JPS60149563A - 1,4-dihydropyridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R is phenyl substituted by Br, Cl, CF3, etc. at the 2- or 3-position, phenyl substituted by Cl at the 2-position or 2,1,3-benzoxadiazol-4-yl; R<1> is 1-3C alkyl; R<2> is acetylor cyclopropyl, provided that R<2> is acetyl when R is 2,3-dichlorophenyl or 2,1,3-benzoxadiazol-4- yl]. EXAMPLE:Methyl 2-oxopropyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxyl ate. USE:A medicine for preventing or treating ischemic heart diseases, cerebral circulatory disorder, hypertension, etc. or complications thereof. PREPARATION:For example, a compound expressed by formula II is reacted with a compound expressed by formula III to give a compound expressed by formula IV, which is then reacted with an acid in an aqueous solvent containing the acid to afford the aimed compound expressed by formula I (R<2> is acetyl).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula [wherein R is at the 2nd or 3rd position, Br1Cjl, CFB
, OMelSMelS (0)Me, or S (02
)Me, a phenyl group substituted with C1 at the 2 and 3 positions
R1 is a straight or branched alkyl group having 1 to 3 carbon atoms, R2 is an acetyl or cyclopropyl group, (However, R is 2,3-dichlorophenyl group or 2.1.3-benzoxadiazole-4
In the case of -yl group, R2 represents only an acetyl group].

2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dimethyl The reaction for synthesizing carboxylate derivatives is called the Hant÷zsch reaction, and its variants are widely known (e.g., Ann, 215°1 (1982); Ber, 1982).
15.2914 (1882), 17.1521 (1
884), 17.2903 (1884), Touma 133
8 (1887).

31, 743 (1898); J, Chem, S.
oc, 413 (1943); J, Amer, C
C11e, Soc, 71.4003 (1949)
; J.

Org, Chem, 30.1914 (1965)
See etc. ).

In addition, 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate derivative is
It is also well known that Natur%
Wissenshaften, 58.578 (197
1) ;Arzneim, -Forsch,, ,2
2.1 (1972); J, Pharm.

Pharmacol, 24.917 (1972)
; J, Pharm, Sci.

62, 580 (1973); J, Med, Cb
em, , 17.956 (1974); Be I
g-P at-* 689t 377; USP
See at-p 3m485, 847, etc. ).

One of these known compounds is dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (generic name: nifedipine, US Pat. 3. 485° 847) was marketed as a pharmaceutical with coronary vasodilatory action.

However, there are still problems with sustainability and side effects. In addition, it has been reported that nifedipine is extremely unstable to light, which poses a major difficulty in formulation (e.g., Basic and Clinical *6 p. 259
(1972); Arzneim, -Forsch.

μ, 2188 (1978); Pharmaceutical Journal February υ, 1
149 (1981), etc. ).

Under these circumstances, research is being conducted to find even better 1,4-dihydropyridine-3,5-dicarboxylate derivatives, and many patent applications have been filed (
For example, JP 51-12632゜53-95976
, 54-70284.55-9083.55-4067
8, 55-47657.55-64570.55-64
571゜56-127356, Special Publication No. 51-1263
2.55-29989゜55-29990.55-50
See 021.56-37225.56--47185, etc. ).

However, the compounds described in these documents leave room for investigation in issues such as therapeutic efficacy, drug absorption from the gastrointestinal tract, side effects, toxicity, and photostability.

Research closely related to the present invention has also been conducted, and patent applications have been filed (for example, Japanese Patent Laid-Open No. 55-9083,
6-127356.54-103876, 57-823
15 etc.).

Diethyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (JP-A-1986-
103876, 57-82315) has been reported to have approximately the same vasodilatory effect as nifedipine (for example, J. Cardiov).

Pharmacol, 4352 (1982), etc.).

In addition, the present inventors have also filed several patent applications closely related to the present invention (for example, Japanese Patent Laid-Open No. 58-6766
8.58-146565. Patent 58-Shin 89574, etc.).

As a result of further research, the present inventors found that the compound (I) of the present invention has strong vasodilatory and antihypertensive effects, is long-lasting, and does not increase or decrease heart rate. This discovery led to the completion of the present invention.

Compounds of the present invention (D is ischemic heart disease, cerebral circulation disorder,
It is industrially useful as a drug for preventing or treating hypertension, hypertension, etc., or for preventing or treating these complications.

Compound (I) of the present invention can be produced as follows.

1. When R2 is an acetyl group, benzylidene acetoacetate represented by the general formula (R and R1 have the same meanings as above) and 2,2-ethylenedioxypropyl 3-aminocrotonate (JP-A-Show) represented by the formula 58-67668), or allyl aldehyde represented by the general formula R-CHOIV (1< has the same meaning as above), and the general formula % formula % (R1 has the same meaning as above). acetoacetate in a solvent inert to the reaction such as methanol, ethanol, isopropyl alcohol or without a solvent.
After reacting at 0 to 150°C for 1 to 40 hours to obtain a compound represented by the general formula (R and R1 have the same meanings as above), an aqueous solvent containing an acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, etc. methanol, ethanol, isopropyl alcohol, acetone, etc.) at room temperature or under heating.
Compound (I) of the present invention can be produced by reacting for 10 hours.

2. When R2 is a cyclopropyl group, compound (II) (R is Br at the 2nd or 3rd position, C4
゜The phenyl group substituted with CF8, -OMe, SMe, S(0)Me, or S(02)Me is R1
has the same meaning as above) and cyclopropylmethyl 3-aminocrotonate (compound described in JP-A-58-67668) represented by the formula, or compound (IV) (R is Br at the 2nd or 3rd position). %
C1l, CFB, OMe, SMe, S (0)M
e or S(02)Me-substituted phenyl group,
R1 has the same meaning as above), Compound (vn), and Compound (V) are mixed at 50 to 150°C in a solvent inert to the reaction such as methanol, ethanol, isopropyl alcohol, or in the absence of a solvent. Compound (I) can be produced by reacting for 40 hours.

The compound (I) of the present invention can be used alone or together with other compositions, such as tablets, troches, gunpowder, granules, powders,
It can be used in the form of capsules, ampoules, freshly divided tablets, etc. Other compositions include, for example, starch, dextrin, sucrose milk 11f, silicic acid, carboxymethyl cellulose, cellulose, gelatin, polyvinylpyrrolidone, glycerin, agar, calcium carbonate, sodium hydrogen carbonate, paraffin, cetyl alcohol, stearate, Examples include kaolin, bentonite, talc, calcium stearate, magnesium stearate, polyethylene glycol, water, ethanol, isopropyl alcohol, and propylene glycol.

The appropriate daily dose for oral administration of the compound (I) of the present invention is 0.005 to 20 mg per body weight I Kr. Naturally, depending on the condition at the time of administration,
It should be increased or decreased as appropriate.

The method for producing the compound (I) of the present invention will be explained in detail by giving further examples.

Example 1 2.3-dichlorobenzaldehyde 4.8F, methyl acetoacetate 3.4F and 2,2-ethylenedioxypropyl 3-aminocrotonate 5.52 were added to ethanol 5
Reflux for 5 hours with 0-. After the reaction, the solvent was distilled off and recrystallized from a silica gel column chromatography mixture to give colorless needle crystals, 2,2-ethylenedioxypropylmethyl 4-(2,3-dichlorophenyl)-1, melting point 136-138°C. ,4-dihydro-2,6-dimethylpyridine-3
, 5-dicarboxylate (3.4 t) was obtained. NMR(C
D(J8)J=11.7Hz1Δshi=8.4),5.
50 (IH,, s ), 5.97 (IH, brs )
, 6.97-"7.43 (3H, m). Next, 1 of this
．． 5f, ethanol 20m7! A mixture of 1-1 methanesulfonic acid and 10-1 water was added to the mixture, and the mixture was refluxed for 3 hours.

After the reaction, the solvent was distilled off, the residue was dissolved in dichloromethane, washed with water, dried (magnesium sulfate), and the solvent was distilled off. The residue was crystallized from 9-hexane. Recrystallized from a dichloromethane-hexane mixture to give pale yellow needle-like crystals, melting point 161-1.
Methyl 2-oxopropyl 4-(2,3-
Dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate 17 was obtained. NMR (CDC68) δ 1.99 (3H1S),
2, 30.2.32 (6H1 Hiroshi each), 3.60 (3H,S), 4.58
(2H, ABtype, b, J-16, 5Hz,
Δν=7.2 ), 5.52 (IH,s ), 6.
16 (IH.

brs), 5.98-7.40 (3H, m).

Example 2 Methyl 2'-bromobenzylidene acetate 8
．． 5f, 6v of 2,2-ethylenedioxypropyl 3-aminocrotonate and 50ml of ethanol were refluxed for 4 hours. After the reaction, the solvent was distilled off and crystallized. 2,2-ethylenedioxypropyl methyl 4-(2-bromophenyl)- was recrystallized from an isopropyl alcohol-isopropyl ether mixture to give pale yellow needle-like crystals, melting point 133-136°C.
1,4-dihydro-2,6-dimethylpyridine-3,5
-dicarboxylate 7.11 was obtained. NMR (CDC
/3) δ: 1.31 (3H1S), 2.30 (3
H,S ), 2.32(3H,s ), 3.63(3
H,s), 3.89 (4H,s), 4.06 (2H
, ABtypeb.

J=12.0Hz, △ν=10.6), 5.39(
LH,S), 5.69 (1H1brs), 6.82
-7.53 (4H1m), then 31 of this is ethanol 807! Nitokaji, methanesulfonic acid 1 tnl and water 2
0rn1. Add a mixture of and reflux for 2 hours. After the reaction, the solvent was distilled off, the residue was dissolved in dichloromethane, washed with water, and dried (
Magnesium sulfate), the solvent was distilled off, and the residue was crystallized from isopropyl ether-hexane. Recrystallized from isopropyl ether, pale yellow needle crystals, melting point 92-106°C
2.5f of methyl 2-oxopropyl 4-(2-bromophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate was obtained. NMR
(cDcgB)δ: 1.93 (3H,S), 2.
33 (6H,S), 3.63 (3H1s), 4
．． 57 (2H,s), 5.42 (IHLS),
5.92 (IH, bts), 6.83-7.57
(4H, m).

The following compound was obtained in the same manner as in Example 2.

Example 3 Ethylenedioxypropyl methyl 4-(2-chlorophenyl)=1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate. Recrystallized from an isopropyl alcohol-isopropyl ether mixture to give colorless needle-like crystals, melting point 123-127°C. From this, methyl 2
-oxopropyl 4-(2-chlorophenyl)-1,
4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate was obtained. Isopropyl ether
Recrystallized from hexane, pale yellow needle crystals, melting point 126-
130'C6 Example 4 Ethylenedioxypropyl isopropyl 4-(2-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate. Pale yellow oil. NMR (CDCn3) δ: 1.05.1, 24
(6H, eachd, J = 6.3Hz), 1.
34 (3H, S), 2.30 (6H, S), 3.91 (
4H,s), 3.93 (IH,ABtyped.

J = 11.7Hz), 4.13 (IH, ABt
yped, J = 11.7Hz), 4, 96 (
IH, m, J = 6.3Hz), 5.41 (IH
ls ), 5.71 (lH, brs ), 6.90-7
．． 47 (4H, m). From this, 2-oxopropyl isopropyl 4-('2-chlorophenyl)-1
,4-dihydro-2,6-dimethylpyridine-3,5-
A pale yellow oil of dicarboxylate was obtained. NMR(c
Dca 3) δ: 1.03.1.24 (6H1eac
hd, J = 6.3Hz), 1.93 (3H1S
), 2.31 (6H1g), 4.55 (2H1s)
, 4.96 (IH, m1J =6.3Hz7.5.4
3 (IHls), 5.83 (IH, brs), 6.
93-7.47 (4H, m).

Example 5 Ethylenedioxypropyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)pyridine-3,5-dicarboxylate. Pale yellow oil. NMR (CDCl 8') δ: 1.28 (
3H1s), 2.28 (6H,s), 3.57 (3H
, s ), 3.88 (4H, 'S), 4.02 (2H,
ABtypeb J=11.7Hz, △C24.3'
), 5.56 (IH, brs ), 5.93 (IH
lbrs), 7.07-7.73 (4H, m). From this, 2-oxopropylmethyl 1,4-dihydro-2,6-dimethyl-4-(2-1lifluoromethylphenyl)pyridine-3,5-dicarboxylate was obtained. Recrystallized from dichloromethane-n-hexane, colorless needle crystals, melting point 144-147°C.

Example 6 2.2-ethylenedioxypropyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-methoxyphenyl)pyridine-3,5-dicarboxylate. Recrystallized from a dichloromethane-hexane mixture to give colorless needle-like crystals,
Melting point 128-132°C. From this, 2-oxopropyl methyl 1,4-dihydro-2,6-dimethyl-4-
(2-methoxyphenyl)pyridine-3,5-dicarboxylate was obtained. Recrystallization from isopropyl alcohol-isopropyl ether mixture gives colorless needle-like crystals, melting point 1.
59-162℃.

Example 7 2.2-ethylenedioxypropyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-methylsulfinylphenyl)pyridine-3,5-dicarboxylate. Recrystallized from a dichloromethane-hexane mixture to give a pale yellow prism product, melting point 94-97°C. From this, 2-oxopropyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-methylsulfinylphenyl)pyridine-3,5-dicarboxylate was obtained. Recrystallized from a dichloromethane-hexane mixture to give colorless prism crystals,
Melting point 204-207°C.

Example 8 2.2-Ethylenedioxypropyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-methylsulfonylphenyl)pyridine-3,5-dicarboxylate, pale yellow oil. NMR (CDCl8) δ: 1.28
(3H18), 2.23.2.26 (6H1each
s ), 3, 29 (3H,s ), 3.58 (3H
1s ), 3.86 (4H,s ), 3.99 (2H
, ABtypeb, J=11.7Hz, △ν=4.
7), 5, 77 (IH, brs), 6.18 (IH
ls), 7.15-7.93 (4H, m). From this, 2-oxopropylmethyl 1,4-dihydro-2,
6-dimethyl-4-futa(2-methylsulfonylphenyl)pyridine-3,5-
Dicarboxylate was obtained. Recrystallized from dichloromethane-isopropyl alcohol to give yellow needle-like crystals, melting point 117.
-125℃.

Example 9 -1,4-dihydro-2,6-dimethylpyridine-3,
5-dicarboxylate, pale yellow oil. NMR (CD
CJ8δ: 1.29 (3H,s), 2.31.2.
34 (6H, eachs), 3.61 (3HSs)
, 3.80-4.03 (m, 6H, 3,96 (512
H, C03CH2)], 5.48 (IH, S), 6.1
7 (IHlbrs), 7.20-7, 38 (2H,
m), 7.50-7.72 (IH, m). from now,
Methyl 2-oxopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate was obtained. Recrystallized from dichlormechne-isopropyl ether, yellow prismatic crystals, melting point 162-164°C.

Example 10 9-chlorobenzaldehyde 7f, A-1! ) Refluxing 5.82 f of methyl acetate and 7.8 f of cyclopropylmethyl 3-aminocrotonate with 80 rnl of ethanol for 6 hours. After the reaction, the solvent was distilled off, the residue was separated and purified by silica gel column chromatography (ether), and recrystallized from isopropyl ether to give colorless needle crystals with a melting point of 128-130°C.
-(2-chlorophenyl')-1,4-dihydro-2,
6-dimethylpyridine-3,5-dicarboxylate 1
．． I got 5r.

NMR(CDCl9)δ: 0.07-0.60
(41-1, m), 0.87-1.36 (IH, m)
, 2.31.2.33 (6H1eachs), 3.
63 (3H, s), 3.83 (2H, d, J=7.0
H2), 5.43 (IHLS), 5.62 (IH, br
s), 6.90-7.47 (4H, m) In the same manner as in Example 10, the following compound was obtained.

Example 11 Cyclopropylmethyl methyl 4-(3-10lophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate, colorless prismatic crystals (isopropyl alcohol-isopropyl ether), melting point 1
24-128℃.

Example 12 Cyclopropylmethyl Methyl, 4-(2-bromophenyl)-1,4-dihydryl-2,6-dimethylpyridine-3,5-dicarboxylate, pale yellow flakes (isopropyl ether) ether), melting point 140-142
℃.

Example 13 Cyclopropylmethyl methyl 1,4-dihydro-2
,6-dimethyl-4-(3-trifluoromethylphenyl)pyridine-3,5-dicarboxylate, colorless needles (dichloromethane-hexane), melting point 124-1
27℃.

Example 14 8 g of methyl 2'-trifluoromethylbenzylidene acetate, 57 g of cyclopropylmethyl 3-aminocrotonate and 50 rnl of isopropyl alcohol,
Reflux for 18 hours. After the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ether-hexane).
1:2) and recrystallized from a dichloromethane-hexane mixture to give colorless needle crystals, melting point 124-12.
Cyclopropylmethyl methyl 1,4-dihydro-2,6-dimethyl-4-<24 trifluoromethylphenyl) NMR (CD(J8) δ: 0.02-
0.59 (4H, m), 0.78-1.33 (IH,
m), 2.29.2.30 (6H, each),
3.59 (3H, s), 3.78 (IHld d,
J = 1. manufactured by IH, 12.0Hz), 3.87 (IH, d
d, J=19.0.12.0H2), 5.58 (IH
, s), 5.82 (IH, brs), 7.07-7.
85 (4HXm).

The following compound was obtained in the same manner as in Example 14.

Example 15 Cyclopropylmethyl isopropyl 4-(2-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate, pale yellow oil,
NMR (CDC13) a: 0.06-0.59 (
4H, m), 0.90-1.33 [7H, m11.0
4.1.23 (6H.

eachd, J=6.3Hz) :], 2.28
(6H,S), 3.83 (2H,' d, J=7.
2H2), 4.96 (IH1brs'), 6.90-
7.48 (4H11n).

Example 16 Cyclopropylmethyl methyl 1,4-dihydro-2
,6-dimethyl-4- ('2-methylthiophenyl)
Pyridine-3,5-dicarboxylate, pale yellow needles (isopropyl alcohol-ether), melting point 137-
141℃.

Example 17 Cyclopropylmethyl methyl 1,4-dihydro-2
, 6-dimethyl-4-(2-methylsulfinylphenyl)pyridine-3,5-dicarboxylate, pale yellow oil, NMR (CDC68) δ: 0. @1-0.59
(4H, m), 0.80-1.31 (IH, m), 2
．． 28 (6H1S), 2.46 (3H,S), 3.
60 (3H1S), 3.85 (2H1d1J=7.2
H2), 5.47 (1) (, s ), 5.72 (I
Hlbrs), 6.97 7.43 (4H, m).

Example 18 Cyclopropylmethyl methyl 1,4-dihydro-2
, 6-dimethyl-4-(2-methylsulfonyl)pyridine-3,5-dicarboxylate, yellow prism product (
isopropyl alcohol-isopropyl ether), melting point 157-161°C.

Example 19 Cyclopropylmethyl methyl 4- (2,1°3-
Benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate, yellow needles (dichloromethane-isopropyl ether), Ri point 158-160°C.

Next, the results of pharmacological tests on the compound (I) of the present invention and some known compounds will be explained by giving examples.

Control compounds Nifedipine (compound described in US Pat, 3.485.847) Felodipine (compound described in Japanese Patent Publication No. 55-9083) Nicardipine (compound described in Japanese Patent Publication No. 55-45075) Hydralazine-treated dogs were treated with bentoparbital sodium 30W/Kr
(iv) The animals were anesthetized and, under artificial respiration, blood flow in the vertebral, 9th, coronary, and large 1111L arteries was measured using an electromagnetic flowmeter.

Blood pressure was also measured at the same time. The test drug is 1 part in ethanol.
%, diluted 10 times with 80% polyethylene glycol 400 solution, further diluted with 0.9% physiological saline, and administered 3 μf/Kj intravenously.

The vasodilatory effect was expressed as the value obtained by dividing the rate of increase in blood flow of the sample x half-life of action by that of nifedipine, using nifedipine as a control. The results are shown in Table 1.

Table 1 Vasodilatory Effect As is clear from Table 1, the compound of the present invention has a significantly superior vasodilatory effect compared to the known compounds nifedipine and nicardipine. Furthermore, the compounds of the present invention are long-acting and are useful as cerebral vasodilators or coronary vasodilators.

Effect on blood pressure in spontaneously hypertensive rats (SHR) Tail artery systolic pressure was measured non-invasively using SHR without anesthesia. Heart rate was also measured at the same time. The specimen was dissolved in 70% polyethylene glycol solution, 3 yt/Kg
was administered orally.

The results are shown in Table 2.

As is clear from Table 2, the compound (I) of the present invention has a significantly superior antihypertensive effect compared to the control compounds (nifedipine, felodipine, nicardipine, hydralazine). Furthermore, the compound (I) of the present invention is long-acting and is industrially useful as an antihypertensive drug.

As mentioned above, the compound (I) of the present invention has a strong vasodilatory effect,
has an antihypertensive effect, is long-lasting, and does not increase heart rate at doses that exhibit a desirable degree of effect;
Alternatively, it is industrially useful as a drug for preventing or treating ischemic heart disease, cerebral circulation disorder, hypertension, etc., or complications thereof.

Old procedure amendment (spontaneous) April 5, 1980 Commissioner of the Japan Patent Office Kazuo Wakasugi 1. Indication of the case 1982 Patent Application No. 4115 3. Person making the amendment 4. Specification of the specification to be amended ( 1) “Cyclopropylmethyl methyl 4-(2,1,
3-penzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate" and "2-oxopropyl methyl 4-(
2,1,3-benzoxadiazol-4-yl)-1
,4-dihydro-2,6-dimethylpyridine-3,5-
Dicarboxylate” is corrected.

that's all

Claims (1)

[Claims] General formula [wherein R is at the 2nd or 3rd position, Br, C4, CFB,
OMe, SMelS (0) Mel or S (02)
a phenyl group substituted with Me, a phenyl group substituted with C1 at the 2 and 3 positions, or a 2.1.3-benzoxadiazol-4-yl group; R1 is a straight chain having 1 to 3 carbon atoms; or a branch i-chain alkyl group, R2 is an acetyl or cyclopropyl group (provided that R is a 2,3-dichlorophenyl group or a 2.1.3-benzoxadiazole-4
-yl group R2 represents only an acetyl group). 1,4-dihydropyridine derivative represented by