JPS59216873A - 1,4-dihydropyridine derivative - Google Patents

Abstract

NEW MATERIAL:A 1,4-dihydropyridine derivative expressed by formula I (R is lower alkyl, e.g. methyl, ethyl or propyl). EXAMPLE:Cyclopropylmethyl methyl 4-( 2, 3-dichlorophenyl )-1, 4-dihydro-2, 6-dimethylpyridine-3,5-dicarboxylate. USE:With powerful vasodilator and hypotensive action, useful as a preventing and treating agent for ischemic heart diseases, cerebral circulatory disorder or hypertension or a complication thereof, having great prolonged action, and stable to light. PREPARATION:An aminocrotonate expressed by formula II is reacted with an acetoacetate expressed by formula III and benzaldehyde expressed by formula IVin an inert solvent, e.g. ethanol or isopropyl alcohol, to afford the aimed compound expressed by formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an ester moiety containing a cyclopropylmethyl group represented by the general formula (wherein B means a lower alkyl group such as methyl, ethyl, propyl, etc.). The present invention relates to a novel 1,4-dihydropyridine derivative.

2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate by reacting benzylidene acetoacetate derivative and β-aminocrotonate derivative, or benzylidene acetoacetate, acetoacetate derivative, and ammonia. The reaction for synthesizing derivatives is called the Hant-zsch reaction, and its modifications are widely known (e.g., Ann, 215.1 (1982); Ber, 2002).
Fox, 2914 (1882), 17.1521 (18
84), Dan, 2903 (1884), Dish, 1338
(188 full 31.743 (1898); J, Che
m, 8oe, , 413 (1943); JAmer
, Chem, Soe, , 7L 4003 (19
49) ; J. Orlg, Ohem, 30° 1914 (1965), etc. ).

In addition, 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate derivative is
It is also well known that it exhibits interesting pharmacological effects such as vasodilation and antihypertensive effects (for example, Natur-wi
ss+enshaf ten, 58.578 (19
71) Pickled Arzne in, -Forsch,.

2L 1 (1972); J, Pharm, Pha
rmacol, 24.917 (1972) it
T.

Pharm, 8e1. , 62.580 (1975)
; J, Med, Chem, 17.956 (1
974) HBelg, Pat, 689.377
; US Pat., 5.485.847, etc. ).

One of these known compounds is dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (common name i
Near x Shibin, US Pat, , 5.48
5.847 D) 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 Research, 259).
1972); Arzneim, -For8eh, 4h2
188 (1978); Pharmaceutical Journal, -υ11.1149 (
(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. 51-12632
゜55-29989, 55-29990, 55-5
0021, 56-57225, 56-47185, etc. ).

In addition, research closely related to the present invention has also been conducted.
A patent application has been filed (Japanese Patent Application Laid-open No. 55-9083.56-1
2735/,).

However, the compounds described in these documents still have room for consideration in their therapeutic efficacy, absorption of drugs from the gastrointestinal tract, side effects, toxicity, photostability, and other aspects of their practical use.

The present inventors have already discovered that alkyl cyclopropylmethyl 2.6-cymethyl-4-(3
-Nitrophenyl) -1,4-dihydropyridine-5-dicarboxylate derivatives have excellent pharmacological effects, low toxicity, and excellent photostability, and have applied for a patent (Patent 57-028591).

This time, the present inventors replaced the 3-nitrophenyl group of (1) with 2.
The inventors have now completed the present invention by discovering that the compound (I) of the invention has strong vasodilatory and antihypertensive effects, as well as long-lasting effects.

The compounds of the present invention are stable against light and are industrially useful as pharmaceuticals for preventing or treating ischemic heart disease, cerebral circulation disorder, hypertension, etc., or complications thereof.

Compound (I) of the present invention can be produced as follows. That is, aminocrotonate represented by the general formula and Me (X)O
H2002B Acetoacetate represented by N (wherein R has the same meaning as above),
The compound of the present invention can be produced by reacting benzaldehyde represented by the formula in a solvent inert to the reaction such as ethanol, isopropyl alcohol, butanol, etc.

Similarly, benzylidene acetoacetate represented by the formula (wherein R has the same meaning as above) and a seal, or the formula Me (300H2
002Cf (2-(acetoacetate represented by ■,
It can also be produced by heating (1), (2) and ammonia, ammonium carbonate, charcoal M7 [ammonium, etc.] in a melt similar to the above.

The compound (I) of the present invention can be used alone or together with other compositions, such as anchor agents, lozenges, gunpowder, granules, powders,
It can be used in the form of capsules, ampoules, halves, etc. Other compositions include, for example, starch, dextrin, sucrose, lactose, silicic acid, carboxymethylcellulose, cellulose, gelatin, polyvinylpyrrolidone, glycerin, agar, calcium carbonate, sodium bicarbonate, paraffin, cetyl alcohol, Examples include stearate, kaolin, bentonite, talc, calcium stearate, magnesium stearate, polyethylene glycol, water, ethanol, isopropyl alcohol, propylene glycol, and the like.

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

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

Example 1 2.6-cyclobenzaldehyde 8.6 g, cyclopropylmethyl 3-aminocrotonate 7,7 f s
Methyl acetoacetate 5.7g and ethanol 5
Reflux the 0@1 mixture for 8 hours. Then, the solvent was distilled off to obtain an oily substance. Purify by column chromatography (silica gel, isopropyl ether) and crystallize the obtained oil from dichloromethane-hexane. Recrystallized from dichloromethane-hexane to give cyclopropylmethyl methyl 4-(
2,3-dichlorophenyl)-1,4-dihydro-2,
Colorless needles of 6-dimethylpyridine-6,5-dicarboxylate, mp 13B-142°, 6.7f (33
%).

NMR (CDC65) δ: O, OO-[], 59 (4T
'(, m), (1,86-1,27 (1H, m), 2.
30 and 2.32 (each 3H,s),'>,6
2 (3B S), 3.85 (2H, d.

J=6. qT-T illusion, 5.48 (IH, S), 5.71
(IH, brs), 6.95-7.40 (3H, m
).

Example 2 2.3-dichlorobenzaldehyde 7.6q, cyclopropylmethyl 3-aminocrotonate 6.8g1 ethyl acetoacetate 5.1y Yohiethanol 50m
/ and operate in the same manner as in Example 1. The obtained oil was crystallized from isopropyl ether-hexane.

Recrystallization from ether-hexane yielded ethyl cyclopropylmethyl 4-(2j-dichlorophenyl)-1,
Colorless needle-like crystals of 4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (C6 as crystal solvent)
■1<), mp76-78°, bp 220°(
5.0, bath 1 temperature), 6.4 g (31%) was obtained.

NMR (CDC7?3) δ: 0.00-0.59 (
41 (, m), 0.86-1.27 (1, H, m), t
18 (3H, t, J=ZI Hz), 2.31
(6H,s), 3.83 (2H,d, J=7.3
Hz), 4.08 (2H,, q, J=7.1Hz)
, 5.50 (IH-s), 5.76 (IH, brs),
6.95-742 (3H, m).

Example 3 8 g of 2.6-dichlorobenzaldehyde, 6.6 y of cyclopropylmethyl 3-aminocrotonate, 7.1 f of furovir acetoacetate and 80 y of ethanol. /
Operated in the same manner as in Example 1. The obtained oil crystallized on standing and was recrystallized from ether-hexane to give cyclopropyl propyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-6
．． Colorless needle crystals of 5-dicarboxylate (containing '/, C6H1a as crystallization solvent) mp103-106.
6.0 g (30%) was obtained.

NMB(ODC6s) δ:D, 03-0.59(J(,
m), 0.69-1.80 (6H, m).

230 (6I-L s ), 3.81 (2H, d,
J=6.9Hz), 3.90(2H,t, J=6.
8Hz), 5.49 (IH, 8), 5.67 (IH, b
rs), 6.94-7.42 (5H,m).

Example 4 Methyl 2.3-dichlorobenzylideneacetoacetate 14 g, cyclopropylmethyl 3-amic o)*
-1-Bfz A mixture of 50.1 ethanol was refluxed for 8 hours, and then operated in the same manner as in Example 1, and cyclopropylmethyl
Methyl 4-(2,3-dichlorophenyl) -1,4
-dihydropyridine-6,5-dicarboxylate8.
2 g (39%) was obtained.

Example 5 A mixture of 8.6y of 2.3-dichlorobenzaldehyde, 7.7g of cyclopropylmethyl acetoacetate, 9fI of methylacetoacetate and 80fIt of ethanol was refluxed for 8 hours, the reaction solvent was distilled off, and the residue was dissolved in ethyl acetate and water. The organic layer was separated, washed with water, dried over magnesium sulfate, and the solvent was distilled off.
2,3-dichlorophenyl)-1,4-dihydro-2,
6-dimethylpyridine-3,5-dicarboxylate 6
．． Obtained 8g.

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

Compound A dichloropropylmethyl methyl 1,4-dihydro-2,6-dimethylpyridine-6,5-dicarboxylate Compound B: ethyl cyclopropylmethyl 1,4-dihydro-2,6-dimethylpyridine-3 .5-dicarboxylate compound C dichloropropylmethyl propyl 1,4-dihydro-2,6-dimethylpyridine-3.5-dicarboxylate compound D: nifedipine compound E: ethyl methyl 4-(2,3- dichlorophenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (JP-A-55-90
83).

Bentoparbital sodium 30 Pf/kg
(iv) The animals were anesthetized and, under artificial respiration, blood flow in the vertebral, general, coronary, and femoral arteries was measured using an electromagnetic flowmeter. Blood pressure was also measured at the same time. The test drug was dissolved in ethanol to a concentration of 1%, and then dissolved in 80% polyethylene glycol 4.
The solution was diluted 10 times with 0.00 solution, further diluted with 0.9% physiological saline, and administered into the femoral vein.

The results are shown in Tables 1 and 2.

Table 1 Table 2 As shown in Tables 1 and 2, the compound (I) of the present invention has an excellent vasodilatory effect, being more specific to the known compounds (fedipine) and E. In addition, the wood-invented compound mountain lasts for a long time, making it more desirable as a medicine. In particular, compounds A and B are outstanding.

The caudal artery systolic pressure was determined non-invasively using Action 8111 (71) under anesthesia. Heart rate was also measured at the same time.
% polyethylene glycol solution and administered orally.

The results are shown in Table 3.

Table 5 As shown in Table 3, the compounds of the present invention had almost no effect on heart rate except for compounds A- (E showed excellent long-lasting hypotensive action. 1) with fezibin).

As described above, the compounds of the present invention have strong and long-lasting effects, have a high safety factor, and are industrially very useful as pharmaceuticals.

Patent applicant: Marco Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1,4-dihydropyridine derivative represented by the general formula (wherein R means a lower alkyl group such as methyl, ethyl, propyl, etc.)