TW491846B - Pyrroloindole derivative and its production intermediate - Google Patents

Abstract

To obtain a new methoyl-pyrroloindole derivative of antibacterial and anti-tumor activatity, its optical isomers, pharmaceutical acceptable salts, and production intermediates. This carbamoyloxy group-containing compound is shown by formula I [R1 is OH or pyrrolidinyl; (n) is 1 or 2; R2 is a C1-4 lower alkyl group; X-Y or Y-X is CH2, CHOH, CH2-CH2, O-CH2, NMe-CH2; Z is Cl or Br; Ar1 is a group of formula II (Z2, Z3 are O or NH; m is 0 or an integer of 1-4); Ar2 is any of the above mentioned a, b, c or d], its optical isomer and pharmaceutical acceptable salt thereof, and its production intermediate.

Description

491846 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 ____ V. Description of the invention (1) [Detailed description of the invention] [Technical field to which the invention belongs] The present invention is a novel product with antibacterial and antitumor activity Pyrroloindole derivatives of carbamateoxy, their optically active substances and pharmacologically acceptable salts, and intermediates for their production. [Previous technology] Antibiotic CC-1 065 with antibacterial activity and antitumor activity was disclosed in "J. Antibiotics" Vol. Λ 1211 (1978), same volume 34, 1119 (1981) ), USP4169888 'and similarly constructed D u 〇ca 1 myci η Α and the like are disclosed in I? 〇 8 7/0 6 2 6 5, EP 0 3 1 8 0 5 6, " Journal of Antibiotics (J ♦ Antibiotics), Vol. 42, page 1229 (1989), Japanese Patent Application Laid-Open No. 4-99774. The derivatives of CC-1065 are disclosed in EP0359454, Japanese Patent Application Laid-Open No. 60-193989, and Japanese Patent Publication No. 2-502005, while the derivatives of Duoealroycin are disclosed in Japanese Patent Application Laid-Open No. 3-7287. It is disclosed in Kaiping No. 3-12837 No. 9, EP0354583, and EP0406749. They are directly derived from the basic skeleton of natural objects, or derived from chemical modification of natural objects. Furthermore, a derivative having a trifluoromethyl group on the Dg ## ring derived by chemical synthesis is disclosed in Japanese Patent Application Laid-Open No. 6-1 1 6 2 6 9 by the inventor. [Problems to be Solved by the Invention] The present inventors and the like are committed to the exploration of solid tumors that are also effective and are @ 丨 生 t 啦 pyroloindole derivatives. As a result, the trifluoromethyl derivative was successfully found on the% ng # 嗔 ring, and was disclosed in JP-A-6-116269 (please read the precautions on the back before filling this page) --- βΓ. 1Τ -Am This paper size is applicable to China National Standard (CNS) A4 specification (210 × 297 mm)

Αγ 491846 A7 B7 V. Description of Invention (2) Gazette. Japanese Unexamined Patent Application Publication No. 6-11662 shows a precursor of a methacryl prodrug (P r 0 d r u g) having a cyclic amine represented by Formula A. B: For example, NCO-HOCH2CH2N "NCQ- The purpose of the present invention is to provide an active substance (a compound in which B is hydrogen in formula A) formed in the living body. The drug body is more excellent, and is a prodrug body of a pyrroloindole derivative which is effective for solid tumors and has low toxicity. [Means for Solving the Problem] The present inventors have issued the following general formula (1) ( (Read the notes on the back before filling in this page)

(1) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (where R1 is 0H, pyrrolidinyl, η is 1 or 2, R2 is (^ ~ 〇4 low alkyl, X-Υ or Υ-X is CH2, CHOH, CH2-CH2 > 〇-CH2-NMe-CH2, Z1 is C1 or Br, Ar 1 is Panyi 5 — This paper size applies Chinese National Standard (CNS) A4 (210X 297 mm) 491846 A7 B7 V. Description of the invention (3) (where Z2 is 0, NH, hi is an integer of 0 or 1 to 4) b. (Where ffi is an integer of 0 or 1 to 4)

C XC- (〇Me), (Please read the notes on the back before filling this page) (where m is an integer of 0 or 1 to 4) d.

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (wherein, Z3 is 0, ΗΗ, Ar * 2 is any one of 逑 a, b, C, or d.) Pyrrole with amine methyloxy group as shown The acene indole derivative, its optically active substance and pharmacologically acceptable salt are suitable for the purpose of being a prodrug drug, and completed the present invention. The present invention relates to the general formula (2)

This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 6 491846 A7 B7 V. Description of the invention (4) (where R1 is OR3 (R3 is a protective group for hydroxyl group), η is 1 or 2, R2 is Ci ~ C4 lower alkyl, X-Υ is CH2, CHOH, CH2-CH2, 〇-CHz, NMe-CH2, Z1 is Cl or Br, Ar1 is (where Z2 is 0, NH, ffl is 0 Or an integer from 1 to 4) b · ^ xO " (OMe) m (where ffi is an integer of 0 or 1 to 4) c · J〇0 " < 〇_m (wherein is 0 or 1 Integer to 4) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (Read the precautions on the back before filling out this page) d. X% e- (where Z3 is 0, NH and Ar2 are a, b 'Any of C or d) protected pyrrolopindole derivatives, and the general formula (2) for this paper is applicable to China National Standard (CNS) A4 (210X297 mm). 491846 A7 B7 V. Description of the invention (5

Ar1 (where R 1 is 0 R 3 (R 3 is a protecting group for a hydroxyl group), η is 1, R 2 is a methyl group, X-Y is 0-CH2, Z1 is Cl, and Ar1 is

Protected pyrroloindole derivatives shown by OMe. These derivatives can be used as intermediates for the production of the aforementioned pyrroloindole derivatives having an aminomethyloxy group. In addition, the present invention relates to the above-mentioned protected intermediates for the production of the pyrroloindole derivatives. The general formula (3)

[X (Please read the notes on the back before filling in this page --- Order-printed by R4 OR3 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economics (where R3 is a protective group for hydroxyl groups and R 4 is a hydrogen atom or Benzyl.) The morpholine derivative and its optically active substance and its salt shown. In the general formulae (1) and (2), C 2 to C 4 lower alkyl of R 2 means methyl, ethyl , Isopropyl, third butyl, etc., and methyl is particularly preferred. Moreover, as the protective group of the hydroxyl group represented by R3, a third butyldimethylsilyl group, a triethylsilyl group, Isopropylsilyl and tertiary butylbiphenylsilyl This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm)-8-491846 A7 B7 V. Description of the invention (6) Alkyl, methyl Oxymethyl, tert-butoxymethyl, tetrahydropyranyl, etc., especially K tert-butyldimethylsilyl is preferred. In the present invention, a particularly preferred aspect is the following general formula ( 4) shown

(Please read the precautions on the back before filling this page) ⑷ The best ones are those compounds in which R1 is pyrrolidinyl and XY is (: 1] 2 (Compound I), R1 is 0H and XY is CH2-CH2 Compound (Compound H), R1 is 0H and XY or YX is 0- (: Compound (Compound I of [12], R1 is 0H and X-Y or YX is HMe-CH2 Compound (Compound IV), its Guangyue Active body. Compounds I to IV, and their optically active bodies can be made into pharmacologically acceptable salts, such as hydrochloride salts. The racemic form of the chemical compound and its optically active body represented by the general formula (1) above can be based on It is manufactured by a known method (for example, Japanese Patent Application Laid-Open No. 6-1 1 6269). The compound represented by the general formula (1) can be used alone or in combination with a co-rib rib allowable in a formulation on K to produce an antibacterial, Antitumor composition. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. For example, a compound represented by general formula (I) or a salt thereof can be dissolved in a physiological saline solution and an aqueous solution of glucose, mannitol, lactose, etc. Or a pharmaceutical composition of the general formula (1) According to the conventional method, freeze-drying and adding sodium chloride to the powder are used to make powder injections. The pharmaceutical composition may contain additives known in the formulation field, such as salt allowed on the surface, as needed. 9 This paper is suitable for China National Standard (CNS) A4 specification (210 × 29? Mm) 491846 A7 B7 V. Description of the invention (7) The solution-like pharmaceutical composition may be used as it is, or powder injection M for distilled water for injection, physiological saline and glucose, mannose Aqueous solutions of sugar alcohol, lactose, etc. are dissolved at the time of use and used for intravenous administration. In addition, they can be intra-arterial, intra-peritoneal, intra-thoracic, etc. if desired. Economy Printed by the Ministry of Standards and Staff ’s Consumer Cooperatives (please read the precautions on the back before filling out this page). Oral preparations include tablets, ampoules, etc., and they contain the preparations. The dosage is based on the age of the patient, Dairy animals can be administered in the range of 0. 0 0 0 1 to 100 millimeters, divided into several times, or intermittently. [Effects of the invention] General chemical properties are cyclically stable substances, and In the α-position of the nitrogen, the pyrrolopindole derivative introduced with hydroxyalkyl or pyridoxyl has a suitable rate of decomposition, and the precursor drug body is of the same nature as the precursor drug body. The broad safety field makes the burden of chemotherapy for cancer patients based on the following experimental examples and implementation inventions, but not the experimental examples and examples [Examples] Capsules, powders, granules, well-known pharmaceutical auxiliary ribs Symptoms vary, but for humans including g / kg / day. For example, it can be 1 day 丨 ® 1 to 4 times per week or 2 to 4 weeks of amine methylamine consisting of amines is mostly chemical The present invention, which has a carbamoyl group consisting of a cyclic amine, has a carbamoyl group, and has the property of generating an active body in vivo and under chemical conditions. This shows the first completion of this invention. The compound solid tumor of the present invention is also effective, and antitumor activity is observed under low toxicity, so reduction is expected. The usefulness of the present invention is exemplified, but the present invention is limited. 10 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 491846 Μ B7 V. Description of invention (8) Example 1

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). (1S) -chloromethyl-5-hydroxy-3- [5- (7-methoxybenzofuran 2-ylcarbonyl) amino-1 基 -Π? | No-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydro-0itpyr [3, 2-e] ind 10.2 mg (15 μmol) of indole-8-carboxylic acid methyl ester and 7 * 6 mg (38 μmol) of 4-nitrophenyl chloroformate were dissolved in tetrahydrofuran and triethylamine was added dropwise under ice cooling. 4.2 microliters (30 mol). After 1 hour, 4.4 microliters (45 micromoles) of (2S) -pyrrolidine-2-methanol was added dropwise and stirred for 2 hours, and further stirred at room temperature for 2 hours. Put into 3 ml of saturated saline and 3 ml of ethyl acetate and extract. After drying the anhydrous M sodium sulfate, the residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: propane = 1: 1). To obtain (1S) -chloromethyl-5-{[((2S) -hydroxymethylpyrrolidin-1-ylcarbonyl] oxy) -3- [5- (7-methoxybenzofuran-2- Carbonyl) amino-1H-ind «-2-ylcarbonyl] -7-trifluoromethyl-1,2, 3, 6-tetrahydroterms: pyrro [3, 2-e] Cl-8-carboxy Methyl ester 8.5 mg (701) NMR (DMS〇-dc) δ: 1.80-2. 10 (4H, m), 3. 30-3. 80 (6H, m), 3. 8 3- 4. 20 (Ό 2H, m), 3. 9 2 (3H, s), 4. 〇l (3H, s), 4. 42 (1H, brs), 4. 60 (1H, d, J = 9 5Hz), 4. 7 9 (1H, t, J = 9. 3Hz), 7.10 (1H, dd · J = l · 0Hz, 8. 1Hz), 7.21 (1H, d, J = l 5Hz), 7.28 (1H, t, J = 7. 8Hz), 7 • 37 (1H, dd, J = 1.0 Hz, 7. 8Hz), 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 = l. 5Hz), 10.41 (1H, s), 11.70 (1H, s), 13. 06 (lH, brs). This paper size is applicable to China National Standard (CNS) A4 specification (2IOX297) Centimeter _ Ί] - 491846 A7 B7 V. invention is described (Example 2 H0 9

(Please read the precautions on the back before filling in this page) H0 · K The same method as in Example 1 was obtained from (1S) -chloromethyl-5-hydroxy-3-[5-(7-methoxybenzofuran -2-ylcarbonyl) amino-l-I-indol-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydrocole: pyrrolo [3,2 -e] earmole _8 Methyl monocarboxylate 20.4 mg (30 μmol) and (2S, 4R)-4-hydroxypyrrolidine-2-methanol 10. mg (90 μmol) to obtain (1S) -chloroform -5-{[((4R) -hydroxy- (2S) -hydroxymethylpyrrolidine-boxycarbonyl] oxy} -3- [5- (7-methoxybenzofuran-2-ylcarbonyl) Amino-1H-indol-2-ylcarbonyl] -7-trifluoromethyl-1,2, 3, 6-tetrahydropyrrolo [3, 2-e] ^ indole-8-carboxylic acid methyl ester 17 .3 mg (701). NMR (DM S Ο-d,) δ: 1. 80-2. 20 (2Η, m), 3. 3 4-3. 80 (6Η, m), 3. 90-4. 3 5 (

D Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy 2Η, m), 3.92 (3Η, s), 4.01 (3Η, s), 4 · 3 5-4 · 50 (2Η, m), 4 · 60 (1Η, d, J = ll · 2Ηζ), 4 · 7 5-4 · 8 Ι (ΙΗ, ιη), 5. 08-5. 15 (lH, m), 7. 10 (lH, d, J = 8.3Hz), 7.21 (1H, d, J = 1.5Hz), 7.28 (1H, t, J = 7.8Hz), 7.37 (lH, d, 7.8Hz), 7.50 (lH, d , J = 8.8Hz), 7.60 (lH, dd, J = 1.5Hz, 8.8Hz), 7.75 (1H, s), 8.18-8. 30 (2H, m), 10. 41 (1H, s), 11. 71 (1H, s), 13. 0 9 (1H, brs). Example factory Ha This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 12 491846 A7 B7 V. Description of the invention (10) (Please read the precautions on the back before filling this page) Μ Example 1 The same method, from (1S) -chloromethyl-5-hydroxy-3- [5- (7-methoxy Benzofuran-2-ylcarbonyl) amino-1A-indol-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-0] in 20.4 mg (30 μmol) of indole-8-carboxylic acid methyl ester and 13 * 9 mg (90 μmol) of (2S)-(^ pyrrol-1-ylmethyl) pyrrolidine, and (1S)- Chloromethyl- 5-{[(2S)-(Pyrrolidin-1-ylmethyl) pyrrolidine-butyl Carbonyl] oxy} -3-[5-(7-methoxybenzofuran-2-ylcarbonyl) amino-1 I-earm-2-ylcarbonyl] -7-trifluoromethyl-1,2 , 3, 6-tetrahydropyrrolo [3, 2-e] indole-8-carboxylic acid methyl ester, and then treated with 0.5 ml of 3M hydrogen chloride-ethyl acetate in 0.5 ml of methanol to obtain 18.2 mg of hydrochloride ( 681). NMR (DMS〇-dg) δ: 1.80-2. 30 (8Η, m), 2. 9 5-4. 0 5 (10H, m), 3. 91 (3H, s), 4.00 ( 3H, s), 4.28 (lH, m), 4.41 (lH, m), 4.61 (lH, m), 4.80 (lH, m), 7.10 (lH, d, J = 8.3

Hz), 7. 2 2 (1H, s), 7. 28 (1H, t, J = 7. 8Hz), 7. 3 7 (1H, d, J = 7. 8Hz), 7. 51 (1H, d, J = 8. 8Hz), 7. 61 (1H, dd, J = 1.5 Hz, 8. 8 Hz), 7. 7 6 (1H, s), 8. 19-8. 31 (2H, m) , 9.71 (1H, brs), 10.43 (1H, s), 11.67 (1H, s), 13.20 (1H, brs).

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs in the same manner as in Example 1 from (IS) -chloromethyl-5-hydroxy-3- [5-(7-methoxybenzofuran-2 -Ylcarbonyl) amino-1H-ind «-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] earthworm" Duo-8 " 13 * 6 mg of methyl carboxylate (20 micromolar) and 6.9 mg of (21 ^)-piperidine-2-methanol (60 micron) This paper is in accordance with the Chinese National Standard (CNS) A4 specification (210X 297 mm), 9 491846 A7 B7 V. Description of the invention (11) Mol), obtain (is) -chloromethyl-5-{[((2RS) -hydroxymethylpiperidin-1-ylcarbonyl] oxy} -3- [ 5- (7-methoxybenzofuran-2-ylcarbonyl) amino-1H-indole-2-ylcarbonyl] -7-trifluoromethyl-1, 2, 3, 6-tetrahydropyrrolo [3, 2-e] Indole-8-carboxylic acid methyl ester 1 2 5 mg (76%). NMR (DMSO-dg) δ: 1.40-1.85 (6H, m), 3.2 5-3.95 (8H, m), 3.91 (3H, s), 4.00 (3 H, s) f4.42 (lH, m) , 4.60 (lH, d, J = 10.7Hz), 4.80 (lH, tf J = 9.8Hz), 7.10 (1 H, d, J = 8.3Hz), 7.21 (1H, s ), 7. 28 (1H, t, J = 7. 8Hz), 7. 3 6 (1H, d, J = 7. 8Hz), 7. 49 (1H, d, J = 8. 8Hz), 7. 60 (1H, dd, J = 2.0Hz, 9.3Hz), 7.75 (1H, s), 8.21 (2H, m), 10.41 (1H, s), 11.74 (1 H, s). Example 5 ---------:-. (Please read the precautions on the back before filling this page

, 1T F3C CO $ Me

0 OMe HCI 4 Printed in the same way as in Example 3 by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, using (IS) -chloromethyl-5-hydroxy-3-[5- (7-methoxybenzofuran 2-ylcarbonyl) amino-l-indol-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8 Methyl monocarboxylate 27.2 mg (40 μmol) and (2RS) -4-methylpiperin-2-methanol 13 * 0 mg (100 μmol) to obtain (1S) -chloroform -5--5-[[((2RS) -hydroxymethyl-4-methylpiperin-1-ylcarbonyl] oxy} -3- [5- (7-methoxybenzofuran-2-ylcarbonyl) Amino-1H-indole-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylic acid methyl ester salt 18,8 mg (5 4¾ 4 14) This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 491846 A7 B7 V. Description of the invention (I2 NMR (DMS 〇- d 6) δ: 2. 88 (3Η, s), 3. 0 5-3. 9 5 (10Η, m). 3. 9 2 (3Η, s), 4. 0 〇 (3H, s), 4. 14 (1H, m) , 4 · 2 0-4 · 50 (2H, m), 4 · 61 (1H, d, J = ll. 2Hz), 4 · 81 (1H, t, J = 9 · 3Hz) · 7. 10 (1H ， D, J = 7. 8Hz), 7. 2 2 (1H, s), 7. 28 (1H, t, J = 7. 8Hz), 7.36 (1H, d, J = 7.8Hz), 7.50 (lH, d, J = 9. 3Hz), 7.61 (1H, d, J = 10.3Hz ), 7.76 (1H, s), 8.21-8 · 31 (2H, m), 10.00 (1H, br), 10.43 (1H, s), 11.6 6 (1H , Br), 13 · 11 (1H, brs). Example C02Me (Please read the precautions on the back before filling this page) HO Cl

HCI H Printed in the same manner as in Example 3 by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economy, using (IS) -chloromethyl-5_hydroxy-3- [5- (7-methoxybenzofuran-2- Carbonyl) amino-l-indol-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-S-carboxylic acid Methyl esters 20,4 mg (30 micromoles) and (2RS)-4-methylpiperin-2-ethanol 12.4 mg (90 micromoles) to obtain (1S) -chloromethyl-5- { [(2RS) -Hydroxyethyl-4-methylpiperin-1-ylcarbonyl] oxy} -3- [5- (7_methoxybenzofuran-2-ylcarbonyl) amino-1H- Indole-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] ^-8-carboxylic acid methyl ester hydrochloride 16 * 5 Mg (62S;). NMR (DMSO-d,) δ: 1. 8 0-2. 50 (2H, m), 2. 8 6 (3H, s), 3. 0 5-3. 9 5 (1 0H, m

D), 3. 9 2 (3Ht s), 4. 00 (3H, s), 4. 08 (1H, m), 4. 43 (1H, m), 4. 5 9 (1H, m), 4 8 0 (1H, m), 4. 9 4 (1H, m), 7 · 10 (1H · d, J = 7. 8Hz), 7. 2 2 (1H, d, J = 2.0Hz), 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. 7 6 (1H, s), 8.21 -8 · 3 2 (2H, m), 10 · 0 5 (1H, brs ), 10 · 43 (1H, s), 11. 6 7 (1H, s), 13. 17 (1H, brs). 15 This paper size applies to China National Standard (CNS) A4 (210X297 mm) 491846 A7 B7

Ο ΟΜθ (Read the precautions on the back of the page before filling in this page) Μ Example 1 The same method as described in (IS) -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 -Methyl carboxylate 20 + 4 mg (30 mold mole) and (31 ^)-morpholine-3-methanol 10.5 mg (90 mold mole) to obtain (1S) -chloromethyl-5- {[ (3RS) -Hydroxymethylmorphofluoren-4-ylcarbonyl] oxy} -3- [5- (7-methoxybenzopyran-2-ylcarbonyl) amino-1 [{-indole 2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3, 2-e] ^^-8-carboxylic acid methyl ester 17 * 5 mg (71¾). NMR (DM S 〇 d 6) δ: 3. 15-4 · 0 5 (11H, m) · 3 · 9 2 (3H, s) · 4 · 00 (3H · s), 4 · 2 9 (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 = 2.0 Hz), 7.28 (1H, t, J = 8. 3Hz), 7.36 (1H, d, J = 7.8Hz), 7.4 9 (1H , d, J = 8.8Hz), 7.60 (1H, dd, J = 2.0Hz, 8.8Hz), 7. 7 5 (1H, s), 8. 21 (2H, m), 10.41 (1H, s ), 11. 73 (1H, s), 13. 08 (1H, brs). Example 8

In the same manner as in Example 1 of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, (IS) -Chloromethyl-5-hydroxy-3-[5-[(7-methoxybenzofuran-2-yl Carbonyl) amino] -l-indol-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3, 2-e] 4l ^ -8-carboxyl Methyl ester 81.7 mg (0.12 mmol) and (3R) -morpholine-3-methanol 42.2 mg (0.36 mmol) to obtain (1 $)-chloromethyl-5-[(31. -Hydroxymethylmorpholine 16 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) 491846 A7 ___ B7_ V. Description of the invention (14) -4-ylcarbonyl) oxy] -3- [ 5-[(7-methoxybenzofuran-2-ylcarbonyl) amino] -1H-earmdol-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydro 62.9 mg (6U) of parro [3,2-e] indine-8-carboxylic acid methyl ester. NMR (DMSO-dJ δ: 3. 15-4. 15 (11Η, m), 3. 91 (3Η. S), 4. 00 (3Η, s), 4. 30 ο (1Η, m), 4. 42 (1Η, m), 4.60 (1Η, d, J = 10. 7Hz) f 4.80 (1H, t, J = 10. 3Hz), 7.10 (1H.d, 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 · 0Hz) · 7. 7 6 (1H, s) · 8. 21 (2H · s), 10. 42 (1H, s) , 11 · 74 (1H, br s), 12 · 78, 13 · 09 (all 1H, brsX 2, in each rotomer) · Example 9 (Please read the precautions on the back before filling this page)

In the same manner as in Example 1, from (IS) -chloromethyl-5-hydroxy-3- [5-[(7-methoxybenzofuran-2-ylcarbonyl) amino] -1I-indole 2-ylcarbonyl) -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-8-carboxylic acid methyl ester 81 * 7 mg (0.12 mmol) and (3S ) -Morphidine 3-methanol 42.2 mg (.36 mmol), obtained (1S) -chloromethyl_5 _ [(3S) -hydroxymethyl-Morphine Consumers Cooperatives, Central Standards Bureau, Ministry of Economic Affairs, India Fluoren-4-ylcarbonyl) oxy] -3-[5-[(7-methoxybenzofuran-2-ylcarbonyl) amino] -1H-indole-2-ylcarbonyl] -7-tri Fluoromethyl-1,2,3,6-tetrahydropyrrolo [3, 2-e] indole-8-carboxylic acid methyl ester 69.7 mg (70¾). NMR (DMSO-dg) δ: 3. 10-4. 15 (11Η, m), 3. 91 (3Η, s), 4. 00 (3Η, s), 4. 28 (1Η. M), 4. 43 (lH, m), 4.60 (1H, d, J = ll. 0Hz), 4.80 (1H, t, J = 10.5Hz), 7. 10 (1H, d, J = 7. 3Hz ), 7. 23 (1H, d, J = 2.0 Hz), 7. 28 (1H, t, J = 7.8 Hz), 7. 3 7 (lH, d, J = 7.8 Hz), 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. 7 3 (1H, s), 12. 8 5, 13. 11 (all 1H, brsX 2, in each rotational isomer) · 17 This paper size applies to China Standard (CNS) A4 specification (210X297 mm) 491846 A7 B7 V. Description of the invention (15 Example 1 0

(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] indole-8-carboxylic acid methyl ester 1.02 g (1.5 mmol) Central Standard of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperative and 0.51 g of 4-nitrophenyl chloroformate (2 * 55 mmol) was dissolved in 50 ml of tetrahydrofuran and triethylamine 313 + 6 µl (2.25 mmol) was dripped under ice-cooling. ear). After 1.5 hours, (3S)-3- (third butyldimethylsilyloxy) methylmorpholine hydrochloride 0,80 g (3.0 mmol) and triethylamine 0.52 ml (3.75 Millimoles) and stir for a while. 50 ml of ethyl acetate diluted and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1) and purified by M. (1S) -chloromethyl-5-[(3S)-(third butyldimethylsilyloxy) methylmorphin-4-ylcarbonyl) oxy] -3- [5- [ (7-methoxybenzofuran-2-ylcarbonyl) amino] -1 fluorene-indol-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrole And [3,2-e] indole-8-carboxylic acid methyl ester 1 ♦ 08 g (77¾). NMR (DMS〇-d6) δ: 0.04, 0.07 (all 6H, sX2, in each rotomer), 0.8 5 · 0.86 (all 9H, sX2, in each rotomer) Middle), 3.15-4.10 (10H, no, 3.91 (31 ^ sh 3H, s) f4.19 (lH, m), 4.40 (lH, m) t4.59 (lH, d, J = 11.2Hz) f4.80 (lHtt, J = 10.7Hz), 7.10 (1H, d, J = 7. 8Hz), 7. 2 2 (1H, s), 7. 28 (1H, t, J = 8. 1Hz), 7. 3 7 (1H, df J = 7. 6Hz), 7. 50 (1H, d, J = 8. 8Hz), 7. 60 (1H, ddf J = 2. 0Hz, 9 0Hz), 7. 7 6 (1H, s), 8. 17 (2H, m), 10. 4 2 (lHt s), 11. 69 (1H, s), 13. 09 (1H, brs). 18 (Please read the notes on the back before filling out this page) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 491846 A7 B7 V. Description of invention (1 6) Example 11

Μ 实 _ Example 10 The same method, from (1S) -chloromethyl-bu hydroxy — [5-[[7-methoxybenzofuran-2-ylcarbonyl] amine]-丨 indole-2 " " Alkylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-0] 1,1 嚷 -8-carboxylic acid methyl ester 1.36 g (2 * 0 millimoles) and (3R) -tris (third butyl dimethylmethsalyloxy) methylmorphine hydrochloride 丨 · 07 g (4.0 millimoles), obtained ( 1S) -chloromethyl-5-[(3R)-(third butyldimethylsilyloxy) methylmorpholine ~ 4-ylcarbonyl) oxy] -3- [5 _ [(7- Methoxybenzofuran-2-ylcarbonyl) amino] _1H-° 31indole-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3, 2-e] Methyl indole-8-carboxylate 1.58 g (8U). (Please read the precautions on the back before filling this page) NMR (DMSO-dp) printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs δ: 0.07, 0.08 (all 6H, sX2, in each rotomer), 0 6 867, 0.874 (all 9H, sX2, in each rotomer) 3. 15-4. 10 (10H, m), 3. 91 (3H, s), 4. 0 〇 (3H, s ) · 4. 21 (lH, m) · 41 · (1Η · m), 4 · 5 9 (1H, d · J = 10 · 5Hz) · 4. 80 (1H, t, J = 10 · 2Hz) , 7 .10 (1H, d, J = 7. 6Hz), 7. 22 (1H. S). 7. 28 (1H, t, J = 7. 8Hz), 7. 37 (1H, d, J = 7.8Hz), 7.50 (1H, d. J = 8.8Hz), 7.60 (lHf dd, J = 2.0Hz.8.8Hz), 7.76 (1H. S), 8.18 (1H, s), 8. 20 (1H, s). 10 · 42 (1H · s), 11. 6 9 (1H, s) · 13. 0 8 (1H, brs). Example 1 2 This paper size is applicable to Chinese National Standard (CNS) A4 Specifications (210X297 mm) 19 491846 A7 B7 V. Description of the invention (17)

(Please read the precautions on the back before filling out this page) 〇OMe will be (IS) -chloromethyl-5-[(3S)-(third butyldimethylsilyloxy) methylmorphone- 4-ylcarbonyl) oxy] -3-C5-[(7-methoxybenzofuran-2-ylcarbonyl) amino] -ylcarbonyl] -7-trifluoromethyl-1,2,3, Suspend 1,03 g (1,1 mmol) of 6-tetrahydropyrrolo [3,2-e] ° 3l methyl-8-carboxylate in 2 ml of ethyl acetate and 8 ml of isopropanol. 5.5 ml of the prescribed hydrochloric acid-isopropanol solution was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was ice-cooled, 10 ml of isopropyl ether was added, and the mixture was stirred for 15 minutes. The crystals were collected by filtration and washed with M isopropyl ether to obtain (1 S) -chloromethyl-5-[(3R) -hydroxyl as colorless crystals. Methylmorpholine-4-ylcarbonyl) oxy] -3- [5-[(7-methoxybenzofuran-2-ylcarbonyl) amino] -1H-indole-2-ylcarbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-fluorenic acid methyl ester 0.83 g (9.22 g). This substance was consistent with that obtained in Example 8. Example 13

Printed in Example 12 by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, using (1 S) -chloromethyl-5-[(3 R)-(second butyl dimethylmethacetin ) Methylmorpho-4 -ylcarbonyl) oxy] -3-[5-[(7-methoxybenzopyran-2-ylcarbonyl) amino]-ΙΗ-indole-2-basic Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 20 491846 A7 B7 V. Description of the invention (is) carbonyl] -7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [ 1,41 g (1,5 mmol) of 3,21] indole-8-carboxylic acid methyl ester to obtain (1S) -chloromethyl-5-[(3S) -hydroxymethylmorpholine as colorless crystals Fluoren-4-ylcarbonyl) oxy] -3- [5-[(7-methoxybenzofuran-2-ylcarbonyl) amino] -1l-indol-2-ylcarbonyl] -7-tri Fluoromethyl-1,2,3,6-tetrahydropyrrolo [3, 2-e] indole-8-carboxylic acid methyl ester 1.20 g (97¾). This substance was consistent with that obtained in Example 9. Example 1 4

[X Order (3R) -4-benzylmorphofluorene-3-methanol 1,04 g (5.0 mmol), tert-butyldimethylchlorosilane 0.83 g (5 * 5 Mol) and Imidazole 0 * 41 g (6 * 0 mmol) in 5 ml of dichloromethane was reacted overnight at room temperature. Μ Silica gel column chromatography (hexane: ethyl acetate = 5: 1) was purified by Μ to obtain colorless crystals of (3S)-3- (third butyldimethylsilyloxy) methyl-4-benzyl Morpholine 1.53 g (95¾). Example 1 5 Ί — 1Τ (Please read the precautions on the back before filling in this page)

1T printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs in the same manner as in Example 14 from (3S) -4-fluorenylmorpholine-3-methanol 1 + 24 g (6.0 mmol), obtained (3R) -3- (Third-butyldimethylsilyloxy) methyl-4-fluorenylmorphoam 1.82 g (94¾) as a colorless oil. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 21 491846 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (19) Example 16

Let (3R) -morpholine-3-methanol 84 * 8 mg (0.72 mmol), tert-butyldimethylchlorosilane (K11 g (0.72 mmol) and imidazole 59 * 1 mg ( 0.87 mmol) in 1 ml of dichloromethane, and reacted at room temperature for 2 hours. Silica gel column chromatography (dichloromethane: methanol: acetone = 15: 1: 0, 5) was purified by M to obtain a colorless oil. (3S) -3- (third butyldimethylsilyloxy) methylmorpholine 0 ♦ 15 g (92%). Example 17 [N ^ V ^ 〇Si (tBu) Me2 H HCI Order (3S)-3- (Third-butyldimethylsilyloxy) methyl-4-benzylmorphofluorene 1.19 g (3.7 mmol) at 10% Hydrogenation (1 atm) was performed in 5 ml of ethanol and 0.3 2 ml of chloroform in the presence of 0,36 g of palladium / carbon for 4 hours. The filtrate obtained by filtering the catalyst was concentrated. The precipitated crystals were washed with ether and colorless. (3S) -3- (Third-butyldimethylsilyloxy) methylmorphine hydrochloride 0 * 96 g (96¾). Example 1 8 [N], / 05ΚιΒϋ} Μθ2 H HCI -ϋϋ -m ϋ mu i ϋ · ^ a—Β— ----- i--I -1 ··-·· 1.1_1 (Please read the notes on the back first Then fill out this page)

、 1T This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 22 491846 A7 B7 V. Description of the invention (20 Μ The same method as in Example 17, using (3R) -3- (third butyl di Methylsilyloxy) methyl-4-benzylmorphobut 1,82 g (5,6 mmol), colorless crystals of (3 R) -3-(third butyl dimethylformamide) Silyloxy) methylmorphine hydrochloride 1 ♦ 13 g (74¾). Spring test example 1 The decomposition reaction under chemical conditions will be 0.1 Μ aqueous citric acid solution and 0.2 Μ disodium hydrogen phosphate aqueous solution Properly mix and adjust to pH 7.4, dilute 10 times with K water as each buffer solution. Add a proper amount of 0.1M citric acid aqueous solution to the 5Cv / v 5¾ N, Η-dimethylacetamide solution of each buffer, and separately Adjust to ρ Η 7.4. Dissolve each test compound K 5 μM in these buffers and use it as a test solution. Put each test solution in a glass vial and store in a 37 ° C thermostat. Over time High-speed liquid chromatography (ΗPLC) was used to quantitatively analyze the residual rate of the test compound and calculate the half-life (t ^: hours). The experimental results are shown in Table 1. [Table 1] Test compound half-life (t%: hour) Test compound half-life (t &: hour) Example 1 > 8 Example 5 1.7 ^ Example 2 > 8 Example 6 5, 8 ^ Example 3 1.0 Example 7 1.7 ^ Example 4 > 8 The average half-life of each diastereomer printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs * The average value of the compounds of the present invention in pΗ7.4 buffer Rapidly decomposed to produce activity 23 (Please read the precautions on the back before filling out this page) This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 491846 A7 B7 V. Description of the invention (21 body. Experiment Example 2 Evaluation of M5076 / ADR (Doxorubicin Tolerant Strain) Transplanted Mice Subcutaneously M5 076 / ADR (Doxorubicin Tolerant Strain) cells were subcutaneously administered to the lateral abdomen of female mice (BDF1 糸, 8 weeks of age). 3.0 × 106 were removed from each body, and a single injection of the test compound solution M into the tail vein was performed on the ninth day after transplantation. The tumor was removed 13 days after the administration, the weight was measured, and the solvent was administered to the subject. Group average tumor weight (c) relative to the average tumor weight of the administered group T) ratio, the antitumor effect was judged. The results are shown in Table 2. [Table 2] Test compound administration amount (mg / kg) T / C Example 4 1 * 0 0.01 Example 5 1. 0 0.01 Example 7 1,0 0 * 02 The compound of the present invention exhibits excellent antitumor effect on M5076 / ADR (adriamycin resistant strain) cells. (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 2 4 This paper size applies to China National Standard (CNS) A4 (210X 297 mm)

Claims (1)

491846 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 6. Application for patents Wr " A8 B8 C8 D8 '88. 6. Amendment 1. A pyrrolo with amine methylethoxyl shown in general formula (1) Vermidol derivatives ^ Ar1 〇⑴ (where R 1 is Ο Η, pyrrolidinyl, η is 1 or 2, R 2 is Ci ~ C 4 lower alkyl, XY or YX is CH 2., CHOH, CH2-CH2, 0 -CH2, NMe-CH2, Z1 is Cl or Br, Ar1 is-(OMe) m (where Z2 is 0, NH, in is an integer of 0 or 1 to 4) θ Er (where, Z 3 is 0 , N Η, A Γ 2 is a stilbyl group) and its optically active substance and a pharmacologically acceptable salt. 2. For example, a pyrroloindole derivative having a carbamoyloxy group having a carbamoyloxy group in the scope of patent application 1, It is as shown in the following general formula (1) 0) This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) ^ J ------ (Please read the precautions on the back before filling this page), 11 491846 A8 B8 C8 D8 Patent Application Scope (Wherein R 1 is a pyrrolidinyl group, η is 1, R 2 is a methyl group, X-Y is C Η 2, Z 1 is C 1, and Ar * 1 is) and its optically active substance and pharmacology Allowed salt ° ΟΜθ 3. For example, a pyrroloindole derivative having a carbamoyloxy group with a carbamoyloxy group, which is represented by the following general formula (1) (wherein R1 It is methyl, χ-Υ is CH2-CH. Please read the notes on the back and then fill in fl. This is printed as C1 by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs and A) and its optically active substance. ~ 0 I 4 * As the pyrroloindole derivative with amine methyloxy group in the first patent application scope, it is as shown in the following general formula (1) (Wherein R1 is OH, η is 1, R2 is methyl, χ-Χ or Υ-χ is 0 -CH2, Z 1 is C 1, Ar * 1 is) and its optically active substance ϋ H OMe 5. For example, a pyrroloindole derivative with a carbamoyloxy group having a carbamoyloxy group is as shown in the following general formula (1). The paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297). Mm) 491846 A8 B8 C8 D8 6. Scope of patent application (where R1 is 0H, η is 1, R2 is methyl, XY or YX is NMe-CH2, Z1 is C1, A is) R nm ^ mrmmm ± m ^ m salt + —A kind of protected pyrroloindole derivative shown by the following general formula (2) (please read the precautions on the back before filling this page) Z1 (2) Ar1 Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs (where R 1 is 0 R 3 (R 3 is a protective group for hydroxyl groups), η is 1 or 2, R 2 is CrC * low alkyl, XY is CH2, CHOH, CHz-CH2-〇-CH2, NMe-CH2, Z1 is C1 or Br, Ar1 is a · " " ίΟ (where Z2 is 0, NH, m is 0 or 1 ~ Integer of 4) • {〇Μβ) π e · 〇 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 3 491846 A8 B8 C8 D8 6. The scope of patent application (where Z 3 is 0, N Η · and A r 2 are the a group described above). 7. The protected pyrrolofurindole derivative as claimed in item 6 of the patent application, which is as shown in the following general formula (2). R (2) Ar1 (where R 1 is 0 R 3 (R 3 is a protective group for a hydroxyl group), η is 1, R 2 is a methyl group, X-Υ is O-CH 2, Z1 is U, and Ar 1 is Please read the back note first ΟΜθ The order is as follows: The morpholine derivative R3 based on the general formula (3) is R3 alkanesilylmethylditributadiene is 3 R Chinese or proton hydrogen is 4 R printed by the staff consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Salt making and physical activity light and base iir This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 4