JPH10265473A - Pyrroloindole derivative and its production intermediate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound excellent in formation of activator in an organism, useful as a prodrug effective against solid tumor and having low toxicity. SOLUTION: This carbamoyloxy group-containing compound is shown by formula I [R<1> is OH or pyrrolidinyl; (n) is 1 or 2; R<2> is a 1-4C alkyl; X-Y or Y-X is CH2 , CHOH, CH2 -CH2 , etc.; Z<1> is Cl or Br; Ar<1> is a group of formula II (Z<2> is O or NH; (m) is 0 or 1-4), etc.] such as (1S)-chloromethyl-5- [(2S) hydroxymethylpyrrolidin-1ylcarbonyl]oxy}-3-[5(7-methoxybenzofuran-2-yl carbonyl) amino1H-indol2-ylcarbonyl]-7trifluoromethyl-1,2,3,6-tetrahydropyrrolo[ 3,2- e]indole-8carboxylic acid methyl ester.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel pyrroloindole derivative having a carbamoyloxy group having antibacterial and antitumor activities, an optically active form thereof, a pharmacologically acceptable salt thereof, and an intermediate thereof. It is.

[0002]

2. Description of the Related Art As an antibiotic having antibacterial activity and antitumor activity, CC-1065 is described in "Journal of Antibiotics", Vol. 31, pp. 1211 (1978), pp. 34, 1119. (1981
US Pat. No. 4,169,888, and also Duocarmycin A and its analogs having a similar structure are described in WO87 / 98.
No. 06265, EP0318056, "Journal
Of Antibiotics (J. Antibiotics) 42
Volume, p. 1229 (1989), JP-A-4-99774
No. 6,086,045. Further, derivatives of CC-1065 are disclosed in EP 0 359 454 and JP-A-60-1931989.
And Japanese Unexamined Patent Publication (Kokai) No. Hei 2-502005, and derivatives of duocarmycins are disclosed in JP-A-3-7287, JP-A-3-128379, and EP035458.
No. 3, EP0406749. These are all utilizing the basic skeleton of natural products as they are or derived from chemical modification of natural products. Further, a derivative having a trifluoromethyl group on a pyrroloindole ring, which is derived by chemical synthesis, is disclosed by the present inventors in JP-A-6-116269.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have sought to find a pyrroindole derivative which is effective against solid tumors and has low toxicity. As a result, a derivative having a trifluoromethyl group on the pyrroloindole ring was successfully found and disclosed in Japanese Patent Application Laid-Open No. 6-116269. JP-A-6-116269 discloses a prodrug having a carbamoyl group comprising a cyclic amine represented by the formula A.

[0004]

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An object of the present invention is to form an active substance (a compound in which B is hydrogen in the formula A) in vivo, which is superior to the prodrug compound disclosed in Examples of JP-A-6-116269, and An object of the present invention is to provide a prodrug of a pyrroloindole derivative which is effective against tumors and has low toxicity.

[0006]

Means for Solving the Problems The present inventors have the following general formula (1):

[0007]

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Wherein R ¹ is OH, a pyrrolidinyl group, n
Is 1 or 2, R ² is a C ₁ -C ₄ lower alkyl group, X-
Y or YX is CH ₂ , CHOH, CH ₂ —CH ₂ , O
—CH ₂ , NMe—CH ₂ and Z ¹ are Cl or Br, Ar
¹ is

[0009]

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Wherein Z ² is O, NH, m is 0 or 1
An integer of 4)

[0011]

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(Where m is 0 or an integer of 1 to 4)

[0013]

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(Wherein m is 0 or an integer of 1 to 4)

[0015]

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[0016]

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Wherein Z ³ is O, NH, and Ar ² is any of the groups a, b, c and d. The present inventors have found that a pyrroloindole derivative having a carbamoyloxy group represented by the formula (1), an optically active form thereof and a pharmacologically acceptable salt thereof are suitable for the purpose as the above-mentioned prodrug, and have completed the present invention.

The present invention further provides a compound of the general formula (2)

[0019]

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Wherein R ¹ is OR ³ (R ³ is a hydroxyl-protecting group), n is 1 or 2, R ² is a C ₁ -C ₄ lower alkyl group, XY is CH ₂ , CHOH, CH ₂ —CH ₂ , OC
H ₂ , NMe—CH ₂ , Z ¹ is Cl or Br, Ar ¹ is

[0021]

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(Wherein Z ² is O, NH, m is 0 or 1 to
An integer of 4)

[0023]

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(Wherein m is 0 or an integer of 1 to 4)

[0025]

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(Wherein, m is 0 or an integer of 1 to 4)

[0027]

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[0028]

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(Wherein Z ³ is O, NH, Ar ² is a,
b, c or d). ) Is a protected pyrroloindole derivative represented by
Further, the following general formula (2)

[0030]

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Wherein R ¹ is OR ³ (R ³ is a hydroxyl-protecting group), n is 1, R ² is a methyl group, XY is O—CH ₂ , Z
¹ is Cl, Ar ¹ is

[0032]

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Is shown. ), Which are protected pyrroloindole derivatives. These derivatives are used as intermediates for producing the above-mentioned pyrroloindole derivatives having a carbamoyloxy group.

Furthermore, the present invention provides an intermediate for producing the above protected pyrroloindole derivative, which is represented by the following general formula (3):

[0035]

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Wherein R ³ represents a hydroxyl-protecting group and R ⁴ represents a hydrogen atom or a benzyl group, and a morpholine derivative, an optically active form thereof, and a salt thereof.

In the general formulas (1) and (2), C ₁ of R ²
The lower alkyl group -C _4, a methyl group, an ethyl group, an isopropyl group, means a like t- butyl group, preferably a methyl group. Examples of the hydroxyl-protecting group represented by R ³ include t-butyldimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldiphenylsilyl, methoxymethyl, t-butoxymethyl, and tetrahydropyranyl. And a t-butyldimethylsilyl group is particularly preferable.

A particularly preferred embodiment of the present invention is represented by the following general formula (4):

[0039]

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More preferably, a compound wherein R ¹ is a pyrrolidinyl group and XY is CH ₂ (compound I), wherein R ¹ is OH
Wherein X—Y is CH ₂ —CH ₂ (compound II),
Compounds wherein R ¹ is in OH X-Y or Y-X is O-CH ₂ (Compound III), compounds wherein R ¹ is OH is X-Y or Y-X is NMe-CH ₂ (Compound IV), These optically active substances are mentioned. Compounds I to IV and their optically active forms can be pharmacologically acceptable salts, for example, hydrochlorides.

The racemic form of the compound represented by the above general formula (1) and the optically active forms thereof can be produced according to a known method (for example, JP-A-6-116269). The compound represented by the general formula (1) can be used alone or together with one or more pharmaceutically acceptable auxiliaries as an antibacterial or antitumor composition.

For example, a compound represented by the general formula (1) or a salt thereof is dissolved in a physiological saline solution or an aqueous solution of glucose, mannitol, lactose or the like to prepare a suitable pharmaceutical composition.

Alternatively, a salt of the compound represented by the general formula (1) is freeze-dried by a conventional method, and sodium chloride or the like is added thereto to obtain a powder injection. The pharmaceutical composition can contain additives known in the pharmaceutical field, for example, pharmaceutically acceptable salts and the like, if necessary.

The pharmaceutical composition in the form of a solution can be dissolved as it is, and the powder injection can be dissolved in distilled water for injection, physiological saline, or an aqueous solution of glucose, mannitol, lactose or the like before use, and used for intravenous administration. If desired, they can be administered intraarterially, intraperitoneally, intrapleurally, and the like.

The oral preparations include tablets, capsules, powders, granules, ampoules and the like, and these include pharmaceutical auxiliaries well known in the field of pharmaceuticals.

The dosage varies depending on the age and symptoms of the patient, but is 0.00001 to 100 mg for mammals including humans.
/ Kg / day. The administration is performed, for example, once or several times a day, or intermittently 1 to 4 times a week or once every 2 to 4 weeks.

[0047]

As a general chemical property, a carbamoyl group composed of a cyclic amine has many chemically stable substances, but a hydroxyalkyl group or a pyrrolyl group is located at the α-position of the nitrogen of the carbamoyl group composed of a cyclic amine of the present invention. The pyrroloindole derivative having a carbamoyloxy group of the present invention into which a dinylalkyl group has been introduced has the property of decomposing at an appropriate rate in vivo and under chemical conditions to produce an active form. A prodrug having such properties has been completed for the first time by the present invention. The prodrug of the compound of the present invention is also effective against solid tumors, has low toxicity, and exhibits antitumor activity in a wide safe range, so that the burden of chemotherapy on cancer patients can be reduced. .

The usefulness of the present invention is shown by the following experimental examples and examples, but the present invention is not limited to the experimental examples and examples.

[0049]

【Example】

 Example 1

[0050]

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(1S) -chloromethyl-5-hydroxy-3- [5- (7-methoxybenzofuran-2-ylcarbonyl) amino-1H-indol-2-ylcarbonyl] -7-trifluoromethyl-1, Methyl 2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate 10.2 mg (15 μmol) and 4-nitrophenyl chloroformate 7.6 mg (38 μmol)
Was dissolved in 1 ml of tetrahydrofuran, and 4.2 μl (30 μmol) of triethylamine was added dropwise under ice cooling. 1
After hours, (2S) -pyrrolidine-2-methanol 4.4
μl (45 μmol) was added dropwise and stirred for 2 hours, and further stirred at room temperature for 2 hours. Extract into 3 ml of saturated saline and 3 ml of ethyl acetate, extract and dry with anhydrous sodium sulfate.
The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: acetone = 1: 1) to give (1S) -chloromethyl-5-{[(2S) -hydroxymethylpyrrolidin-1-yl. Carbonyl] oxy
-3- [5- (7-Methoxybenzofuran-2-ylcarbonyl) amino-1H-indol-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2- e] 8.5 mg (70%) of methyl indole-8-carboxylate were obtained.

NMR (DMSO-d ₆ ) δ: 1.80-2.10
(4H, m), 3.30-3.80 (6H, m), 3.83-4.20 (2H, m), 3.92 (3H, s),
4.01 (3H, s), 4.42 (1H, brs), 4.60 (1H, d, J = 9.5Hz), 4.79 (1
H, t, J = 9.3Hz), 7.10 (1H, dd, J = 1.0Hz, 8.1Hz), 7.21 (1H, d, J
= 1.5Hz), 7.28 (1H, t, J = 7.8Hz), 7.37 (1H, dd, J = 1.0Hz, 7.8H
z), 7.50 (1H, d, J = 8.8Hz), 7.60 (1H, dd, J = 2.0Hz, 9.0Hz), 7.
75 (1H, s), 8.17 (1H, d, J = 10.3Hz), 8.21 (1H, d, J = 1.5Hz), 1
0.41 (1H, s), 11.70 (1H, s), 13.06 (1H, brs).

Embodiment 2

[0054]

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In the same manner as in Example 1, (1S) -chloromethyl-5-hydroxy-3- [5- (7-methoxybenzofuran-2-ylcarbonyl) amino-1H-indol-2-ylcarbonyl]- 7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-
e] 20.4 mg of methyl indole-8-carboxylate
(30 μmol) and 10.5 mg of (2S, 4R) -4-hydroxypyrrolidine-2-methanol (90 μmo
l) to (1S) -chloromethyl-5-{[(4R)-
Hydroxy- (2S) -hydroxymethylpyrrolidine-
1-ylcarbonyl] oxy} -3- [5- (7-methoxybenzofuran-2-ylcarbonyl) amino-1H
-Indol-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3
2-e] Methyl indole-8-carboxylate 17.3m
g (70%).

NMR (DMSO-d ₆ ) δ: 1.80-2.20
(2H, m), 3.34-3.80 (6H, m), 3.90-4.35 (2H, m), 3.92 (3H, s),
4.01 (3H, s), 4.35-4.50 (2H, m), 4.60 (1H, d, J = 11.2Hz), 4.7
5-4.81 (1H, m), 5.08-5.15 (1H, m), 7.10 (1H, d, J = 8.3Hz), 7.
21 (1H, d, J = 1.5Hz), 7.28 (1H, t, J = 7.8Hz), 7.37 (1H, d, 7.8H
z), 7.50 (1H, d, J = 8.8Hz), 7.60 (1H, dd, J = 1.5Hz, 8.8Hz), 7.
75 (1H, s), 8.18-8.30 (2H, m), 10.41 (1H, s), 11.71 (1H, s), 1
3.09 (1H, brs).

Embodiment 3

[0058]

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In the same manner as in Example 1, (1S) -chloromethyl-5-hydroxy-3- [5- (7-methoxybenzofuran-2-ylcarbonyl) amino-1H-indol-2-ylcarbonyl]- 7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-
e] 20.4 mg of methyl indole-8-carboxylate
From (30 μmol) and 13.9 mg (90 μmol) of (2S)-(pyrrolidin-1-ylmethyl) pyrrolidine, (1S) -chloromethyl-5-{[(2S)-(pyrrolidin-1-ylmethyl) pyrrolidin-1-yl Carbonyl] oxy} -3- [5- (7-methoxybenzofuran-2-ylcarbonyl) amino-1H-indole-2
-Ylcarbonyl] -7-trifluoromethyl-1,
After converting into methyl 2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate, methanol 0.1.
Treatment with 0.05 ml of 3M hydrogen chloride-ethyl acetate in 5 ml gave 18.2 mg (68%) of the hydrochloride salt.

NMR (DMSO-d ₆ ) δ: 1.80-2.30
(8H, m), 2.95-4.05 (10H, m), 3.91 (3H, s), 4.00 (3H, s), 4.28
(1H, m), 4.41 (1H, m), 4.61 (1H, m), 4.80 (1H, m), 7.10 (1H, d,
J = 8.3Hz), 7.22 (1H, s), 7.28 (1H, t, J = 7.8Hz), 7.37 (1H, d, J
= 7.8Hz), 7.51 (1H, d, J = 8.8Hz), 7.61 (1H, dd, J = 1.5Hz, 8.8H
z), 7.76 (1H, s), 8.19-8.31 (2H, m), 9.71 (1H, brs), 10.43 (1
H, s), 11.67 (1H, s), 13.20 (1H, brs).

Embodiment 4

[0062]

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In the same manner as in Example 1, (1S) -chloromethyl-5-hydroxy-3- [5- (7-methoxybenzofuran-2-ylcarbonyl) amino-1H-indol-2-ylcarbonyl]- 7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-
e] 13.6 mg of methyl indole-8-carboxylate
From (20 μmol) and 6.9 mg (60 μmol) of (2RS) -piperidine-2-methanol, (1S) -chloromethyl-5-{[(2RS) -hydroxymethylpiperidin-1-ylcarbonyl] oxy} -3- [ 5-
(7-Methoxybenzofuran-2-ylcarbonyl) amino-1H-indol-2-ylcarbonyl] -7-
12.5 mg (76%) of methyl trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate were obtained.

NMR (DMSO-d ₆ ) δ: 1.40-1.85
(6H, m), 3.25-3.95 (8H, m), 3.91 (3H, s), 4.00 (3H, s), 4.42
(1H, m), 4.60 (1H, d, J = 10.7Hz), 4.80 (1H, t, J = 9.8Hz), 7.10
(1H, d, J = 8.3Hz), 7.21 (1H, s), 7.28 (1H, t, J = 7.8Hz), 7.36
(1H, d, J = 7.8Hz), 7.49 (1H, d, J = 8.8Hz), 7.60 (1H, dd, J = 2.0
Hz, 9.3Hz), 7.75 (1H, s), 8.21 (2H, m), 10.41 (1H, s), 11.74
(1H, s).

Embodiment 5

[0066]

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In the same manner as in Example 3, (1S) -chloromethyl-5-hydroxy-3- [5- (7-methoxybenzofuran-2-ylcarbonyl) amino-1H-indol-2-ylcarbonyl]- 7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-
e] 27.2 mg of methyl indole-8-carboxylate
From (40 μmol) and 13.0 mg (100 μmol) of (2RS) -4-methylpiperazine-2-methanol, (1S) -chloromethyl-5-{[(2RS) -hydroxymethyl-4-methylpiperazin-1-ylcarbonyl ] Oxy} -3- [5- (7-methoxybenzofuran-2-ylcarbonyl) amino-1H-indole-2
-Ylcarbonyl] -7-trifluoromethyl-1,
Methyl 2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate hydrochloride 18.8 mg (54 mg
%).

NMR (DMSO-d ₆ ) δ: 2.88 (3H,
s), 3.05-3.95 (10H, m), 3.92 (3H, s), 4.00 (3H, s), 4.14 (1H,
m), 4.20-4.50 (2H, m), 4.61 (1H, d, J = 11.2Hz), 4.81 (1H, t, J
= 9.3Hz), 7.10 (1H, d, J = 7.8Hz), 7.22 (1H, s), 7.28 (1H, t, J =
(7.8Hz), 7.36 (1H, d, J = 7.8Hz), 7.50 (1H, d, J = 9.3Hz), 7.61
(1H, d, J = 10.3Hz), 7.76 (1H, s), 8.21-8.31 (2H, m), 10.00 (1
H, br), 10.43 (1H, s), 11.66 (1H, br), 13.11 (1H, brs).

Embodiment 6

[0070]

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In the same manner as in Example 3, (1S) -chloromethyl-5-hydroxy-3- [5- (7-methoxybenzofuran-2-ylcarbonyl) amino-1H-indol-2-ylcarbonyl]- 7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-
e] 20.4 mg of methyl indole-8-carboxylate
From (30 μmol) and 12.4 mg (90 μmol) of (2RS) -4-methylpiperazine-2-ethanol, (1S) -chloromethyl-5-{[(2RS) -hydroxyethyl-4-methylpiperazin-1-ylcarbonyl was used. ] Oxy} -3- [5- (7-methoxybenzofuran-2-ylcarbonyl) amino-1H-indole-2
-Ylcarbonyl] -7-trifluoromethyl-1,
Methyl 2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate hydrochloride 16.5 mg (62
%).

NMR (DMSO-d ₆ ) δ: 1.80-2.50
(2H, m), 2.86 (3H, s), 3.05-3.95 (10H, m), 3.92 (3H, s), 4.00
(3H, s), 4.08 (1H, m), 4.43 (1H, m), 4.59 (1H, m), 4.80 (1H, m
m), 4.94 (1H, m), 7.10 (1H, d, J = 7.8Hz), 7.22 (1H, d, J = 2.0H
z), 7.28 (1H, t, J = 7.8Hz), 7.37 (1H, dd, J = 1.0Hz, 8.8Hz), 7.
50 (1H, d, J = 8.8Hz), 7.61 (1H, dd, J = 2.0Hz, 8.8Hz), 7.76 (1
H, s), 8.21-8.32 (2H, m), 10.05 (1H, brs), 10.43 (1H, s), 11.
67 (1H, s), 13.17 (1H, brs).

Embodiment 7

[0074]

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In the same manner as in Example 1, (1S) -chloromethyl-5-hydroxy-3- [5- (7-methoxybenzofuran-2-ylcarbonyl) amino-1H-indol-2-ylcarbonyl]- 7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-
e] 20.4 mg of methyl indole-8-carboxylate
From (30 μmol) and 10.5 mg (90 μmol) of (3RS) -morpholine-3-methanol, (1S) -chloromethyl-5-{[(3RS) -hydroxymethylmorpholin-4-ylcarbonyl] oxy} -3- [ 5-
(7-Methoxybenzofuran-2-ylcarbonyl) amino-1H-indol-2-ylcarbonyl] -7-
17.5 mg (71%) of methyl trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate were obtained.

NMR (DMSO-d ₆ ) δ: 3.15 to 4.05
(11H, m), 3.92 (3H, s), 4.00 (3H, s), 4.29 (1H, m), 4.43 (1H,
m), 4.61 (1H, d, J = 10.7Hz), 4.80 (1H, t, J = 9.3Hz), 7.10 (1H,
d, J = 7.3Hz), 7.22 (1H, d, J = 2.0Hz), 7.28 (1H, t, J = 8.3Hz),
7.36 (1H, d, J = 7.8Hz), 7.49 (1H, d, J = 8.8Hz), 7.60 (1H, dd, J
= 2.0Hz, 8.8Hz), 7.75 (1H, s), 8.21 (2H, m), 10.41 (1H, s), 1
1.73 (1H, s), 13.08 (1H, brs).

Embodiment 8

[0078]

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In the same manner as in Example 1, (1S) -chloromethyl-5-hydroxy-3- [5-[(7-methoxybenzofuran-2-ylcarbonyl) amino] -1H-
Indole-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2
-E] Methyl indole-8-carboxylate 81.7 mg
(0.12 mmol) and 42.2 mg (0.36 mmol) of (3R) -morpholine-3-methanol to (1
S) -Chloromethyl-5-[(3R) -hydroxymethylmorpholin-4-ylcarbonyl) oxy] -3-
[5-[(7-methoxybenzofuran-2-ylcarbonyl) amino] -1H-indol-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e 62.9 mg (64%) of methyl indole-8-carboxylate were obtained.

NMR (DMSO-d ₆ ) δ: 3.15-4.15 (1
1H, m), 3.91 (3H, s), 4.00 (3H, s), 4.30 (1H, m), 4.42 (1H, m),
4.60 (1H, d, J = 10.7Hz), 4.80 (1H, t, J = 10.3Hz), 7.10 (1H, d, J
J = 7.3Hz), 7.22 (1H, s), 7.28 (1H, t, J = 7.8Hz), 7.37 (1H, d, J
= 7.8Hz), 7.49 (1H, d, J = 8.5Hz), 7.60 (1H, dd, J = 2.0Hz, 9.0H
z), 7.76 (1H, s), 8.21 (2H, s), 10.42 (1H, s), 11.74 (1H, br
s), 12.78, 13.09 (total 1H, brs × 2, in each rotamer).

Embodiment 9

[0082]

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In the same manner as in Example 1, (1S) -chloromethyl-5-hydroxy-3- [5-[(7-methoxybenzofuran-2-ylcarbonyl) amino] -1H-
Indole-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2
-E] Methyl indole-8-carboxylate 81.7 mg
(0.12 mmol) and 42.2 mg (0.36 mmol) of (3S) -morpholine-3-methanol (1)
S) -Chloromethyl-5-[(3S) -hydroxymethylmorpholin-4-ylcarbonyl) oxy] -3-
[5-[(7-methoxybenzofuran-2-ylcarbonyl) amino] -1H-indol-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e 69.7 mg (70%) of methyl indole-8-carboxylate were obtained.

NMR (DMSO-d ₆ ) δ: 3.10-4.15 (1
1H, m), 3.91 (3H, s), 4.00 (3H, s), 4.28 (1H, m), 4.43 (1H, m),
4.60 (1H, d, J = 11.0Hz), 4.80 (1H, t, J = 10.5Hz), 7.10 (1H, d, J
J = 7.3Hz), 7.23 (1H, d, J = 2.0Hz), 7.28 (1H, t, J = 7.8Hz), 7.3
7 (1H, d, J = 7.8Hz), 7.49 (1H, d, J = 9.0Hz), 7.60 (1H, dd, J = 2.
0Hz, 8.8Hz), 7.76 (1H, s), 8.21 (2H, m), 10.42 (1H, s), 11.73
(1H, s), 12.85,13.11 (total 1H, brs × 2, in each rotame
r).

Embodiment 10

[0086]

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(1S) -Chloromethyl-5-hydroxy-3- [5-[(7-methoxybenzofuran-2-ylcarbonyl) amino] -1H-indol-2-ylcarbonyl] -7-trifluoromethyl- 1,2,3,6
-Tetrahydropyrrolo [3,2-e] indole-8-
1.02 g (1.5 mmol) of methyl carboxylate and 0.51 g of 4-nitrophenyl chloroformate (2.55 m
mol) was dissolved in 50 ml of tetrahydrofuran, and under ice-cooling, 313.6 μl of triethylamine (2.25 mmol) was added.
l) was added dropwise. After 1.5 hours, (3S) -3- (t-
0.80 g (3.0 mmol) of butyldimethylsilyloxy) methylmorpholine hydrochloride and 0.52 ml (3.75 mmol) of triethylamine were added, and the mixture was stirred overnight. After diluting with 50 ml of ethyl acetate, washing with saturated saline and drying over anhydrous sodium sulfate, the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1). (1S) -chloromethyl-5-[(3S)-(t-butyldimethylsilyloxy) methylmorpholin-4-ylcarbonyl) oxy] -3- [5-[(7-methoxybenzofuran-2
-Ylcarbonyl) amino] -1H-indole-2-
Ylcarbonyl] -7-trifluoromethyl-1,2,2
1.08 g (77%) of methyl 3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate was obtained.

NMR (DMSO-d ₆ ) δ: 0.04, 0.07 (t
otal 6H, s × 2, in each rotamer), 0.85,0.86 (total 9H, s
× 2, in each rotamer), 3.15-4.10 (10H, m), 3.91 (3H, s),
4.00 (3H, s), 4.19 (1H, m), 4.40 (1H, m), 4.59 (1H, d, J = 11.2
Hz), 4.80 (1H, t, J = 10.7Hz), 7.10 (1H, d, J = 7.8Hz), 7.22 (1
H, s), 7.28 (1H, t, J = 8.1Hz), 7.37 (1H, d, J = 7.6Hz), 7.50 (1
H, d, J = 8.8Hz), 7.60 (1H, dd, J = 2.0Hz, 9.0Hz), 7.76 (1H, s),
8.17 (2H, m), 10.42 (1H, s), 11.69 (1H, s), 13.09 (1H, brs).

Embodiment 11

[0090]

Embedded image

In the same manner as in Example 10, (1S) -chloromethyl-5-hydroxy-3- [5-[(7-methoxybenzofuran-2-ylcarbonyl) amino] -1H
-Indol-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3
1.36 g of methyl 2-d] indole-8-carboxylate
(2.0 mmol) and 1.07 g of (3R) -3- (t-butyldimethylsilyloxy) methylmorpholine hydrochloride
(4.0 mmol) to (1S) -chloromethyl-5-
[(3R)-(t-butyldimethylsilyloxy) methylmorpholin-4-ylcarbonyl) oxy] -3-
[5-[(7-methoxybenzofuran-2-ylcarbonyl) amino] -1H-indol-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e 1.58 g (84%) of methyl indole-8-carboxylate were obtained.

NMR (DMSO-d ₆ ) δ: 0.07, 0.08 (t
otal 6H, s × 2, in each rotamer), 0.867, 0.874 (total 9
H, s × 2, in each rotor), 3.1
5-4.10 (10H, m), 3.91 (3H, s),
4.00 (3H, s), 4.21 (1H, m), 4.4
1 (1H, m), 4.59 (1H, d, J = 10.5
Hz), 4.80 (1H, t, J = 10.2Hz),
7.10 (1H, d, J = 7.6 Hz), 7.22 (1
H, s), 7.28 (1H, t, J = 7.8 Hz),
7.37 (1H, d, J = 7.8 Hz), 7.50 (1
H, d, J = 8.8 Hz), 7.60 (1H, dd, J)
= 2.0 Hz, 8.8 Hz), 7.76 (1H, s),
8.18 (1H, s), 8.20 (1H, s), 10.
42 (1H, s), 11.69 (1H, s), 13.0
8 (1H, brs).

Embodiment 12

[0094]

Embedded image

(1S) -chloromethyl-5-[(3S)
-(T-butyldimethylsilyloxy) methylmorpholin-4-ylcarbonyl) oxy] -3- [5-[(7
-Methoxybenzofuran-2-ylcarbonyl) amino] -1H-indol-2-ylcarbonyl] -7-
1.03 g (1.1 mmol) of methyl trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate is suspended in 2 ml of ethyl acetate and 8 ml of isopropanol, and cooled under ice-cooling. 5.5 ml of a normal hydrochloric acid-isopropanol solution was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled on ice and isopropyl ether 10m
After stirring for 15 minutes, the crystals were collected by filtration and washed with isopropyl ether, and colorless crystals of (1S) -chloromethyl-5-[(3R) -hydroxymethylmorpholin-4-ylcarbonyl) oxy] -3- [5-[(7-
Methoxybenzofuran-2-ylcarbonyl) amino]
Methyl -1H-indol-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate.
83 g (92%) were obtained. This was consistent with that obtained in Example 8.

Embodiment 13

[0097]

Embedded image

In the same manner as in Example 12, (1S) -chloromethyl-5-[(3R)-(t-butyldimethylsilyloxy) methylmorpholin-4-ylcarbonyl) oxy] -3- [5- [ (7-methoxybenzofuran-2
-Ylcarbonyl) amino] -1H-indole-2-
Ylcarbonyl] -7-trifluoromethyl-1,2,2
1.41 g (1.5 mmol) of methyl 3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate
To (1S) -chloromethyl-5-[(3
S) -Hydroxymethylmorpholin-4-ylcarbonyl) oxy] -3- [5-[(7-methoxybenzofuran-2-ylcarbonyl) amino] -1H-indol-2-ylcarbonyl] -7-trifluoromethyl −
1.20 g (97%) of methyl 1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate
I got This was consistent with that obtained in Example 9.

Embodiment 14

[0100]

Embedded image

(3R) -4-benzylmorpholine-3-
1.04 g (5.0 mmol) of methanol, 0.83 g (5.5 mol) of t-butyldimethylchlorosilane, and 0.41 g (6.0 mmol) of imidazole were reacted in 5 ml of dichloromethane at room temperature overnight. Silica gel column chromatography (hexane: ethyl acetate = 5:
Purification in 1) gave 1.53 g (95%) of (3S) -3- (t-butyldimethylsilyloxy) methyl-4-benzylmorpholine as a colorless oil.

Embodiment 15

[0103]

Embedded image

In the same manner as in Example 14, (3S) -4-
1.24 g of benzylmorpholine-3-methanol (6.
0 mmol) to give 1.82 g (94%) of (3R) -3- (t-butyldimethylsilyloxy) methyl-4-benzylmorpholine as a colorless oil.

Embodiment 16

[0106]

Embedded image

(3R) -morpholine-3-methanol 8
4.8 mg (0.72 mmol), 0.11 g (0.72 mmol) of t-butyldimethylchlorosilane and 59.1 mg (0.87 mmol) of imidazole were reacted in 1 ml of dichloromethane at room temperature for 2 hours. Purification by silica gel chromatography (dichloromethane: methanol: acetone = 15: 1: 0.5) gave a colorless oil (3).
0.15 g (92%) of S) -3- (t-butyldimethylsilyloxy) methylmorpholine were obtained.

Embodiment 17

[0109]

Embedded image

(3S) -3- (t-butyldimethylsilyloxy) methyl-4-benzylmorpholine 1.19 g
(3.7 mmol) 0.36 g of 10% palladium carbon
5 ml of ethanol and 0.32 m of chloroform in the presence of
for 1 hour. The filtrate obtained by removing the catalyst by filtration was concentrated. The precipitated crystals were washed with ether and colorless crystals of (3S) -3- (t-butyldimethylsilyloxy) methylmorpholine hydrochloride 0.96 g (9
6%).

Embodiment 18

[0112]

Embedded image

In the same manner as in Example 17, (3R) -3-
From 1.82 g (5.6 mmol) of (t-butyldimethylsilyloxy) methyl-4-benzylmorpholine, 1.13 g (74%) of colorless crystalline (3R) -3- (t-butyldimethylsilyloxy) methylmorpholine hydrochloride ) Got.

Experimental Example 1 Decomposition reaction under chemical conditions A 0.1 M aqueous citric acid solution and a 0.2 M aqueous disodium hydrogen phosphate solution were appropriately mixed to adjust the pH to 7.4, and the aqueous solution was adjusted to 1 pH with water.
Each buffer was diluted by a factor of 0. 50 v / v of each buffer
An appropriate amount of a 0.1 M aqueous citric acid solution was added to the% N, N-dimethylacetamide solution to adjust the pH to 7.4.
Each test compound was dissolved in these buffers to a concentration of 5 μM to prepare test solutions. Each test solution was placed in a glass vial and stored in a thermostat at 37 ° C. The residual ratio of the test compound was quantitatively analyzed with time using high performance liquid chromatography (HPLC) to determine the half life (t _1/2 : hour). Table 1 shows the results of the experiment.

[0115]

[Table 1]

The compound of the present invention was rapidly decomposed in a buffer solution of pH 7.4 to give an active form.

Experimental Example 2 Evaluation of M5076 / ADR (Adriamycin-Resistant Strain) Mice Subcutaneously Transplanted M5 subcutaneously on the flank of female mice (BDF1, 8 weeks old)
076 / ADR (adriamycin-resistant strain) cells were transplanted at 3.0 × 10 ⁶ cells per solid, and on the 9th day after transplantation, a single test compound solution was injected into the tail vein. Thirteen days after the administration, the tumor was excised and weighed, and the ratio (T) of the average tumor weight (T) of the administration group to the average tumor weight (C) of the solvent administration group was obtained.
/ C) was used to determine the antitumor effect. The results are shown in Table 2.

[0118]

[Table 2]

The compound of the present invention showed an excellent antitumor effect on M5076 / ADR (adriamycin resistant strain) cells.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 265/30 C07D 265/30 C07F 7/18 C07F 7/18 A // C07M 7:00 (72) Inventor Yasuo Omori Tochigi 5905-280 Tomonuma, Nogi-cho, Shimotsuga-gun (72) Inventor Jiro Terashima 2-27-4 Kyodo, Setagaya-ku, Tokyo

Claims (8)

[Claims] [Claim 1] The following general formula (1) (Wherein, R ¹ is OH, pyrrolidinyl group, n is 1 or 2,
R ² is a C ₁ -C ₄ lower alkyl group, XY or YX
Is CH ₂ , CHOH, CH ₂ —CH ₂ , O—CH ₂ , N
Me-CH ₂ , Z ¹ is Cl or Br, Ar ¹ is (Wherein, Z ² is O, NH, m is 0 or an integer of 1 to 4) (Wherein, m is 0 or an integer of 1 to 4) (Wherein m is 0 or an integer of 1 to 4) Embedded image (Wherein, Z ³ is O, NH, and Ar ² is any of the groups a, b, c, and d). A) a pyrroloindole derivative having a carbamoyloxy group, an optically active form thereof, and a pharmacologically acceptable salt thereof. 2. The following general formula (1): (Wherein R ¹ is a pyrrolidinyl group, n is 1, R ² is a methyl group, XY is CH ₂ , Z ¹ is Cl, and Ar ¹ is The pyrroloindole derivative having a carbamoyloxy group according to claim 1, an optically active form thereof, and a pharmacologically acceptable salt thereof. 3. The following general formula (1): (Wherein, R ¹ is OH, n is 1, R ² is a methyl group, XY
Is CH ₂ —CH ₂ , Z ¹ is Cl, Ar ¹ is The pyrroloindole derivative having a carbamoyloxy group according to claim 1 and an optically active substance thereof. 4. The following general formula (1): (Wherein, R ¹ is OH, n is 1, R ² is a methyl group, XY
Or Y—X is O—CH ₂ , Z ¹ is Cl, and Ar ¹ is The pyrroloindole derivative having a carbamoyloxy group according to claim 1 and an optically active substance thereof. 5. The following general formula (1): (Wherein, R ¹ is OH, n is 1, R ² is a methyl group, XY
Or Y—X is NMe—CH ₂ , Z ¹ is Cl, and Ar ¹ is The pyrroloindole derivative having a carbamoyloxy group according to claim 1, an optically active form thereof, and a pharmacologically acceptable salt thereof. 6. The following general formula (2): Wherein R ¹ is OR ³ (R ³ is a hydroxyl-protecting group), and n is 1
Or 2, R ² is a C ₁ -C ₄ lower alkyl group;
_{H 2, CHOH, CH 2 -CH} 2, O-CH 2, NMe-C
H ₂ and Z ¹ are Cl or Br, Ar ¹ is (Wherein, Z ² is O, NH, and m is 0 or an integer of 1 to 4). (Wherein m is 0 or an integer of 1 to 4) (Wherein m is 0 or an integer of 1 to 4) Embedded image (Wherein, Z ³ is O, NH, and Ar ² is a, b, c or d
Any group). ) A protected pyrroloindole derivative represented by the formula: 7. The following general formula (2): (Wherein R ¹ is OR ³ (R ³ is a hydroxyl-protecting group), n is 1, R ² is a methyl group, XY is O—CH ₂ , Z ¹ is Cl,
Ar ¹ is Is shown. The protected pyrroloindole derivative according to claim 6, which is represented by the formula: 8. The following general formula (3): (Wherein, R ³ represents a hydroxyl-protecting group and R ⁴ represents a hydrogen atom or a benzyl group), a morpholine derivative, an optically active form thereof, and a salt thereof.