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

Cyclic indole and heteroindole derivatives, the production and use thereof as medicaments. Download PDF

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Publication number
ZA200401290B
ZA200401290B ZA200401290A ZA200401290A ZA200401290B ZA 200401290 B ZA200401290 B ZA 200401290B ZA 200401290 A ZA200401290 A ZA 200401290A ZA 200401290 A ZA200401290 A ZA 200401290A ZA 200401290 B ZA200401290 B ZA 200401290B
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South Africa
Prior art keywords
branched
straight
chain
alkyl
alkoxy
Prior art date
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ZA200401290A
Inventor
Heinz Weinberger
Thomas Beckers
Mathias Schmidt
Silke Baasner
Bernd Nickel
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Zentaris Gmbh
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Priority claimed from DE10143079A external-priority patent/DE10143079A1/en
Application filed by Zentaris Gmbh filed Critical Zentaris Gmbh
Publication of ZA200401290B publication Critical patent/ZA200401290B/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D515/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D515/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/12Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D515/14Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

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
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.
According to a further aspect of the invention, compounds are provided which are characterized in that
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
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FETS I Er = TS
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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:
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
N-CH;s;
Examples Nos. 985-1314:
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
N-CzHs;
Examples Nos. 1315-1644:
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
N-CgHs;
Examples Nos. 1645-1974:
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
N-2- (CH30) -CgHy;
Examples Nos. 1975-2304:
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
N-3- (CH30) -CgHy;;
Examples Nos. 2305-2634:
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
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) :
Starting material B6: (5~-Methoxy-1H-indol-2-y1l) - (3- methoxyphenyl)methanone “Xr 0 7 o” © 0
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 (7)

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.
ZA200401290A 2001-09-03 2004-02-18 Cyclic indole and heteroindole derivatives, the production and use thereof as medicaments. ZA200401290B (en)

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