ZA200401290B

ZA200401290B - Cyclic indole and heteroindole derivatives, the production and use thereof as medicaments.

Info

Publication number: ZA200401290B
Application number: ZA200401290A
Authority: ZA
Inventors: Heinz Weinberger; Thomas Beckers; Mathias Schmidt; Silke Baasner; Bernd Nickel
Original assignee: Zentaris Gmbh
Priority date: 2001-09-03
Filing date: 2004-02-18
Publication date: 2004-03-23
Also published as: PL370210A1; CN1551885A; NO20040831L; EP1423393A1; MXPA04002034A; IL160441A0; JP2005508898A; BR0212300A; AR036776A1; HUP0401446A2; HUP0401446A3; CA2458399A1; RU2004110412A; KR20040029463A; NZ531642A

Description

Cyclic indole and heteroindole derivatives, their preparation and their use as medicaments

The invention relates to novel substituted indole and heteroindole derivatives of the formula I

R2

Lo

Ca R6 » (1)

R4” op N

Lo

R5 “hy? n to their tautomers, to their stereoisomers, to their mixtures and to their pharmaceutically acceptable salts, to their preparation and to their use as medicaments, in particular as antitumor agents, in mammals, in particular in man.

German patent application dated April 28, 2000 (Patent

ASTA Medica AG with Privatdozent Dr. Mahboobi) describes a process for preparing 2-acylindoles via the corresponding 2-lithioindoles.

Theophil Eicher and Ralph Rohde, Synthesis 1985, pp. 619-625, describe the preparation of 1,2-diphenyl- 3a~azacyclopentalalinden-3-one. A medical application of the compound mentioned is neither disclosed nor suggested.

According to one aspect of the invention, compounds of the formula I are provided

T°

R3._ ZA R1

To] ks 4 J

Y n where

R1 is hydrogen, (C6-Cl4)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents, (Cl1-Cl3)-heteroaryl which contains at least one to four N, NH, O and/or S as ring members and 1s unsubstituted or fully or partially substituted by identical or different substituents, (C3-C8) -cycloalkyl which is unsubstituted or fully or partially substituted by identical or different substituents, or straight- chain or branched (C1l-C20)-alkyl which is unsubstituted or fully or partially substituted by identical or different substituents;

A, B, C or D independently of one another are a nitrogen atom or a carbon atom substituted by

R2-R5;

R2, R3, R4 and R5 independently of one another are a free electron pair (if binding partner A, B, C or

D are a nitrogen atom), hydrogen, halogen, cyano, nitro, hydroxyl, straight-chain or branched (Cl1-C6)-alkyl, straight-chain or branched (C1l-C6)- alkyl which is substituted by one or more halogen atoms, straight-chain or branched (C1-C6)-alkoxy, straight-chain or branched (Cl-C6)-alkoxy which is substituted by one or more halogen atoms, straight-chain or branched (C1-C6)-alkylenedioxy, (Cl1-C6)-alkylcarbonyloxy, (C1-C6)-alkoxy- carbonyloxy, (C1-C6)-alkylthio, (C1-C6)-

alkylsulfinyl, (Cl-C6)-alkylsulfonyl, carboxyl, (C1-C6)-alkyl carboxylate, carboxamide, N-(Cl-C6)- alkylcarboxamide, N,N-di-(Cl1l-C6)-alkyl- carboxamide, (C1-C6)-alkoxy-(Cl-C6)-alkyl, amino, mono- (C1-Cé6) -alkylamino, di-(Cl-C6)-alkylamino, where the two (Cl-C6) radicals together may form a ring which optionally contains one or more NH,

N-(C1l-C6)-alkyl, O or S, (C6-Cl4)-aryl, (C6-Cl4)- aryloxy, (C6-Cl4)-aryl-(Cl-C6)-alkyl, (C6-Cl4) - aryl-(Cl-C6)-alkoxy-(Cl-C6)-alkyl, (C1-C6)-alkyl- carbonyl, (Cl-C6)-alkoxycarbonyl, hydroxyl, where two directly adjacent radicals may be attached to one another;

R6 is (C6-Cl4)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents, (C1l-C13)-heterocaryl which contains at least one to four N, NH, O and/or S as ring members and is unsubstituted or fully or partially substituted by identical or different substituents, (C3-C8) -cycloalkyl which is unsubstituted or fully or partially substituted by identical or different substituents, straight- chain or branched (Cl-Cc20)-alkyl which is unsubstituted or fully or partially substituted by identical or different substituents, where the identical or different substituents are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, (Cl1-C6)-alkyl, (Cl-C6)-alkoxy, carboxyl, (Cl-C6)- alkyl which is substituted by one or more identical or different halogen atoms, (Cl1-C6)- alkoxy which is substituted by one or more identical or different halogen atoms, straight- chain or branched (C2-C6)-alkenyl, straight-chain or branched (C2-C6)-alkynyl, (C3-C8) -cycloalkyl, straight-chain or branched (C1-C6) -alkoxy, straight-chain or branched (C1l-C6)-alkylenedioxy,

(C1-C6) -alkoxy-(C1-C6)-alkyl, (C6-Cl4)-~aryl, (C6-Cl4)-aryl-(Cl-C6)-alkyl, (C6-Cl4) -aryl- (C1-C4) ~alkoxy-(C1l-C6)-alkyl;

X is a carbonyl (C=0), sulfoxide (S=0) or sulfonyl (S02) group;

Y is an oxygen atom or a nitrogen atom substituted by the radical R7 (NR7), where

R7 is (C6-Cl4)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents, (Cl-C13)- heteroaryl which contains at least one to four N, NH, O and/or S as ring members and is unsubstituted or fully or partially substituted by identical or different substituents, (C3-C8) -cycloalkyl which is unsubstituted or fully or partially substituted by identical or different substituents, straight-chain or branched (C1l-C20)-alkyl which is unsubstituted or fully or partially substituted by identical or different substituents, where the identical or different substituents are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, (C1-C6)~ alkyl, (C1-C6) -alkoxy, carboxyl, (Cl-c6)- alkyl which is substituted by one or more identical or different halogen atoms, (C1-C6) ~alkoxy which is substituted by one or more identical or different halogen atoms, straight-chain or branched (C2-C6)-alkenyl, straight-chain or branched (C2-C6)-alkynyl, (C3-C8) -cycloalkyl, straight-chain or branched (Cl1-C6)-alkoxy, straight-chain or branched (C1-C6)-alkylenedioxy, (Cl-C6)-

alkoxy- (Cl-C6)-alkyl, straight-chain or branched mono-(Cl-C6)-alkylamino, straight- chain or branched di-(Cl-C6)-alkylamino where the two (Cl1l-C4)-radicals together may form a ring which optionally contains one or more

NH, N-(Cl-C6)-alkyl, O or S, (C6-Cl4)-aryl, (C6-Cl4) -aryl-(Cl-C6)-alkyl, (C6-Cl4)-aryl- (C1l-C4)-alkoxy-(Cl-C6)-alkyl, {(C1-C6)- alkylcarbonyl, (Cl-C6)-alkoxycarbonyl; n is 0 or 1, with the proviso that, if n = 0,

Z is a carbon atom substituted by the radical RS (C-R8) where

RS8 is (C6-Cl4)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents, (C1l-C13) - heteroaryl which contains at least one to four N, NH, O and/or S as ring members and is unsubstituted or fully or partially substituted by identical or different substituents, (C3-C8)-cycloalkyl which is unsubstituted or fully or partially substituted by identical or different substituents, straight-chain or branched (C1-C20)-alkyl which is unsubstituted or fully or partially substituted by identical or different substituents, where the identical or different substituents are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, (Cl1-C6)- alkyl, (Cl-C6)-alkoxy, carboxyl, (Cl-C6)- alkyl which is substituted by one or more identical or different halogen atoms, (C1-C6) -alkoxy which is substituted by one or more identical or different halogen atoms,

straight-chain or branched (C2-C6)-alkenyl, straight-chain or branched (C2-C6)-alkynyl, (C3-C8) -cycloalkyl, straight-chain or branched (C1-C6)-alkoxy, straight-chain or branched (C1-C6)-alkylenedioxy, straight- chain or branched (C1-C6)-alkylthio, (Cl-C4)- alkylsulfinyl, (C1l-C4)-alkylsulfonvl, (C6-Cl4) -arylthio, (C6~-Cl4) -arylsulfinyl, (C6-Cl4) -arylsulfonyl, (C1l-C6)-alkoxy- (C1l-C6)-alkyl, straight-chain or branched mono- (C1l-Cé6)-alkylamino, straight-chain or branched di-(Cl-C6)-alkylamino where the two (Cl-C4)-radicals together may form a ring which optionally contains one or more NH,

N-(Cl-C6)-~alkyl, 0 or Ss, (C6-Cl4) ~arxryl, (C6-Cl4) -aryloxy, (C6-Cli) -aryl-(Cl-Cb6)- alkyl, (C6-Cl4) -aryl-(Cl-C4)-alkoxy-(Cl-C6)- alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)- alkoxycarbonyl, straight-chain or branched mono-N-(C1l-Cé6)~-alkylcarbonylamino, straight- chain or branched di-N,N-(Cl-C6)-alkyl- carbonylamino, straight-chain or branched mono-N- (C1-C6) -alkoxycarbonylamino, straight- chain or branched di-N,N-(Cl-C6) - alkoxycarbonylamino, straight-chain or branched N-(Cl1l-C6)-alkylcarbonylamino-N- (C1l-C6)-alkylamino, straight-chain or branched N-(Cl-C6)-alkoxycarbonylamino-N- (C1-C6)-alkylamino; and that, if n = 1,

Z is a nitrogen atom; or a tautomer, a stereoisomer, a mixture or a pharmaceutically acceptable salt thereof.

According to a further aspect of the invention, compounds are provided which are characterized in that

R1 is hydrogen, R2, R3, R4 and R5 independently of one another are hydrogen, halogen or (Cl1-C6)-alkoxy, R6 is straight-chain or branched (C1-C20)-alkyl which is unsubstituted or fully or partially substituted by identical or different substituents or is (C6-Cl4)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents from the group consisting of (C1-C6)-alkoxy and halogen, Y is an oxygen atom or the radical N-R7, where R7 is (C6-Cl4)-aryl which 1s unsubstituted or fully or partially substituted by identical or different substituents, X is carbonyl (C=0), Z is a nitrogen atom and n = 1.

Rl is hydrogen, R2, R3, R4 and R5 independently of one another are hydrogen, halogen or (Cl-C6)-alkoxy, R6 is straight-chain or branched (C1-20)-alkyl which is unsubstituted or fully or partially substituted by identical or different substituents or is (C6-Cl4)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents from the group consisting of (Cl-C6)-alkoxy and halogen, n = 0, Z is the radical C-R8, where R8 is (C6-Cl4)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents from the group consisting of (Cl-C6)-alkoxy and halogen, and

X is carbonyl (C=0).

According to a further aspect of the invention, the abovementioned compounds according to the invention are provided for use as medicaments.

According to a further aspect of the invention, the use of one of the abovementioned compounds according to the

B Page 8 invention for controlling tumor disorders in mammals, in particular in man, is provided.

According to a further aspect of the invention, medicaments are provided which comprise at least one of the abovementioned compounds according to the invention together with pharmaceutically acceptable auxiliaries, diluents and/or carriers.

According to a further aspect of the invention, a process for preparing the compounds of the formula I according to the invention

R2 0

Ca R6 (0

RN

RS “hye n in which A, B, C, D, R1, R2, R3, R4, R4, R5, X, Y, Z and n are as defined in claim 1, characterized in that a) the ketone of the formula

Te

Lo]

Cs R6

R5 R9 0 is reacted with aa) oxime or bb) hydrazine derivative

H2N-NH-R7 where R7 is as defined in claim 1, and the resulting product is cyclized with an activated carbonyl, sulfoxide or sulfonyl derivative, or is reacted with cc) phenylacetic acid derivative X1-CO-

CH2-R8, where X1 is a suitable leaving group, such as halogen or (Cl1-C2)-alkoxy, and R8 is as defined in claim 1, followed by cyclization in the presence of base is provided.

The compounds of the formula I according to the invention can be obtained by processes known per se. A suitable process is, for example, the process described below: a) reaction of an indole or heteroindole compound provided, if appropriate, with a suitable nucleofugic leaving group E with organometallic compounds:

I. R2

I EE Ee _

R4 op N Ra” “Xp N R6

RS Ro 0 Rs ke 0 in which

R1, R2, R3, R4, R5, R6, A, B, C and D are as defined at the outset,

RS is hydrogen, straight-chain or branched (C1-C6)- alkylcarbonyl which is unsubstituted or substituted by one or more halogen atoms, straight-chain or branched (C1-C6) -alkoxycarbonyl, substituted (C6-Cl4)-aryl-(Cl)- alkyl, straight-chain or branched (Cl1-C6)-alkylsulfonyl or (C6-Cl4)-arylsulfonyl which is unsubstituted or substituted by (C1-C6)-alkyl,

E is OH, a halogen atom, for example a fluorine, chlorine or bromine atom, (Cl-Cé)-alkoxy, imidazole and

M is Li, Mg-R10, where R10 is a halogen atom, for example a chlorine, bromine or iodine atom; for n = 0: bl) reaction of the 2-acylindole or heteroindole compounds with a reagent having suitable nucleofugic leaving groups, if appropriate with simultaneous or prior removal of the substituent

RY at the indole nitrogen atom: i §

R1 R3 R1 + pA — RE

Ra” “So N Ro E Ra” 0 N

RS R9 O RS ™ 0

R8 where

Rl, R2, R3, R4, R5, R6, R8, R9, A, B, C, D, E and X are as defined at the outset, cl) reaction of the 2-acylindole or heteroindole compounds with base, preferably sodium hydride:

R2 R2

R1 R1

RI =A R3 gh

I | i” base i || R6

J >

Ra” Sp” ON Ra” HTN ls 0 RS X—Z

R8 where

Rl, RZ, R3, R4, R5, R6, R8, A, B, C, D and X are as defined at the outset and 2 is a carbon atom substituted by a radical RS, for n = 1: b2) reaction of the 2-acylindole or heteroindole compounds with unsubstituted or substituted primary amino derivatives:

R2 2

EN Ri Ra pA RI [| + Hz—Y = — Lo . ATT R10 AI Re

RS RO O RS RO Z, R10 where

R1, R2, R3, R4, R5, R6, RY, A, B, C, D and Y are as defined at the outset, Z is a nitrogen atom and

R10 is hydrogen, straight-chain or branched (C1-C6)- alkyl, straight-chain or branched (Cl-Cc6)-alkyl substituted by one or more halogen atoms, straight- chain or branched (Cl1-C6)-alkoxy substituted by one or more halogen atoms, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8) -cycloalkyl, (C1-C6)-alkylcarbonyl, (Cl-C6) - alkoxycarbonyl, (C1l-C6)-alkylsulfinyl, (C1-C6) - alkylsulfonyl, (C1-C6)-alkoxy-(Cl-C6)-alkyl, (C6-C14)- aryl, (C6-Cl4) -aryl-(Cl-C6)-alkyl, (C6-Cl4)-aryl- (C1-Cé6)-alkoxy-(Cl-C6)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl; c2) reaction of the indole or heteroindole compounds with a reagent having suitable nucleofugic leaving groups, if appropriate with simultaneous or prior removal of the substituent R9 at the indole nitrogen atom:

Re 4 ey i

X —_—

Cu R6 AN Cx R6

Rep : + RM R12 re” Sp N

Z

R5 RO Zv, R10 RS x where

Rl, R2, R3, R4, R5, R6, R9, A, B, C, D and X are as defined at the outset, Z is a nitrogen atom and R10 is a hydrogen atom, and

R11 and R12 independently of one another are nucleofugic leaving groups, such as a halogen atom, for example a chlorine, bromine or iodine atom, (Cl-C6)- alkoxy or imidazolide.

However, the preparation is carried out particularly advantageously by reacting an isolated or in situ generated indole or heteroindolecarboximidazolide of the formula II 2

R1

R3

BS.

YY

R58 R98 O in which

R1, R2, R3, R4, R5, RY, A, B, C and D are as defined at the outset, with Grignard reagents, reacting the indole or heteroindole derivatives of the formula III i

R1

Lo (i)

Cx R6 !

SY

RS RO 0 in which

Rl, R2, R3, R4, R5, R6, RI, A, B, C and D are as defined at the outset, with hydroxylamine, cyclizing the indole or heteroindole derivatives of the formula IV a ¢ | | R6 (V)

RATSDTNTY

R5 H N “OH in which

Rl, R2, R3, R4, R5, R6, A, B, C and D are as defined at the outset, with N,N’-carbonyldiimidazole to give the indole or heteroindole derivatives of the formula V

R2 ¢ | | R6 )

Re” ~p NY

R5 A N 0” So” and cyclizing the indole or heteroindole derivatives of the abovementioned formula III in which

Rl, R2, R3, R4, R5, R6, A, B, C and D are as defined at the outset and RS is a hydrogen atom, with unsubstituted or substituted phenylacetyl halides in the presence of, for example, sodium hydride as base, to give the indole or heteroindole derivatives of the formula VI.

R2

SN R1 ol (VI)

Rd “0 N R6

R5 0

R2

The compounds used as starting materials, some of which are commercially available or known from the literature, are obtained by processes known from the literature; furthermore, their preparation is described in the examples. The processes known from the literature are described, for example, in L. and M.

Fieser, Organische Chemie [Organic Chemistry], 2nd edition, 1979, pages 1417 to 1483 and in the literature cited therein on pages 1481-1483, in Houben-weyl-

Miller, Methoden der organischen Chemie [Methods of organic chemistry] and in Ullmanns Encyklopddie der technischen Chemie [Ullmann’s Encyclopedia of Technical

Chemistry].

Furthermore, the resulting compounds of the formula I can be separated into their enantiomers and/or diastereomers. Thus, for example, the resulting compounds of the formula I which occur as racemates can be separated by methods known per se into their enantiomers, and compounds of the formula I having at least 2 asymmetric carbon atoms can, owing to their physicochemical differences, be separated by methods known per se, for example by chromatography and/or

R Page 15 fractional «crystallization, into their diastereomers which, when obtained in racemic form, can then be separated as mentioned above into the enantiomers.

The separation of enantiomers is preferably carried out by column-chromatographic separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as, for example, esters or amides, with the racemic compound.

Furthermore, the resulting compounds of the formula I can be converted into their salts, in particular for pharmaceutical application into their pharmacologically and physiologically acceptable salts, using inorganic or organic acids. Acids suitable for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Moreover, the compounds of the formula I can, if they contain an acidic group, such as a carboxyl group, be converted, if desired, into their salts, in particular, for pharmaceutical applications, into their physiologically acceptable salts, using inorganic or organic bases. Bases suitable for this purpose are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, enthanolamine, diethanolamine and triethanolamine.

Below, the invention is illustrated in more detail by examples; however, the invention is not limited to these examples.

General procedures for preparing the 2-acylindoles according to the invention.

Method A) Isolation of the dimidazol-1-yl(l1H-indol-2- yl)methanones and subsequent reaction with organometallic reagents

With stirring at room temperature, a solution of 72 mmol (11.67 g, 1.2 equivalents) of N,N’- carbonyldiimidazole in 250 ml of tetrahydrofuran was added dropwise to a solution of 60 mmol (11.47 g) of 5-methoxyindole-2-carboxylic acid in 200 ml of tetrahydrofuran, over a period of 60 minutes. After a further 15 minutes of stirring, the solvent was removed using a rotary evaporator and the residue was recrystallized from 220 ml of tetrahydrofuran:hexane = 3:2. This gave imidazol-1-yl-(5-methoxy-1H-indol-2- yl)methanone as an orange-brown solid.

M.p.: >300 (decomp.) 0 A

TLD

N

H

Oo

At 0°C, 2.2 equivalents of the organometallic compound were added dropwise to a solution of 1 equivalent of imidazol-1-yl- (5-methoxy-1H~-indol-2-yl)methanone in tetrahydrofuran (3 ml/mmol) such that the internal temperature did not exceed 5°C. The conversion of the reaction was monitored by thin-layer chromatography (mobile phase ethyl acetate:hexane = 1:1). After the reaction had ended, water (10 ml/mmol) was added to the reaction solution and the pH was adjusted to 6 using concentrated hydrochloric acid. The organic phase was separated off and the aqueous phase was extracted three times with ethyl acetate (in each case 2 ml/mmol). The combined organic phases were dried over magnesium sulfate and the solvent was then removed using a rotary evaporator and the residue was crystallized from alcohol.

Example Al:

Reagent Al: Methylmagnesium chloride, 3.0 M solution in tetrahydrofuran 0

N

H

0 1-(5-Methoxy-1H-indol-2-yl)ethanone

M.p.: 164-167°C (2-propanol)

Example AZ:

Reagent AZ: Phenylmagnesium bromide, 3.0 M solution in diethyl ether - C | ¢g

N

H

0 (5-Methoxy-1H-indol-2-yl)phenylmethanone

M.p.: 164-166°C (n-butanol)

Example A3:

Reagent A3: 3-Methoxyphenylmagnesium bromide, 1.0 M solution in tetrahydrofuran pd

N Oo

H

O

(5-Methoxy-1H-indol-2-yl)- (3-methoxyphenyl)methanone

M.p.: 143-145°C (n-butanol)

Example 24:

Reagent Ad: 4-Methoxyphenylmagnesiumbromide, 0.5 M solution in tetrahydrofuran a Ci | C h

N

H

Oo (5-Methoxy-1H-indol-2-yl) - (4-methoxyphenyl)methanone

M.p.: 155-158°C (n-butanol)

Example AS:

Reagent AS: 4-Chlorophenylmagnesium bromide, 1.0 M solution in diethyl ether

Cl

N

H

O

(4-Chlorophenyl) - (5-methoxy-1H-indol-2-vy1l)methanone

M.p.: 190-192°C (n-butanol)

Example A6:

Reagent A6: 2-Thienyllithium, 1.0 M solution in tetrahydrofuran ase .

N S

H

8] (5-Methoxy-1H-indol-2-yl) thiophen-~2-ylmethanone

M.p.: 152-154°C (n-butanol)

Method B) One-pot variant: Synthesis of the imidazol-1- v1 (lH-indol-2-yl)methanones and subsequent in situ reaction with organometallic reagents with stirring and under an atmosphere of inert gas, a solution of 26 mmol (1.05 equivalents) of N,N’- carbonyldiimidazole in tetrahydrofuran (3 ml/mmol) is, at room temperature, added dropwise to a solution of 25 mmol of an indole-2-carboxylic acid in tetrahydrofuran (2 ml/mmol), over a period of minutes. After a further 60 minutes of stirring, the reaction solution was cooled to 0ec, and 3.5 equivalents of the organometallic compound were added dropwise such that the internal temperature did 20 not exceed 5°C (about 60 minutes). The conversion of the reaction was monitored by thin-layer chromatography (mobile phase ethyl acetate:hexane = 1:1). After the reaction had ended, water (10 ml/mmol) was added to the reaction solution and the pH was adjusted to 6 using concentrated hydrochloric acid. The organic phase was separated off and the aqueous phase was extracted three times with ethyl acetate (in each case 2 ml/mmol). The : combined organic phases were dried over magnesium sulfate and the solvent was then removed using a rotary evaporator and the residue was crystallized from alcohol.

Example Bl:

Starting material: Indole-2-carboxylic acid

Reagent Bl: 2-Methoxyphenylmagnesium bromide, 1.0 M solution in tetrahydrofuran : O o ~ (1H-Indol-2-yl)- (2-methoxyphenyl)methanone

M.p.: 129-130°C (ethanol:water = 4:1)

Example B2:

Starting material: Indole-2-carboxylic acid

Reagent A3: 3-Methoxyphenylmagnesium bromide, 1.0 M solution in tetrahydrofuran

CTC J A ~~

N Oo

H

0 (1H-Indol-2-yl) - (3-methoxyphenyl)methanone

M.p.: 119-121°C (2-propanol)

Example B3:

Starting material: 5-Methoxyindole-2-carboxylic acid

Reagent Al: Methylmagnesium chloride, 3.0 M solution in tetrahydrofuran 0

N

H

0 1-(5-Methoxy-1H-indol-2-yl)ethanone v Page 21

M.p.: 164-167°C (2-propanol)

Example B4:

Starting material: 5-Methoxyindole-2-carboxylic acid

Reagent B4: Ethylmagnesium chloride, 3.0 M solution in tetrahydrofuran 0

N

H

Oo 1-(5-Methoxy-1H-indol-2-yl)propan-1l-one

M.p.: 173-175°C (2-propanol)

Example B5:

Starting material: 5-Methoxyindole-2-carboxylic acid

Reagent A2: Phenylmagnesiumbromide, 3.0 M solution in diethyl ether

N

H

O

(5-Methoxy-1H-indol-2-yl)phenylmethanone

M.p.: 164-166°C (n-butanol)

Example B6:

Starting material: 5-Methoxyindole-2-carboxylic acid

Reagent A3: 3-Methoxyphenylmagnesium bromide, 1.0 M solution in tetrahydrofuran aus

N 0”

H

(5-Methoxy-1H-indol-2-y1l)- (3-methoxyphenyl)methanone

M.p.: 143-145°C (n-butanol)

General procedure for preparing the oxadiaza derivatives according to the invention

Method C) Preparation, isolation and purification of the indol-2-yloximes and subsequent reaction with N,N’-carbonyldiimidazole

Cl) General synthesis of the indol-2-yloximes: 1.5 equivalents of solid hydroxylamine hydrochloride and then, dropwise with stirring, over a period of 5 minutes, 3.0 equivalents of potassium hydroxide, 0.5M in methanol, were added to a suspension of 1 equivalent of the 2-acylindole prepared according to method A or B in ethanol (10 ml/mmol). The reaction solution was heated under reflux for 3-9 hours (monitored by TLC) and, after cooling to room temperature, poured into water (150 ml/mmol) and adjusted to pH 6 using hydrochloric acid (10% in water). The precipitate formed was isolated and recrystallized from alcohol /water. If no precipitate was formed, the organic phase was separated off, the aqueous phase was extracted three times with ethyl acetate (in each case 2 ml/mmol), the combined organic phases were dried over magnesium sulfate, the solvent was removed using a rotary evaporator and the product was subsequently purified by recrystallization, or the crude product was reacted further according to C2 (method D).

Example Cl1.1 (D-81687):

Starting material Al: 1-(5-Methoxy-1H-indol-2- v1)ethanone 0

N

H

“OH 1- (5-Methoxy-1H-indol-2-yl)ethanone oxime

M.p.: 148-150°C (2-propanol)

Example Cl.2 (D-81690):

Starting material B4: 1-(5-Methoxy-1H-indol-2- yl)propan-l-one 0

N

7

Y'OH 1- (5-Methoxy-1H-indol-2-yl)propan-1l-one oxime

M.p.: 163-165°C (2-propanocl)

Example C1.3 (D-70258):

Starting material A2: (5-Methoxy-1H-indol-2-yl)phenyl- methanone ga ¢ | 4g

N

Fl "oH (5-Methoxy-1H-indol-2-yl)phenylmethanone oxime

M.p.: 150-152°C (2-propanol:watexr = 2:3)

Example Cl.4 (D-70745):

Starting material A5: (4-Chlorophenyl)-(5-methoxy-1H- indol-2-yl)methanone

{ - 9g | (I

N

Tl “

OH

(4-Chlorophenyl) - (5-methoxy-1H-indol-2-yl)methanone oxime

Crude product (purity by HPLC: 81%)

C2) Reaction of the 1H-indol-2-ylmethanone oximes with

N,N’-carbonyldiimidazole 1.2 equivalents of solid N,N’-carbonyldiimidazole were added to a solution of 1 equivalent of the 1H-indol-2- ylmethanone oxime in tetrahydrofuran (30 ml/mmol) and the mixture was heated under reflux for 1-3 hours (monitored by TLC). After cooling to room temperature, the reaction solution was poured into water {400 ml/mmol) and the precipitate formed was isolated and crystallized from alcohol. If no precipitate was formed, the organic phase was separated off and the aqueous phase was extracted three times with ethyl acetate (in each case 2 ml/mmol). The combined organic phases were dried over magnesium sulfate and the solvent was then removed using a rotary evaporator and the product was purified by column chromatography on silica gel under atmospheric pressure (mobile phase ethyl acetate:hexane = 1:3).

Example C2.1 (D-81688):

Starting material Ccl.1: 1-(5-Methoxy-1H-indol-2-~ vl) ethanone oxime “TO

Vo

AN

~~ 0” 0 3-Methyl-1,2,5~-oxadiazino[4,5~a] (5-methoxyindol) -6-one v Page 25

M.p.: 217-220°C (2-propanol)

Example C2.2 (D-81691):

Starting material Cl.2: 1-(5-Methoxy-1H-indol-2- vyl)propan-l-one oxime 0

I

PY N

Pd

O Oo 3-Ethyl-1,2,5-oxadiazino[4,5-a] (5-methoxyindol) -6-one

M.p.: 208-212°C (n-butanol)

Example C2.3 (D-70260):

Starting material Cl.3: (5-Methoxy-1H-indol-2- yvl)phenylmethanone oxime

To

PY N

0” ~o” 3-Phenyl-1,2,5-oxadiazino[4, 5-a] (5-methoxyindol) -6-one

M.p.: 198-200°C (n-butanol)

Method D) Direct reaction of the 1H-indol-2-ylmethanone oximes prepared with N,N’-carbonyldiimidazole

The following oxadiaza derivatives were synthesized according to procedure Cl but without purification reacted further according to C2.

Example D1 (D-81362):

Starting material Bl: (1H-Indol-2-y1)-(2- methoxyphenyl)methanone

Cl N | g ~~ 0“ To ~ 3-(2-Methoxyphenyl)-1,2,5-oxadiazino(4,5-alindol-6-one

M.p.: 160-162°C (column chromatography)

Example D2 (D-81361):

Starting material B2: (LH-Indol-2-y1)-(3- methoxyphenyl)methanone g | 9g ~~

N Il 0

AN

0” No” 3-(3-Methoxyphenyl)-1,2,5-oxadiazino[4,5-a]lindol-6-one

M.p.: 129-130°C (column chromatography)

Example D3 (D-81462):

Starting material A3: (5-Methoxy-1H-indol-2-v1)-(3- methoxyphenyl)methanone aduPe

Pre

N= O

AN

0” No” 3-(3-Methoxyphenyl)-1,2,5-oxadiazino[4,5-a] (5- methoxyindol)-6-one

M.p.: 171-173°C (ethanol)

Example D4 (D-70744):

Starting material AS5: (4-Chlorophenyl)- (5-methoxy-1H- indol-2-yl)methanone heudel

To

PP

0” ~o” 3-(4-Chlorophenyl)-1,2,5-oxadiazino(4,5-a)l (5-methoxy- indol) -6-one

M.p.: 227-230°C (n-butanol)

The following compounds according to the invention (examples Nos. 1 to 324) can also be prepared according to the abovementioned synthesis procedures C and D, starting from indol-2-carboxylic acid derivatives with different substituents:

Starting material: 4 R1

CT

R

OH

6 “Spy

H

7 0

Product: (n=1, Z=N) 4

A R1 hl

RS | | R6 67Sp” SN

EE

Examples Nos. 1 to 324: wo.la fc Jo fn fo Tee x Ty

EN EF = Fr = [TTT 2 jenfon Jon [vw lew lew Jo

ENN EN PE PO FF YT a Jes Jon Jew ln Tn e-cmorcw cor Jo

Jos Jon Jeu ln Jn loscmoncan Jo Jo] 6 Jon Jen Jon [vw [oa cmo-can cw Jo 7 lex Jon Jew ln Jn |sacmorcan Joo Jo e Jeu Jon [en lw - [wn [ss coc loo Jo 5 Jen Jew Jon ww sas ccmorocan [cor Jo

Jc Jen fen Jaco Ju few, Jeo) Jo]

EEN EP EO Pe PO FT 12 fc Jon lon Jaco [8 Jew, [eon Jo 12 Jc lon lon Jaco Jv [oomoy-cm Joo) Jo 10 Jc fon Jon Jaccano Ju [3 emoy-cm Jew Jo

Jc fon lon [aco [nv a emory-cm Jeo) Jo 16 lc Jom Jon Jaco [a3 iomorcan |cio) Jo 17 Jc Jen Jou la-cawo [5 [2.4-(cmorce lc lo 16 Jc fen fen Jacano [n [3.a-(cmorican Jc) Jo 19 [con lou [aco [nn [s.s-icmorcan Joo) lo

Jc Jen Jon [acao [5.45 cmorcan [cor Jo 21 fen fon Jou [somo [nw [o-comoren Jc) Jo 22 on [en [en [s-omo |v [a-cmor-ca Joo) Jo

Jon Jon Jon [somo Jn [oo tcmorcan Joo) Jo 24 Jen jen Jou |s-cmo [nw [2.4-(cmor-can Jc Jo 2s Jen Jeu Jon [somo [sn |sa-cmoycan Jeo) Jo 26 Jen [cn Jon |s-cmo [uw [3.5 (cmoj-cam_ Jc) Jo 27 Jon fon Jou |s-cmo [vw [5.4.5 (cmo)-can Jc) Jo 28 Jen fc Jou Jor [vw Jew, coy Jo 29 Jen fe Jon for [x Jom Jew Jo 0 jen fc Jen Jor fw Jew Jeo lo 51 fen Je Jon Jor fn Totemoycm Jew Jo s2 en fc loafer [nv Dvemorcam Jew Jo 53 Jon [c Jon Jor Ju Jeemoycan Jeo) lo sa on [c Jeu or fn [os-cemoycamn Jeo) Jo ss Jen fe Jen Jor [0 [o.a-@mocm [co Jo se Jen lc Jen for Jn [5aomomce Jeo lo 7 len fo enor In [rs imorca low Jo se fon lc Jon fee Ju [s.a5-cmon-can Jc lo 9 Jen Jen fe Joo Tw few Jew Jo a0 Jon fen Jo loon Tw Jew Jew lo a1 Jen [en lc room Jw Jew Jew) lo a2 fen Jou Jo [room Jw Poemorcm Jew Jo a3 fon fer Je lr-om [nw Doomocm Jeo lo aa fon Jon Jc [row [vp Joomocm low Jo as lon fen Jo room Jw Dsoiemorcan Jc Jo 46 fon fon lo [row Jw [a-emoyca co) Jo 7 fon for lc lr-om [nv sa cmo-can Je Jo co lon Jon [c [row [v lsisoemoycan Joo Jo a9 lon fon Jc [room [mn [s.e.s-emo-can Joo) Jo so lon Jou few [w Jew Jom eo Jo 51 Jon fon Jon Jp Jom Jom few) Jo s2 fom Jon fen Ju fom, Jew Jeo Jo 53 Jon fen jon [ula loocmo-ca leo Jo se Jon Jon Jon [ule |socomoca oor Jo ss lou Jom lon [0 Jew, Jocmocm Jc [o s6 lon low Jon ln Jew Jo3omoncm cio Jo 57 Jon fen on [nv Jom, [2.4 cmorcan Jc Jo so loa fom lon [sn few, [somone [cw Jo so lon Jon on [wears [ssocmolican co) Jo 60 cn ou Jon nom |s.as-omocam co) Jo 61 Jon jon [on [scr Jean, Jew eo Jo 62 fon Jon fon [set Jean Jem Jew Jo 63 cn lon Jon [sca Jom Jew, Jeo) Jo oo Jon Jon [on [scr Jew, oomoy-can Jeo) Jo 6s lon jon on [soci Jew, |socomoyca, cio) Jo 66 [on Jou lon ls-c1 ea lomo Jeo) Jo 67 Jon Jen [en [s-c1 Jew, |oscmorican Jeo fo 68 lon Jon Jon |s-cr [om [o.acmorcan Jc Jo 69 lcs [on fon |s-c1 Jeg, |s,a-cmo)can Jc Jo 70 en lon Jon scr Jom s.s-cmopcm Jc Jo 71 Jou fou Jou |s-c1 ems s.e.sicmorscam co) Jo 2 Iv Joudow lw Ju Jew few Jo

CEN rr FE YT EA

EZ Pr Pe Fr PO = YY 7s lw Jew Jen Jn fw lo-cmorcan cor Jo] 76 In Jew Jor ln [x Docmorcs Joo Jo] 7 fw ow Jon fw Jw Jecmocm Joo) Jo 76 lw ow Jos [w |x os cmoicm cio) Jo 7s Iw Jen fer ln lw [oa cmorccsn Joo Jo so Iv Jon Jor Jo [wv [5a-icmoieca co Jo er lv low Joa [w lw [5.5 icmoncm Jeo Jo ez lv Jen fowls [sv [5.45-com0cm joo Jo oa fon wv Jew Je fv Jen Joo) Jo eo fen Iv Jew nw few Joo Jo es fos nw Jew ln fw few Jeo Jo es len Iw ow Jw fw [2 cmor-can Jeo) Jo e7 Jen In Jen fw Jw [scmor-cm Jew) Jo ee fon fw Jew Jn [sv Jacmo-cm Joo Jo eo en Iw Jew ln [wv [23 cnolicen Jeo) Jo so Jen Ju ow [uw fw [2a cmoncan Joo) Jo |] ou Jen [w Jen Jn Jw [sacmoncean Jeo) Jo oz Jen Ju ow Jw fw [5,5 cmorcean Jeo Jo |] os Jen Jw ow [ww 3a5-cmoic co) Jo oa Jon fen Ju Jn Jw few Joo) Jo os Jon fen Jv Jn Tw fem Joo) Jo

EL Fe Ee PE = = o7 Jon Jon Ju Jn Tw [o-tcmoycn cor Jo oe lon Jon [w [vw Iw [cmon Jeo) Jo os Jen fen Inv [nfo Jaccmoycm Jeo) Jo woofer Jon Ju Ju Tw [2.3-(cmorcm co) Jo woson Jou In [ww [2a-icmorecam Jeo) Jo woafcr few Iw Jn Ju [3.4-cmorecwm co) Jo sosfon Jou Iu Jn fw [5.5-(cmoricm cor Jo hoafen Jen |v [on fo [5.45 cmorcan [co Jo wosfon Jon fen fw Jw Jen Tso Jo toslca Jon Jou [uw [wn Jews Iso) Jo 107cn Joa Jos [ww few, Js) Jo osfon Jou Jen fu Ju [o-cmoyca |s©@ Jo poser Jen Jen Jn Ju [semor-cmn [so Jo]

miofen Jon jon Jw J lacicwor-om Js Jo |] hnfew Jon Jon Ju [s+ [2somorcm [so lo uiafen Jou Jon [uw Jw accmorca so) Jo viafen fou Jon [uw Tw lssocomorcan [so Jo nsfen Jeu Jon Ju Jn |sas-emonca [so Jo wise Jon Jon Jaco [nv Joa Js) Jo fe Jon low Jacmo |v Jem Js) Jo sfc Jon fon fecmo ln Jem Js) Jo] ofc Jou Jon Jaco [x looiomoycm |s@ |o 120fc Jou fen Jacmo [nw |socmorcan [si Jo 121fc fon Jon Jaco [nv lo-cmoycm [sw Jo h22fc fen Jon Jaco [nv loscmoncean Js@ Jo 123)c on lon Jaco |v [2acmorcan [sw Jo 2afc fou Jon Jacoo [nv [sac (cmorican [sw Jo 125]c Jou [en Jecmo [nw [3,5-cmoricm [soo 126lc fon [on [ecmo [vn |3.a5-cmorcm [so Jo 127ca lon Jon [scemo |v lew Js Jo 120lon Jon ow [somo [v0 fem Js) Jo 129lca lou lon [s-omo lw lew Js Jo 130cn Jon fen [s-cmo [wv Jocmor-can [so Jo istlon Jon fon [somo [n [soomo-cm [si |o 132 cn Jou Jon [scomo Ju la-omo-con [s©@ Jo 133 lon lon Jon [s-omo Ju [o.3-(cmorican [s©@ Jo 13acn Jon Jor [s-cmo [vw |oa-cmorcan [so Jo 135 [cn Jon Jon [s-omo Ju [s.a-cmorcan [s©@ Jo 136 lon lon on [s-cmo [uw |s,s-(cmorecamn [so Jo 137 cn Jon Jon |s-cmo Ju [3.e,5-(cmorican [s@ Jo salon fc Jen ler Jw Jom fs@ Jo soln Jc Jou Jer [sn Jem Js Jo heolon Je Jon for Jw Jom Js Jo salon Je Jen Jer Jw [oocmor-car [s©@ Jo sazlon Jc Jom for Ju [soomorca [s©@ Jo heslon Jo Jeu Jor fw locomor-can so) Jo sealer Je fen Jer Ju [os cmorcan [so |o aaslon [com fer [vn [2.a-icmorcam [so Jo salen Jc Jen oor [vw [sa emorcan [so Jo werfon fc Jor for [5 [oso cmocan [sw Jo] weelon Jo Jou fer [x [sas-cmorcca [so Jo olen fon Jo Troon Ju Jon Teo Jo wsofen Jou Jo [rom ln Jew Iso) Jo wsijon Jeu Jo [row Je Jew [sor Jo] salen Jon Jc [row [vw o-omoican [so Jo salen Jon fc [room [wv [soomorcan, [so lo salen Jon Jo [room [vw la-cmorcan sw) Jo wssfen fou Jo [room Jw |o-omorican [so Jo use jen Jon Jo |rom x laa-omorca so) Jo 157 (cu Jou Jo Jreom Jw [s0-morcan [so Jo selon Jen Jc [roc [wv |ssoomorican [so Jo salen lon fc [reem [8 |3.45-@moricon [sw Jo soofen Jeu fon Jw Jew Jew Js Jo sonfen fon Jon Jw Jem Jem [so Jo we2fen fou Jou [wo Jew Jew Js) Jo sealer Jen Jon |v Jom |o-cmor-can |sio) Jo] eafon Jeu Jou [wom [ocomorcan so) Jo 165cn Jon [on uw few, la-cmor-cm ls Jo 166 (cn Jen fon [nv [om |e.-(omocan |so) Jo 167 cn fen Jon [vn Jom, |o.e-omorica so) Jo 16efen [on Jon [now [s.a-morcan, [soo iesfon Jon fon [mw [em |s5-cmovicms so) Jo 170fcn lon Jou Jv fem, [3.4.5-cmorcan [so Jo 1r1cn Jon Jon [scar Jews Jew fs Jo 2]cn [on fon [scr few, Jew Js Jo 173fcn Jou Jon [sc Jom Jew ls Jo rales Jen on [scr Joa lo-cmorcan so Jo 175 [on Jon Jon [scr Jew, [socmoy-ca, [sw Jo 76 lca Jon Jom [scr [ew le omo-can [sw lo 1770cn Jon Jen s-cr lea |os-cmorecan so) Jo 178 cn Jon Jon Js-ct few, pa-omorcan [s© Jo 179 lca Jon Jon |s-cr [ems [acmoryican [s©@ Jo asofcu [on or [s-c1 Jew, [3s-(cmon-ca [so Jo 1e1lon [on [or [s-c1 Jew, [5.4.5 (emol-cam [s0) Jo

FETS I Er = TS

Gealn Jom lew lw Jw Jew, fs Jo sto) __|o so6ln Jon Jew [1 | ocworcm so) Jo 0 solu Jon Jorn [x loo cmorcm se Jo] sol fen fen |v lw loacicmoncm [sop Jo] sol Jew Jon Jv Jo [5accmorca [so Jo worly Jen Jen Jn Jo Drsoicmoicm [sip Jo] 1o2lw Jon [en [x Jw [5.as-mopecan [so lo woolen fn Jen Jw fo fem Tso) Jo oslo Iv Jeu fo fw lem Js Jo toslon Iv Jes [x fw ew sip lo wocfen |v few ln Jw [oicmor-cme [so Jo porfen nw Jon [x fo [sicmor-cme [sr Jo poole In Jou ln Tw [ecmor-em Js Jo woofer In few ln Jw [o-cmoican [so Jo zoofen fw Jen wo [oa icmorcan so Jo zorfen Iw Jew no Tw T5acmorcm [so Jo zoafen Iw Jou [wn [ssoicmonean [so Jo 2osfen nw Jen [sn fo [ras mores [so Jo posfen Jos fw Jo fw Jew Tso) Jo zosfen Jon Iw Jn Tw Jew, Js) Jo oslo Jon In Jn fw Jews Tso) Jo zorfes Jos fw Jn fs [ocmocm [so Jo 2oelen Jen In [x Jn [scmoycm [so Jo 2osjen lon In Jn Ju Jacmor-cm [so Jo 2wofes Jean fn Jw [23 cmoican [so Jo eufen Jor [Iw [x fn Dacomoncem [so Jo cizfen Jon [x fn Jw [acomoncmn [so Jo afer fon In Jn Jw [3s-cmoncan [so Jo cufen Jor lw [vn fn [es cmorican [so [0 isla Jon Jon Jo 1s Jon se lo]

EE = FP

ERC = PE PPO = PY un len Jou on [nu Joicao cm mon Jo] 1s fen [on Jen [nw [somorcm Jso Jo olen Jon Jew [n Jw Joccmor cm Joo Jo

2orfos Jou fou nw [as-imorcm [so Jo 2o20cn Jen fon [sw |sa-cmoncm so, Jo 223lcn Jon fon Ju Ju sacicmonem so, Jo 226fen fon Jew [vn lw sooicmoom so, Jo 2oslon [on Jou [+ Tw Das-morcm [so, Jo 226jc Jeu lov Jaco [x low Jeo, Jo 227lc Jen lon Jaco [vw lem Js Jo 2oplc lon fon Jaco [vw low ls, Jo 229c Jen Jon Jaco [vw lo-(cmorcan so, Jo 230fc on Jon [aco ln |oiomoyca [so Jo 2s1fc on Jon Jaco Jn loicmorcam [so, Jo 232lc feu Jou Ja-caro lw [2,3-(cmorcan |so, Jo 2330c Jou lon Jacmo [5 |2.a-cmoncan Jso, [0 23afc Jou lon [acmo [vw [3a-icmoricm [so [0 235]c Jon fen lacco [v5.5 omoricm so, Jo 236lc Jon Jou la-cao Jw [3,4,5-(ca0rican so, Jo 2370cn [on Jon [somo [w Jem Jso, fo 23slca Jou fon |somo Jw Jew so, 5 235lca loa [ov [somo |w Jew, lso, Jo 2a0lca lon lon [somo [w |o-(cmoy-can [so lo 2a1]cn [en Jou [somo [0 [s-icmoy-cm [so, lo 202 ca fon lon [s-cmo [w [acicmor-cn [so, lo 203 cn Joa lon [s-cmo [wn [2,3-(cmojcmm [so Jo 20a fon Jou Jon |s-cmo [nw |a,a-icmoricms so, Jo 20s [on fon fen [s-omo Jw [5,4-(cmor-cun so, Jo 2as [cn on fen [somo Jw [5,5-(cmori-cun so, Jo 207 ca [on [en |s-cmo |w [5.4.5 (cmori-can so, Jo 2eslen Jc Jou Jor Tw Jew Jeo Jo 2aslon Jo on [oor fn Jew Jeo 0 poles Jc Jem Jor [nw Jew so, Jo 2silon lc on [oor [vn [ricmo-cm so, Jo 2s2]en Jc Jem [oor |w [socmoj-cams so, Jo as3loa lc Jom Jer [nw lacmoy-cam so, Jo 2safon [co Jon Jer [wn [23 (cmorican [soo asslow [c Jon [oor [wn [2a-(cmoycan [soo aselen [c fon [oor [uw [sa cmoreca, so, Jo s1lcn Je Jen [or Tx Ds-icmorean Joo Jo]

poole Jogos Ir Doasiemonon [jo ci lon fc [poem [nw few feo. Jo 2sofen loa Jc [rom [x fem Jeo. lo ooifen lon Jc [oom Jw few, Js. Jo pealon fen Jc |room [vn [p-emorcan [so. Jo pesjen Jen lc r-om, Iw [3 emoy-cm so. Jo ceelon Jou lo [room [w laemor-ca so, Jo 2osjen Jen lc [r-om |v [o-tcmorcan so. Jo 266jcn Jon lc [v-om [8 [poa-cworeeam [so Jo poron fen Je Jroom [vn [3a-tcmoycam [so Jo seson [on Jc [room [sv [35-(emoca [so Jo 2esfon lou Jc Jrom Jw [3as-(emoican [so Jo poor Jon Jen Jw Jew, fem, se, lo erafon fou Jou Jw ear Jem Jso, |o oafon Jou en Jw few, few so, Jo 2sfen Jen ew [vn fom, o-temoy-cam [so, Jo 2reon fon Jon [n fear, [s-tewor-can so, Jo 2oslom low Jon lu og [a-mor-can [so Jo 276 lon lon fon wea [23-(emon-can so, Jo 2770cn Jon Jon [Jew [poa-tcmorcan [so Jo o7alon low Jon |w lea [s.4-(moican [so [0 27s fon lon Jon [vw lea [3.5-(cmoican [so Jo 280fcn [cn Jou [nome [3.4.5 cmoyi-ca [so Jo 2s1lon lon lon [sca feat, Jom, so, Jo 202lon Jon Jon [s-c1 fear, Jew, fs, Jo 203 feu Jon fou [sect Jom, Jew [so Jo 28elon loa loa [scr fear, [piemoicar [so Jo 28slcw Jen [on [scr Jom [s-(emoi-cm [so. Jo 2sslon Jon Jon [s-c1 Joa [a-(emor-cm [so [0 207)cu Jen fon [scr Jom, [23 (moncm [so lo oes lon fon Jon [s-c1 Jog [a-omoican [soo 289 leu Jon Jon [s-ci log [3.4-(omolcan [so [0 290 cn [cn [cu |s-ct ome [3.5-(cmorcan [so Jo 201 len [on Jou [scr ome [3,4,5-(cm0)-ca [so

EE I ET = PE = 2o3n Jou fou [us Jew, so, |o oan ow fen Ju Ju Jew, ~~ fso, Jo on er } cd Ca A

2oslu ow jou [ww Looicmor-cm Jso, Jo 2s6lw Jen low [x [8 [s-cmor-can [so, Jo 207 Jom Jou [x lv Jacmorcm so, Jo 2sely Jom Jou Jv [6 oa-omoricm so, Jo 2990 fon feu [o lw [aomoicm so Jo soln fen fon Jn fw Ts,acomoican so, Jo porn fen Jon fw fo lss(cmorcan [so Jo soon Jon fon |v fw s.a5-cmoican [so Jo soos Iw low [ww lew Jso, Jo salon Iw few Jw Jw ews Jso, Jo sosfon [w Jou Jw Jw Jew [so Jo sosfon Iw Jeu lw [6 loocmoy-cm so, Jo sorfon In Jen fn fw Tsocmor-cmn [so, Jo soslon [w fou [Jw lacmor-cam so, Jo sosfon [w Jeu lw fw os-cmorcm [so, Jo sofon [w few [uw Jw Jo.accmorcw so, Jo sion Iv Jon nw [3,a-cmodicm so, Jo sialon nv Jou [vw Jw lasocomovcm so, Jo sislon In Jon Jw Tw [3,45 cmojscoms [so Jo sieon Jen Iw [uw fw ew Tso, Jo sasfos Jon fw Jn Jw ews fs Jo

EEC EM PO = PN FA surfer Jeu Iv lo Jw Jo-cmor-ca [so Jo selon Jou Iv lm Jw [soemoj-can so, Jo soon Jon Iv Jn Jw loocmoy-ca [so Jo saofon Jon Iw |v Jw losicmorcan so, Jo sonon Joan Ju Jv loacmoca [so Jo s220cn Jou Iw Jw fw lsa-tcmoiecan so, [0 saslen Jon fw Jw lw [ssocmoyecan so, Jo baafon Jon Iw Ju Jw [sas-cmorican [so Jo

Analogously, in accordance with the general procedure E given below, it is possible to prepare the following compounds according to the invention (examples 325 to

Examples Nos. 325-654:

A, C, D, R, Rl, R6 and X have the meanings given in examples Nos. 1-324 given above, and Y is in each case

NH;

Examples Nos. 655-984:

N-CH;s;

Examples Nos. 985-1314:

N-CzHs;

Examples Nos. 1315-1644:

N-CgHs;

Examples Nos. 1645-1974:

N-2- (CH30) -CgHy;

Examples Nos. 1975-2304:

N-3- (CH30) -CgHy;;

Examples Nos. 2305-2634:

N-4- (CH30) -C¢Hy.

E) General procedure for preparing the 1,2,4- triazino[4,5-alindole derivatives according to the invention 2 equivalents corresponding to monosubstituted hydrazine derivative and glacial acetic acid (0.5 ml/mmol) were added to a suspension of 1 equivalent of the 2-acylindole prepared according to method A or B in n-butanol (10 ml/mmol), and the mixture was heated under reflux for 16 hours (monitored by TLC). After «cooling to room temperature, the reaction solution was poured into water (150 ml/mmol), the organic phase was separated off and the aqueous phase was extracted three times with ethyl acetate (10 ml/mmol). The combined organic phases were dried over magnesium sulfate, and the solvent was carefully removed using a rotary evaporator and the crude product was dissolved in tetrahydrofuran (7.5 ml/mmol) . 1.3 equivalents of N,N’-carbonyldiimidazole and then 2.1 equivalents of sodium hydride (75% strength dispersion in white oil) were added to this solution, and after 2 hours at room temperature, the mixture was heated under reflux for 48 hours. After cooling to room temperature, the reaction solution was poured into water (150 ml/mmol), the solid was isolated and the product was purified by column chromatography on silica gel under atmospheric pressure (mobile phase diethyl ether:hexane = 1.2).

Example E1 (D-70746):

Starting material A5: (4-Chlorophenyl)- (5-methoxy-1H- indol-2-yl)methanone

Reagent El: Phenylhydrazine pews bey! a 2-Phenyl-6-{4-chlorophenyl)-1,2,4-triazino[4,5-a) (5- methoxyindol) -3-one

M.p.: 155-158°C

F) General procedure for preparing the pyrrolo- [1,2-a]indole derivatives according to the invention

A little at a time, 1.1 equivalents of solid sodium hydride (60-75% dispersion in mineral oil) were added to a solution of 1 equivalent of the 2-acylindole prepared according to method A or B in N,N’'- dimethylformamide (10 ml/mmol), and after 5 minutes of stirring at room temperature, the mixture was heated at 90°C for one hour. The mixture was then cooled back to room temperature, 1.1 equivalents of the appropriately substituted phenylacyl halide were added dropwise and the mixture was once more heated at 90°C for three to eight hours (monitored by TLC). After cooling to room temperature, the reaction solution was poured into water (150 ml/mmol) and the precipitate formed was isolated and purified by column chromatography on silica gel under atmospheric pressure (mobile phase diethyl ether: hexane = 1:3).

Example F1 (D-80786):

Starting material A5: (4-Chlorophenyl)- (5-methoxy-1H- indol-2-yl)methanone eu es lo

CO

1-(4-Chlorophenyl) -6-methoxy-2-phenyl-3a-aza- cyclopentalalinden-3-one

M.p.: 152-155°C

Example F2 (Db-80815):

Starting material B6: (5-Methoxy-1H-indol-2-y1)- (3- methoxyphenyl)methanone a 0 7 0”

CD

6-Methoxy-1- (3-methoxyphenyl)-2-phenyl-3a-aza- cyclopental[a]inden-3-one

M.p.: 111-113°C

Example F3 (D-80816) :

AN

6-Methoxy-1, 2-bis(3-methoxyphenyl) -3a-aza- cyclopentala] inden-3-one

M.p.: 1l1l2-114¢°c¢C

Example F4 (D-80819):

Starting material Ad: (5-Methoxy-1H-indol-2-y1) - (4- methoxyphenyl)methanone fenUen ]

C0

F

2-(4-Fluorophenyl)-6-methoxy-1- (4-methoxyphenyl) -3a- azacyclopentalalinden-3-one

M.p.: 157-160°C

The following compounds according to the invention (examples Nos. 2635 to 3842) can be prepared according to synthesis procedure F above, starting from indole-2- carboxylic acid derivatives with different substituents:

Starting material: 4

A R1

CU

R

H

7 o]

Product: (n=0, Z=C-R8) 3 Ri i

R Cc | | RB 6 <p N

I

X

R8

Claims

Claims:

1. A compound of the formula I R2

Ro. oh R1 FN LA (0) AE I RS “ye n where R1 is hydrogen, (C6-Cl4)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents, (C1l-C1l3)-hetercaryl which contains at least one to four N, NH, O and/or S as ring members and is unsubstituted or fully or partially substituted by identical or different substituents, (C3-C8) -cycloalkyl which is unsubstituted or fully or partially substituted by identical or different substituents, or straight- chain or branched (C1-C20)-alkyl which is unsubstituted or fully or partially substituted by identical or different substituents; A, B, C or D independently of one another are a nitrogen atom or a carbon atom substituted by RZ2-R5; R2, R3, R4 and R5 independently of one another are a free electron pair (if binding partner A, B, C or D are a nitrogen atom), hydrogen, halogen, cyano, nitro, hydroxyl, straight-chain or branched (C1-C6)-alkyl, straight-chain or branched (C1-C6)- alkyl which is substituted by one or more halogen atoms, straight-chain or branched (Cl-C6)-alkoxy, straight-chain or branched (C1-C6)-alkoxy which is substituted by one or more halogen atoms, straight-chain or branched (C1l-C6) ~alkylenedioxy, (C1-C6) -alkylcarbonyloxy, (Cl-Cé6)-alkoxycarbonyl- oxy, (C1-C6)-alkylthio, (C1 C6) alkylsulfinyl, (C1-C6)-alkylsulfonyl, carboxyl, (Cl-C6)-alkyl carboxylate, carboxamide, N-(Cl-C6)-alkyl- carboxamide, N,N-di- (C1l-C6)-alkylcarboxamide, (C1l-C6)-alkoxy- (C1l-C6)-alkyl, amino, mono-(Cl-C6)- alkylamino, di-(Cl-C6)-alkylamino, where the two (C1-C6) radicals together may form a ring which optionally contains one or more NH, N-{(Cl-C6)- alkyl, O or §, {(C6-Cl14) ~aryl, (C6-Cl4) -aryloxy, (C6-Cl4)-aryl-(Cl-C6)~alkyl, (C6-Cld)-aryl- (C1-C6) ~alkoxy- (C1-C6)-alkyl, (C1-C6)-alkyl- carbonyl, (C1-C6)-alkoxycarbonyl, hydroxyl, where two directly adjacent radicals may be attached to one another; R6 is (C6-Cl4)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents, (C1-C13)-heteroaryl which contains at least one to four N, NH, O and/or S as ring members and is unsubstituted or fully or partially substituted by identical or different substituents, (C3-C8) -cycloalkyl which is unsubstituted or fully or partially substituted by identical or different substituents, straight- chain or branched (C1-C20)-alkyl which is unsubstituted or fully or partially substituted by identical or different substituents, where the identical or different substituents are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, (C1-C6)-alkyl, (Cl-C6)-alkoxy, carboxyl, (C1-C6) - alkyl which is substituted by one or more identical or different halogen atoms, (C1-C6) - alkoxy which is substituted by one or more identical or different halogen atoms, straight-

chain or branched (C2-C6)-alkenyl, straight-chain or branched (C2-C6)-alkynyl, (C3-C8) -cycloalkyl, straight-chain or branched (C1-C6) ~alkoxy, straight chain or branched (Cl-C6)-alkylenedioxy, (Cl-C6)-alkoxy-(Cl-C6)-alkyl, (C6-Cl4a) -aryl, (C6-Cl4)-aryl-(Cl-C6)-alkyl, (C6-Cl4) -aryl- (Cl-C4)-alkoxy-(C1l-C6)-alkyl; X is a carbonyl (C=0), sulfoxide (S=0) or sulfonyl (S03) group; Y is an oxygen atom or a nitrogen atom substituted by the radical R7 (NR7), where R7 is (C6-Cl4)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents, (C1-C13)- hetercaryl which contains at least one to four N, NH, O and/or S as ring members and is unsubstituted or fully or partially substituted by identical or different substituents, (C3-C8) -cycloalkyl which is unsubstituted or fully or partially substituted by identical or different substituents, straight-chain or branched (C1-C20)-alkyl which 1s unsubstituted or fully or partially substituted by identical or different substituents, where the identical or different substituents are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, (Cl-C6)- alkyl, (Cl-C6)-alkoxy, carboxyl, (C1l-C6) - alkyl which is substituted by one or more identical or different halogen atoms, (C1l-C6) ~alkoxy which is substituted by one or more identical or different halogen atoms, straight-chain or branched (C2-C6)-alkenyl,

straight-chain or branched (C2-C6)-alkynyl, (C3-C8) -cycloalkyl, straight-chain or branched (Cl1-C6)-alkoxy, straight-chain or branched (C1l-C6) alkylenedioxy, (C1-C8) - alkoxy-(C1-C6b)-alkyl, straight-chain or branched mono-(C1-C6)-~alkylamino, straight- chain or branched di- (C1-C6)-alkylamino where the two (Cl-C4)-radicals together may form a ring which optionally contains one or more NH, N-(Cl-C6)-alkyl, O or S, (C6-Cl4)-aryl, (C6-Cl4)-aryl- (Cl-C6)-alkyl, (C6-Cl4) -aryl- (C1-C4)-alkoxy-(Cl-C6)-alkyl, (C1-C6) ~ alkylcarbonyl, (Cl-C6)-alkoxycarbonyl; nn is 0 or 1, with the proviso that, if n = 0, Z is a carbon atom substituted by the radical RS (C-R8) where R8 is (C6-Cl4)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents, (C1-C13)- heteroaryl which contains at least one to four N, NH, O and/or S as ring members and is unsubstituted or fully or partially substituted by identical or different substituents, (C3-C8) -cycloalkyl which is unsubstituted or fully or partially substituted by identical or different substituents, straight-chain or branched (C1-C20)-alkyl which is unsubstituted or fully or partially substituted by identical or different substituents, where the identical or different substituents are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, (C1l-C6)- : alkyl, (C1-C6)-alkoxy, carboxyl, (C1-C6)-

alkyl which is substituted by one or more identical or different halogen atoms, (C1-C6)~-alkoxy which is substituted by one or more identical or different halogen atoms, straight-chain or branched (C2-C6)-alkenyl, straight-chain or branched (C2-C6)-alkynyl, (C3-C8)~cycloalkyl, straight-chain or branched (Cl1-C6)-alkoxy, straight-chain or branched (Cl-C6) -alkylenedioxy, straight- chain or branched (Cl-C6)-alkylthio, (Cl-C4)- alkylsulfinyl, (Cl-C4)-alkylsulfonyl, (C6-Cl4)-arylthio, (C6-Cl4) -arylsulfinyl, (C6-Cl4) -arylsulfonyl, (Cl-C6)-alkoxy- (C1l-C6)-alkyl, straight-chain or branched meno- (Cl-C6) -alkylamino, straight-chain or branched di-(Cl-Cé6)-alkylamino where the two (Cl1l-C4)-radicals together may form a ring which optionally contains one or more NH, N-(C1-C6)-alkyl, 0 or S, (C6-Cl4)-aryl, (C6-Cl4) -arvloxy, (C6-Cl4) -aryl-(Cl-C6)- alkyl, (C6-Cl4) -aryl-(Cl-C4)-alkoxy-(Cl-C6)~ alkyl, (Cl-C6)-alkylcarbonyl, (Cl-C6)- alkoxycarbonyl, straight-chain or branched mono-N- (C1-C6)-alkylcarbonylamino, straight- chain or branched di-N,N- (Cl1-C6) -alkyl- carbonylamino, straight-chain or branched mono-N- (C1l-C6) —alkoxycarbonylamino, straight- chain or branched di-N,N-(Cl-C6) ~ alkoxycarbonylamino, straight-chain or branched N- (C1l-C6)-alkylcarbonylamino-N- (Cl-C6)-alkylamino, straight-chain or branched N-(Cl-C6)-alkoxycarbonylamino-N-

(Cl-Cb)-alkylamino;

and that, if n = 1, Z is a nitrogen atom;

N Page 106 or a tautomer, a stereoisomer, a mixture or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1, characterized in that R1 is hydrogen, RZ, R3, R4 and R5 independently of one another are hydrogen, halogen or (C1-C6) -alkoxy, R6 is straight-chain or branched (C1-C20)-alkyl which is unsubstituted or fully or partially substituted by identical or different substituents or is (C6-Cl4)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents from the group consisting of (Cl-C6)-alkoxy and halogen, Y is an oxygen atom or the radical N-R7, where R7 is (C6-Cl4)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents, X is carbonyl (C=0), Zz is a nitrogen atom and nn = 1.

3. A compound as claimed in claim 1, characterized in that R1 is hydrogen, R2, R3, R4 and R5 independently of one another are hydrogen, halogen or (C1-Cb) -alkoxy, R6 is straight-chain or branched (C1-20)-alkyl which is unsubstituted or fully or partially substituted by identical or different substituents or is (C6-Cl4)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents from the group consisting of (Cl-C6)-alkoxy and halogen, n = 0, Z 1s the radical C-R8, where R8 is (C6-Cl4)- aryl which is unsubstituted or fully or partially substituted by identical or different substituents from the group consisting of (C1-C6)-alkoxy and halogen, and X ig carbonyl (C=0).

4. A compound as claimed in any of claims 1 to 3 for use as a medicament.

5. The use of a compound as claimed in any of claims 1 to 3 for controlling tumor disorders in mammals, in particular in man.

6. A medicament, comprising at least one compound as claimed in any of claims 1 to 3 together with pharmaceutically acceptable auxiliaries, diluents and/or carriers.

7. A method for preparing compounds of the formula I § a C R6 » (1) Ra” tue Fo RE X Z Y n in which A, B, C, D, R1, R2, R3, R4, R4, R5, X, Y, Z and n are as defined in claim 1, characterized in that b) the ketone of the formula R2 EN R1 Lo C R6 UY R5 R9 0 is reacted with aa) oxime or bb) hydrazine derivative H2N-NH-R7 where R7 is as defined in claim 1, and the resulting product is cyclized with an activated carbonyl, sulfoxide or sulfonyl derivative, or is reacted with cc) phenylacetic acid derivative X1-CO-CH2-R8, where X1 is a suitable leaving group, such as halogen or

&

(C1-C2)-~alkoxy, and R8 is as defined in claim 1, followed by cyclization in the presence of base.