JPH02240081A - 1,4-dihydropyridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by the formula (R1 represents H or methyl; R2 represents N-morphoryl or pyridyl; n is 1 or 2). EXAMPLE:Bis[2-(N-morphoryl)ethyl]-4-[2-(5,6-dihydro-1,4-dithiinyl)]-2, 6-dimethyl-1,4- dihydropyridine-3,5-dicarboxylate. USE:An antitumor agent without hypotensive action as side effect. PREPARATION:A 2-formyl-1,4-dithiene or 2-formyl-3-methyl-1,4-dithiene is heated together with a beta-aminocrotonic ester and an acetoacetic ester optionally in the presence of an organic solvent with or without refluxing.

Description

Detailed Description of the Invention [Industrial Application Field 1] The present invention relates to a novel 1,4-dihydropyridine derivative having excellent drug-implanting activity, and more specifically to a novel 1,4-dihydropyridine derivative useful as a therapeutic drug for tumors, etc. Concerning hydroviridine derivatives. [Prior Art] Many compounds are already known as 1.4-7 hydropyridine derivatives. Among these known 1,4-cyhydropyridine derivatives, there are many compounds known to have potency activity, but
Those with a large WS content have pharmacological activity on the circulatory system, and only a small number of other medicinal activities have been reported to have anti-inflammatory effects, hepatoprotective effects, etc. On the other hand, regarding 1,4-nohydropyridine derivatives that have some pharmacological activity against tumors, Japanese Patent Publication No. 55500577 describes a 1,4-nohydropyrinone compound that does not have a substituent at the 4-position. It has been described that it has a metastasis-suppressing effect on certain types of tumors. Further, JP-A-60-6613 describes antitumor and antitumor metastasis agents containing II4-dihydrobiridine as an active ingredient, such as II7edivin and nimonopine. Further, JP-A-62-87516 describes a method for treating malignant tumors using a combination of platinum coordination compounds and compounds such as 27-edipine and nimodibin. Furthermore, JP-A No. 64-31781 discloses that a compound represented by the formula (I) in which % R2 is replaced with a 7-alkyloxy group and n is replaced with an integer from 2 to 4 has the effect of suppressing tumor cells that have acquired resistance. It has been described that it has the effect of significantly increasing sensitivity. [Problem to be Solved by the Present Invention 1] However, the inventions described in the above-mentioned JP-A-60-6613 and JP-A-62-87516 do not allow the use of compounds having calcium pathway blocking activity as antitumor drugs. However, it is used in combination with an antitumor drug, a coordination compound, and has the disadvantage that it is not necessarily practical in terms of its effectiveness. JlO: All of the calcium pathway disruptors used in the above invention have a strong antihypertensive effect (hypertensive lowering effect), and are drugs that exert effects on the heart, blood vessels, etc. even in very small amounts. The drawback is that when such drugs are used in large doses to the extent that they exhibit antitumor effects, they inevitably have adverse effects on the heart and vascular system, such as significantly lowering blood pressure. Furthermore, JP-A-64-31
The compounds described in Publication No. 781 do not have strong side effects, but many have antihypertensive effects, and are not necessarily satisfactory when used in combination with antitumor drugs. As a result of extensive screening of hydropyridine derivatives for their effectiveness in combination with antitumor drugs and antihypertensive effects, we found that certain compounds significantly reduce the sensitivity of tumor cells, especially tumor cells that have acquired resistance, to antitumor drugs. [Means for Solving the Problems] According to the present invention, the formula (+) ( In the formula, R represents a hydrogen atom or a methyl group, R represents an N-morpholyl group or a bilinol group, and n represents an integer of 1 or 2. Ru. In the present invention, the above formula <
Among the 1,4-nohydropyridine derivatives represented by 1), compounds in which R2 is a biridyl group and n is an integer of 1 have a particularly pronounced drug sensitivity enhancing effect.
Among these, the most preferable compound is R, where R is a methyl group, and R,
is a 4-pyridyl group and n is an integer of 1, 4-[2-(
3-methyl-5,6-nohydro1,4-dithienyl)
1-2+6 monomethyl-1,4-dihydropyridine-3
, 5-dicarboxylic acid bis(4-bilinormethyl) ester. Compounds with these specific substituents have a more pronounced drug sensitivity enhancement effect than other compounds, and almost no hypotensive effect is observed as a side effect, as will be described in detail in the test examples below. It is a particularly useful compound as a medicine because it is absent, or even if it is present, it is so small that it can be seen in practice.

All of the 1,4-dihydrobiridine derivatives represented by the above formula (I) can be produced from conventional methods using well-known reactions used for the production of 1,4-dihydrobiridines. For example, 2-formyl-1,4-dichene or 2-formy-3-methyl-1,4-dichene is heated or heated with β-7 minocrotonic acid ester and V7 cetoacetate in the presence or absence of an organic solvent. a flow reaction (method A), or 2-formyl-1,4-dichene or 2-formyl-3-methyl-
1. It is produced by reacting 4-nochene with acetate acetate and aqueous ammonia in the presence or absence of an organic solvent, preferably by heating to reflux (method B). The reactions used in these production methods range from 1.4 to 1.4
- Known reactions used in the production of dihydropyridine compounds (for example, Japanese Patent Publication No. 46-40625, No. 56
This reaction is basically the same as the reaction used in the methods described in JP-A-37225, JP-A-60-214'786, etc. Therefore, the 1,4-cyhydropyridine derivative of the present invention can be produced not only by the above-mentioned method but also by appropriately applying other reactions described in these known documents. The raw material compounds used in the above production method are all known compounds and can be easily obtained or produced by those skilled in the art as needed. That is, 7
Both cetoacetate and β-7 minocrotonic acid ester are compounds that are commonly used as raw materials for the production of 1,4-cyhydropyridine compounds, and can be obtained as commercially available products as needed. Can be synthesized. Also, 2-formyl-1,4-nochen or 112
-Formyl-3-methyl-1,4-dichene is 1,4
- It can be produced by using dichene or 2-methyl-1,4-dichene as a raw material, reacting it with dimethylform 7mide, l/phosphorus oxychloride, and then hydrolyzing the obtained product. end. Specifically, Machiyami Sho 64
It can be produced by the method described in JP-A-31781. According to the present invention, the reaction product produced by the above method,
That is, the 1,4-cihydropyrinone derivative represented by the formula (!) can be prepared by conventional methods such as extraction with a solvent, chromatography, etc.
can be separated from the reaction mixture and purified by crystallization, etc. [Example j] Next, an example will be shown and a synthesis example of the 1,4-nohydropyrinone derivative according to the present invention and the results of a chemical embedding test conducted to confirm its usefulness will be explained. It goes without saying that the scope is not limited to these examples. Example 1 4-[2-(5.6-dihydro-1,4-dithinyl-2,6-nomethyl-1,4-nohydropyridine-3,
Synthesis of 5-nocarboxylic acid bis[2-(N-morpholyl)ethyl]ester 2-*lumyl-1t4-7fene5
, O O g (0.034 mol), acetoacetic acid-2-(N-morpholyl)ethyl ester 1 6.6 g
(0.07 7 mol) and 28% aqueous ammonia 15
Dissolve ml in Improvil alcohol 25-1 and add 20
Heat reflux was performed in the dark. After cooling, the reaction solution was concentrated, the residue was dissolved in ethyl acetate, and impurities were extracted and removed with a small amount of water. After drying the ethyl acetate layer with sodium sulfate, the solvent was distilled off and the residue was subjected to silica del column chromatography with a mixed solvent of chloroform and methanol. 12.10 g (yield: 11.4%) of the desired product was obtained as colored crystals. The analytical values for this substance are as follows. Melting point: 1 1 3.5 -
1 1 5.0℃■ R: ν 1 piece cm-3290 (NH), 1690 (C=0), 1270 (C
-0) NMR (CDCI,,THS,PPM)2
．． 31 (6Ls, 2.6th CI!.) 2.36-2.7
6 (I2H, m+2xcOOcHz (jil+2x morpholine ring 3rd and 5th positions CH.) 3.02 (4+1, s+ 9 chis- ring SCH2C
H2S) 3.53-3.83 (8H, s.2X morphone+) C I+ at position 2.6 of the ring. )3.96-4.4
9 (4H mountain 2XcOOcflLLCHz) 4.72 (I
H. s, 4th position 11) 5.69 (Ill, b, N}l) 6.05 (IH, s = vinyl H) Example 2 4-[2-(5.6-dihydro 1.4-dithinyl)
]-2. 6-dimethyl-1,4-dihydropyrinone-3,5-dicarboxylic acid bis(2-bilinormethyl)
Ester Imanari 2-Formylu 1.4 Inochen 3.00tr (0.0
21 mol), 8.20 g (0.04 3 mol) of acetoacetic acid-2-pyridylmethyl ester and 3.1 ml of 28% ammonia-7 water were mixed with isobrobyl alcohol 25-1
Dissolve in water and heat under reflux for 20 hours. After cooling, the reaction solution was concentrated, the residue was dissolved in ethyl acetate, and impurities were extracted and removed with a small amount of water. After drying the ethyl acetate layer with Glauber's salt,
The crystals precipitated by concentrating the solvent were collected by filtration and recrystallized with ethyl alcohol to give 3.37 g of the target substance as yellow crystals (
A yield of 33.2% was obtained. The analytical values for this substance are as follows.

Melting point: 1 6 1.0-1 6 2.0°C IR: ν! !
1 light C' 3340 (NH). 1700 (C=0), 126
0(C-0)NMR(CDCIs-TNS-PPM)
2.35 (6Ls.2.6th place ell3) 3.05 (4L
s, nochen! l SCHtCLS) 4.93 (IH,
s, 4th place ■) 5.29 (4H.ABQ, 2X COOCL) 5.93
(XI, b, NH) 8.00 (IH.s, vinyl H) 7.05 7.40 (4H, mi2X birinone ring 3.
5th position}1) 7.48-7.74 (2H+my2X birinone ring 4th position H) 8.50 (2H, d.2X birinone ring 6th position H) Example 3 4-(2-(5.6-cyhydro- 1,4-dithienyl)
]-2. 6-monomethyl-1,4-dihydrobiridine-3,5-nocarboxylic acid bis(3-pyridylmethyl)
Synthesis of ester 2-formyl-1.4-nochen4. OOg(0.02
7 mol), 7cetoacetic acid-3-bilinolmethyl ester 1
1. 4 g (0.059 mol) and 28% ammonia water 151 were dissolved in isofurobil alcohol 251, and the mixture was heated under reflux for 20 hours. After cooling, the reaction solution was concentrated, the residue was dissolved in ethyl acetate, and impurities were extracted and removed with a small amount of water. After drying the ethyl acetate layer with Glauber's salt, the solvent was concentrated, and the residue was subjected to silica del column chromatography with a mixed solvent of chloroform and methanol.The obtained crystals were recrystallized with isobrobyl ether. 512.40 g (yield: 17.6%) of the target product was obtained as yellow crystals.

The analytical values for this substance are as follows.

Melting point: 137.0-139.0°C IR: ν”” am −' 3200 (N1{). 1685 (C=O). 1195(
C-0) NMR (CDCI., MS, PPM) 2
．． 30 (6H, s, 2.6th CH,) 3.30 (4H,
st:) Chen III SCHzCH*S)4.7
3 (IH, s, 4th place + 1) 5.15 (4i1.^BQ, 2XCOOCH2) 5.8
4 (I}1.s, vinyl H) 6.10 (I.11, b.NH) 7.10-7.29 (2H. ring, 2 x birinone ring 5th position■
)7,53 7.73 (2H.m, 2X birinone ring 4
Position II) 8.32-8.70 (4}1,m,2X birinone ring 2.8 position 11) Example 4 4-(2-(3-methyl-5,6-cyhydro1.4-
nothiinyl)]-2. Synthesis of 6-dimethyl-1,4-dihydrobilinone-3,5-nocarboxylic acid bis(4-pyrinlmethyl) ester 2-formyl-3-methyl-1,4-nochen 5.0
0g (0.044 mol), acetoacetic acid-4-pyridylmethyl ester 2 0.0g (0.103 mol)
and 9.51 ml of 28% aqueous ammonia were dissolved in 30 ml of isobrovir 7 lefur, and heated under reflux for 2 days. After cooling, the reaction solution was concentrated, and the residue was dissolved in ethyl acetate.
Impurities were extracted and removed with a small amount of water. After drying the ethyl acetate layer with Glauber's salt, the solvent was distilled off, and the residue was subjected to silica del column column chromatography using a mixed solvent of ethyl acetate and acetate to obtain crystals. The crystals were then recrystallized from ethyl acetate to obtain 2.32 g (yield: 14.6%) of the desired substance as pale yellow crystals. The analysis value of this substance is the following j11
It's wa. Melting, α: 1 70.0-1 7 2.0℃ Engineering R: νk8
r e, −+ 325(](Nu), 1685(C=O), 11
90 (C-0), 1080 (C-0) NMR (C
DCh. Ding MS. PPM) 1.90 (3}1+s, dithi L7 ring Cll,) 2.30
{6}1. s. 2.6th place CL) 2.85-3.23 (4
H, 1+ dichen ring SCl12CM2S)5.17(4
}! , ^Bq, 2XCOOCHz) 5.30 (IH.s
．． 4th position ■) 6.03 (IH, b, Ni+) 7,07 7.23 (4H+II, 2X birinone ring 3
．． 5-position 11) 8.45-8.57 (4Ls, 2X birinone ring 2,6-position H) Example 5 4-[2-(5,6-nohydro-1,4-cytiinyl)
]-2. 6-monomethyl-1,4-dihydropyrinone-3,5-nocarboxylic acid bis(4-biridylmethyl)
Synthesis of esters 7.30 g (0.49
9 mol), acetoacetic acid-4-pyrinolmethyl ester 2
1.80 g (0.113 mol) and 28% ammonia water 121 were dissolved in isopropyl alcohol 901, and 4
Heating and refluxing was performed for 8 hours. After cooling, the reaction solution was concentrated, the residue was dissolved in ethyl acetate, and impurities were extracted and removed with a small amount of water. After drying the ethyl acetate layer with Glauber's salt, the solvent was concentrated, and the precipitated crystals were collected by filtration and recrystallized with chloroform to obtain the target substance 4.79Fi (yield 19.4%) as pale yellow crystals.
) was obtained. The analytical values for this substance are as follows.

Melting point: 2 1 3.0-2 1 5.5℃ R: ν
! ! 70111 1690 (C=0), 1100.1195 (C-0)N
M R (CDCI,.TMS.PPH)2.35(
6H*s, 2-6th position C}I. ) 3, OS (4H, st dichen ring SCH2CII2S) 4.98 (IH, s, 4
Place I1) 5.20 (4}1,^Bq * 2 X COOCH
2) 5.97 (IH, s, vinyl 11) 6.30 (I1, b, N}l) 7.27 (4H.d, 2x pyridine ring 3.4 position ■) 8.
53 (4H = d, 2X Hi-V ring 2,6-position H) Example 6 4-[2-(5.6-nohydro 1,4-cytiinyl>1-2,6-dimethyl-1,4-cyhydro Synthesis of pyridine-3,5-dicarboxylic acid bis(2-(2-bilinol)dityl 1 ester) 2-formyl-1,4-dichene 5.00 bi(0.?3
4 mol), acetoacetic acid-2-(2-bilicyl)ethyl ester 1 6.0 g (0.07 4 mol) and 128
% ammonia water 17ml to Imbrovir alcohol 50%
1 and heated under reflux for 20 hours. After cooling, the reaction solution was concentrated, the residue was dissolved in ethyl acetate, and impurities were extracted and removed with a small amount of water. After drying the ethyl acetate layer with sodium sulfate, the solvent was concentrated, and the residue was subjected to silica gel chromatography using a mixed solvent of chloroform and methanol. Target substance 3.74g (yield 20.9%)
I got it. The analytical values for this substance are as follows. Melting point:
131.0-133.0°C IR:ν! R spoon c1 3120 (NH), 1680 (C= 0), 109
0(C- 0)NMR (CDCI■TMS.PP
N) 2.21 (6H, s. 2.8th CI{,) 2.97
(411, s. nochen ring SGHzCHzS) 3.13
(4H, L, 2XCOOCI2CHz) 4.35
4.60(4H,m-2XCOOC}I2)4.61(
I11. s, 4th position H) 5.87 (E.s. vinyl H) 5.75 (I}1, b, Nil) 6.97-7.20 (4}1.
5th position H) 7.45-7.87 (2}!, Shun. 2x pyridine ring 4th position H) 8.47 (4H.a, 2x pyridine ring 6th position H) (blank below) Example 7 (Test Example) Enhancement effect of anticancer drug in pincristin-resistant tumor-bearing mice CDF, 10' pincristin (■C
R) Resistant murine leukemia (P3 8 8/VCR) cells were transplanted intraperitoneally, and the compound of the present invention and VCR were intraperitoneally administered once a day for 5 days, and then observed to determine the survival date of each cell. The survival rate (T/C)% was determined compared to the control. The enhancing effect (TjV)% of the anticancer drug was calculated using the following formula. The positive control compound was nicarnovine (nieardipine).
) was administered intraperitoneally on day 10 and 11. The results are shown in Tables 1 to 4. In the table, Compound 1 is in Major Example 1, Compound 2 is in Example 2, Compound 3 is in Example 3, and Compound 4 is in Example 3.
indicates the compound obtained in Example 4. Anticancer drug enhancement effect (T/V) % = Average survival days when VCR is administered alone Example 8 (Test Example) Anticancer drug enhancement effect in pincristin-resistant tumor-bearing mice CDF. 106 pincristin (VCR) in mice
Resistant murine leukemia (P3 8 8/VCR) cells were intraperitoneally transplanted, and from 1 day later, the compound of the present invention and VCR were administered once a day.
The compound of the present invention was administered orally, and VCR was administered intraperitoneally for 10 days. Observe the progress and calculate the number of days each patient survived,
The survival rate (T/C)% was determined compared to the control. The enhancing effect (T/V)% of the anticancer drug was determined in the same manner as described above. The results are shown in Table 5 (A). In the table, Compound 4 indicates the compound obtained in Example 4. In addition, using the antitumor drug-sensitive P388/S mouse P388 leukemia cells, VOR was administered alone in the same manner as above, and the number of days of survival was determined. The results are shown in the tJSs table (B
) is shown. (The following is a blank space) [Effects of the Invention j The 1,4-dihydropyrinone derivative according to the present invention enhances its action when used in combination with an antitumor drug. The effect is particularly pronounced in clones that have acquired susceptibility to antitumor drugs. For example, the pincristin-resistant clone P3
In mice transplanted with 8 8/VCR cells, almost no survival effect was observed when the anti-malignant drug was administered alone, but a clear survival effect was observed when the compound of the present invention was administered in combination.
Average survival time is 116-15 days compared to when CR alone is administered.
This increases to 6%. This life extension effect is remarkable when comparing the life extension rate (T/C%). Cardiac systolic blood pressure was measured using (SHR), and the antihypertensive effects of the compounds of the present invention and the positive control compound were investigated. Blood pressure was measured using a tail volume change measuring device after keeping the animals warm for 5 minutes in a 55°C heating box. The compound of the present invention is 100 mg/k
A single dose was administered intraperitoneally at
A single dose was administered into the g″ra cavity.Blood pressure measurements were performed before and 60 minutes after administration.Nicardipine was used as a positive control compound.The results are shown in the 6th column.In the table, the compound Compounds 1 to 4 were prepared as described above (Example 7
) has the same meaning. (Margin below) This is almost comparable to the survival effect when VCR is administered alone to the sex clone P388/S, and VCR
ii sex is completely ri. It can be said that he was obeyed. Furthermore, the compound of the present invention has a very weak calcium pathway blocking effect, which is observed in many 1,4-dihydrobiridine compounds, and has very few side effects such as lowering of blood pressure. Therefore, the compounds of the invention are useful in the treatment of tumors that have acquired intoxication properties.

Patent applicant: Nikken Chemical Co., Ltd. Procedural amendment (voluntary) March 31, 1999

Claims (1)

[Claims] 1. Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 represents a hydrogen atom or a methyl group, and R_1 represents a hydrogen atom or a methyl group,
2 represents an N-morpholyl group or a pyridyl group, and n is 1
or represents an integer of 2. ) A 1,4-dihydropyridine derivative represented by: 2. The 1,4-dihydropyridine derivative according to claim 1, wherein R_1 is a hydrogen atom and R_2 is a pyridyl group. 3. 1, according to claim 2, wherein R_2 is a 2-pyridyl group or a 3-pyridyl group, and n is an integer of 1;
4-dihydropyridine derivative. 4. The 1,4-dihydropyridine derivative according to claim 1, wherein R_1 is a methyl group and R_2 is a pyridyl group. 5. The 1,4-dihydropyridine derivative according to claim 4, wherein R_2 is a 4-pyridyl group and n is an integer of 1.