JPS60258194A - Dihydropyridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R1, R2, R3, R4 are lower alkyl; Ar is naphthyl, phenyl which may be substituted with 1-3 different or identical substituents selected from nitro, halogen, alkyl, hydroxy, cyano and others). EXAMPLE:Ethyl 1,4-dihydro-5-dimethoxyphosphinyl-2,6-dimethyl-4(3-nitrophenyl)- 3-pyridinecarboxylate. USE:Antihypertension, remedy for circulatory disorders, antiarteriosclerotic. PREPARATION:For example, the reaction of a compound of the formula: ArCHO such as m-nitrobenzaldehyde with another compound of formula II (such as ethyl 3-aminocrotonate and the third compound of formula III (such as dimethyl 2-oxopropyl phosphonate is carried out.

Description

[Detailed description of the invention] The present invention relates to dihydrohyridine derivatives.

Object, Structure, and Effects of the Invention The di-0-lysine derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1).

[In the formula, R□, R2, R3 and R4 are the same or different and represent a lower alkyl group. Ar is a naphthyl group or 1 to 3 substituents of at least one selected from the group consisting of a nido group, a halogen atom, a lower alkyl group that may have a halogen atom, a cyano group, and a cyano group. indicates a phenyl group. ] In this specification, Ri, R2, R
Examples of lower alkyl groups represented by 3 and R4 include direct groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl/5ee-butyl/butyl, pentyl, isopentyl, neopentyl, and hesiyl groups. Examples include chain or branched alkyl groups having 1 to 6 carbon atoms. The position of the substituent on the phenyl group represented by Ar is not particularly limited, and the substituents may be the same or different. Examples of halogen atoms as substituents on phenyl groups include fluorine, chlorine, bromine, and iodine atoms, and examples of lower alkyl groups that may have halogen atoms include methyl, ethyl, propyl, isopropyl, butyl, and l-butyl, 7-fluoro-methyl, ttsuk00
Methyl, 7-no-7 methyl, 7-iodomethyl, difluoromethyl, trifluoromethyl, tric-00 methyl,
Tripromethyl, 2.2.2-trifudioethyl,
2.2.2-) Ri-o'-ethyl, 2,2,2-trip-o'e-ethyl groups, etc. can be exemplified. Specific examples of phenyl groups having 1 to 3 substituents of at least one selected from the group consisting of a nido group, a halogen atom, a lower alkyl group that may have a halogen atom, a cyano group, and a cyano group. Examples include, for example, 2-nido-phenyl, 3-nido-phenyl, 4-nido-phenyl, 2-di-olphenyl, 3-phenyl, 4-fluorophenyl, 4-
Iodophenyl, 3-trifluoro D-methylphenyl,
3-(2,2,2-)lifluoroethyl)phenyl, 2
-Methylphenyl, 3-methylphenyl 12-cyanophenyl, 3-cyanophenyl, 3,5-di-tert-butyl-4-dihydro+diphenyl, 2-di0o-5-
nido0 phenyl, 2,3-zig00 phenyl, 2,4-
Dikoo phenyl S2-di0-6-fluorophenyl, 5-di00-2-nido-0 phenyl, 2,3-; Examples include 0 phenyl group, 2,4,6-trimethyl, and 1 phenyl group.゛Also, examples of the naphthyl group include ■-naphthyl and 2-j phthyl groups.

The di-0-lysine derivative represented by the above general formula (1) has excellent vasodilation, hypotensive and anti-arteriosclerotic effects, is an antihypertensive agent, and a therapeutic agent for cardiac or cerebral circulation disorders. , is useful as an anti-arteriosclerosis agent, etc.

The compound of the present invention represented by the above general formula (1) can be manufactured by various methods, and examples thereof include the following method.

(1) <W’) [In the formula, R1, R2, R3, Ra and Ar are the same as above.

] A compound of general formula (It) used as a starting material,
The compound of general formula @) and the compound of general formula (IV) are both known compounds or compounds that can be easily produced according to conventionally known methods [J.

Am, Cktm, 5tyC,, 67, lO17 (19
45), Tetrahetron Letter, 21.1961 (19
65) etc.].

The above reaction is carried out without a solvent or in a suitable solvent. As the solvent, any known solvent that is inert to the reaction can be used, such as alcohols such as methanol and ethanol, and aromatic hydrocarbons such as benzene, tornidi, and silane. Examples include halogenated hydrocarbons such as 000 form and methylene chloride, ethers such as tetrahydrofuran, hyridine, acetic acid, acetonitrile, and N,N-dimethylformamide. The proportions of the compound of general formula (1), the compound of general formula (・■), and the compound of general formula (mV) are not particularly limited and can be appropriately selected from a wide range. It is preferable to use about 1 to 1.57 units of each of the other two compounds for each compound IY. The above reaction normally proceeds suitably at about 20 to 200°C, preferably about 50 to 150°C,
Generally completed in 0.5 to 20 hours.

The novel phosphorylated hyridine derivative (1) produced by the above method can be prepared by reaction by appropriately using conventionally known separation and purification means such as concentration, extraction, crystallization, reprecipitation, recrystallization, etc. It can be isolated and purified from the mixture.

The compounds of the present invention may be used alone or together with other compositions, for example:
It can be administered orally or parenterally in the form of tablets, capsules, granules, powders, injections, and the like. The dosage varies depending on the administration route, symptoms, patient's weight, age, etc., but in the case of oral administration, it is usually about D1-50 per day for adults,
It is preferable to administer the drug in several doses.

Example Examples are listed below.

Example 1 A mixture of m-nitrobenzaldehyde (1,6F), ethyl 3-amic acid (1,3f), dimethyl (2-amic acid) phosphonate (1,7f) and 10 ml of isopropanol was prepared. After heating under reflux for 20 hours, the solvent was distilled off. Remove the residue (silica gel 15011.0)
The powder obtained by purification with 0 form-methanol (101) was recrystallized from beef starch into ethyl acetate to give a 1,4-dimethane with a melting point of 188 to +90°C.
Cyphosphinyl-2,6-; Methyl-4(3-nido0
Phenyl)-3-hyridinecarboxylic acid ethyl ester was obtained.

Examples 2 to 12 The compounds shown in the table below are produced in the same manner as in the above examples.

1,: NMR(CDCl, ) Example 2 δ-! , Wataru 5 (3H, t, J=7, QHx, C00
CH2C1l 3) 3, 70 (3H, d, J-11,
2ng, -so<ocn3)) -3,84~4.24 (27/, m, -COOCH,
CD3) 5, 58 (IH, d, J-9, 2HI,
(:'(4)-”)6,38(1#, bread d
, J-3,6Hz, 〉NIL)11・Example 12 δ-1,26(3H,t, /-7,QRz, COOCC
00CII2C, 38 (+8H, r, -CCCH,)
3X2)? 3, 10 (3H, d, J-11, 2H1, -1:<Q
C"3))3,33(3#,d,/-11,2H
z, - nose (OCI!, )) 4, 11 (2#, q,
J-7,Qllr, C00CH,CH,)4,53
(IH, d, /-10,8H1,C(4)-#)5,
00 (1'//, s, -OH)5.89(IH,
brtrad d. Tsuru Hill Phone 06-203
-0941 (Shimoto 6, Contents of the amendment to the number of inventions to be increased by amendment l Page 13 of the specification, line 4 r 3.10 J is r
Corrected to 3.15J.

2. Page 13 of the specification, line 5 r3.33J is replaced by r3.
Corrected to 50J.

(that's all)

Claims (1)

[Claims] ■ General formula [In the formula, R□, R2, R3 and R1 are the same or different and represent a lower alkyl group. Ar is a naphthyl group or at least one selected from the group consisting of a nido group, a halogen atom, a lower alkyl group that may have a halogen atom, a cyano group, and a cyano group as a substituent. Indicates the phenyl group that it has. ] A dihydrohirijishi derivative represented by.