JPH04178327A - Compound having multiple drug resistance-mitigative effect - Google Patents

Abstract

PURPOSE:To provide a medicine capable of enhancing sensitivity to carcinostatic agent for resistant cancerous cells leading to mitigating the resistance, containing, as active ingredient, an ethylenediamine compound or its salt. CONSTITUTION:The objective multiple drug resistance-mitigative agent for cancerous cells, containing, as active ingredient, a compound of the formula (R is H or lower alkyl; Ar is 1-3 F, NO2, methoxy, methoxycarbonyl or CN- substituted benzene ring ; iQ is 5-isoquinoline ring) or its salt, for example, N-[2-(2,4-difluoro-alpha-methylcinnamylamino)ethyl]-5-isoquinolinesulf onamide. Said compound can be administered either in a combination, as a sole pharmaceutical preparation, with a carcinostatic agent, or in the form of a combined agent with a carcinostatic agent, to enhance the therapeutic effect of the carcinostatic agent. For the present compound, therapeutic effects will be equivalent to the case with reducing the dosage of the combined carcinostatic agent, leading to mitigating the side effects due to said carcinostatic agent.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention provides the general formula (A) SO2NHCH, CH, NHCHC=CH-Ar1Q, which has the effect of reducing multidrug resistance on cancer cells.
CH.

(However, R is hydrogen or lower alkyl, A is a benzene ring substituted with 1 to 3 fluorine, nitro, methquino, methquine carbonyl, or nano, and IQ is 5 to isoquinolino ring.) It relates to a compound or its salt.

[Conventional technology]

The ethyleneamine compound represented by the general formula (A) was produced by the present inventors and has an inhibitory effect on various protein kinases, and affects vascular smooth muscle, resulting in vasodilation, improved cerebral circulation, and stenosis. It has been confirmed that this compound has preventive therapeutic effects such as treatment of heart disease and antithrombosis.

[Problem to be solved by the invention]

This phenomenon has become a serious clinical problem, as cancer drugs become less effective as chemotherapy-based cancer treatment continues, and become ineffective especially in the case of recurrence. In addition, there are some cancers, such as colon cancer and stomach cancer, that are difficult to respond to anticancer drugs from the beginning, and one of the reasons for this is either acquired resistance or natural resistance at the cellular level. The anticonvulsants currently in use rely on cytotoxicity as the basis of their efficacy, and when administered in large doses, they cannot avoid serious side effects, which is a major obstacle to achieving complete remission with cancer chemotherapy. Is this one of the factors?The use of relatively mild anticonvulsants with few side effects even in the early stages of cancer may be difficult to use, as there is a high risk of promoting immune formation in cancer cells as mentioned above. We have no choice but to refrain from using anticancer drugs, which have a strong anticancer effect from the beginning and are naturally dangerous to the human body, despite the serious side effects they cause patients. It was a trend.

[First Means to Solve the Problems] In order to solve the above problems, the present invention provides a general formula C for reducing the resistance of cancer cells to anticonvulsants and increasing the therapeutic effect of anticonvulsants.
The present invention proposes the use of an ethylenenoamine compound represented by A) or a salt thereof.

That is, the compound of the present invention, which was produced by the present inventors and filed as Japanese Patent Application No. 1-325959, is obtained by substituting a specific group on the non-amyl moiety of a 1-nialkylene amine compound.
It is thought that it may have an anticonvulsant effect in itself, and as a result of inhibiting cancer cells, it reduces resistance to anthracycline anticonvulsants such as atriamainone and hinka alkaloid anticonvulsants such as hinkristine. It's hard to think about how it works. Therefore, the compound of the present invention can be formulated alone and used in combination with an anticonvulsant such as hinkristine, vinblastine, or atriamynon, or can be administered to patients as a combination.

The compounds of the present invention increase the sensitivity of resistant cancer cells to antifungal agents and reduce resistance.

Therefore, the same therapeutic effect can be obtained even if the dose of the concomitant anticonvulsant is reduced, so it is possible to reduce the side effects of the anticonvulsant, and it is considered to be a clinically useful drug.

As shown in the general formula (A), the compound according to the present invention has one amino group substituted with non-namyl and the other amino group substituted with 5
- It is an ethylenenoamine compound bound with isoquinoline sulfonic acid, and the benzene ring in the nnnamyl group is 1 to 3.
A substituent selected from fluorine, nitro, methoxyno, methoxycarbonyl, and cyano has a methyl group at the alpha position of the nnnamyl group, and a lower alkyl group is further substituted at the beta position. Examples] The present invention will be specifically explained below with reference to Examples, but the present invention is not limited to these Examples.

In addition, the non-defective objects in Examples were measured using a nuclear magnetic resonance spectrometer JEOL-JNM-FX200 (manufactured by JEOL Ltd.).

Example! N-[:2-(2,4-difluoro-α-methylannamylamino)ethylcy 5-isoquinolinesulfonic acid amide 730 g of N-(2-aminoethyl)-5-isoquinolinesulfonic acid amide was dissolved in 150 ml of methanol, 2
, 637 g of 4-difluorohenzalacetone were added, and the mixture was stirred at room temperature for 36 hours. Then, while cooling with ice water, 1.32 g of sodium tetrahydridoborate was added, and the mixture was stirred for 30 minutes. After the reaction solution was concentrated to about 1/2 volume under reduced pressure, 300 ml of ethyl acetate was added and washed three times with water.

The aqueous layer was extracted with 100 ml of ethyl acetate, washed with water in the same manner, and then combined with the ethyl acetate layer, washed twice with saturated brine, and dried over anhydrous macanenium sulfate. After filtering the mixture,
The solvent was distilled off under reduced pressure, and the residue was separated and purified using a silica gel column (200 g of silica gel, developing solvent: 5% methanol/chloroform) to recover the remaining raw material and obtain 6.88 g of the target product as a colorless amorphous substance. Ta.

'H-NMR (CDCl2.δppm): 1.06 (
3H, d, J=6.4Hz), 1.3-2.2 (2H,
br), 2.57-2.67 (2H, m), 2.9
6(2f(.

t, J=5.6H2), 3.04(IH, dQ, J=
8.0.6.4Hz).

5.81 (IH7dd, J=16.1.8.0Hz),
6.35 (IH, d, J=16.1Hz), 6.7
9 (IH, d, J = 8.3Hz and LH, dd
d.

J=17.6.8.8.2.0Hz), 7.30(I
H, ddd, J=14.9°8.3.2.0H2),
7.69 (IH, dd, J=8.3.7.3H2).

8.29(IH, dt, J=8.3.1.0 [(z),
8.42-8.47 (2H.

m), 8.70 (18, d, J=6.1Hz), 9.
35 (IH9d, J=1.0Hz) The following compound was obtained in a similar manner.

Example 2 N-C2-Cα-methyl-2-nitronnamylamino)ethylcou 5-isoquinolinosulfonic acid amide pale yellow amorphous 1)(-MR(CDCIj, δppm): 1.08(
3H, d, J = 6.4Hz).

1.3-2.6(2)1. br), 2.61-2.6
7 (2H, m), 2.99 (21 (.

ti=5.6Hz), 3.09(lH, dQ, J=
7.8.6.4t+z), 5.73(IH, dd, J
= 15.6,7.81z), 6.73CIH,d,
J-15,6Hz), 7.36-7.56(3H, m
), 7.68 (lH, dd, J = 8.3°7.3H
z), 7.92 (IH, dd, J=7.9.1.2t
iz)', 8.42-847 (2H, m), 8.8
7 (IH, d, J-6, 1Hz), 9.31 (ltl
, d, J = 1.0 Hz) Example 3 N-[2-(4-Methoquino-α-methylnonnamylamino)ethylcou 5-isoquinolinesulfonic acid amide colorless substance'H-NMR (CDCl2.δppm): 1.05 (
3H, d, J = 6.4t(z).

1.5-2.5 (2H9br), 2.56-2.63 (
2H, m), 2.96 (2H.

t, J = 5.6Hz), 3.02 (IH, dql
= 8.0. 6.4Hz), 3.81 (3H,s)
, 5.64 (IH, ddl= 1.5.9.8.0H
z), 6.21 (IH, d, J=15.9Hz),
6.83 (2H, dm, J=8.8Hz).

7.20 (2H, dm, J=8.8Hz), 7.67 (
IH, dd, J=8.3. 73Hz), 8.19(l
H,brd,J=8.3Hz),8.44(IH
, dd, J-7, 3, 1, 2 Hz), 8.44 (III
, d, J = 6.1Hz), 8.69 (IH, dl =
6.1.1(z), 9.34(LHld, J= 1
．． 01(z) Example 4 N-[:2-(4-methquincarbonyl~α-methylnonnamylamino)ethylcou 5-isoquinoline sulfonamide 2 HCI colorless amorphous I R(KBr) cm-': 3420, 3200-2
300.1720.1605°1345.1280'H-NMR (DtO) δppm: 1.59 (3H,
d, J = 6.7Hz), 319 (2H, brt)
, 3.38(2)[,brt), 4.01(3H,
s), 4.16 (IH, m), 6.28 (IH, dd
, J= 15.9.8.9Hz), 6.83(IH,
dl = 15.9Hz), 7.51 (2H, d, J =
8.4Hz), 7.94 (2H, d, J= 8.4
Hz), 8.10 (IH, brt), 8.64 (1
B.d.

J = 8.6Hz), 8.76 (2H, brt), 8
．． 98 (LH, d, J = 7.0Hz), 9.72 (I
H,s) Example 5 N-(2-(3,4-diftquine-α-methylcinnamylamino)ethylcou 5-isoquinolinesulfonic acid amide 2HC1 colorless amorphous') I-NMR (D, 0) δppm: 1.56 (3H
, d, J = 6.7) 1z), 3.1-3.2 (2B2
m), 3.35-3.45 (2H, m:i, 3.8
4 (311, s).

3.91 (3H, s), 4.0-4.15 (lH, m
), 6.0(lH, ddl=15.6.9.0t(z
), 6.64 (I) I, d, J = 15.611z)
, 692 (3H, s), 8.07 (LH, tl=
8.0Hz), 8.60 (IH, d, J-8, 0H
z), 8.73 (IH, d, J = 8.0IIz),
8.73 (lH, dl-6,7Hz), 8.95 (
II (,d, J=6.7)12), 9.68(l)1
．． s) Example 6 N-(2-(α-methyl-3,4,5-trimethoquinnonnamylamino)ethyl-5-isoquinoline sulfonamide 2HC1 Colorless amorphous 'H-NMR (D20) δpl)m : 1.65 (3t
(, d, J=6.4Hz), 3.2-3.5 (4B9m
), 3.84 (3H, S), 3.91 (6H, s)
, 4.1-4.3 (LH, m), 6.13 (lH,
ddl= 14.1.8.8t(z), 6.70(LH
, d, J= 14.1f(z), 6.67(2H,s
), 8.16 (IH, t.

J = 8.0Hz), 8.17 (LH, d, J = 8
．． 0Hz), 8.75-885 (2H, m), 9.
02 (1t1.d, J=7.0Hz), 9.80(
IH,s) Example 7 N (2-(2,4,5-trimethoquino-α-methylnonnamylamino)ethylcy 5-isoquinolinesulfonic acid amide colorless amorphous 'H-NMR (CDC13) δppm: 1.07 ( 3
H, d, J = 6.35Hz).

2.62 (2H, m), 2.95 (2H, m), 3
．． 05 (1B, m), 3.81 (3H, s), 3
．． 86 (3H, s), 3.90 (3H, s),
5.70 (IH, dd.

J= 16.11. 7.82Hz), 6.49(lH
, s), 6.58 (LH, d, J-16, 11Hz
), 6.90 (111, s), 7.68 (1B, d
d, J = 8.3°7.32Hz), 8.19 (IH
ldl, ~8.30Hz), 8.44 (2H, m).

8.69 (H, d, J = 6.35t(z), 9.3
5 (IH, s).

N-) 1 is 2 Unknown Example 8 N-C2-(2,4,6-trimethquine-α-methylnonnamylamino)ethylcy 5-isoquinolinesulfonic acid amide colorless amorphous 'H-NMR (CDCl2) δppm+ 1 .04(
3H, d, J = 6.35Hz).

2.63 (2H, m), 2.95 (3H, m), 3
．． 80 (6H,s), 3.8i (3tLs),
6.11 (IH, dd, J= 16.11.7.81H
z), 6.12(2f(,s), 6.48(lH,
d, J=16.11Hz), 7.65 (IH, dd.

J=8.30. 7.32Hz), 8.16(I
H, d, J = 8.30Hz).

8.43 (2H,brd), 8.66(IH,d,J=
6.35Hz), 9.33(IH,s), N-H is 2
Unidentified reference example trans -4-(4-anophenyl)-3-methyl-3-buten-2-one 197 g of 4-anobenzaldehyde was added to 20 ml of toluene.
1 and 3-triphenylphosphoranylidene-2-
5.48 g of butanone was added and the mixture was heated under reflux for 2 hours. The cold soaked toluene was distilled off under reduced pressure, and 2.58 g of colorless crystals were obtained from the fraction that was applied to a silica gel column and eluted with chloroform and hexane-ethyl acetate (3 liters).

'H-NMR(CDCl2)δl)l)m: 2.04
(3H, d, J=1.46Hz).

2.48(3H,s), 7.48(if(,d,J=
1.46) 1z), 7.50 (2H.

dj=8.31Hz), 7.71(2H,d,J=
8.31 Hz) Example 9 N-(2-(4-Noanoα,β-dimethylnonnamylamino)ethylcy-5-isoquinolinesulfonic acid amide 2.58 g of the product of the reference example was dissolved in 150 ml of ethanol, and N-( 4.20 g of 2-aminoethyl)-5-isoquinolinesulfonic acid amide was added and heated under reflux for 6 hours. After cooling, the reaction mixture was cooled with water and added 1 portion of sodium borohydride while stirring.
．． After that, saturated sodium bicarbonate aqueous solution was added to the reaction solution, which was stirred at room temperature for 2 hours, and 150 ml of chloroform was added.
1 was extracted three times. The organic layers were combined, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue was applied to a silica gel column and eluted with chloroform:methanol (20:1) to obtain 21 g of a colorless amorphous substance.

'H-NMR (CDC13) δppm: 1. ．． 06(
3H, d, J = 6.59Hz).

1.68 (3H, d, J=1.22Hz), 2.54
(2H,m,), 2.9C1~3.1(1(3H,m
), near5.4(IH,br,), 6.23(
LH, brs).

7.26 (2H, d, J = 8.30H), 7.60 (
2H, d, J = 8.30Hz).

7.72 (IH, ddl=8.30.7.32Hz),
8.21 (IH, d.

J=8.30Hz), 8.44(2H, m),
8.70 (IHld, J=6.35Hz), 9.36
(IH, s), one of N-H is unknown. The following compound was prepared by the same method as f2.

Example 10 N-[2-(4-Methoquino-α,β-nomethylannamylamino)ethylcy 5-isoquinolinesulfonic acid amide colorless amorphous 'H-NMR (CDC13) δppm: 1.02 (3
H, dl = 6.51Hz).

1.61 (3H, d, J = 1.22Hz), 2.5
2(2t(,m), 2.94(3H.

m), 4.80 (3H, s), 6.09 (ill,
brs), 6.85 (2H, d.

J=8.30Hz), 7.12(2t(,d, J=8
．． 3Hz), 7.6g(1)1゜dd, J=8.3
0.7.32Hz), 8.19 (IH, d, J= 8
．． 30Hz).

8.45 (2H,brd), 8.70(l)I, d, J
= 6.35Hz), 9.36(1,H.

s), antitumor effect against two unknown JP388/s of N-H (in vivo
)2 Example number Number of cases Survival days T/C (%) 1
Phosphate 3 8.3 948 Phosphate 3 9.0 102 vs. control 1% CMC
68,8+00 5 Phosphate 3 9.7 1046 Phosphate 3 10.0 1077 Phosphate 3
10.0 107 Control saline 6 9.
3 100 animals 5 weeks old CDF, male mouse Number of transplanted cells 1X106 cells/body (ip
) Administration schedule = Once a day for 5 consecutive days (1p) Dose 100mg/K
g/day control animal dose: 10ml Nihincristin resistance alleviation effect test Cin vitro
)'.

Approximately 1 x 10'ce1. I/ ml of hinkristi/
The compound of the present invention or herapamil (control) dissolved in DMSO was added to resistant P388 cells to a final concentration of 2 μM, and 0.57 ml was dispensed into a 24-well plate (manufactured by Sumitomo Bakelite), and vincristine was added to each. 48 hours after adding 30 μl, it was measured using a Kohl Kabi 7noter. The IC50 value was calculated based on the number of B cells and the IC50 value (nM) of the concomitant compound vincristine Example 3 l 13 Example 6 218 Example 7 407 Herapamil 3.12 [Multi-drug resistance alleviation effect test (in vivo: l: Hincristine-resistant P388 cells were suspended in Hanks solution,
10.1 ml of 1×106 cells were intraperitoneally transplanted into a 5-week-old CDP male mouse, and from the next day, vincristine alone, vincristine, and a fixed amount of the compound of the present invention were intraperitoneally administered to the above-mentioned mice (5 mice per group) for 5 days. Administer T/V (
The resistance-reducing effect was determined based on the percentage of survival days in the group administered with the compound of the present invention relative to the survival days in the vincristine alone administration group.

Vincristine was prepared by dissolving vincristine sulfate for injection (manufactured by Shionogi & Co., Ltd.) in physiological saline, and the compound of the present invention was dissolved in physiological saline or 1% CMCNa/physiological saline. When using two drugs together, mix a drug solution (or suspension) at twice the concentration at a volume ratio of 1.1 and mix it with the mouse weight 1.
1 ml of O per 0 g was administered.

Example compound T/V (%)

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (However, R is hydrogen or lower alkyl, Ar is substituted with 1 to 3 fluorine, nitro, methoxy, methoxycarbonyl, or cyano A multidrug resistance alleviating agent for cancer cells, which comprises a compound represented by the following formula (wherein a benzene ring is a 5-isoquinoline ring, and iQ is a 5-isoquinoline ring) or a salt thereof.