NZ531642A - 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

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Publication number
NZ531642A
NZ531642A NZ531642A NZ53164202A NZ531642A NZ 531642 A NZ531642 A NZ 531642A NZ 531642 A NZ531642 A NZ 531642A NZ 53164202 A NZ53164202 A NZ 53164202A NZ 531642 A NZ531642 A NZ 531642A
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New Zealand
Prior art keywords
branched
straight
chain
alkyl
ch3o
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NZ531642A
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 NZ531642A publication Critical patent/NZ531642A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic 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
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic 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
    • C07D471/12—Heterocyclic 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
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic 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
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic 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
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic 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
    • C07D515/02—Heterocyclic 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
    • C07D515/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic 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
    • C07D515/12—Heterocyclic 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
    • C07D515/14—Ortho-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)

Abstract

Substituted, annelated indole and heteroindole derivatives of formula (I), tautomers, stereoisomers, mixtures and pharmaceutically acceptable salts thereof and the production and use thereof as medicaments, in particular as anti-tumour agents in mammals, in particular humans is disclosed, wherein the substituents are as defined in the specification.

Description

New Zealand Paient Spedficaiion for Paient Number 531 642 531642 Cyclic indole and heteroindole derivatives, their preparation and their use as medicaments The invention relates to novel substituted indole and 5 heteroindole derivatives of the formula I 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-azacyclopenta[a]inden-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 R2 Page 2 where R1 is hydrogen, (C6-C14)-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, 0 and/or S as ring members and is unsubstituted or fully or 10 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 15 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 20 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, 25 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 (C1-C6)-alkoxy, straight-chain or branched (C1-C6)-alkoxy which is 30 substituted by one or more halogen atoms, straight-chain or branched (C1-C6)-alkylenedioxy, (C1-C6)-alkylcarbonyloxy, (C1-C6)-alkoxy- carbonyloxy, (C1-C6)-alkylthio, (C1-C6)- Page 3 alkylsulfinyl, (C1-C6)-alkylsulfonyl, carboxyl, (C1-C6)-alkyl carboxylate, carboxamide, N-(C1-C6)-alkylcarboxamide, N,N-di-(C1-C6)-alkyl- carboxamide, (C1-C6)-alkoxy-(C1-C6)-alkyl, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, where the two (C1-C6) radicals together may form a ring which optionally contains one or more NH, N- (C1-C6)-alkyl, 0 or S, (C6-C14)-aryl, (C6-C14)-aryloxy, (C6-C14)-aryl-(C1-C6)-alkyl, (C6-C14)-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; is (C6-C14)-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, 0 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, (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 (C1-C6)-alkoxy, straight-chain or branched (C1-C6)-alkylenedioxy, Page 4 (C1-C6)-alkoxy-(C1-C6)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl, (C6-C14)-aryl- (C1-C4)-alkoxy-(C1-C6)-alkyl; is a carbonyl (C=0), sulfoxide (S=0) or sulfonyl (S02) group; is an oxygen atom or a nitrogen atom substituted by the radical R7 (NR7), where R7 is (C6-C14)-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, 0 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, (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 (C1-C6)-alkoxy, straight-chain or branched (C1-C6)-alkylenedioxy, (C1-C6)- Page 5 alkoxy-(C1-C6)-alkyl, straight-chain or branched mono-(C1-C6)-alkylamino, straight-chain or branched di-(C1-C6)-alkylamino where the two (C1-C4)-radicals together may form a ring which optionally contains one or more NH, N-(C1-C6)-alkyl, O or S, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl, (C6-C14)-aryl-(C1-C4)-alkoxy-(C1-C6)-alkyl, (C1-C6)- alkylcarbonyl, (C1-C6)-alkoxycarbonyl; n is 0 or 1, with the proviso that, if n = 0, Z is a carbon atom substituted by the radical R8 (C-R8) where R8 is (C6-C14)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents, (C1-C13)- heteroaryl which contains at least one to 2 0 four N, NH, 0 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 25 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 30 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, (C1-C6)-35 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, II Page 6 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 5 branched (C1-C6)-alkylenedioxy, straight- chain or branched (C1-C6)-alkylthio, (C1-C4)-alkylsulfinyl, (C1-C4)-alkylsulfonyl, (C6-C14)-arylthio, (C6-C14)-arylsulfinyl, (C6-C14)-arylsulfonyl, (C1-C6)-alkoxy- (C1-C6)-alkyl, straight-chain or branched mono-(C1-C6)-alkylamino, straight-chain or branched di-(C1-C6)-alkylamino where the two (C1-C4)-radicals together may form a ring which optionally contains one or more NH, 15 N-(C1-C6)-alkyl, 0 or S, (C6-C14)-aryl, (C6-C14)-aryloxy, (C6-C14)-aryl-(C1-C6)- alkyl, (C6-C14)-aryl-(C1-C4)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)- alkoxycarbonyl, straight-chain or branched 20 mono-N-(C1-C6)-alkylcarbonylamino, straight- chain or branched di-N,N-(C1-C6)-alkylcarbonylamino, straight-chain or branched mono-N-(C1-C6)-alkoxycarbonylamino, straight-chain or branched di-N,N-(C1-C6)- 2 5 alkoxycarbonylamino, straight-chain or branched N-(C1-C6)-alkylcarbonylamino-N- (C1-C6)-alkylamino, straight-chain or branched N-(C1-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.
Page 7 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 (C1-C6)-alkoxy, R6 is 5 straight-chain or branched (C1-C20)-alkyl which is unsubstituted or fully or partially substituted by identical or different substituents or is (C6-C14)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents from 10 the group consisting of (C1-C6)-alkoxy and halogen, Y is an oxygen atom or the radical N-R7, where R7 is (C6-C14)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents, X is carbonyl (C=0), Z is a nitrogen atom 15 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 20 another are hydrogen, halogen or (C1-C6)-alkoxy, R6 is straight-chain or branched (Cl-20)-alkyl which is unsubstituted or fully or partially substituted by identical or different substituents or is (C6-C14)-aryl which is unsubstituted or fully or partially 25 substituted by identical or different substituents from the group consisting of (C1-C6)-alkoxy and halogen, n = 0, Z is the radical C-R8, where R8 is (C6-C14)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents from 30 the group consisting of (C1-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 35 provided for use as medicaments.
According to a further aspect of the invention, the use of one of the abovementioned compounds according to the Page 8 invention for controlling tumor disorders in mammals, in particular in man, is provided.
According to a further aspect of the invention, 5 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 .(I) in which A, B, C, D, Rl, 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 R2 R3^b^A I R4 VD R1 l R5 M R9 O R6 is reacted with aa) oxime or bb) hydrazine derivative H2N-NH-R7 where R7 is as defined in claim 1, and the 25 resulting product is cyclized with an activated carbonyl, sulfoxide or sulfonyl derivative, or is reacted with cc) phenylacetic acid derivative Xl-CO-CH2-R8, where XI is a suitable leaving group, such as Page 9 halogen or (C1-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 10 below: a) reaction of an indole or heteroindole compound provided, if appropriate, with a suitable nucleofugic leaving group E with organometallic 15 compounds: R2 rKb^A \ /R1 Vy R6—M R2 R3^ JL -R1 B R4" ^lj>' R5 R9 O R4' R5 R9 O in which Rl, R2, R3, R4, R5, R6, A, B, C and D are as defined at the outset, R9 is hydrogen, straight-chain or branched (C1-C6)-25 alkylcarbonyl which is unsubstituted or substituted by one or more halogen atoms, straight-chain or branched (C1-C6)-alkoxycarbonyl, substituted (C6-C14)-aryl-(CI)-alkyl, straight-chain or branched (C1-C6)-alkylsulfonyl or (C6-C14)-arylsulfonyl which is unsubstituted or 30 substituted by (C1-C6)-alkyl, E is OH, a halogen atom, for example a fluorine, chlorine or bromine atom, (C1-C6)-alkoxy, imidazole and Page 10 M is Li, Mg-RlO, where RIO 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 10 nucleofugic leaving groups, if appropriate with simultaneous or prior removal of the substituent R9 at the indole nitrogen atom: R2 I R3. ^ R4' Wr R5 R9 O R6 ,R8 R2 I R3^ B R1 R4' -D I R5 N I O R8 R6 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 i I R4 D A /R1 M- R5 O R6 R8 base R2 RTXiC "VrV R5 X Z R6 where Page 11 Rl, R2, R3, R4, R5, R6, R8, A, B, C, D and X are as defined at the outset and Z is a carbon atom substituted by a radical R8, for n = 1: b2) reaction of the 2-acylindole or heteroindole compounds with unsubstituted or substituted primary amino derivatives: where Rl, R2, R3, R4, R5, R6, R9, A, B, C, D and Y are as defined at the outset, Z is a nitrogen atom and RIO is hydrogen, straight-chain or branched (C1-C6)-alkyl, straight-chain or branched (C1-C6)-alkyl substituted by one or more halogen atoms, straight-20 chain or branched (C1-C6)-alkoxy substituted by one or more halogen atoms, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkylsulfinyl, (C1-C6)- alkylsulfonyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C6-C14)-25 aryl, (C6-C14)-aryl-(C1-C6)-alkyl, (C6-C14)-aryl- (C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl; c2) reaction of the indole or heteroindole compounds 30 with a reagent having suitable nucleofugic leaving groups, if appropriate with simultaneous or prior removal of the substituent R9 at the indole nitrogen atom: Page 12 R2 R3^\ /R1 --S-Vy" Rir R12 R5 R9 Z^/R10 R2 R1 f R4 S—/' rMr" R5 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 RIO i"s a hydrogen atom, and Rll and R12 independently of one another are nucleofugic leaving groups, such as a halogen atom, for example a chlorine, bromine or iodine atom, (C1-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 in which Rl, R2, R3, R4, R5, R9, A, B, C and D are as defined at 2 5 the outset, with Grignard reagents, reacting the indole or heteroindole derivatives of the formula III Page 13 in which Rl, R2, R3, R4, R5, R6, R9, A, B, C and D are as 5 defined at the outset, with hydroxylamine, cyclizing the indole or heteroindole derivatives of the formula IV . (IV) 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 15 indole or heteroindole derivatives of the formula V and cyclizing the indole or heteroindole derivatives of the abovementioned formula III in which Page 14 Rl, R2, R3, R4, R5, R6, A, B, C and D are as defined at the outset and R9 is a hydrogen atom, with unsubstituted or substituted phenylacetyl halides in the presence of, for example, sodium hydride as base, 5 to give the indole or heteroindole derivatives of the formula VI.
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 15 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-Miiller, Methoden der organischen Chemie [Methods of 20 organic chemistry] and in Ullmanns Encyklopadie der technischen Chemie [Ullmann's Encyclopedia of Technical Chemistry].
Furthermore, the resulting compounds of the formula I 25 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 30 least 2 asymmetric carbon atoms can, owing to their physicochemical differences, be separated by methods known per se, for example by chromatography and/or R2 ,R1 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, 10 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 15 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 20 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 25 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, 30 cyclohexylamine, enthanolamine, diethanolamine and triethanolamine.
Below, the invention is illustrated in more detail by examples; however, the invention is not limited to 35 these examples.
General procedures for preparing the 2-acylindoles according to the invention.
Page 16 Method A) Isolation of the imidazol-l-yl(lff-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 10 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 22 0 ml of tetrahydrofuran:hexane = 15 3:2. This gave imidazol-l-yl-(5-methoxy-lff-indol-2-yl)methanone as an orange-brown solid.
M.p.: >300 (decomp.) At 0°C, 2.2 equivalents of the organometallic compound were added dropwise to a solution of 1 equivalent of imidazol-l-yl-(5-methoxy-lH-indol-2-yl)methanone in tetrahydrofuran (3 ml/mmol) such that the internal 25 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 30 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 Page 17 evaporator and the residue was crystallized from alcohol.
Example Al: Reagent Al: Methylmagnesium chloride, 3.0 M solution in tetrahydrofuran 1-(5-Methoxy-lH-indol-2-yl)ethanone M.p.: 164-167°C (2-propanol) Example A2: Reagent A2: Pheny lmagnesium bromide, 3.0 M solution in diethyl ether (5-Methoxy-IH-indol-2-y1)phenylmethanone M.p.: 164-166°C (n-butanol) Example A3: Reagent A3: 3-Methoxyphenylmagnesium bromide, 1.0 M solution in tetrahydrofuran o o o Page 18 (5-Methoxy-lH-indol-2-yl)-(3-methoxyphenyl)methanone M.p.: 143-145°C (n-butanol) Example A4: Reagent A4: 4-Methoxyphenylmagnesiumbromide, 0.5 M solution in tetrahydrofuran (5-Methoxy-lH-indol-2-yl)-(4-methoxyphenyl)methanone M.p.: 155-158°C (n-butanol) Example A5: Reagent A5: 4-Chlorophenylmagnesium bromide, 1.0 M solution in diethyl ether CI o (4-Chlorophenyl)-(5-methoxy-lH-indol-2-yl)methanone M.p.: 190-192°C (n-butanol) Example A6: Reagent A6 : 2-Thienyllithium, tetrahydrofuran 1.0 M solution in Page 19 s 1 o (5-Methoxy-IH-indol-2-y1)thiophen-2-ylmethanone M.p.: 152-154°C (n-butanol) Method B) One-pot variant: Synthesis of the imidazol-l-yl (lff-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 15 tetrahydrofuran (2 ml/mmol) , over a period of 20 minutes. After a further 60 minutes of stirring, the reaction solution was cooled to 0°C, and 3.5 equivalents of the organometallic compound were added dropwise such that the internal temperature did 2 0 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 25 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 30 evaporator and the residue was crystallized from alcohol.
Example Bl: Starting material: Indole-2-carboxylic acid Page 2 0 Reagent B1: 2-Methoxyphenylmagnesium bromide, 1.0 M solution in tetrahydrofuran (lH-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 (lff-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 O O 1-(5-Methoxy-lH-indol-2-yl)ethanone Page 21 M.p.: 164-167°C (2-propanol) Example B4: Starting material: 5-Methoxyindole-2-carboxylic acid 5 Reagent B4: Ethylmagnesium chloride, 3.0 M solution in tetrahydrofuran 1-(5-Methoxy-lH-indol-2-yl)propan-l-one M.p.: 173-175°C (2-propanol) Example B5: Starting material: 5-Methoxyindole-2-carboxylic acid 15 Reagent A2: Pheny lmagnesiumbromide, 3.0 M solution in diethyl ether (5-Methoxy-lH-indol-2-yl)phenylmethanone M.p.: 164-166°C (n-butanol) Example B6: Starting material: 5-Methoxyindole-2-carboxylic acid 25 Reagent A3: 3-Methoxyphenylmagnesium bromide, 1.0 M solution in tetrahydrofuran Page 22 (5-Methoxy-lH-indol-2-yl)-(3-methoxyphenyl)methanone M.p.: 143-145°C (n-butanol) General procedure for preparing the oxadiaza 5 derivatives according to the invention Method C) Preparation, isolation and purification of the indol-2-yloximes and subsequent reaction with N,N'-carbonyldiimidazole CI) 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 15 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 2 0 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 25 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 30 reacted further according to C2 (method D).
Page 23 Example CI.1 (D-81687): Starting material Al: 1-(5-Methoxy-lH-indol-2-yl)ethanone 1-(5-Methoxy-lff-indol-2-yl)ethanone oxime M.p.: 148-150°C (2-propanol) Example CI.2 (D-81690) Starting material yl)propan-l-one .O B4 : 1-(5-Methoxy-IH-indol-2- 1-(5-Methoxy-lH-indol-2-yl)propan-l-one oxime M.p.: 163-165°C (2-propanol) Example CI.3 (D-70258): Starting material A2 : (5-Methoxy-lH-indol-2-yl)phenyl-methanone (5-Methoxy-1H-indol-2-yl)phenylmethanone oxime 20 M.p.: 150-152°C (2-propanol:water = 2:3) Example CI.4 (D-70745): Starting material A5: (4-Chlorophenyl)-(S-methoxy-lH-indol^-yl) methanone Page 24 CI OH (4-Chlorophenyl) - (5-methoxy-lif-indol-2-yl)methanone oxime Crude product (purity by HPLC: 81%) C2) Reaction of the lH-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 lff-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 CI.1: 1-(5-Methoxy-lH-indol-2-yl)ethanone oxime 3-Methyl-l,2,5-oxadiazino[4,5-a](5-methoxyindol)-6-one Page 25 M.p.: 217-220°C (2-propanol) Example C2.2 (D-81691): Starting material CI.2: 1-(5-Methoxy-lff-indo1-2-5 yl)propan-l-one oxime 3-Ethyl-l,2,5-oxadiazino[4,5-a](5-methoxyindol)-6-one M.p.: 208-212°C (n-butanol) Example C2.3 (D-70260): Starting material CI. 3: (5-Methoxy-lff-indol-2-yl)phenylmethanone oxime 3-Phenyl-l,2,5-oxadiazino[4,5-a](5-methoxyindol)-6-one 15 M.p.: 198-200°C (n-butanol) Method D) Direct reaction of the lH-indol-2-ylmethanone oximes prepared with N, N'-carbonyldiimidazole The following oxadiaza derivatives were synthesized 20 according to procedure CI but without purification reacted further according to C2.
Example Dl (D-81362): Starting material Bl: (1H-Indol-2-yl)-(2- methoxyphenyl)methanone Page 2 6 3-(2-Methoxyphenyl)-1,2,5-oxadiazino[4,5-a]indol-6-one M.p.: 160-162°C (column chromatography) Example D2 (D-81361): 3-(3-Methoxyphenyl)-1,2,5-oxadiazino[4,5-a]indol-6-one M.p. : 129-130°C (column chromatography) Example D3 (D-81462): Starting material A3: (5-Methoxy-lff-indol-2-yl) - (3-methoxyphenyl)methanone Starting material methoxyphenyl)methanone B2 : (Iff-Indol-2-yl) - (3- J II o*VN 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 A5: (4-Chlorophenyl)-(5-methoxy-lH-indol-2-yl)methanone Page 2 7 CI I 11 Page 38 E) General procedure for preparing the 1,2,4-triazino[4,5-a]indole 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 10 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 15 (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 20 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 25 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 El (D-70746): Starting material A5: (4-Chlorophenyl)-(5-methoxy-lH-indol-2-yl)methanone Reagent El: Phenylhydrazine Page 39 2-Phenyl-6-(4-chlorophenyl)-1,2,4-triazino[4,5-a](5-methoxyindol)-3-one 5 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'-15 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 2 0 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 25 silica gel under atmospheric pressure (mobile phase diethyl ether: hexane = 1:3).
Example Fl (D-80786): Starting material A5: (4-Chlorophenyl)-(5-methoxy-lH-30 indol-2-yl)methanone Page 40 CI 1-(4-Chlorophenyl)-6-methoxy-2-phenyl-3a-aza-cyclopenta[a]inden-3-one M.p.: 152-155°C Example F2 (D-80815): Starting material B6: (5-Methoxy-lH-indol-2-yl)-(3 methoxyphenyl)methanone 6-Methoxy-l-(3-methoxyphenyl)-2-phenyl-3a-aza-cyclopenta[a]inden-3-one M.p.: 111-113 ° C Example F3 (D-80816): Starting material B6: (5-Methoxy-lH-indol-2-yl)-(3 methoxyphenyl)methanone 6-Methoxy-l,2-bis(3-methoxyphenyl)-3a-aza-cyclopenta[a]inden-3-one M.p.: 112-114°C Page 41 Example F4 (D-80819): Starting material A4: (5-Methoxy-l.Ff-indol-2-yl) - (4-methoxyphenyl)methanone F 2-(4-Fluorophenyl)-6-methoxy-l-{4-methoxyphenyl)-3a-azacyclopenta[a]inden-3-one M.p.: 157-160°C The following compounds according to the invention 10 (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 Product: (n=0, Z=C-R8) R8 Page 42 no. a c d r Rl r6 r8 x 2635 ch ch ch h h ch3 ch3 c(o) 2636 ch ch ch h h ch3 c2h5 c(o) 2637 ch ch ch h h ch3 c6h5 c(o) 2638 ch ch ch h h ch3 2- (ch30) -c5h4 c(o) 2639 ch ch ch h h ch3 3- (ch30) -c6h4 c(o) 2640 ch ch ch h h ch3 4- (ch30) -c6h4 c(o) 2641 ch ch ch h h ch3 2,3-(ch30)2-c6h3 c(o) 2642 ch ch ch h h ch3 2,4- (ch30) 2-c6h3 c(o) 2643 ch ch ch h h ch3 3 , 4- (ch30) 2-c6h3 c(o) 2644 ch ch ch h h ch3 3 , 5- (ch30) 2~c6h3 c(o) 2645 ch ch ch h h ch3 3,4,5- (ch30) 3-c6h2 c(o) 2646 ch ch ch h h c2h5 ch3 c(o) 2647 ch ch ch h h c2h5 c2h5 c(o) 2648 ch ch ch h h c2h5 c6h5 c(o) 2649 ch ch ch h h c2h5 2- (ch30) -c6h4 c(o) 2650 ch ch ch h h c2h5 3-(ch30)-c6h4 c(o) 2651 ch ch ch h h c2h5 4- (ch30) -c6h4 c(o) 2652 ch ch ch h h c2h5 2,3- (ch30)2-c6h3 c(o) 2653 ch ch ch h h c2h5 2,4- (ch30)2-c6h3 c(o) 2654 ch ch ch h h c2h5 3,4 - (ch30) 2-c6h3 c(o) 2655 ch ch ch h h c2h5 3,5- (ch30) 2-c6h3 c(o) 2656 ch ch ch h h c2h5 3,4,5- (ch30) 3-c6h2 c( 0) 2657 ch ch ch h h c6h5 ch3 c(o) 2658 ch ch ch h h c6h5 c2h5 c(o) 2659 ch ch ch h h c6h5 c6h5 c(o) 2660 ch ch ch h h c6h5 2- (ch30) -c6h4 c( 0) 2661 ch ch ch h h c6h5 3- (ch30) -c6h4 c(o) 2662 ch ch ch h h c6h5 4- (ch30) -c6h4 c( 0) 2663 ch ch ch h h c6h5 2,3- (ch30)2-c6h3 c(0) 2664 ch ch ch h h c6h5 2,4- (ch30)2-c6h3 c(o) 2665 ch ch ch h h c5h5 3,4- (ch30)2-c6h3 c(o) 2666 ch ch ch h h c6h5 3,5- (ch30)2-c6h3 c(0) 2667 ch ch ch h h c6h5 3,4,5- (ch30) 3-c6h2 c(0) 2668 ch ch ch h h 2- (ch30) -c6h4 ch3 c(o) 2669 ch ch ch h h 2- 2-c6h3 c(o) 2798 c ch ch 4- c6h5o h 2- (ch30)-c6h4 3,5- (ch30)2-c6h3 c(o) 2799 c ch ch 4- c6h5o h 2- (ch30) -c6h4 3,4,5- (ch30)3-c6h2 c(o) 2800 c ch ch 4- c6h5o h 3- (ch30) -c6h4 ch3 c(o) 2801 c ch ch 4- cgh5o h 3- (ch30) -c6h4 c2h5 c(o) 2802 c ch ch 4- c6h5o h 3- (ch30) -c6h4 c6h5 c(o) 2803 c ch ch 4- c6h5o h 3- (ch30) -c6h4 2- (ch30) -c6h4 c(o) 2804 c ch ch 4- c6h5o h 3- (ch30) -c6h4 3- (ch30) -c6h4 c(o) 2805 c ch ch 4- c6h5o h 3- (ch30) -c6h4 4- (ch30) -csh4 c(o) 2806 c ch ch 4- c6h5o h 3- (ch30) -c6h4 2,3- (ch30)2-c6h3 c(o) 2807 c ch ch 4- c6h5o h 3- (ch30) -c6h4 2,4- (ch30)2-c6h3 c(o) 2808 c ch ch 4- c6h5o h 3- (ch30) -c6h4 3,4- (ch30) 2-c6h3 c(o) 2809 c ch ch 4- c6h5o h 3- (ch30) -c6h4 3 , 5- (ch30) 2-c6h3 c(o) 2810 c ch ch 4- c6h5o h 3- (ch30)-c6h4 3,4,5- (ch30) 3-c6h2 c(o) Page 50 2811 c ch ch 4- c6h5o h 4-(ch30)-c6h4 ch3 c(o) 2812 c ch ch 4- c6h5o h 4- (ch30) -c6h4 c2h5 c(o) 2813 c ch ch 4- c5h5o h 4- (CH3O) -c6h4 c6h5 c(o) 2814 c ch ch 4- c6h5o h 4- (CH3O) -c6h4 2- (CH3O) -c6h4 c(o) 2815 c ch ch 4- c6h5o h 4- (CH3O) -c6h4 3- (CH3O) -c6h4 c(o) 2816 c ch ch 4- c6h5o h 4- (CH3O) -c6h4 4- (CH3O) -c6h4 c(o) 2817 c ch ch 4- c6h5o h 4- (ch30)-c6h4 2,3- (CH3O) 2-c6h3 c(o) 2818 c ch ch 4- c6h5o h 4- (CH3O) -c6h4 2,4- (ch30)2-c6h3 c(o) 2819 c ch ch 4- c6h5o h 4- (ch30)-c6h4 3,4- (ch30)2-c6h3 c(o) 2820 c ch ch 4- c6h5o h 4-(ch30)-c6h4 3,5-(ch30)2-c6h3 c(o) 2821 c ch ch 4- c6h5o h 4- (CH3O) -c6h4 3,4,5-(ch30)3-c6h2 c(o) 2822 c ch ch 4- c6h5o h 2,3-(ch30)2- c6h3 ch3 c(o) 2823 c ch ch 4- c6h5o h 2,3- (ch30)2- c6h3 c2h5 c(o) 2824 c ch ch 4- c6h5o h 2,3- (ch30)2- c6h3 c6h5 c(o) 2825 c ch ch 4- c6h5o h 2,3-(ch30)2-c6h3 2- (CH3O) -c5h4 c(o) 2826 c ch ch 4- c6h5o h 2,3-(ch30)2- c6h3 3- (ch30) -c6h4 c(o) 2827 c ch ch 4- c6h5o h 2,3- (ch30)2- c6h3 4- (ch30) -c6h4 c(o) 2828 c ch ch 4- c6h5o h 2,3-(ch30)2- c6h3 2,3- (ch30)2-c6h3 c(o) Page 51 2829 c ch ch 4- c6h5o h 2,3- (ch30) 2- c6h3 2,4- (CH3O) 2-c6h3 c(o) 2830 c ch ch 4- c6h5o h 2,3- (ch30) 2- c6h3 3,4- (ch30)2-c6h3 c(o) 2831 c ch ch 4- c6h50 h 2,3- (CH3O) 2- c6h3 3,5- (CH3O) 2-c6h3 c(o) 2832 c ch ch 4- c6h50 h 2,3 - (ch30) 2- c6h3 3,4,5- (ch30) 3-c6h2 c(o) 2833 c ch ch 4- c6h5o h 2,4-(ch30)2- c6h3 ch3 c(o) 2834 c ch ch 4- c6h50 h 2 , 4-(ch30) 2-c6h3 c2h5 c(o) 2835 c ch ch 4- c6h50 h 2,4- (ch30)2- c6h3 c6h5 c(o) 2836 c ch ch 4- c6h50 h 2 , 4- (ch30) 2~ c6h3 2- (ch30) -c6h4 c(o) 2837 c ch ch 4- c6H5o h 2,4-(ch30)2- c6h3 3- (ch30) -c6h4 c(o) 2838 c ch ch 4- c6h50 h 2 , 4-(ch30) 2- c6h3 4-(ch30)-c6h4 c(o) 2839 c ch ch 4- c6h50 h 2 , 4-(ch30)2- c6h3 2,3- (CH3O) 2~c6h3 c(o) 2840 c ch ch 4- c6h50 h 2,4-(ch30)2-c6h3 2,4 - (ch30) 2-c6h3 c(o) 2841 c ch ch 4- c6h5o h 2,4-(ch30)2-c6h3 3,4-(ch30)2-c6h3 c(o) 2842 c ch ch 4- c5h5o h 2,4-(ch30)2-c6h3 3,5- (ch30) 2-c6h3 c(o) 2843 c ch ch 4- c6h5o h 2,4- (ch30) 2~ c6h3 3,4,5-(ch30)3-c6h2 c(o) 2844 c ch ch 4- c6h5o h 3 , 4-(ch30) 2-c6h3 ch3 c(o) 2845 c ch ch 4- c6h5o h 3,4-(ch30)2-c6h3 c2h5 c(o) 2846 c ch ch 4- c6h5o h 3,4- (ch30) 2~ c6h3 c6h5 c(o) Page 52 2847 c ch ch 4- c6h5o h 3,4-(ch30)2- c6h3 2- (ch30) -c6h4 c(o) 2848 c ch ch 4- c6h5o h 3,4-(ch30)2- c6h3 3- (ch30) -c6h4 c(o) 2849 c ch ch 4- c6h5o h 3,4-(ch30)2- c6h3 4- (ch30) -c6h4 c(o) 2850 c ch ch 4- c6h5o h 3,4-(ch30)2- c6h3 2,3- (ch30) 2-c6h3 c(o) 2851 c ch ch 4- c6h5o h 3 , 4-(ch30)2~ c6h3 2,4-(ch30)2-c6h3 c(o) 2852 c ch ch 4- c6h5o h 3,4-(ch30)2- c6h3 3,4-(ch30)2-c6h3 c(o) 2853 c ch ch 4- c6h5o h 3,4-(ch30)2- c6h3 3 , 5- (ch30) 2-c6h3 c(o) 2854 c ch ch 4- c5h5o h 3,4-(ch30)2- c6h3 3,4,5- (ch30) 3-c6h2 c(o) 2855 c ch ch 4- c6h5o h 3,5-(ch30)2-c6h3 ch3 c(o) 2856 c ch ch 4- c6h5o h 3 , 5-(ch30) 2- c6h3 c2h5 c(o) 2857 c ch ch 4- c6h5o h 3,5-(ch30)2-c6h3 c6h5 c(o) 2858 c ch ch 4- c6h5o h 3 , 5-(ch30)2-c6h3 2- (ch30) -c6h4 c(o) 2859 c ch ch 4- c6h5o h 3,5-(ch30)2-c6h3 3- (ch30) -c6h4 c(o) 2860 c ch ch 4- c6h5o h 3,5-(ch30)2-c6h3 4- (ch30) -c6h4 c(o) 2861 c ch ch 4- c6h5o h 3,5- (ch30)2-c6h3 2,3- (ch30) 2"c6h3 c(o) 2862 c ch ch 4- c6h5o h 3,5-(ch30)2-c6h3 2 , 4- (ch30) 2-c6h3 c(o) 2863 c ch ch 4- c6h5o h 3,5- (ch30)2-c6h3 3 , 4 - (ch30) 2-c6h3 c(o) 2864 c ch ch 4- c6h5o h 3,5- (ch30)2-c6h3 3 , 5- (ch30) 2-c6h3 c(o) Page 53 2865 c ch ch 4- c6h5o h 3,5-(ch30)2- c6h3 3,4,5- (ch30) 3-c6h2 c(o) 2866 c ch ch 4- c6h5o h 3,4,5- (CH3O) 3- c6h2 ch3 c(o) 2867 c ch ch 4- c6h5o h 3,4,5- (ch30) 3- c6h2 c2h5 c(o) 2868 c ch ch 4- c6h5o h 3,4,5- (CH3O) 3- c6h2 c6h5 c(o) 2869 c ch ch 4- c6h5o h 3,4,5- (ch30) 3- c6h2 2- (CH3O) -c5h4 c(o) 2870 c ch ch 4- c6h5o h 3,4,5- (CH3O) 3- c6h2 3- (CH3O) -c6h4 c(o) 2871 c ch ch 4- c6h5o h 3,4,5- (ch30)3-c6h2 4- (ch30) -c6h4 c(o) 2872 c ch ch 4- c6h5o h 3,4,5- (ch30)3- c6h2 2,3- (ch30)2-c6h3 c(o) 2873 c ch ch 4- c6h50 h 3,4,5- (ch30) 3-c6h2 2,4- (ch30)2-c6h3 c(o) 2874 c ch ch 4- c6h5o h 3,4,5- (ch30) 3- c6h2 3,4- (ch30)2-c6h3 c(o) 2875 c ch ch 4- c6h5o h 3,4,5- (ch30) 3- c6h2 3,5- (ch30)2-c6h3 c(o) 2876 c ch ch 4- c6h5o h 3,4,5- (ch30)3- c6h2 3,4,5- (ch30)3-c6h2 c(o) 2877 ch ch ch -ch30 h ch3 ch3 c(o) 2878 ch ch ch -CH3O h ch3 c2h5 c(o) 2879 ch ch ch -CH3O h ch3 c6h5 c(o) 2880 ch ch ch -CH3O h ch3 2- (ch30) -c6h4 c(o) 2881 ch ch ch -CH3O h ch3 3- (ch30) -c6h4 c(o) 2882 ch ch ch -CH3O h ch3 4- (ch30) -c6h4 c(o) 2883 ch ch ch -CH3O h ch3 2,3- (ch30)2-c6h3 c(o) 2884 ch ch ch -CH3O h ch3 2,4- (ch30)2-c6h3 c(o) 2885 ch ch ch -CH3O h ch3 3,4- (ch30)2-c6h3 c(o) 2886 ch ch ch -CH3O h ch3 3,5-(ch30)2-c6h3 c(o) 2887 ch ch ch -chjo h ch3 3,4,5- (ch30)3-c6h2 c(o) 2888 ch ch ch -CH3O h C2H5 ch3 c(o) Page 54 2889 ch ch ch -ch30 h c2h5 c2h5 c(o) 2890 ch ch ch -CH3O h c2h5 c6h5 c(o) 2891 ch ch ch -CH3O h c2h5 2- (CH3O) -c6h4 c(o) 2892 ch ch ch -CH3O h c2h5 3- (CH3O) -c6h4 c(o) 2893 ch ch ch -CH3O h c2h5 4- (CH3O) -c6h4 c(o) 2894 ch ch ch -CH3O h c2h5 2,3- (ch30)2-c6h3 c(o) 2895 ch ch ch -CH3O h c2h5 2,4- (ch30)2-c6h3 c(o) 2896 ch ch ch -CH3O h C2H5 3,4- (ch30)2-c6h3 c(o) 2897 ch ch ch -CH3O h c2h5 3 , 5- (CH3O) 2-c6h3 c(o) 2898 ch ch ch -CH3O h c2h5 3,4,5- (ch30)3-c6h2 c(o) 2899 ch ch ch -CH3O h c6h5 ch3 c(o) 2900 ch ch ch -CH3O h c6h5 c2h5 c(o) 2901 ch ch ch -CH3O h c6h5 c6h5 c(o) 2902 ch ch ch -CH3O h c6h5 2- (CH3O) -c6h4 c(o) 2903 ch ch ch -CH3O h c6h5 3- (CH3O) -c6h4 c(o) 2904 ch ch ch -CH3O h c6h5 4- (ch30)-c6h4 c(o) 2905 ch ch ch -CH3O h c6h5 2,3- (CH3O) 2-c6h3 c(o) 2906 ch ch ch -CH3O h c6h5 2 , 4- (CH3O) 2-c5h3 c(o) 2907 ch ch ch -CH3O h c6h5 3 , 4- (ch30) 2-c6h3 c(o) 2908 ch ch ch -CH3O h c6h5 3,5-(ch30)2-c6h3 c(o) 2909 ch ch ch -CH3O h c6h5 3,4,5- (ch30)3-c6h2 c(o) 2910 ch ch ch -CH3O h 2- (CH3O) -c6h4 ch3 c(o) 2911 ch ch ch -CH3O h 2- (CH3O) -c6h4 c2h5 c(o) 2912 ch ch ch -CH3O h 2- (CH3O) -c6h4 c6h5 c(o) 2913 ch ch ch -CH3O h 2- (CH3O) -c6h4 2- (ch30) -c6h4 c(o) 2914 ch ch ch -ch30 h 2- (CH3O) -c6h4 3- (ch30) -c6h4 c(o) 2915 ch ch ch -CH3O h 2- (CH3O) -c6h4 4-(ch30)-c6h4 c(o) 2916 ch ch ch -CH3O h 2- (CH3O) -c6h4 2,3- (ch30)2-c6h3 c(o) 2917 ch ch ch -CH3O h 2- (CH3O) -c6h4 2,4-(CH30)2-cgh3 c(o) 2918 ch ch ch -CH3O h 2- (CH3O) -c6h4 3,4- (ch30)2-c6h3 c(o) 2919 ch ch ch -CH3O h 2- (CH3O) -c6h4 3,5-(ch30)2-c6h3 c(o) 2920 ch ch ch -CH3O h 2- (CH3O) -c6h4 3,4,5- (CH3O) 3-c6h2 c(o) 2921 ch ch ch -CH3O h 3- (ch30)-c6h4 ch3 c(o) 2922 ch ch ch -CH3O h 3- (ch30)-c6h4 c2h5 c(o) 2923 ch ch ch -CH3O h 3- (CH3O) -c6h4 2- (ch30)-c6h4 c(o) 2924 ch ch ch -CH3O h 3- (CH3O) -c6h4 4- (CH3O) -c6h4 c(o) Page 55 2925 ch ch ch -ch30 h 3- (CH3O) -c6h4 2,3- (CH3O) 2-c6h3 c(o) 2926 ch ch ch -CH3O h 3- (CH3O) -c6h4 2,4- (ch30)2-c6h3 c(o) 2927 ch ch ch -CH3O h 3- (CH3O) -c6h4 3,4- (ch30)2-c6h3 c(o) 2928 ch ch ch -CH3O h 3- (CH3O) -c6h4 3,5- (ch30)2-c6h3 c(o) 2929 ch ch ch -CH3O h 3- (CH3O) -c6h4 3,4,5- (ch30)3-c5h2 c(o) 2930 ch ch ch -CH3O h 4- (ch30)-c6h4 ch3 c(o) 2931 ch ch ch -CH3O h 4- (ch30)-c6h4 c2h5 c(o) 2932 ch ch ch -CH3O h 4- (ch30) -c6h4 c6h5 c(o) 2933 ch ch ch -CH3O h 4- (CH3O) -c6h4 2-(ch30)-c6h4 c(o) 2934 ch ch ch -CH3O h 4- (ch30) -c6h4 3-(ch30)-c6h4 c(o) 2935 ch ch ch -CH3O h 4- (CH3O) -c6h4 4- (ch30) -c6h4 c(o) 2936 ch ch ch -CH3O h 4- (ch30)-c6h4 2,3- (CH3O) 2-c6h3 c(o) 2937 ch ch ch -CH3O h 4- (ch30)-c6h4 2,4- (ch30)2-c6h3 c(o) 2938 ch ch ch -CH3O h 4- (ch30) -c6h4 3,4- (ch30)2-c6h3 c(o) 2939 ch ch ch -CH3O h 4- (ch30)-c6h4 3,5- (CH3O) 2-c6h3 c(o) 2940 ch ch ch -CH3O h 4- (ch30)-c6h4 3,4,5- (ch30)3-c6h2 c(o) 2941 ch ch ch -CH3O h 2,3-(ch30)2-c6h3 ch3 c(o) 2942 ch ch ch -CH3O h 2,3- (ch30)2- c6h3 c2h5 c(o) 2943 ch ch ch -CH3O h 2,3-(ch30)2- c6h3 c6h5 c(o) 2944 ch ch ch -CH3O h 2,3- (ch30)2- c6h3 2- (ch30) -c6h4 c(o) 2945 ch ch ch -CH3O h 2,3- (ch30)2- c6h3 3-(ch30)-c6h4 c(o) 2946 ch ch ch -CH3O h 2,3- (ch30)2- c6h3 4- (ch30) -c6h4 c(o) 2947 ch ch ch -CH3O h 2,3- (ch30) 2-c6h3 2,3- (ch30)2-c6h3 c(o) 2948 ch ch ch -CH3O h 2,3-(ch30)2- c6h3 2,4- (ch30)2-c6h3 c(o) 2949 ch ch ch -CH3O h 2,3- (CH3O) 2~ c6h3 3 , 4- (ch30) 2-c6h3 c(o) 2950 ch ch ch -CH3O h 2,3- (ch30)2- c6h3 3 , 5- (ch30) 2-c6h3 c(o) Page 56 2951 ch ch ch -ch30 h 2,3-(ch30)2- c6h3 3,4,5- (ch30)3-c6h2 c(o) 2952 ch ch ch -CH3O h 2,4-(ch30)2- c6h3 ch3 c(o) 2953 ch ch ch -CH3O h 2,4-(ch30)2- c6h3 c2h5 c(o) 2954 ch ch ch -CH3O h 2,4-(ch30)2- c6h3 c6h5 c(o) 2955 ch ch ch -CH3O h 2 , 4- (CH3O) 2- c6h3 2- (CH3O) -c6h4 c(o) 2956 ch ch ch -CH3O h 2,4-(ch30)2- c6h3 3- (ch30)-c6h4 c(o) 2957 ch ch ch -CH3O h 2,4-(ch30)2- c6h3 4- (CH3O) -c6h4 c(o) 2958 ch ch ch -CH3O h 2,4-(ch30)2- c6h3 2,3- (CH3O) 2-c6h3 c(o) 2959 ch ch ch -CH3O h 2,4-(ch30)2-c6h3 2 , 4- (ch30) 2-c6h3 c(o) 2960 ch ch ch -CH3O h 2,4-(ch30)2-c6h3 3 , 4- (ch30) 2-c6h3 c(o) 2961 ch ch ch -CH3O h 2,4-(ch30)2- c6h3 3 , 5- (ch30) 2-c6h3 c(o) 2962 ch ch ch -CH3O h 2,4-(ch30)2- c6h3 3,4,5- (CH3O) 3-c6h2 c(o) 2963 ch ch ch -CH3O h 3,4-(ch30)2- c6h3 ch3 c(o) 2964 ch ch ch -CH3O h 3,4-(ch30)2- c6h3 c2h5 c(o) 2965 ch ch ch -CH3O h 3,4- (ch30)2-c6h3 c5h5 c(o) 2966 ch ch ch -CH3O h 3,4- (ch30)2-c6h3 2- (ch30) -c6h4 c(o) 2967 ch ch ch -CH3O h 3,4- (ch30)2-c5h3 3- (CH3O) -c6h4 c(o) 2968 ch ch ch -CH3O h 3,4- (ch30)2- c6h3 4- (ch30)-c6h4 c(o) Page 57 2969 ch ch ch -ch30 h 3,4-(ch30)2- c6h3 2,3-(ch30)2-c6h3 c(o) 2970 ch ch ch -CH3O h 3,4-(ch30)2- c6h3 2 , 4- (ch30) 2-c6h3 c(o) 2971 ch ch ch -CH3O h 3,4- (ch30)2- c6h3 3,4-(ch30)2-c6h3 c(o) 2972 ch ch ch -CH3O h 3 , 4-(ch30)2- c6h3 3,5- (ch30) 2-c6h3 c(o) 2973 ch ch ch -CH3O h 3,4-(ch30) 2- c6h3 3,4,5- (ch30)3-c6h2 c(o) 2974 ch ch ch -CH3O h 3,5- (ch30)2- c6h3 ch3 c(o) 2975 ch ch ch -CH3O h 3,5-(CH3O)2- c6h3 c2h5 c(o) 2976 ch ch ch -CH3O h 3,5- (CH3O) 2- c5h3 c6h5 c(o) 2977 ch ch ch -CH3O h 3 , 5-(CH3O)2- c6h3 2-(ch30)-c6h4 c(o) 2978 ch ch ch -CH3O h 3,5- (ch30)2- c6h3 3- (ch30) -c6h4 c(o) 2979 ch ch ch -CH3O h 3,5- (ch30)2- c6h3 4- (ch30) -c6h4 c(o) 2980 ch ch ch -CH3O h 3,5-(ch30)2- c6h3 2,3- (ch30) 2-c6h3 c(o) 2981 ch ch ch -CH3O h 3,5-(ch30)2- c6h3 2 , 4- (ch30) 2-c6h3 c(o) 2982 ch ch ch -CH3O h 3,5-(ch30)2- c6h3 3 , 4- (ch30) 2-c6h3 c(o) 2983 ch ch ch -CH3O h 3 , 5- (ch30) 2-c6h3 3,5- (ch30)2-c6h3 c(o) 2984 ch ch ch -CH3O h 3,5- (ch30)2-c6h3 3,4,5- (ch30)3-c6h2 c(o) 2985 ch ch ch -CH3O h 3,4,5- (ch30)3- c6h2 ch3 c(o) 2986 ch ch ch -CH3O h 3,4,5- (ch30) 3- c6h2 c2h5 c(o) Page 58 2987 ch ch ch -ch30 h 3,4,5- (CH3O) 3- c6h2 c6h5 c{0) 2988 ch ch ch -CH3O h 3,4,5- (ch30) 3- c5h2 2- (CH3O) -c5h4 c(o) 2989 ch ch ch -CH3O h 3,4,5- (ch30)3- c6h2 3- (CH3O) -c6h4 c(o) 2990 ch ch ch -CH3O h 3,4,5- (ch30) 3-c6h2 4- (CH3O) -c6h4 c(o) 2991 ch ch ch -CH3O h 3,4,5-(CH3O) 3-c6h2 2,3- (ch30)2-c6h3 c(o) 2992 ch ch ch -CH3O h 3,4,5- (CH3O) 3- c6h2 2,4- (ch30)2-c6h3 c(o) 2993 ch ch ch -CH3O h 3,4,5- (CH3O) 3- c6h2 3,4- (ch30)2-c6h3 c(o) 2994 ch ch ch -CH3O h 3,4,5- (ch30)3- c6h2 3,5- (ch30)2-c6h3 c(o) 2995 ch ch ch -CH3O h 3,4,5- (ch30) 3- c6h2 3,4,5- (CH3O) 3-c6h2 c(o) 2996 ch c ch 6-f h ch3 ch3 c(o) 2997 ch c ch 6-f h ch3 c2h5 c(o) 2998 ch c ch 6-f h ch3 c6h5 c(o) 2999 ch c ch 6-f h ch3 2- (CH3O) -c6h4 c(o) 3000 ch c ch 6-f h ch3 3- (CH3O) -c6h4 c(o) 3001 ch c ch 6-f h ch3 4- (ch30)-c6h4 c(o) 3002 ch c ch 6-f h ch3 2,3- (ch30)2-c6H3 c(o) 3003 ch c ch 6-f h ch3 2,4- (ch30)2-c6H3 c(o) 3004 ch c ch 6-f h ch3 3,4- (ch30)2-c6H3 c(o) 3005 ch c ch 6-f h ch3 3,5-(ch30)2-c6h3 c(o) 3006 ch c ch 6-f h ch3 3,4,5- (ch30) 3-csh2 c(o) 3007 ch c ch 6-f h c2h5 ch3 c(o) 3008 ch c ch 6-f h C2H5 c2h5 c(o) 3009 ch c ch 6-f h c2h5 c6h5 c(o) 3010 ch c ch 6-f h c2h5 2-(ch30)-c6h4 c(o) 3011 ch c ch 6-f h c2h5 3- (ch30) -c6h4 c(o) 3012 ch c ch 6-f h C2H5 4- (CH3O) -c6h4 c(o) 3013 ch c ch 6-f h c2h5 2,3- (ch30)2-c6h3 c(o) Page 59 3014 ch c ch 6-f h c2h5 2,4- (ch30) 2-c6h3 c(o) 3015 ch c ch 6-f h c2h5 3,4-(ch30)2-c6h3 c(o) 3016 ch c ch 6-f h c2h5 3,5- (ch30)2-c6h3 c(o) 3017 ch c ch 6-f h c2h5 3,4,5- (ch30) 3-c6h2 c(o) 3018 ch c ch 6-f h c6h5 ch3 c{0) 3019 ch c ch 6-f h c6h5 c2h5 c(o) 3020 ch c ch 6-f h c6h5 c6h5 c(o) 3021 ch c ch 6-f h c6h5 2- (ch30) -c5h4 cio) 3022 ch c ch 6-f h c6h5 3- (ch30) -c5h4 c(o) 3023 ch c ch 6-f h c6h5 4- (ch30) -c6h4 c(o) 3024 ch c ch 6-f h c6h5 2,3- (ch30) 2-c6h3 c(o) 3025 ch c ch 6-f h c6h5 2,4- (ch30)2-c6h3 c(o) 3026 ch c ch 6-f h c6h5 3,4- (ch30)2-c6h3 c(o) 3027 ch c ch 6-f h c6h5 3,5- (ch30)2-c6h3 c(o) 3028 ch c ch 6-f h c6h5 3,4,5- (ch30) 3-c6h2 c(o) 3029 ch c ch 6-f h 2- (ch30) -c6h4 ch3 c(o) 3030 ch c ch 6-f h 2- (ch30) -c6h4 c2h5 c(o) 3031 ch c ch 6-f h 2-(ch30)-c6h4 c6h5 c(o) 3032 ch c ch 6-f h 2- (ch30) -c6h4 2- (ch30) -c6h4 c(o) 3033 ch c ch 6-f h 2- (ch30) -c6h4 3-(ch30)-c6h4 c(o) 3034 ch c ch 6-f h 2- (ch30) -c6h4 4- (ch30) -c6h4 c(o) 3035 ch c ch 6-f h 2- (ch30) -c6h4 2,3-(ch30)2-c6h3 c(o) 3036 ch c ch 6-f h 2- (ch30) -c6h4 2,4- (ch30)2-c6h3 c(o) 3037 ch c ch 6-f h 2- (ch30) -c6h4 3 , 4- (ch30) 2-c6h3 c(o) 3038 ch c ch 6-f h 2- (ch30) -c6h4 3,5- (ch30)2-c6h3 c(o) 3039 ch c ch 6-f h 2- (ch30) -c6h4 3,4,5- (ch30) 3-c6h2 c(o) 3040 ch c ch 6-f h 3- (ch30) -c6h4 ch3 c(o) 3041 ch c ch 6-f h 3- (ch30) -c6h4 c2h5 c(o) 3042 ch c ch 6-f h 3- (ch30) -c6h4 c6h5 c(o) 3043 ch c ch 6-f h 3- (ch30) -c6h4 2- (ch30) -c6h4 c(o) 3044 ch c ch 6-f h 3- (ch30) -c6h4 3- (ch30) -c6h4 c(o) 3045 ch c ch 6-f h 3- (ch30) -c6h4 4- (ch30)-c6h4 c(o) 3046 ch c ch 6-f h 3- (ch30) -c6h4 2,3- (ch30)2-c6h3 c(o) 3047 ch c ch 6-f h 3- (ch30) -c6h4 2 , 4- (ch30) 2-c6h3 c(o) 3048 ch c ch 6-f h 3- (ch30) -c6h4 3,4- (ch30)2-c6h3 c(o) 3049 ch c ch 6-f h 3- (ch30) -c6h4 3 , 5- (ch30) 2-c6h3 c(o) Page 60 3050 ch c ch 6-f h 3- (ch30) -c6h4 3,4,5- (ch30) 3-c6h2 c(o) 3051 ch c ch 6-f h 4- (ch30) -c6h4 ch3 c(o) 3052 ch c ch 6-f h 4- (ch30) -c6h4 c2h5 c(o) 3053 ch c ch 6-f h 4- (ch30) -c6h4 c5h5 c(o) 3054 ch c ch 6-f h 4- (ch30) -c6h4 2- (ch30) -csh4 c(o) 3055 ch c ch 6-f h 4- (ch30) -c6h4 3- (ch30) -c6h4 c(o) 3056 ch c ch 6-f h 4- (ch30)-c6h4 4- (ch30)-c6h4 c(o) 3057 ch c ch 6-f h 4- (ch30) -c6h4 2,3- (ch30) 2-c6h3 c(o) 3058 ch c ch 6-f h 4- (ch30) -c6h4 2,4-(ch30)2-c6h3 c(o) 3059 ch c ch 6-f h 4- (ch30) -c6h4 3,4- (ch30) 2-c6h3 c(o) 3060 ch c ch 6-f h 4- (ch30) -c6h4 3,5-(ch30)2-c6h3 c(o) 3061 ch c ch 6-f h 4- (ch30) -c6h4 3,4,5-(ch30)3-c6h2 c(o) 3062 ch c ch 6-f h 2,3- (ch30)2-c6h3 ch3 c(o) 3063 ch c ch 6-f h 2,3- (ch30)2- c6h3 c2h5 c(o) 3064 ch c ch 6-f h 2,3- (ch30)2- c6h3 c6h5 c(o) 3065 ch c ch 6-f h 2,3- (ch30)2-c6h3 2- (ch30)-c6h4 c(o) 3066 ch c ch 6-f h 2,3- (ch30)2- c6h3 3- (ch30)-c6h4 c(o) 3067 ch c ch 6-f h 2,3- (ch30)2- c6h3 4- (ch30)-c6h4 c(o) 3068 ch c ch 6-f h 2,3- (ch30)2- c6h3 2,3- (ch30) 2-c6h3 c(o) 3069 ch c ch 6-f h 2,3- (ch30)2- c6h3 2 , 4- (ch30) 2-c5h3 c(o) 3070 ch c ch 6-f h 2,3- (ch30) 2- c6h3 3 , 4- (ch30) 2-c6h3 c(o) 3071 ch c ch 6-f h 2,3- (ch30) 2- c6h3 3 , 5- (ch30) 2-c6h3 c(o) 3072 ch c ch 6-f h 2,3- (ch30)2- c6h3 3,4,5- (ch30) 3-c6h2 c(o) 3073 ch c ch 6-f h 2,4- (ch30)2- c6h3 ch3 c(o) Page 61 3074 ch c ch 6-f h 2,4- (ch30)2- c6h3 c2h5 c(o) 3075 ch c ch 6-f h 2,4- (ch30)2- c6h3 c6h5 c(o) 3076 ch c ch 6-f h 2,4-(ch30)2-c6h3 2- (ch30) -c6h4 c(o) 3077 ch c ch 6-f h 2 , 4- (ch30) 2- c6h3 3-(ch30)-c6h4 c(o) 3078 ch c ch 6-f h 2,4- (ch30) 2- c6h3 4-(ch30)-c6h4 c(o) 3079 ch c ch 6-f h 2,4 - (ch30) 2-c6h3 2,3- (ch30) 2-c6h3 c(o) 3080 ch c ch 6-f h 2 , 4- (ch30) 2~ c6h3 2 , 4- (ch30) 2-c6h3 c(o) 3081 ch c ch 6-f h 2,4- (ch30)2- c6h3 3,4- (ch30)2-c6h3 c(o) 3082 ch c ch 6-f h 2,4- (ch30)2- c6h3 3,5- (ch30) 2-c6h3 c(o) 3083 ch c ch 6-f h 2 , 4-(ch30) 2~ c5h3 3,4,5- (ch30) 3-c6h2 c(o) 3084 ch c ch 6-f h 3,4- (ch30)2- c6h3 ch3 c(o) 3085 ch c ch 6-f h 3,4- (ch30)2- c6h3 c2h5 c(o) 3086 ch c ch 6-f h 3 , 4- (ch30) 2- c6h3 c6h5 c(o) 3087 ch c ch 6-f h 3,4- (ch30)2- c6h3 2- (ch30) -c6h4 c(o) 3088 ch c ch 6-f h 3 , 4- (ch30) 2- c6h3 3- (ch30) -c6h4 c(o) 3089 ch c ch 6-f h 3,4-(ch30)2- c6h3 4-(ch30)-c6h4 c(o) 3090 ch c ch 6-f h 3,4- (ch30)2- c6h3 2,3- (ch30) 2-c6h3 c(o) 3091 ch c ch 6-f h 3 , 4- (ch30) 2- c6h3 2,4- (ch30) 2-c6h3 c(o) Page 62 3092 ch c ch 6-f h 3 , 4-(ch30) 2- c6h3 3 , 4- (ch30) 2-c6h3 c(o) 3093 ch c ch 6-f h 3,4-(CH3O) 2- c6h3 3,5-(ch30)2-c6h3 c(o) 3094 ch c ch 6-f h 3,4-(ch30)2-c6h3 3,4,5- (ch30)3-c6h2 c(o) 3095 ch c ch 6-f h 3 , 5- (ch30) 2-c6h3 ch3 c(o) 3096 ch c ch 6-f h 3 , 5- (ch30) 2- c6h3 C2H5 c(o) 3097 ch c ch 6-f h 3 , 5-(ch30) 2-c6h3 c6h5 c(o) 3098 ch c ch 6-f h 3,5-(ch30>2-c6h3 2- (ch30) -c6h4 c(o) 3099 ch c ch 6-f h 3,5- (ch30)2- c6h3 3- (ch30) -csh4 c(o) 3100 ch c ch 6-f h 3 , 5-(ch30) 2-c6h3 4- (ch30) -c6h4 c(o) 3101 ch c ch 6-f h 3,5-(ch30)2- c6h3 2,3- (ch30)2-c6h3 c(o) 3102 ch c ch 6-f h 3,5-(ch30) 2- c6h3 2 , 4- (ch30) 2-c6h3 c(o) 3103 ch c ch 6-f h 3,5-(ch30)2-c6h3 3,4- (ch30)2-c6h3 c(o) 3104 ch c ch 6-f h 3,5-(ch30)2-c6h3 3 , 5- (ch30) 2-c6h3 c(o) 3105 ch c ch 6-f h 3,5-(ch30) 2~ c6h3 3,4,5- (ch30)3-c6h2 c(o) 3106 ch c ch 6-f h 3,4,5- (ch30)3- c6h2 ch3 c(o) 3107 ch c ch 6-f h 3,4,5- (ch30)3- c6h2 c2h5 c(o) 3108 ch c ch 6-f h 3,4,5- (ch30)3- c6h2 c6h5 c(o) 3109 ch c ch 6-f h 3,4,5- (ch30)3- c6h2 2- (ch30) -c6h4 c(o) Page 63 3110 ch c ch 6-f h 3,4,5- (CH3O) 3- c6h2 3- (ch30)-c6h4 c(o) 3111 ch c ch 6-f h 3,4,5- (CH3O) 3- c6h2 4- (ch30)-c6h4 c(o) 3112 ch c ch 6-f h 3,4,5- (CH3O) 3- c6h2 2,3-(ch30)2-c6h3 c(o) 3113 ch c ch 6-f h 3,4,5- (ch30)3- c6h2 2,4-(ch30)2-c6h3 c(o) 3114 ch c ch 6-f h 3,4,5- (ch30)3- c6h2 3 , 4- (ch30) 2-c6h3 c(o) 3115 ch c ch 6-f h 3,4,5- (ch30)3-c6h2 3,5 - (ch30) 2-c6h3 c(o) 3116 ch c ch 6-f h 3,4,5- (ch30)3- c6h2 3,4,5- (ch30)3-c6h2 c(o) 3117 ch ch c 7-ch3 h ch3 ch3 c(o) 3118 ch ch c 7-CH3 h ch3 c2h5 c(o) 3119 ch ch c 7-CH3 h ch3 c6h5 c(o) 3120 ch ch c 7-CH3 h ch3 2- (ch30) -c6h4 c(o) 3121 ch ch c 7-CH3 h ch3 3- (ch30) -c6h4 c(o) 3122 ch ch c 7-ch3 h ch3 4- (ch30) -c6h4 c(o) 3123 ch ch c 7-CH3 h ch3 2,3-(ch30)2-c6h3 c(o) 3124 ch ch c 7-CH3 h ch3 2 , 4- (CH3O) 2-c6h3 c(o) 3125 ch ch c 7-CH3 h ch3 3,4- (ch30)2-c6h3 c(o) 3126 ch ch c 7-CH3 h ch3 3,5- (CH3O) 2-c6h3 c(o) 3127 ch ch c 7-CH3 h ch3 3,4,5- (ch30)3-c6h2 c(o) 3128 ch ch c 7-CH3 h c2h5 ch3 c(o) 3129 ch ch c 7-CH3 h c2h5 c2h5 c(o) 3130 ch ch c 7-CH3 h C2H5 c6h5 c(o) 3131 ch ch c 7-CH3 h C2H5 2- (CH3O) -c6h4 c(o) 3132 ch ch c 7-CH3 h c2h5 3- (ch30)-c6h4 c(o) 3133 ch ch c 7-CHj h c2h5 4- (CH3O) -c5h4 c(o) 3134 ch ch C 7-CH3 h C2H5 2,3- (CH3O) 2-c6h3 c(o) 3135 ch ch c 7-CH3 h C2H5 2 , 4- (CH3O) 2-c5h3 c(o) 3136 ch ch c 7-CH3 h C2H5 3 , 4- (CH3O) 2-c6h3 c(o) 3137 ch ch c 7-CH3 h c2h5 3 , 5- (CH3O) 2-c6h3 c(o) 3138 ch ch c 7-CH3 h C2H5 3,4,5- (ch30)3-c6h2 c(o) Page 64 3139 ch ch c 7-CH3 h c6h5 ch3 c(o) 3140 ch ch c 7-CH3 h c6h5 c2h5 c(o) 3141 ch ch c 7-CH3 h c6h5 c6h5 c(o) 3142 ch ch c 7-ch3 h c6h5 2- (CH3O) -c6h4 c(o) 3143 ch ch c 7-CH3 h c6h5 3- (CH3O) -c6h4 c(o) 3144 ch ch c 7-CH3 h c6h5 4- (CH3O) -c6h4 c(o) 3145 ch ch c 7-CH3 h c6h5 2,3- (ch30) 2-c6h3 c(o) 3146 ch ch c 7-CH3 h c6h5 2,4- (ch30)2-c6h3 c(o) 3147 ch ch c 7-CH3 h c6h5 3,4 - (ch30) 2-c5h3 c(o) 3148 ch ch c 7-CH3 h c6h5 3,5 - (CH3O) 2-c6h3 c(o) 3149 ch ch c 7-CH3 h c6h5 3,4,5-(ch30)3-c6h2 c(o) 3150 ch ch c 7-CH3 h 2- (CH3O) -c6h4 ch3 c(o) 3151 ch ch c 7-CH3 h 2-(ch30)-c6h4 c2h5 c(o) 3152 ch ch c 7-CH3 h 2- (CH3O) -c6h4 c6hb c(o) 3153 ch ch c 7-CH3 h 2-(ch30)-c6h4 2- (CH3O) -c6h4 c(o) 3154 ch ch c 7-CH3 h 2- (CH3O) -c6h4 3- (CH3O) -c5h4 c(o) 3155 ch ch c 7-CH3 h 2- (CH3O) -c6h4 4-(ch30)-c6h4 c(o) 3156 ch ch c 7-ch3 h 2- (CH3O) -c6h4 2,3- (ch30)2-c6h3 c(o) 3157 ch ch c 7-CH3 h 2- (CH3O) -c6h4 2,4- (ch30)2-c6h3 c(o) 3158 ch ch c 7-CH3 h 2- (CH3O) -c6h4 3,4- (ch30)2-c5h3 c(o) 3159 ch ch c 7-CH3 h 2- (CH3O) -c6h4 3,5- (ch30)2-c6h3 c(o) 3160 ch ch . c 7-CH3 h 2- (CH3O) -c6h4 3,4,5- (ch30)3-c6h2 c(o) 3161 ch ch c 7-CH3 h 3- (ch30)-c6h4 ch3 c(o) 3162 ch ch c 7-CH3 h 3- (CH3O) -c6h4 C2H5 c(o) 3163 ch ch c 7-CH3 h 3- (CH3O) -c6h4 c6h5 c(o) 3164 ch ch c 7-CH3 h 3-(ch30)-c6h4 2- (ch30)-c6h4 c(o) 3165 ch ch c 7-CH3 h 3- (CH3O) -c6h4 3- (ch30)-c6h4 c(o) 3166 ch ch c 7-CH3 h 3-(ch30)-c6h4 4- (ch30)-c6h4 c(o) 3167 ch ch c 7-CH3 h 3- (ch30)-c6h4 2,3- (CH3O) 2-c6h3 c(o) 3168 ch ch c 7-ch3 h 3- (CH3O) -c6h4 2 , 4- (ch30) 2-c6h3 c(o) 3169 ch ch c 7-CH3 h 3- (CH3O) -c6h4 3,4 - (CH3O) 2-c6h3 c(o) 3170 ch ch c 7-CH3 h 3- (CH3O) -c6h4 3,5- (ch30)2-c6h3 c(o) 3171 ch ch c 7-CH3 h 3- (CH3O) -c6h4 3,4,5-(ch30)3-c6h2 c(o) 3172 ch ch c 7-CH3 h 4- (CH3O) -c6h4 ch3 c(o) 3173 ch ch c 7-CH3 h 4- (CH3O) -c6h4 c2h5 c(o) 3174 ch ch c 7-CH3 h 4- (CH3O) -c6h4 c6h5 c(o) Page 65 3175 ch ch c 7-ch3 h 4- (CH3O) -c6h4 2- (CH3O) -c6h4 c(o) 3176 ch ch c 7-CH3 h 4-(ch30)-c6h4 3- (CH3O) -c6h4 c(o) 3177 ch ch c 7-CH3 h 4- (ch30) -c6h4 4- (CH3O) -c6h4 c(o) 3178 ch ch c 7-CH3 h 4- (CH3O) -c6h4 2,3 - (CH3O) 2-c6h3 c(o) 3179 ch ch c 7-ch3 h 4-(ch30)-c6h4 2 , 4- (ch30) 2-c6h3 c(o) 3180 ch ch c 7-CH3 h 4- (ch30) -c6h4 3,4-(ch30)2-c6h3 c(o) 3181 ch ch c 7-CH3 h 4- (CH3O) -c6h4 3,5-(ch30)2-c6h3 c(o) 3182 ch ch c 7-CH3 h 4- (CH3O) -c6h4 3,4,5- (ch30)3-c6h2 c(o) 3183 ch ch c 7-CH3 h 2,3- (CH3O) 2- c6h3 ch3 c(o) 3184 ch ch c 7-CH3 h 2,3-(ch30)2- c6h3 c2h5 c(o) 3185 ch ch c 7-CH3 h 2,3-(ch30)2- c6h3 c6h5 c(o) 3186 ch ch c 7-CH3 h 2,3- (CH3O) 2~ c6h3 2- (ch30) -c6h4 c(o) 3187 ch ch c 7-CH3 h 2,3-(CH3O) 2- c6h3 3- (CH3O) -c6h4 c(o) 3188 ch ch c 7-CH3 h 2,3- (ch30) 2-c6h3 4- (CH3O) -c6h4 c(o) 3189 ch ch c 7-CH3 h 2,3- (ch30)2-c6h3 2,3 - (ch30) 2-c6h3 c(o) 3190 ch ch c 7-CH3 h 2,3- (CH3O2- c6h3 2 , 4- (ch30) 2-c6h3 c(o) 3191 ch ch c 7-CH3 h 2,3-(ch30)2-c6h3 3,4- (ch30)2-c6h3 c(o) 3192 ch ch c 7-CH3 h 2,3-(ch30)2-c6h3 3,5- (ch30)2-c6h3 c(o) 3193 ch ch c 7-CH3 h 2,3-(ch30)2-c6h3 3,4,5- (ch30)3-c6h2 c(o) 3194 ch ch c 7-CH3 h 2,4-(ch30)2-c6h3 ch3 c(o) 3195 ch ch c 7-CH3 h 2,4-(ch30)2-c6h3 c2h5 c(o) 3196 ch ch c 7-CH3 h 2,4-(ch30)2-c6h3 c6h5 c(o) Page 66 3197 ch ch c 7-ch3 h 2,4- (CH3O) 2- c6h3 2- (ch30) -c6h4 c(o) 3198 ch ch c 7-CH3 h 2,4-(ch30)2- c6h3 3- (ch30)-c6h4 c(o) 3199 ch ch c 7-CH3 h 2,4-(ch30)2- c6h3 4- (CH3O) -c6h4 c(o) 3200 ch ch c 7-CH3 h 2,4- (ch30)2- c6h3 2,3- (ch30) 2-c6h3 c(o) 3201 ch ch c 7-CH3 h 2,4-(ch30)2- c6h3 2 , 4- (ch30) 2-c6h3 c(o) 3202 ch ch c 7-CH3 h 2,4- (ch30)2- c6h3 3,4-(ch30)2-c6h3 c(o) 3203 ch ch c 7-CH3 h 2,4-(ch30) 2- c6h3 3 , 5- (ch30) 2-c6h3 c(o) 3204 ch ch c 7-CH3 h 2,4-(ch30)2- c6h3 3,4,5-(ch30)3-c6h2 c(o) 3205 ch ch c 7-CH3 h 3,4-(ch30)2-c6h3 ch3 c(o) 3206 ch ch c 7-CH3 h 3,4-(ch30)2- c6h3 c2h5 c(o) 3207 ch ch c 7-CH3 h 3,4-(ch30)2- c5h3 c6h5 c(o) 3208 ch ch c 7-CH3 h 3,4-(ch30)2- c6h3 2- (CH3O) -c6h4 c(o) 3209 ch ch c 7-CH3 H 3,4-(ch30)2- c6h3 3- (CH3O) -c6h4 c(o) 3210 ch ch c 7-CH3 h 3,4- (ch30)2- c6h3 4- (CH3O) -c6h4 c(o) 3211 ch ch C 7-CHj H 3,4- (ch30)2- c6h3 2,3- (CH3O) 2-c6h3 c(o) 3212 ch ch c 7-CH3 H 3,4- (ch30)2-c6h3 2 , 4- (ch30) 2"c6h3 c(o) 3213 ch ch c 7-CH3 H 3,4- (ch30)2-c6h3 3 , 4- (ch30) 2-c6h3 c(o) 3214 ch ch C 7-CH3 h 3,4- (ch30)2- c6h3 3 , 5- (ch30) 2-c6h3 c(o) Page 67 3215 ch ch c 7-CH3 h 3 , 4- (CH3O) 2- c6h3 3,4,5- (CH3O) 3-c6h2 c(o) 3216 ch ch c 7-CH3 h 3,5-(ch30)2-c6h3 ch3 c(o) 3217 ch ch c 7-CH3 h 3,5-(ch30) 2~ c6h3 c2h5 c(o) 3218 ch ch c 7-CH3 h 3 , 5- (CH3O) 2- c6h3 c6h5 c(o) 3219 ch ch c 7-CH3 h 3 , 5- (ch30) 2- c6h3 2- (ch30) -c6h4 c(o) 3220 ch ch c 7-CH3 h 3,5-(ch30)2-c6h3 3- (ch30) -c6h4 c(o) 3221 ch ch c 7-CH3 h 3,5-(ch30)2-c6h3 4- (ch30) -c6h4 c(o) 3222 ch ch c 7-CH3 h 3,5- (CH3O) 2- c6h3 2,3- (ch30)2-c6h3 c(o) 3223 ch ch c 7-CH3 h 3,5 - (ch30) 2- c6h3 2,4-(ch30)2-c6h3 c(o) 3224 ch ch c 7-CH3 h 3 , 5-(ch30) 2~ c5h3 3,4-(ch30)2-c6h3 c(o) 3225 ch ch c 7-CH3 h 3,5-(ch30)2~ c6h3 3 , 5- (ch30) 2-c6h3 c(o) 3226 ch ch c 7-CH3 h 3 , 5- (CH3O) 2- c6h3 3,4,5- (ch30)3-c6h2 c(o) 3227 ch ch c 7-CH3 h 3,4,5- (CH3O) 3- c6h2 ch3 c(o) 3228 ch ch c 7-CH3 h 3,4,5- (ch30)3- c6h2 c2h5 c(o) 3229 ch ch c 7-CH3 h 3,4,5- (ch30)3- c6h2 c6h5 c(o) 3230 ch ch c 7-CH3 h 3,4,5- (ch30)3-c6h2 2- (CH3O) -c6h4 c(o) 3231 ch ch c 7-CH3 h 3,4,5- (ch30)3-c6h2 3- (CH3O) -c6h4 c(o) 3232 ch ch c 7-CH3 h 3,4,5-(CH3O) 3-c6h2 4- (ch30) -c6h4 c(o) Page 68 3233 ch ch c 7-ch3 h 3,4,5- (ch30>3- c6h2 2,3- (ch30)2-c6h3 c(o) 3234 ch ch c 7-CH3 h 3,4,5- (ch30) 3-c6h2 2,4- (ch30)2-c6h3 c(o) 3235 ch ch c 7-CH3 h 3,4,5- (CH3O) 3- c6h2 3,4-(ch30)2-c6h3 c(o) 3236 ch ch c 7-CH3 h 3,4,5- (CH3O) 3- c6h2 3,5- (ch30)2-c6h3 c(o) 3237 ch ch c 7-CH3 h 3,4,5- (CH3O) 3- c6h2 3,4,5- (CH3O) 3-ceh2 c(o) 3238 ch ch ch h c6h5 ch3 ch3 c(o) 3239 ch ch ch h c6h5 ch3 c2h5 c(o) 3240 ch ch ch h c6h5 ch3 c6h5 c(o) 3241 ch ch ch h c6h5 ch3 2- (CH3O) -c6h4 c(o) 3242 ch ch ch h c6h5 ch3 3- (ch30) -c6h4 c(o) 3243 ch ch ch h c6h5 ch3 4- (ch30)-c6h4 c(o) 3244 ch ch ch h c6h5 ch3 2,3- (ch30) 2-c6h3 c(o) 3245 ch ch ch h c6h5 ch3 2,4- (ch30)2-c6h3 c(o) 3246 ch ch ch h c6h5 ch3 3,4- (ch30)2-c6h3 c(o) 3247 ch ch ch h c6h5 ch3 3,5- (ch30) 2-c6h3 c(o) 3248 ch ch ch h C6hs ch3 3,4,5- (ch30) 3-c6h2 c(o) 3249 ch ch ch h c6h5 c2h5 ch3 c(o) 3250 ch ch ch h Csh5 c2h5 c2h5 c(o) 3251 ch ch ch h c6h5 c2h5 c6h5 c(o) 3252 ch ch ch h c6h5 c2h5 2- (ch30) -c6h4 c(o) 3253 ch ch ch h c5h5 c2h5 3- (ch30) -c6h4 c(o) 3254 ch ch ch h c6h5 c2h5 4- (ch30) -c6h4 c(o) 3255 ch ch ch h C6hs c2h5 2,3- (ch30)2-c6h3 c(o) 3256 ch ch ch h c6h5 c2h5 2 , 4- (ch30) 2-c6h3 c(o) 3257 ch ch ch h c6h5 c2h5 3 , 4- (ch30) 2-c6h3 c(o) 3258 ch ch ch h c6h5 c2h5 3,5-(ch30)2-c6h3 c(o) 3259 ch ch ch h c6h5 c2h5 3,4,5- (ch30) 3-c6h2 c(o) 3260 ch ch ch h C6hs c6h5 ch3 c(o) 3261 ch ch ch h C6hs c6h5 c2h5 c(o) 3262 ch ch ch h C6hs c6h5 c6h5 c(o) 3263 ch ch ch h c6h5 c6h5 2- (ch30)-c6h4 c(o) Page 69 3264 ch ch ch h c6h5 c6h5 3- (ch30)-c6h4 c(o) 3265 ch ch ch h c6h5 c6h5 4- (ch30)-c6h4 c(o) 3266 ch ch ch h c6h5 c6h5 2,3- (ch30) 2-c6h3 c(o) 3267 ch ch ch h c6h5 c6h5 2,4- (ch30)2-c5h3 c(o) 3268 ch ch ch h c6h5 c6h5 3,4- (ch30)2-c6h3 c(o) 3269 ch ch ch h c6h5 c6h5 3,5- (ch30) 2-c6h3 c(o) 3270 ch ch ch h c6h5 c6h5 3,4,5- (ch30) 3-c6h2 c(o) 3271 ch ch ch h c6h5 2-(ch30)-c6h4 ch3 c(o) 3272 ch ch ch h c6h5 2- (ch30) -c6h4 c2h5 c(o) 3273 ch ch ch h c6h5 2-(ch30)-c6h4 c6h5 c(o) 3274 ch ch ch h c6h5 2- (ch30) -c6h4 2- (ch30) -c6h4 c(o) 3275 ch ch ch h c6h5 2- (ch30) -c6h4 3- (ch30)-cgh4 c(o) 3276 ch ch ch h c6h5 2- (ch30) -c6h4 4- (ch30)-c6h4 c(o) 3277 ch ch ch h c6h5 2-(ch30)-c6h4 2,3-(ch30)2-c5h3 c(o) 3278 ch ch ch h C6hs 2-(ch30)-c6h4 2,4- (ch30) 2-c6h3 c(o) 3279 ch ch ch h c6h5 2- (ch30) -c6h4 3,4-(ch30)2-c6h3 c(o) 3280 ch ch ch h c6h5 2- (ch30) -c6h4 3,5- (ch30)2-c6h3 c(o) 3281 ch ch ch h c6h5 2- (ch30) -c6h4 3,4,5- (ch30) 3-c6h2 c(o) 3282 ch ch ch h c6h5 3- (ch30) -c6h4 ch3 c(o) 3283 ch ch ch h c6h5 3- (ch30) -c6h4 c2h5 c(o) 3284 ch ch ch h c6h5 3- (ch30) -c6h4 c6h5 c(o) 3285 ch ch ch h C6hs 3- (ch30) -c6h4 2- (ch30) -c6h4 c(o) 3286 ch ch ch h c6h5 3-(ch30)-c6h4 3- (ch30) -c6h4 c(o) 3287 ch ch ch h c6h5 3- (ch30) -c6h4 4- (ch30) -c5h4 c(o) 3288 ch ch ch h c6h5 3- (ch30) -c6h4 2,3- (ch30) 2-c6h3 c(o) 3289 ch ch ch h c6h5 3-(ch30)-c6h4 2,4- (ch30)2-c6h3 c(o) 3290 ch ch ch h c6h5 3- (ch30) -c6h4 3 , 4- (ch30) 2-c6h3 c(o) 3291 ch ch ch h c6h5 3- (ch30) -c6h4 3,5- (ch30)2-c6h3 c(o) 3292 ch ch ch h c6h5 3- (ch30)-c6h4 3,4,5- (ch30) 3-c6h2 c(o) 3293 ch ch ch h c6h5 4- (ch30)-c6h4 ch3 c(o) 3294 ch ch ch h c6h5 4- (ch30) -c6h4 c2h5 c(o) 3295 ch ch ch h c6h5 4-(ch30)-c5h4 c6h5 c{0) 3296 ch ch ch h c6h5 4- (ch30) -c6h4 2- (ch30)-c6h4 c(o) 3297 ch ch ch h c6h5 4-(ch30)-c6h4 3- (ch30) -c6h4 c(o) 3298 ch ch ch h c6h5 4-(ch30)-c6h4 4- (ch30) -c6h4 c(o) 3299 ch ch ch h c6h5 4- 2- c6h3 2- (ch30) -c6h4 c(o) 3341 ch ch ch h c6h5 3 , 5- (ch30) 2~ c6h3 3- (ch30)-c6h4 c(o) 3342 ch ch ch h c6h5 3,5-(ch30)2-c6h3 4- (ch30) -c6h4 c(o) 3343 ch ch ch h c6h5 3,5- (ch30)2- c6h3 2,3 - (ch30) 2-c6h3 c(o) 3344 ch ch ch h c6h5 3 , 5- (ch30) 2- c6h3 2,4- (ch30)2-c6h3 c(o) 3345 ch ch ch h c6h5 3,5- (ch30)2-c6h3 3,4- (ch30)2-c6h3 c(o) 3346 ch ch ch h c6h5 3,5-(ch30)2- c6h3 3,5- (ch30)2-c6h3 c(o) 3347 ch ch ch h c6h5 3,5-(ch30) 2-c6h3 3,4,5- (ch30) 3-c6h2 c(o) 3348 ch ch ch h c6h5 3,4,5- (ch30) 3-c6h2 ch3 c(o) 3349 ch ch ch h c6h5 3,4,5- (ch30) 3- c6h2 c2h5 c(o) 3350 ch ch ch h C6hs 3,4,5- (ch30) 3- c6h2 c6h5 c(o) 3351 ch ch ch h c6h5 3,4,5- (ch30)3- c6h2 2- (ch30) -c6h4 c(o) 3352 ch ch ch h c6h5 3,4,5- (ch30) 3- c6h2 3- (ch30)-c6h4 c(o) 3353 ch ch ch h c6h5 3,4,5- (ch30) 3- c6h2 4- (ch30) -c6h4 c(o) 3354 ch ch ch h c6h5 3,4,5- (ch30) 3- c6h2 2,3- (ch30) 2-c6h3 c(o) Page 73 3355 ch ch ch h c6h5 3,4,5- (ch30>3- c6h2 2 , 4- (ch30) 2-c6h3 c(o) 3356 ch ch ch h c6h5 3,4,5-(ch30) 3-c6h2 3,4-(ch30)2-c6h3 c(o) 3357 ch ch ch h c6h5 3,4,5- (ch30) 3-c6h2 3,5-(ch30)2-c6H3 c(o) 3358 ch ch ch h c6h5 3,4,5- (ch30)3-csh2 3,4,5- (ch30) 3-c6h2 c(o) 3359 ch ch ch -Cl c6h5 ch3 ch3 c(o) 3360 ch ch ch -Cl c5h5 ch3 c2h5 c(o) 3361 ch ch ch -Cl c6h5 ch3 c6h5 c(o) 3362 ch ch ch -Cl c6h5 ch3 2- (ch30) -c6h4 c(o) 3363 ch ch ch -Cl c6h5 ch3 3- (ch30) -c6h4 c(o) 3364 ch ch ch -Cl c6h5 ch3 4- (ch30) -c6h4 c(o) 3365 ch ch ch -Cl c6h5 ch3 2,3-{ch30)2-c6h3 c(o) 3366 ch ch ch -Cl c6h5 ch3 2,4- (ch30) 2-c6h3 c(o) 3367 ch ch ch -Cl c6h5 ch3 3,4- (ch30) 2-c6h3 c(o) 3368 ch ch ch -Cl c6h5 ch3 3 , 5- (ch30) 2-c6h3 c(o) 3369 ch ch ch -Cl c6h5 ch3 3,4,5- (ch30) 3-c6h2 c(o) 3370 ch ch ch -Cl c6h5 c2h5 ch3 c(o) 3371 ch ch ch -Cl c6h5 c2h5 c2h5 c(o) 3372 ch ch ch -Cl c6h5 c2h5 c6h5 c(o) 3373 ch ch ch -Cl c6h5 c2h5 2- Results of the pharmacological tests The in vitro tests in selected tumor models showed the 20 following pharmacological activities.
Example 1: Antiproliferative properties Substances D-70260, D-70744, D-80815, D-80816 and 25 D-80819 (Ex. C2.3, D4, F2, F3 and F4) were examined for their antiproliferative activity in a proliferation assay (Scudiero et al., Cancer Res., 48: 4827-33, 1987) using established tumor cell lines. The test used determines mitochondrial dehydrogenase activity and 30 permits the cell vitality and indirectly the cell number to be determined. The cell lines used are the human cell lines HeLa/KB (CCL17), SK-OV-3 (HTB77), Page 94 Example Code No. " ^ Concentration [jig/ml] KB/HeLa SK-OV- 3 -, ' MCF-7.
L1210 C2.3 D-70260 3.16 90.7 68.9 4.1 91.3 D4 D-70744 3.16 74.6 55.2 1.9 77.1 F2 D-80815 3.16 1.7 0 8.1 0 F3 D-80816 3 .16 91.7 66.1 18.2 94.7 F4 D-80819 3 .16 0 6.6 0 21.8 MCF-7 (HTB22) and the murine leukemia cell line L1210 (CCL219) . These are very well characterized, established cell lines obtained from ATCC and cultured.
The results summarized in Tab. 1 show highly potent antiproliferative action of substances D-70260, D-70744 and D-80816 (Ex. C2.3, D4 and F3) . In contrast, the structurally related compounds D-80815 and D-80819 (Ex. F2 and F4) show no significant action. Accordingly, there are defined structure-activity relationships.
Table 1. Antiproliferative activity of different derivatives in the XTT cytotoxicity test with cell lines HeLa/KB, SK-OV-3, MCF-7 and L1210. What is stated is the inhibition in percent at a concentration of 3.16 £tg/ml- Page 95 [>80816 Fig. 1 Graphical representation of the concentration-dependent antiproliferative activity of D-80816 (Ex. 5 F3) in the XTT cytotoxicity test with cell lines HeLa/KB, SK-OV-3, MCF-7 and L1210 (A).
Example 2: Effect of D-80816 (Ex. F3) in the hollow fiber model in vivo To determine the availability and efficacy in the animal model (naked mouse), the cell lines HeLa/KB, MCF-7 and L1210 were cultured in hollow fibers implanted i.p. or s.c. (Hollingshead et al., Life 15 Sciences 57_, 131-41, 1995) . The test substance D-80816 is administered four times, in a dose of 100 mg/kg i.p. After the end of the therapy on day 5, the fibers are explanted and the cell vitality of the tumor cells obtained is determined using the XTT assay. D-80816 20 shows maximum inhibition of 100% for all cell lines and implantation sites, at a general toxicity of LD5o>1 000 mg/kg (i.p.).
Table 2. In vivo activity of D-80816 (dose: 4 x 25 100 mg/kg i.p.) in the hollow fiber test with tumor cell lines HeLa/KB, MCF-7 and L1210.
Page 96 Examplej.-- Jfc- . i Code No.
V " LD 50 [mg/kg] Inhibition of ; proliferation in the hollow fiber . . [%J F3 D-80816 >1 000 mg/kg i.p.
KB (i.p.) 100% KB (s.c.) 100% L1210 (i.p.) 100% L1210 (s.c.) 100% MCF7 (i.p.) 100% MCF7 (s.c.) 100% Example 3: Cell-cycle-specific action of D-80816 in the RKOp27 model The RKOp27 cell system (M. Schmidt et al. 0ncogenel9 (20) : 2423-9, 2000) was used as a model to examine the cell-cycle-specific action. RKO is a human colon carcinoma line in which the cell cycle inhibitor p27Kipl is expressed induced by the Ecdyson expression 10 system, resulting in a cell cycle arrest specifically in G1 (Fig. 2). A substance with unspecific action inhibits proliferation independently of whether the RKO cell is arrested in Gl or not. In contrast, cell-cycle-specific substances, such as, for example, tubulin 15 inhibitors, are only cytotoxic when cells are not arrested and are undergoing the cell cycle. Here, D-80816 shows a cell-cycle-specific action, i.e. a concentration-dependent antiproliferative action can only be measured in non-induced cells which are not 20 arrested in Gl of the cell cycle (Fig. 3). Accordingly, a defined molecular mechanism of action of D-80816 and derivatives has to be assumed.
Page 97 p27 kipl seeding drug exposure j n . -27h -3h oh •*•/■ inducer WITT J 72 h Fig. 2 Schematic representation of the induced expression of p27/kipl leading to a cell cycle arrest in Gl, and the treatment sequence of cells +/- inductor (muristerone A) and test substance. c o MM <4-1 £ ic £ 0s 0 i ' T 1 1 1 1 -3 -2-10 1 Conc(log) ptA / D-80816 Fig. 3 Antiproliferative effect of D-80816 (Ex. F3) on RKO colon carcinoma cells arrested in the Gl phase of the cell cycle (induced) or undergoing the cell cycle, i.e. proliferating exponentially.
Description of the methods used XTT test for cellular dehydrogenase activity The adherently growing tumor cell lines HeLa/KB, SK-OV-3, MCF-7, L1210 and RKO were cultured under 20 standard conditions in a fumigation incubator at 37°C, 5% CO2 and 95% atmospheric humidity. On experimental day 1, the cells are detached using trypsin/EDTA and 100- 75 ' 50 " 25 * RKO p27 induced non-induced Page 98 pelleted by centrifugation. Subsequently, the cell pellet is resuspended in the respective culture medium at the appropriate cell count and reacted in a 96-well microtiter plate. The plates are then cultured 5 overnight in the fumigation incubator. The test substances are prepared as 10 mM stock solutions in DMSO and, on experimental day 2, diluted to the appropriate concentrations using culture medium. The substances in culture medium are then added to the 10 cells and incubated in the fumigation incubator for 45 h. As a control, cells which are not treated with the test substance are used. For the XTT assay, 1 mg/ml of XTT (sodium 3'-[1-(phenylaminocarbony1)-3,4-tetrazolium]bis(4-methoxy-6-nitro)benzenesulfonic acid) 15 is dissolved in RPMI-1640 medium without Phenol Red. Additionally, a 0.3 83 mg/ml PMS (N-methyldibenzo-pyrazine methylsulfate) solution in phosphate-buffered saline solution (PBS) is prepared. On experimental day 4, 75 ^I/well of XTT-PMS mixture is pipetted onto the 2 0 cell plates which in the meantime have been incubated with the test substances for 45 h. For this, shortly before use, the XTT solution is mixed with the PMS solution in the ratio 50:1 (v:v) . The cell plates are then incubated in the fumigation incubator for a 25 further 3 h and the optical density (OD490 nm) is determined in a photometer.
By means of the OD490 nm determined, the percentage inhibition is calculated relative to the control and plotted semilogarithmically in the form of a 30 concentration-activity curve. The IC50 is calculated by means of a regression analysis from the concentration-activity curve using the program Graphpad. i Determination of the antiproliferative activity in the 35 hollow fiber model in vivo The tumor cell lines HeLa/KB, MCF-7 and L1210 are introduced into hollow fibers made of poly(vinylidene) fluoride (5xl06 cells/ml) and transplanted into the Page 99 physiological compartments of the naked mouse (intraperitoneal, i.p., or subcutaneously, s.c.). In each test animal, a total of 6 hollow fibers are transplanted (3 i.p. and 3 s.c.), containing the tumor 5 cell lines in question. One group of 6 animals is treated with the test substance (i.p., lx daily for a total of 4 days) (ok?) . Animals treated only with the solvent tylose serve as control group. One day after the last application of substance, the hollow fibers 10 are explanted. The number of metabolically active, vital cells for each hollow fiber is determined using the XTT assay (see above) . From this, the antitumor activity of the test substance is determined in % inhibition relative to the control.
Cell cycle analysis using the RKOp27 model The assay is carried out in 96-well plates. By inducible expression of p27kipl, the growth of the cells is completely arrested, but the cells do not die. By 20 comparing the efficacy on induced and non-induced cells, it is possible to draw conclusions on the mechanism of action (cell cycle specificity) of the therapeutics. Non-induced cells are seeded in a cell count which is about four times higher, since, compared 25 to uninduced cells, there are no more divisions during the assay (2xl04 cells/well induced, about 0.6xl04 cells/well non-induced). The controls are untreated cells ( + /- induction) . Induction is carried out using 3 mM of muristerone A. On day 1, the cells are sown 30 ( + /- muristerone A) and incubated at 37°C for 24 h. On day 2, the test substance is added (control DMSO) and the samples are incubated at 37°C for a further 48 h before a standard XTT assay is carried out (see above).
The compounds according to the invention can be used as medicaments in the treatment of diseases, in particular tumor diseases, in mammals, in particular man.

Claims (13)

Page 100 Administration can be orally, topically or parenterally (i.m., i.v., s.c.) in the form of suitable administration forms. 5 Examples of suitable administration forms which may be mentioned are: Example I Tablet comprising 50 mg of active compound 10 Composition: (1) Active compound 50.0 mg (2) Lactose 98.0 mg (3) Corn starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg 15 (5) Magnesium stearate 2.0 mg Sum: 215 . 0 mg Preparation: (1), (2) and (3) are mixed and granulated using an 20 aqueous solution of (4) . (5) is mixed with the dried granules. This mixture is compacted to tablets. Example II Capsule comprising 50 mg of active compound 25 Composition: (1) Active compound 50.0 mg (2) Corn starch, dried 58.0 mg (3) Lactose, powdered 50.0 mg (4) Magnesium stearate 2.0 mg 30 Sum: 160.0 mg Preparation: (1) is ground with (3) . With vigorous mixing, this mixture is added to the mixture of (2) and (4). This 35 powder mixture is, in a capsule filling machine, filled into hard gelatin capsules size 3. WO 03/020731 Page 101 PCT/EP02/09539 Claims:
1. A compound of the formula I R2 ' R1 r4^dxjk-r6 ,(l> XX-' RS XJL, H where Rl is hydrogen, (C6-C14)-aryl which is unsubstituted 10 or fully or partially substituted by identical or different substituents, (C1-C13)-heteroaryl which contains at least one to four N, NH, 0 and/or S as ring members and is unsubstituted or fully or partially substituted by identical or different 15 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 20 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; 25 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 30 (C1-C6)-alkyl, straight-chain or branched (C1-C6)- alkyl which is substituted by one or more halogen atoms, straight-chain or branched (C1-C6)-alkoxy, straight-chain or branched (C1-C6)-alkoxy which is Page 102 substituted by one or more halogen atoms, straight-chain or branched (C1-C6)-alkylenedioxy, (C1-C6)-alkylcarbonyloxy, (C1-C6)-alkoxycarbonyl-oxy, (C1-C6)-alkylthio, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, carboxyl, (C1-C6)-alkyl carboxylate, carboxamide, N-(C1-C6)-alkyl- carboxamide, N,N-di-(C1-C6)-alkylcarboxamide, (C1-C6)-alkoxy-(C1-C6)-alkyl, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, where the two (C1-C6) radicals together may form a ring which optionally contains one or more NH, N-(C1-C6)-alkyl, 0 or S, (C6-C14)-aryl, (C6-C14)-aryloxy, (C6-C14)-aryl-(C1-C6)-alkyl, (C6-C14)-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; is (C6-C14)-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, 0 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, (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- Page 103 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, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl, (C6-C14)-aryl- (C1-C4)-alkoxy-(C1-C6)-alkyl; is a carbonyl (C=0), sulfoxide (S=0) or sulfonyl (S02) group; is an oxygen atom or a nitrogen atom substituted by the radical R7 (NR7), where R7 is (C6-C14)-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, (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, Page 104 straight-chain or branched (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, straight-chain or branched (C1-C6)-alkoxy, straight-chain or branched (C1-C6)-alkylenedioxy, (C1-C6)-5 alkoxy-(C1-C6)-alkyl, straight-chain or branched mono-(C1-C6)-alkylamino, straight-chain or branched di-(C1-C6)-alkylamino where the two (C1-C4)-radicals together may form a ring which optionally contains one or more 10 NH, N-(C1-C6)-alkyl, 0 or S, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl, (C6-C14)-aryl-(C1-C4)-alkoxy-(C1-C6)-alkyl, (C1-C6)- alkylcarbonyl, (C1-C6)-alkoxycarbonyl; 15 n is 0 or 1, with the proviso that, if n = 0, Z is a carbon atom substituted by the radical R8 (C-R8) where 20 R8 is (C6-C14)-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, 0 and/or S as ring members and is 25 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 30 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 35 selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxyl, (C1-C6)- Page 105 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, 5 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-10 chain or branched (C1-C6)-alkylthio, (C1-C4)- alkylsulfinyl, (C1-C4)-alkylsulfonyl, (C6-C14)-arylthio, (C6-C14)-arylsulfinyl, (C6-C14)-arylsulfonyl, (C1-C6)-alkoxy- (C1-C6)-alkyl, straight-chain or branched 15 mono-(C1-C6)-alkylamino, straight-chain or branched di-(C1-C6)-alkylamino where the two (C1-C4)-radicals together may form a ring which optionally contains one or more NH, N-(C1-C6)-alkyl, O or S, (C6-C14)-aryl, 20 (C6-C14)-aryloxy, (C6-C14)-aryl-(C1-C6)- alkyl, (C6-C14)-aryl-(C1-C4)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)- alkoxycarbonyl, straight-chain or branched mono-N-(C1-C6)-alkylcarbonylamino, straight-25 chain or branched di-N,N-(C1-C6)-alkyl carbonylamino , straight-chain or branched mono-N-(C1-C6)-alkoxycarbonylamino, straight-chain or branched di-N,N-(C1-C6)- alkoxycarbonylamino, straight-chain or 30 branched N-(C1-C6)-alkylcarbonylamino-N- (C1-C6)-alkylamino, straight-chain or branched N-(C1-C6)-alkoxycarbonylamino-N- (C1-C6)-alkylamino; 35 and that, if n = 1, Z is a nitrogen atom; Page 106 or a tautomer, a stereoisomer, a mixture or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1, wherein Rl is hydrogen, R2, 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-C14)-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-C14)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents, X is carbonyl (C=0), Z is a nitrogen atom and n = 1.
3. A compound as claimed in claim 1, wherein Rl is hydrogen, R2, R3, R4 and R5 independently of one another are hydrogen, halogen or (C1-C6)-alkoxy, R6 is straight-chain or branched (Cl-20)-alkyl which is unsubstituted or fully or partially substituted by identical or different substituents or is (C6-C14)-aryl which is unsubstituted or fully or partially substituted by identical or different substituents from the group consisting of (C1-C6)-alkoxy and halogen, n = 0, Z is the radical C-R8, where R8 is (C6-C14)-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 is carbonyl (C=0).
4. A compound as claimed in any one of claims 1 to 3 for use as a medicament. ,—, [INTELLECTUAL PROPERTY OFFlUt OF N.Z. 26 NOV 2004 n co c i r\ Page 107
5. The use of a compound as claimed in any one of claims 1 to 3 in the manufacture of a medicament for the treatment or control of tumor disorders in 5 mammals.
6. The use according to claim 5 wherein the mammal is a human. 10 7. A medicament, comprising at least one compound as claimed in any one of claims 1 to 3 together with pharmaceutically acceptable auxiliaries, diluents and/or carriers. 15 8. A method for preparing compounds of the formula I .
7. Page 108 substituted by one or more halogen atoms, straight-chain or branched (C1-C6)-alkoxycarbonyl, substituted (C6-C14)-aryl-(CI)-alkyl, straight-chain or branched (C1-C6)-alkylsulfonyl and 5 unsubstituted or (C1-C6)-alkyl-substituted
8. (C6-C14)-arylsulfonyl, 1.) (when n = 1) with 1.1) (when Y = oxygen)hydroxylamine or 10 1.2) (when Y = NR7) 15 is reacted with aa) oxime or bb) hydrazine derivative H2N-NH-R7 where R7 is as defined in claim 1, and cyclizing the resulting product with an activated carbonyl, sulfoxide or sulfonyl derivative, 20 or 2.) (when n = 0) with a phenylacetic acid derivative X1-CO-CH2-R8, where XI is a suitable leaving group, such as halogen or (C1-C6)-alkoxy, 25 and R8 is as defined in claim 1, followed by cyclization in the presence of base.
9. A compound of Formula I, substantially as herein 30 described with reference to the examples as exemplified in the specification or part thereof.
10. A compound of Formula I according to any one of claims 1 to 4, substantially as herein described 35 with reference to the examples as exemplified in the specification or part thereof. IPONZ 26 NOV 2004 Page 109
11. The use according to claim 5 or claim 6, substantially as herein described with reference to the examples and methods as exemplified in the specification or part thereof. •5
12. The medicament according to claim 7, substantially as herein described with reference to the examples and methods as exemplified in the specification or part thereof. 10
13. The method according to claim 8, substantially as herein described with reference to the examples and methods as exemplified in the specification or part thereof. 15 END OF CLAIMS IPONZ 26 NOV 20M
NZ531642A 2001-09-03 2002-08-27 Cyclic indole and heteroindole derivatives, the production and use thereof as medicaments NZ531642A (en)

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