JPH02124890A - Pyrrolo-1,4-benzodiazepine derivative, its production and antitumor agent containing the derivative as active component - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 is H, lower alkyl, aralkyl or acyl; R2 is substituted phenyl, substituted indolyl, pyrrolyl, 2-oxocycloalkyl, 2-oxoalkyl or cyano). EXAMPLE:1,2,3,10,11,11a-Hexahydro-9-hydroxy-11-(2,4,6-trimethoxyphenyl )-5H- pyrrolo[2,1-C][1,4]benzodiazepin-5-one. USE:An antitumor agent. PREPARATION:The objective compound is produced by reacting a compound of formula II (R is lower alkyl) with a silylation agent preferably at -50-+80 deg.C in the presence of a hydrogen halide acceptor such as triethylamine and reacting the reaction product with a compound of formula H-R2 (R2 is substituted phenyl, substituted indolyl, 2-oxocycloalkyl, 2-oxoalkyl or cyano) in the presence of a Lewis acid (e.g., zinc chloride).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel pyrrolo-1,4-benzodiazepine derivative, a method for producing the same, and an antitumor agent containing the same as an active ingredient.

[Conventional technology]

Many compounds having a pyrrolo-1,4-benzodiazepine structure are known. Among them, some anti-1
1. Anti-inflammatory, antibacterial, and antiprotozoal effects have been reported. (
For example, JP-A-59-137409, JP-A-57
-131791, JP-A-58-41878) has a pyrrolo-1,4-benzodiazepine structure, and its 9
A substance having a hydroxyl group in position and a 3-indolyl group in position 11 was isolated from a bacterial culture and named tilivarine. A chemical synthesis method for tirivarine has also been reported (N, Mohr and H, Budzik
iewicz, Tetra hedron, 3fi+
147 (1982), see).

The present inventors have previously invented an advantageous method for producing tilivarine and its analogues (JP-A-63-66161, JP-A-63-66162, JP-A-63-66).
However, the compound of the present invention and the pharmacological action of the present invention found in the compound of the present invention are not known.

[Problems to be Solved by the Invention] An object of the present invention is to provide a novel pyrrolo-1,4-benzodiazepine derivative, a method for producing the same, and a useful antitumor agent containing the same as an active ingredient.

[Means to solve the problem]

The present inventors synthesized a novel pyrrolo-184-benzodiazepine compound that had not been published in any literature, studied its pharmacological action, and found that a specific compound had a strong antitumor action and completed the present invention.

That is, the present invention provides (1)-Formula (1) (wherein R1 is a hydrogen atom, a lower alkyl group, an aralkyl group, or an acyl group; aRl is a substituted phenyl group, a substituted indolyl group, a pyrrolyl group, a 2-oxo A pyrrolo-1,4-benzodiazepine derivative represented by (2) - format (wherein R8 has the same meaning as above, R2 represents a lower alkyl group, ) in the presence of a Lewis acid after treating it with a silylating agent! (-R, (III') (R2 represents a substituted phenyl group, a substituted indolyl group, a 2-oxocycloalkyl group, a 2-oxoalkyl group, or a cyano group)) A method for producing a pyrrolo-1,4-benzodiazepine derivative represented by general formula (1), and (3) an antitumor agent containing the derivative as an active ingredient.

-S In formula (1), examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, an isopropyl group, and the like. Examples of the aralkyl group include benzyl group and phenethyl group, and examples of the acyl group include acyl groups derived from aliphatic or aromatic carboxylic acids.
More specifically, acetyl group, propanoyl group, pivaloyl group, benzoyl group, etc. are preferred.

The compound of general formula (1) is disclosed in JP-A-63-66161, JP-A-63-66162, and JP-A-63-66.
It can be produced by applying the methods disclosed in Japanese Patent Application Laid-open No. 184 and Japanese Patent Application Laid-Open No. 63-66185.

That is, a compound represented by the formula - (wherein R+ has the same meaning as above and R is an alkyl group) is treated with a silylating agent such as chlorotrisilane in an organic solvent, and then treated with trimethoxy in the presence of a Lewis acid. It can be produced by reacting with benzene, indole, 3-methylindole, linear and cyclic ketones, pyrroles, sodium cyanide, potassium cyanide, hydrogen cyanide, and the like.

Straight chain and cyclic ketones include acetone, methyl ethyl ketone, cyclohexanone, cyclopentanone, and the like.

-i Regarding the production of a compound in which R3 is other than hydrogen in the compound of formula (1), when R is hydrogen and 6- Group carboxylic acids and their reactive derivatives are reacted to form a compound of the general formula (1) in which R4 is other than hydrogen.
) can also be produced.

The method of the invention is carried out in an organic solvent. The organic solvent used is not particularly limited as long as it is inert to the reaction of the present invention.Specifically, the following solvents may be mentioned. Hydrocarbon or hydrogen halide solvents such as benzene, toluene, xylene, hexane, heptane, cyclohexane, chlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, or tetrachloroethane; ester solvents such as ethyl acetate or butyl acetate , ethereal solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, or glycolic solvents such as ethylene glycol dimethyl ether, nitromethane, nitropropane, acetonitrile, formamide,
Acetamide, N,N-dimethylformamide, N,N
- a nitrogen-containing solvent such as dimethylacetamide, pyridine, picoline, quinoline, N-methylpyrrolidone or N,N-dimethylimidazolidinone, or carbon disulfide,
Examples include sulfur-containing or phosphorus-containing solvents such as dimethyl sulfoxide, phosphoric triester, or hexamethylphosphoramide. Of course, solvents that can be used are listed here.
These solvents are not limited to those listed above, and these solvents may be used alone or in combination of two or more.

As a specific method of treatment with a silylating agent, formula -71 (
A silylating agent is added to a solution of the compound represented by If) in an organic solvent, preferably from 170"C to 100"C.
C1 Particularly preferred is a method in which the treatment is carried out at a temperature of -50''C to 80''C. At this time, as a hydrogen halide scavenger, triethylamine, pyridine, picoline or N,
The reaction is accelerated if it is carried out in the presence of a tertiary amine such as N-dimethylaniline. It is also possible to further accelerate the reaction by adding an alkali metal or alkaline earth metal such as sodium bromide, potassium bromide, sodium iodide or potassium iodide.

The treatment time with the silylating agent is not limited, but it is usually completed in a short time, and it is sufficient to carry out the treatment in a range of 10 minutes to 5 hours.

Various Lewis acids can be used, including zinc chloride, aluminum chloride, aluminum bromide, stannic chloride, titanium tetrachloride, and boron trifluoride. Lewis acids are usually used alone, but there is no problem in using two or more types in combination.

Regarding the subsequent reaction, the reaction temperature is preferably -20 to 100"C, particularly preferably 0 to 80"C.The reaction time is arbitrarily selected depending on the reaction temperature.

When the compound of the present invention is used as an antitumor agent, the dosage,
The dosage form varies depending on the physical properties of the compound and the symptoms to be administered.
1 to 1000 mg per day for adults can be administered orally, e.g., as tablets, granules, powders, suspensions, capsules, etc., or parenterally, e.g., as suppositories, injections, isotonic solutions for blood transfusions. .

The general manufacturing method of the pharmaceutical composition of the present invention includes, for example, a method of dissolving the compound of the present invention in an arbitrary amount of oil selected from cottonseed oil, corn oil, peanut oil, olive oil, etc. to prepare a non-aqueous injection; In the presence of a suitable surfactant, the compound of the present invention can be prepared as an emulsion into an aqueous injection, or as a tablet by adding crystalline cellulose and light anhydrous silicic acid as an adsorbent to the compound of the present invention. Examples include adding corn starch etc. as an activator and finally adding magnesium stearate to form a formulation, but the method is not limited to the above manufacturing method, and it is also possible to formulate the formulation using other normal manufacturing methods. It is.

〔Example〕

Next, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to the following examples.

Production example-1 L-prolinal dimethylacecour hydrochloride L-butyloxycarbonyl-prolinal dimethylacecour 246 ml was added with 2 d of 10% hydrogen chloride-methanol,
After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure and L
- Prolinal dimethyl acetal hydrochloride was obtained as a brown solid. This was recrystallized from methanol-ethyl acetate.

mp 110'C~112°C IR (Nujol method) vmax cta-'; 2
700.1600.1480, 1160.1090.1
000.960.900 Elemental analysis value Ct HI&C
IN (CHN as h Calculated value 46.28 8.88 7.71 Analyzed value
46.02 8.61 7.50 Production example-2 N-(2-amino-3-hydroxybenzoyl)-L-
Dissolve 22.8 mmole of prolinal dimethylacetal L-prolinal dimethylacecour hydrochloride in 150 ml of dimethylformamide (DMF), add 2.91 g of 3-hydroxyanthranilic acid and 19 mmole, and add diethyl phosphate cyanide (DEPC) under ice cooling. 3.
After adding a solution of 10g, 19sa+ole/DMF38affi, diisopropylethylamine 1.43
41.8 mmole of rnllz was added dropwise over 10 minutes. The reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 2 h before adding D E P C 0.93 g, 5.7 mm.
A solution of ole/D MF19mffi was added and stirred at room temperature for 1.5 hours.

Concentrate under reduced pressure, add 350 d of benzene to the residue, and add 50 ml of water! Washed x3 times. Salt was added to the aqueous layer, and the mixture was extracted 100Xd times with benzene/ethyl acetate (5:1). The organic layers were combined, dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain an oil. This was purified by silica gel column chromatography (chloroform, methanol, benzene 15
1:3) L, 3.28 g of amorphous material was obtained,
It was then recrystallized from diethyl ether to obtain N-(3-amino-2-hydroxybenzoyl)-L-prolinal dimethyl acecure.

mp 99.5-101°C (α) m ”+192° (C-1,0, methanol) Elemental analysis value C+-Hz.CHN as N2O4 Calculated value 59.99 7.19 9.99 Analysis value
59.67 6.85 10.05-i Compounds in which R1 is other than hydrogen in formula (If) can also be produced by substantially the same method.

Using the compound of the general formula (II) thus produced as a raw material, a compound of the -M formula (III) is reacted to obtain a compound of the Ichigo formula (R).

Example-1 1,2,3,10,11,1la-hexahydro-9-
Hydroxy-11-(2,4,6-)rimethoxyphenyl)-5H-pyrrolo(2,1-C) (1°4]benzodiazepin-5-one (compound-1) under argon atmosphere,
N-(2-amino-3-hydroxybenzoyl)-L-
Prolinal dimethyl acecool 140■ (0.5ma
+ole), sodium iodide 300mg (2.0m
mole), acetonitrile 5mj! , pyridine 0.2
A mixture of 0 m
0 mmole) was added thereto, and the mixture was stirred at the same temperature for 30 minutes. Add 1.3.5-)rimethoxybenzene lam to this reaction mixture.
ole, stirred at room temperature for 30 minutes, and added 273 m of zinc chloride.
g (2,0Imm01e) was added thereto, and the mixture was stirred at room temperature overnight and then at 50°C for 3 hours. After cooling, 5 m of saturated sodium bicarbonate solution was added to the reaction mixture, 100 m of ethyl acetate was added, insoluble matter was removed by filtration, the filtrate was separated, and the organic layer was separated into 5 alin.
e Washed twice with 50 ad. After drying the organic layer and distilling off the solvent, the residue was purified with a silica gel column to obtain the desired 1.2
, 3.10.11.1la-hexahydro-9-hydroxy-11-(2,4,6-)rimethoxyphenyl)
-5H-pyrrolo(2,1-C)(1,4)benzodiazepin-5-one was obtained.

Yield 69% mp 229-234°C Decomposition (recrystallized from methanol) (α) o ”・'+44@(C=0.5, C) Chirsul; hoxide hereafter abbreviated as DMSO) IR (Nujol method) vmax cm -'; 33
70.3100.1620.1590.1450.13
70.1210.1155' HN M R (CDCI
i+DMSO-d&)δppm1.39-2.00(4
H, m), 3.60 (s), 3.82 (s), 3.4
6-3.98 (m) or more 11H, 4, 26-4.56 (
IH, s), 4.82 (IH, br), 5.12 (I
H, d, J-9Hz) 6.14 (2H, s), 6.57
(II, t, J-7Hz), 6.86 (LH.

d, d, J = 7.0Hz, 21 (z), 7.38 (18
, d, d, J = 7Hz.

2Hz), 7.86 (IH, s) Elemental analysis value Ct, Hz a N s OsH Calculated value 65.61 6.29 7.29 Analysis value
65.55 6.24 7.31 Example-2 1,2,3,10,11,1la-hexahydro-9-
Hydroxy-11-(3-methylindol-2-yl)-5H-pyrrolo(2,1-C)(1)benzodiazepin-5-one (compound-2) by substantially the same method as in the production example of compound-1 , 1.3.5-) Produced using 3-methylindole instead of rimethoxybenzene.

mp248-251°C (decomposition) Recrystallization solvent: methanol [α) D”-'+67° (C-0,5, dimethyl sulfoxide) 'H-NMR (CDC1a+di-DMSO) δppm
1.38-1.44 (IH, o+), 1.69-1.9
1 (38, s), 2.27 (3H, s), 3.57-3
．． 62 (IH, m), 3.66-3.73 (IH, pot)
, 4.22-4.28 (IH, m), 4.78 (IH.

d, J=9Hz), 4.99(IH,s), 6.57
(IH, t, J=8Hz) 6.83 (IH, s, J=8
．． 1Hz), 6.99 (11, d, J=8Hz), 7.
08 (1B, t, J=7.7Hz), 7.22 (18
, d, J-8, 111z) 7.29 (IH, d, J-8
, 111z), 7.48 (IH, d, J = 8.1Hz)
9.86 (11,s), 10.91 (IH,s) Example-3 1,2,3,10,11,1la-hexahydro-9-
Hydroxy-11-(N-methyl-2-pyrrolyl)-5
H-pyrrolo(2,1-C)(1,4)benzodiazepin-5-one (compound-3) in place of 1.3.5-)rimethoxybenzene by substantially the same method as in the production example of compound-1. was produced using N-methylpyrrole.

Yield 79% mp 145-147°C (recrystallized from methanol-benzene) [α]. ■・$+118” (C=0.5, DM
SO) IR (Nujol method) ymax ell-'
; 3380.3180°1620, 1590.156
0S1490.1440.12651230.690 'H-NMR (CDC1,') δppm1.71-1.
76 (IH, a), 1.83-1, 97 (3B,
m), 3.61 (3H, s), 3.70-3.87
(3H, m), 4.29 (IH.

d, J=9.7Hz), 4.45 (IH, br), 6
．． 00 (IH, t, J-2, 2Hz), 6.51-6.
54 (2H, m), 6.70 (IH, br) 6.79 (
LH, t, J-7, 9Hz), 6.88 (III, dd
,J.

7.9Hz, 2.2Hz), 7.40(Ill, d
d, J=7.9Hz, 2.2Hz) Example-4 1,2,3,10,11,l1a-hexahydro-9-
Hydroxy-11-(2-oxocyclohexyl)-5
H-pyrrolo(2,1-C)(1,4)benzodiazepin-5-one (compound-4) In substantially the same manner as in the production example of compound-1, instead of 1.3.5-trimethoxybenzene, , was produced using cyclohexanone.

Yield 40% m p 188-191.5°C Decomposition (recrystallized from chloroform) IR (Nujol method) vmax ell-'; 33
50.3050.1700.1610.1550.14
601375.1265.745'HNMR (CDC1s+DMSO-di) δppm
1.57-2.59 (13H, m), 3.59 (I
H, d, d, d, J・11.5Hz, 6.0Hz, 6.
0Hz), 3.81 (18, d, d, d, J=11.
5Hz, 7.5Hz, 4.0Hz), 3.93 (IH
, d, t, J-11, 5Hz, 7.0Hz), 4.1
3 (IH, d, J-12Hz), 4.73 (II (, b
r), 6.67 (18, t, J=7.5Hz), 6.
86 (IH, d, d, J-7, 511z, 1.311z
), 7.22 (IH, dd.

J=7.5+(Z, 1.3112), 8.79(IL
s) Example-5 1, 2. 3.10.11.1la-hexahydro-
9-hydroxy-11-(2-oxopropyl)-5H
-pyrrolo(2,1-C)(1,4)benzodiazepine-
5-one (Compound-5) 1.3.
It was produced using acetone instead of 5-trimethoxybenzene.

Yield 41% mp 171-172℃ decomposition (recrystallized from water-containing methanol) [α) o''+231' (Cm0.13, DMS
O) IR (sudicol method) ν1IlaX Cm-';
3340, 3080.1715.1610.1595.
15601465.1440.1365.1270.1
170.770'H-NMR (CDCI3+DMSO-
da) δppm1.60-2.42(m), 2.2
Hs) or above 7) 1.2.57 (2M, d, J-8Hz)
, 3.34-4.16 (4H, m), 4.52-4.7
6 (IH, a+), 6.64-7.34 (3H, m),
9.10 (IH, s) Example-6 1,2,3,10,11,1la-hexahydro-9hydroxy-11-cyano-5H-pyrrolo[2°1-C]
(1,4) Benzodiazepin-5-one (compound 9I-6
a, 6b) N(2-amino-3-hydroxybenzoyl)-L-prolinal dimethylacecool 14 under argon atmosphere
To a mixture of 0 mg, 450 mg of sodium iodide, 5 rnl of acetonitrile, and 0.283 of pyridine, 0.381 a of chlorotrimethylsilane was added under cooling with ice-methanol.
After stirring at -20'C for 30 minutes, add bMH sodium hydrogen 11041II, sodium cyanide 49
Then, 272 mg of zinc chloride was added to the reaction mixture and stirred at 50°C for 21 hours. After cooling, Compound-6 was purified by silica gel column chromatography in substantially the same manner as in the production example of Compound-1.
A73■ and 49 mg of compound-6b were obtained.

Compound-6a m p 208-210 'C (decomposition) Recrystallization solvent: methanol-ethyl acetate ((r) e''''+333° (Cm0.5, DMS
O) IR, (sudicol method) ν+1laX Cam-'
13350.3100.1620.1570.143
0.12601225.1200.1160.720'
HNMR (CDC1s+DMSO-da)
δppm1.96-2.10 (3H, a+), 2.2
1-2.31 (IH, a+), 3.54-3.69 (2
)1. Durability, 3.87-3.92 (ill, turtle), 4.3
8 (IH, d, J-11,0Hz), 4.80-5
．． 60 (IH.

br), 6.86 (IH, t, J-7,8Hz),
6.97 (IH, d, J = 7.8Hz), 7.06 (I
H, d, J-7, 8Hz), 9.74 (IH, s)”
C-NMR (CDC1i+MSO-da) δ;
22.37 (t), 28.60 (t), 46.46 (t
), 55.45(d) 57.72(d), 117.22
(d), 119.99(d), 122.3T(
d), 119.43(s), 129.08(s)
), 130.60(s), 148.83(s)
, 167.52(s) MS spectrum (m/e)2
16 (M'-HCN) Compound'#-6b m p 19B-200, 5°C (decomposition) Recrystallization solvent: methanol-ethyl acetate [α].・'+555° (C-0,5, DMSO
)IR (sudicol method) vmax as-';33
50.3100, 10.1590.1560.146
01375.1200.750'H-NMR (CDCI!+DMSO-da) δ
ppm1.81-1.90 (IH, m), 1.92-2
．． 09 (28, m), 2.39-2.46 (IH, m)
, 3.56-3.64 (IH, m), 3.82-3.8
9 (ILm), 3.97-4.05 (ill, m), 4
．． 99 (18, s), 6.40 (IH, br, s)
, 6.57 (IH, t.

J=8.0Hz), 6.85(IH,d, J-8,0H
z), 7.38 (18°d, J=8.0Hz), 9.8
0(ILbr,s)”CNMR(CDC1s+DMSO
-di) δ; 22.17 (t), 30.23 (t), 4
8.6Ht), 53.10(d) 57.82(d), 6
5.37(d), 115.37(d), 116.
77(d), 117.57(a), 117.7
2(s), 122.81(d), 132.6
9(s), 144.92(s), 165.44
(s) MS spectrum (m/e) 216 (M”-HCN) Compound-6a Compound-6b Example-7 1,2,3,10,11,1la-hexahydro-9-
Hydroxy-11-cyano-5H-pyrrolo[2゜1-C
)(1,4)benzodiazepin-5-one (compound 6a
1 g of the title compound, 123 g of lactose, and 20 g of corn starch are mixed well, and mixed with 5 g of hydroxypropylcellulose and 1 portion of water.
Mix and granulate with the solution dissolved in 00m and dry at 50°C for 4 hours. Add 1 g of Magnesium Stearate JA to this, mix well, and press into tablets using a tablet machine at a weight of 150 cm per tablet.

Example-8 1,2,3,10,11,1la-hexahydro-9-
Hydroxy-11-cyano-5H-pyrrolo[2゜1-C
)(1,4)benzodiazepin-5-one (compound 6a
5 g of the title compound, 120 g of milk and 25 g of corn starch are thoroughly mixed. This is filled into hardened capsules in an amount of 150 mg using a capsule filling machine to obtain capsules.

Example-9 1,2,3,10,11,1la-hexahydro-9-
Hydroxy-11-cyano-5H-pyrrolo[2゜1-C
)(1,4)benzodiazepin-5-one (compound 6a
) Title compound 20■,
Then, take 0.85 g of sodium chloride and dissolve it in an appropriate amount of distilled water for injection to make a total volume of 100 d to prepare an injection.

Example 10 The antitumor activity test results of representative compounds of the present invention are shown below.

Growth inhibition test for cultured tumor cells (L5178Y) Tumor cells were tested in Dulbecco's modified Eagle medium (manufactured by Hinaga Pharmaceutical Co., Ltd.) supplemented with 10% live fetal serum, 1100 u/rd, streptomycin, 100 U/d, penicillin, and L-glutamine.
The cells were cultured at 37°C for 13 days. Test compounds were added at the beginning to give final concentrations of 100.30.10.3.1.0.3 and 0.1 μg/rtdl, respectively. After culturing, the number of viable cells was measured by the Triban-Blue-Guy exclusion method, and the growth inhibition rate was calculated from the ratio of the number of viable cells in the test compound-added group and the non-added group, and the 50% growth-inhibitory concentration (IC50: μg/rr11) was determined.

The results are shown in Table-1.

Table-1

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R_1 represents a hydrogen atom, a lower alkyl group, an aralkyl group, or an acyl group. R_2 represents a substituted phenyl group. , a substituted indolyl group, a pyrrolyl group, a 2-oxocycloalkyl group, a 2-oxoalkyl group, or a cyano group. 2. After treating the compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (In the formula, R_1 has the same meaning as above and R_2 represents a lower alkyl group) with a silylating agent, Lewis Reacting with a compound represented by H-R_2(III) (R_2 represents a substituted phenyl group, a substituted indolyl group, a 2-oxocycloalkyl group, a 2-oxoalkyl group, or a cyano group) in the presence of an acid. A method for producing a derivative according to claim 1, characterized in that: 3. An antitumor agent comprising the pyrrolo-1,4-benzodiazepine derivative according to claim 1 as an active ingredient.