cry.

1.1 1.9 (12H, m, -(Cjj*)a-
)2.20 (6H,m, -CH,X2)3.58
(3H,s, -COOCH3)3.8-4.1(4
H9m, -COoCfl! 2-9-Cd, -N8) base Example 9 2.6-dimethyl-4-(2-chloro-3-pyridyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid
3-methyl ester 5-(8-(1-imidazolyl)
[Octyl] ester: Properties: Pale yellow viscous oil IR value: Sylime saw-1 ax 3280, 3100.3050.2925.1690.
1642°1500, 1406.1270.1210.
1110.1090°750,662 NuR value: δCDCJ.

1.1-2.0 (12H,m, -(C3t)a-
) 2.30 (6H, s, -C mountain x 2) 3.60 (
3H,s, -COOCL)7.68 (IH,d
, d, J, = 8.1Hz, J, -2,2Hz.

8.10 (IH, dld, Jl-5, 1H1, J, -
2.2Hz.

Example 10 2.6-dimethyl-4-(2-chlorophenyl)-1,
4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(8-(1-imidazolyl)octyl) ester: Properties: Colorless viscous oil IR value: Silk film cIn-1 ax 3051, 2923. 1690.1640.1500.
1379°1300, 1270.1210.1100.
1017.750°62 NMR value: δCDC-es 1.0-2.0 (12H, m, -(cut)s-)
2.30 (6H, broad s, -CH5X2
)3.60 (3H,s, -COOCf(s))3.
8-4.1 (4H9ml-Cooc!!",-cHjN
)■ Example 11 2.6-dimethyl-4-C2-fluorophenyl)-1
,4-dihydropyridine-3,5-dicarboxylic acid 3-
Methyl ester 5-(8-(1-imidazolyl)octyl)ester Melting point j 110-112.5°C Properties: Pale yellow crystal IR value, νKBrm-” aX 3190.3070, 2923, 1689, 1505,
1484°1430, 1304, 1273, 1208,
1114,1019°58 NMR value: δCDC type.

1.27-2.15 (12H,m, -(C!1s)
a-) 2.28 (6H,s, -Cdan, x2) 3.58
(3f(,s,-COOCH,)3.91 (2H,
t, J = 7Hz, -COOCH2-)3.97
(2H, t, J=7Hz, -c mountain N\) Example 12 2.6-dimethyl-4-(2,3-dichlorophenyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid
3-methyl ester 5-[8-(1-imidazolyl)
Octyl] ester molecular formula C2? H3SC-etNs
o4 colorless crystalline powder (EtzO), rnp137-1
38°, KBr −1 1R value 'max' 2923, 1692.1636.1507.1301.
1273°1203, 1113 NMR (200MHz, CDCAs) δ: 1
．． 05-1.35 (8 ratio broad s, -(CI
! *)*-)1.54 (2H, quintet, J
-7,IH2+ -CHx-)1.76 (2H,br
oad, quintet, Ja-7, lHz.

-Mount C-) 2.31 and 2.32. (6H,sX2.-cdan,×
2) 3.61 (3H,s, -CωCp%) 3.9
2 - (2H, t, J=6Hz, -COOC) (t
-) 3-90-4.14 (2Hlm, CHtN
X) 5.44 (IH, S, C, once) 7.02-7.36 (3H, m, Aromatic
)i)■' Example 13 2.6-dimethyl-4-(2-)lifluoromethylphenyl)-1,4-dihydropyridine-3°5-dicarboxylic acid 3-methyl ester 5-[8-(1-imidazolyl) ) octyl] ester molecular formula C! a H34Fs
Ns O4 colorless crystalline powder (Et, 0), mp 70
-74°IH value: KBr-1 max Qll 2922, 1691.1642.1505.1305.
1275°1209, 1113 NMR (200iVIHz, CDC-13z
) δ: 1.25 (8H+ broad s + (C
H2)4-)1.49 (2H, broad quin
tet, J-6,8f (z.

-cH2-) 1.76 (2H, broad quintet, J
-6,8)tz.

-C day, -) 2.31 and 2.32 (6H, sx2.-C) (3x
2) 3.59 (3H,s, -COOCH3) 3.9
2 (2H, t, J=6Hz, -COOCH-)3.9
04.14 (2H, rn, CHt-N()5.54 (
IH, s, C4 once) 6-05 (I H9s, tN■)

[Brief explanation of the drawing]

FIG. 1 is a graph showing the increase in coronary blood flow by administration of the compound of Example 1, FIG. 2 of the compound of Example 9, and FIG. 3 of the compound of Example 11. That's all for IH Kannen - \Continuation of page 1

Claims (1)

[Claims] (In the formula, R1 and R2 are the same or different, a hydrogen atom represents a carbon atom or a nitrogen atom, and B represents a straight chain or branched alkylene group having 7 to 16 carbon atoms) 1,4-dihydropyridine derivatives represented by: