AU1504900A - Substituted benzo(de)isoquinoline-1,3-diones - Google Patents

Substituted benzo(de)isoquinoline-1,3-diones Download PDF

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AU1504900A
AU1504900A AU15049/00A AU1504900A AU1504900A AU 1504900 A AU1504900 A AU 1504900A AU 15049/00 A AU15049/00 A AU 15049/00A AU 1504900 A AU1504900 A AU 1504900A AU 1504900 A AU1504900 A AU 1504900A
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conh
formula
het
pct
group
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AU15049/00A
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Gerhard Barnickel
Sabine Bernotat-Danielowski
Ralf Dr. Devant
Daljit Dhanoa
Todd Graybill
Werner Mederski
Guido Melzer
Peter Raddatz
James Rinker
Richard Soll
Zhengdong Wu
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Merck Patent GmbH
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Description

WO 00/31039 PCT/EP99/08560 Substituted benzo [de] isoquinoline-1, 3-diones This application is a continuation-in-part of Serial No. 09/199,409, the entirety of which is 5 incorporated by reference herein. The invention relates to substituted benzo[de] isoquinoline-1,3-diones of the formula I R1 o N 0 (CHR) R 2 10 in which R is H, A or CH 2 -Ph, R is -Het, -N- [ (CH 2 ) s-OH] 2, -N- [(CH 2 ) s-OA] 2, -NA- (CH 2 ) s-Ar, -NA- (CH 2 ) m-R 5 , -Y- (CH 2 ) m-R 5 , 15 -Y- (CH 2 ) 2 -NHA, -Y- (CH 2 ) 2 -NH- (CH 2 ) s-OH, -Y- (CH 2 ) 2
-NA
2 , -Y- (CH 2 ) m-OH, -Y- (CH 2 ) n- (CHR4) -R', -Y- (CH 2 ) n-R 4 , R 4 , -Y- (CH 2 ) n-Het- (CH 2 ) o-R , -Y- (CH 2 ) n-Ar' - (CH 2 ) o-R 6 -Het- (CH 2 ) n-Ar, -Het-Het, -Y- (CH 2 ) s-Ar' - (CH 2 ) 0
-R'
1 , -Y- [X-O] t- [X 1 0] u-X 2
-R
5 or -Y- (CH 2 ) n-NA- (CH 2 ) o-R 5 , 20 R 2 is H, OH, OA, COOH, COOA, CH(Ph)-Ph, Ar, Het, R 5 , R7 or R8 R3 is CH 3 , R 4 is -CH=CH 2 , -Ar, COOA, COOH o
H
3 C H H N H H I I I I N NCS or -N-CI N 0 NAr 0 O 25 R 5 is NH 2 , NHA, NA 2 , NHAr, -NH-(CH 2 )n-OH or -NH- (CH 2 ) n-OA, R 6 is H or R5 R7 is -Ar'-(CH 2 )n-R or -Ar'-(CH2)n-R5 WO 00/31039 PCT/EP99/08560 -2 R8 is CONH 2 , CONHA, CONA 2 , CONH-(CH 2 )o-Ar, CONH- (CH 2 ) -Het, CONH- (CH 2 ) -R 5 , CONH- (CH 2 ) -CH (Ar ) Ar 2 , CONH- (CH 2 ) o-CH (A) -Ph, CONH- (CH 2 ) o-Ar' -NH-CO-Ar, CONH-Ar'-Het or CHA-CONH 2 , 5 R" is -NH-(C=NH)-NH 2 , -NH-(C=NH)-NHA, -NH-(C=NH)-NA 2 ,
-NA-(C=NH)-NH
2 , -NA-(C=NH)-NHA or -NA-(C=NH)-NA 2 , Ar' is phenylene, cycloalkylene or biphenylene, which is unsubstituted or mono- or disubstituted by A, OH, OA, Hal, CN, NH 2 , NHA, NA 2 , NO 2 , CF 3 , CO-A, SO 2
NH
2 , SO 2 NAH, 10
SO
2
NA
2 , Ar is phenyl, cycloalkyl, naphthyl, cyclohex-l-enyl, biphenyl, bicyclohexyl, 4-cyclohexyl-phenyl, benzo[1,3]dioxol-5-yl, or indanyl, which is unsubstituted or mono-, di- or trisubstituted by 15 A, OH, OA, O-Ph, O-CH 2 -Ph, 0-Ph-CH 3 , O(cycloalkyl), Hal, CN, NH 2 , NHA, NA 2 , NH-C(O)A, (CH 2 )n-NH 2 , (CH 2 )n NHA, (CH 2 )n-NA 2 , NO 2 , CF 3 , C(O)A, S0 2 -Ph, SO 2
NH
2 ,
SO
2 NAH, SO 2
NA
2 or SO 2 NA-Ph, Arl and Ar2 20 are each independently phenyl, Het is a saturated, partially or completely unsatura ted mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or 0 atoms can be present and the heterocyclic 25 radical can be mono- or disubstituted by CN, Hal, OH, OA, CF 3 , A, NO 2 , CO, CO-A or R Het 1 is an unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or 0 atoms can be present 30 and/or can be mono- or disubstituted by Hal, OH, OA, A is unbranched or branched alkyl having 1-6 C atoms, Hal is F, Cl, Br or I, 35 X, 1 2 X X2 in each case independently of one another are alkylene having 1 to 12 C atoms, Y is 0, S or NH i is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, WO 00/31039 PCT/EP99/08560 -3 m is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, n,o in each case independently of one another are 0, 1, 2, 3 or 4, s is 1, 2, 3 or 4, 5 t is 0, 1 or 2, u is 1 or 2, where if R2 is Ar or H, R1 is not
H
2 -NGC
(CH
2 ). C
H
2 and their pharmaceutically tolerable salts and 10 solvates. Similar compounds having a benzo[de]iso quinoline-1,3-dione parent structure as dyes are disclosed in US 4,200,752, FR 2 271 216 A and Chemical Abstracts, Vol. 111, No. 20, November 1989. 15 US 3,821,383 describes benzo[de]isoquinoline acetic acid derivatives as active compounds in a pharmaceutical preparation against diabetes mellitus. Similar benzo[de]isoquinolines are also disclosed in EP 0 243 841 A and DE 37 07 652 A, which carry 20 alkylamino groups mainly in the 2-position. These derivatives are suitable for the treatment of solid tumours and certain forms of leukemia, as well as for the control of viral disorders. The benzo[de]iso quinoline derivatives from US 5,235,045 are mainly 25 present alkylated or alternatively fluoroalkylated in the 2-position and cause a chemical change to the lipid membrane of viruses or other target cells. The invention is based on the object of finding novel compounds having valuable properties, in parti 30 cular those which can be used for the production of medicaments. It has been found that the compounds of the formula I and their salts or solvates have very valuable pharmacological properties together with good 35 tolerability. They act especially as GPIbIX inhibitors, in particular inhibiting the interaction of this WO 00/31039 PCT/EP99/08560 -4 receptor with the ligand von Willebrand factor (vWF) This action can be demonstrated, for example, by a method which is described by S. Meyer et al. in J. Biol. Chem. 1993, 268, 20555-20562. The GPIbIX 5 alpha-thrombin receptor (N.J. Greco, Biochemistry 1996, 35, 915-921) can also be blocked by the compounds mentioned. The significance of GPIbIX as an adhesion receptor on platelets, which mediates the primary interaction of 10 platelets with an arteriosclerotically modified vascular wall via binding to the vWF expressed there, has been described by many authors (e.g. Z.M. Ruggeri in Thromb. Hemost. 1997, 78, 611-616) . The activation of another platelet adhesion receptor, GPIIbIIIa, 15 following the GPIbIX-vWF interaction, leads to platelet aggregation and thus to thrombotic vascular occlusion. A GPIbIX antagonist can thus prevent the start of thrombus formation and thus also release of active substances from the platelets which, for example, 20 promote thrombus growth and have an additional trophic action on the vascular wall. This has been shown with inhibitory peptides or antibodies in various experi mental models (e.g. H Yamamoto et al., Thromb. Hemost. 1998, 79, 202-210). 25 In the case of higher shear forces, the block ing action of GPIbIX inhibitors exerts its maximum effect, as described by J.J. Sixma et al. in Arteriosclerosis, Thrombosis, and Vascular Biology 1996, 16, 64-71. According to the flow chamber method 30 used there, the compounds of the formula I can be characterized as GPIbIX inhibitors in whole blood. The inhibition of thrombus formation of the GPIbIX inhibitors can be measured by a modified Born method (Nature 1962, 4832, 927-929) using botrocetin or 35 ristocetin as an aggregation stimulant. The compounds of the formula I according to the invention can therefore be employed as pharmaceutical active compounds in human and veterinary medicine. They act as adhesion receptor antagonists, in particular as WO 00/31039 PCT/EP99/08560 -5 glycoprotein IbIX antagonists, and are suitable for the prophylaxis and/or therapy of thrombotic disorders and sequelae deriving therefrom. The preferentially best action is to be expected in the case of thrombotic 5 disorders in the arterial vascular system, but GPIbIX inhibitors also have an effect in the case of thrombotic disorders in the venous vascular bed. The disorders are acute coronary syndromes, angina pectoris, myocardial infarct, peripheral circulatory 10 disorders, stroke, transient ischaemic attacks, arteriosclerosis, reocclusion/restenosis after angio plasty/stent implantation. The compounds can further more be employed as anti-adhesive substances where the body comes into contact with foreign surfaces such as 15 implants, catheters or cardiac pacemakers. Comparison medication introduced onto the market which may be mentioned are aspirin and GPIIbIIIa antagonists. The invention relates to the compounds of the 20 formula I and their salts or solvates, and to a process for the preparation of these compounds and their salts or solvates, characterized in that a) a compound of the formula I is liberated from one of its functional derivatives by treating with a 25 solvolysing or hydrogenolysing agent, or b) a compound of the formula II R9 0 0 0 30 in which
R
9 is Cl, Br, NO 2 or R 1 , and
R
1 has the meaning indicated in Claim 1 is reacted with a compound of the formula III 35 H 2 N-(CHR)i R2 III WO 00/31039 PCT/EP99/08560 -6 in which R, R 2 and i have the meanings indicated in Claim 1, and, if necessary, the radical R 9 is converted into a radical Ri, 5 or (c) a compound of the formula IV R9 IV o N 0 H in which
R
9 is Cl, Br, NO 2 or R 1 , where 10 R' has the meaning indicated in Claim 1 is reacted with a compound of the formula V L -- (CHR)i- R 2 v in which L is Cl, Br, or I, OH or a reactive esterified OH group and R, R2 and i have the meanings indicated in 15 Claim 1 and, if appropriate, the radical R9 is converted into a radical R 1 , or (d) a radical R and/or R 2 and/or R 9 is converted into 20 another radical R and/or R 2 and/or R 9 by, for example - converting an amino group into a guanidino group by reaction with an amidinating agent, - reacting an aryl bromide or iodide to give the 25 corresponding coupling products by means of a Suzuki coupling with boronic acids, - reducing a nitro group, sulfonyl group or sulfoxyl group, - etherifying an OH group or subjecting an OA 30 group to ether cleavage, - alkylating a primary or secondary amino group, - partially or completely hydrolysing a CN group, - cleaving an ester group or esterifying a carboxylic acid radical, WO 00/31039 PCT/EP99/08560 -7 - or carrying out a nucleophilic or electrophilic substitution, and/or (e) a base or acid of the formula I is converted into 5 one of its salts or solvates. The compounds of the formula I can have a chiral centre and therefore occur in a number of stereoisomeric forms. All these forms (e.g. R and S forms) and their mixtures (e.g. the RS forms) are 10 included in the formula I. The compounds according to the invention also include so-called prodrug derivatives, i.e. compounds of the formula I modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly 15 cleaved in the body to give the active compounds according to the invention. Furthermore, free amino groups as substituents of compounds of the formula I can be provided with appro priate conventional protective groups. 20 Solvates of the compounds of the formula I are understood as meaning adducts of inert solvent molecules to the compounds of the formula I which are formed on account of their mutual power of attraction. Solvates are, for example, mono- or dihydrates or 25 alcoholates. The abbreviations used have the following meanings: BOC tert-butoxycarbonyl CBZ benzyloxycarbonyl 30 DCC dicyclohexylcarbodiimide DMF dimethylformamide Et ethyl Fmoc fluorenylmethoxycarbonyl Me methyl 35 Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl OBut tert-butyl ester OMe methyl ester OEt ethyl ester POA phenoxyacetyl WO 00/31039 PCT/EP99/08560 -8 Ph phenyl TFA trifluoroacetic acid In the above formulae, A is alkyl and has 1 to 6, preferably 1, 2, 3 or 4 C atoms. Alkyl is preferably 5 methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, additionally also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, l-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 10 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl 1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl,. Ar is preferentially phenyl, preferably - as indicated - monosubstituted phenyl, specifically 15 preferentially phenyl, o-, m- or p-methylphenyl, o-, m or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m or p-aminophenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- or 20 p-sulfonamoylphenyl, o-, m- or p-nitrophenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-phenoxyphenyl, o-, m- or p-(phenylmethox)yphenyl, 0-, m- or p (trifluoromethyl)phenyl, o-, m- or 25 p-(trifluoromethoxy)phenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-iodophenyl, 4-benzenesulfonyl-phenyl, 4-(4 chloro-phenoxy)-phenyl, furthermore preferentially 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 30 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 35 2-chloro-3-methyl-, 2-chloro-4-methyl-, 2-chloro-5 methyl-, 2-chloro-6-methyl-, 3-chloro-2-methyl-, 4 chloro-2-methyl-, 5-chloro-2-methyl-, 3-chloro-4 methyl-, 3-chloro-5-methyl-, 4-chloro-3-methylphenyl, 2-bromo-3-methyl-, 2-bromo-4-methyl-, 2-bromo-5- WO 00/31039 PCT/EP99/08560 -9 methyl-, 2-bromo-6-methyl-, 3-bromo-2-methyl-, 4-bromo 2-methyl-, 5-bromo-2-methyl-, 3-bromo-4-methyl-, 3-bromo-5-methyl-, 4-bromo-3-methylphenyl, 2-iodo-3 methyl-, 2-iodo-4-methyl-, 2-iodo-5-methyl-, 2-iodo-6 5 methyl-, 3-iodo-2-methyl-, 4-iodo-2-methyl-, 5-iodo 2-methyl-, 3-iodo-4-methyl-, 3-iodo-5-methyl-, 4-iodo 3-methylphenyl, 2-chloro-3-methoxy-, 2-chloro-4 methoxy-, 2-chloro-5-methoxy-, 2-chloro-6-methoxy-, 3 chloro-2-methoxy-, 4-chloro-2-methoxy-, 5 10 chloro-2-methoxy-, 3-chloro-4-methoxy-, 3-chloro-5 methoxy-, 4-chloro-3-methoxyphenyl, 2-chloro-3 hydroxy-, 2-chloro-4-hydroxy-, 2-chloro-5-hydroxy-, 2-chloro-6-hydroxy-, 3-chloro-2-hydroxy-, 4 chloro-2-hydroxy-, 5-chloro-2-hydroxy-, 3-chloro-4 15 hydroxy-, 3-chloro-5-hydroxy-, 4-chloro-3-hydroxy phenyl, 3-fluoro-4-methoxy, 4-fluoro-3-methoxyphenyl, 2-chloro-3-fluoro-, 2-chloro-4-fluoro-, 2-chloro-5 fluoro-, 2-chloro-6-fluoro-, 3-chloro-2-fluoro-, 4 chloro-2-fluoro-, 5-chloro-2-fluoro-, 3-chloro-4 20 fluoro-, 3-chloro-5-fluoro-, 4-chloro-3-fluorophenyl, 2-fluoro-3-methyl-, 2-fluoro-4-methyl-, 2-fluoro-5 methyl-, 2-fluoro-6-methyl-, 3-fluoro-2-methyl-, 4 fluoro-2-methyl-, 5-fluoro-2-methyl-, 3-fluoro-4 methyl-, 3-fluoro-5-methyl-, 4-fluoro-3-methylphenyl, 25 2,5- or 3,4-dimethoxyphenyl, 3-diethylaminomethyl-4 hydroxy-phenyl, 1-dimethylamino-2-(toluene-4-sulfonyl) phenyl-4-yl, N-ethyl-2-methyl-N-phenyl-5-yl benzenesulfonamoyl, 3-cyclopentyloxy-4-methoxy-phenyl, 3,4-bis-benzyloxy-phenyl, 2-cyano-4,5-dimethoxyphenyl, 30 5-chloro-2,4-dimethoxy-phenyl, 2-cyano-3,4 dimethoxyphenyl or 3,4,5-trimethoxy-phenyl, furthermore, however, also preferentially unsubstituted naphthyl, cyclohex-1-enyl, benzo[1,3]-dioxol-5-yl, 4 cyclohexyl-phenyl, bicyclohexyl or indanyl. 35 Furthermore, however, Ar is also preferentially unsubstituted biphenyl - as indicated - or alternatively monosubstituted biphenyl, specifically preferentially biphenyl-4-yl or biphenyl-3-yl, 2'-methylbiphenyl-4-yl, 3'-methylbiphenyl-4-yl, WO 00/31039 PCTIEP99/08560 - 10 4' -methylbiphenyl-4-yl, 2' -methylbiphenyl-3-yl, 3' -methylbiphenyl-3-yl, 4' -methylbiphenyl-3-yl, 2-methylbiphenyl-4-yl, 3-rethylbiphenyl-4-yl, 2-methylbiphenyl-3-yl, 4-methylbiphenyl-3-yl, 2'-tert 5 butylbiphenyl-4-yl, 3' -tert-butylbiphenyl-4-yl, 4' -tert-butylbiphenyl-4-yl, 2' -tert-butylbiphenyl-3-yl, 3' -tert-butylbiphenyl-3-yl, 4' -tert-butylbipheriyl-3-yl, 2-tert-butylbiphenyl-4-yl, 3-tert-butylbiphenyl-4-yl, 2-tertbutylbiphenyl-3-yl, 4-tert-butylbiphenyl-3-yl, 10 2'-isopropylbiphenyl-4-yl, 3'-isopropylbiphenyl-4-yl, 4 '-isopropylbiphenyl-4-yl, 2'-isopropylbipheriyl-3-yl, 3'-isopropylbiphenyl-3-yl, 4 '-isopropylbiphenyl-3-yl, 2-isopropylbiphenyl-4-yl, 3-isopropylbiphenyl-4-yl, 2-isopropylbiphenyl), 4-isopropylbiphenyl-3-yl, 15 2'-fluorobiphenyl-4-yl, 3'-fluorobiphenyl-4-yl, 4' -fluorobiphenyl-4-yl, 2' -fluorobiphenyl-3-yl, 3' -fluorobiphenyl-3-yl, 4' -fluorobiphenyl-3-yl, 2-fluorobiphenyl-4-yl, 3-fluorobiphenyl-4 -yl, 2-fluorobiphenyl-3-yl, 4-fluorobiphenyl-3-yl, 20 2 '-methoxybiphenyl-4-yl, 3'-methoxybipheriyl-4-yl, 4' -rethoxybiphenyl-4-yl, 2' -methoxybiphenyl-3-yl, 3' -methoxybiphenyl-3-yl, 4' -methoxybiphenyl-3-yl, 2 methoxybiphenyl-4-yl, 3-methoxybiphenyl-4-yl, 2-methoxybiphenyl-3-yl, 4-methoxybiphenyl-3-yl, 25 2'-nitrobiphenyl-4-yl, 3'-nitrobiphenyl-4-yl, 4 '-nitrobiphenyl-4-yl, 2'-nitrobiphenyl-3-yl, 3' -nitrobiphenyl-3-yl, 4' -nitrobiphenyl-3-yl, 2-nitrobiphenyl-4-yl, 3-nitrobiphenyl-4-yl, 2-nitro biphenyl-3-yl, 4-nitrobiphenyl-3-yl, 30 2 '-trifluoromethylbiphenyl-4-yl, 3'-trifluoromethylbiphenyl-4-yl, 4 '-trifluoromethyl biphenyl-4-yl, 2' -trifluoromethylbiphenyl-3-yl, 3' -trifluoromethylbiphenyl-3-yl, 4 '-trifluoromethyl biphenyl-3-yl, 2-trifluoromethylbiphenyl-4-yl, 3-tri 35 fluoromethylbiphenyl-4-yl, 2-trifluoromethylbiphenyl-3 yl, 4-trifluoromethylbiphenyl-3-yl, 2' -trifluoromethoxybiphenyl-4-yl, 3' -trifluoromethoxy biphenyl-4-yl, 4' -trifluoromethoxybiphenyl-4-yl, 2' -trifluoromethoxybiphenyl-3-yl, WO 00/31039 PCT/EP99/08560 - 11 3'-trifluoromethoxybiphenyl-3-yl, 4'-tri fluoromethoxybiphenyl-3-yl, 2-trifluoromethoxybiphenyl 4-yl, 3-trifluoromethoxybiphenyl-4-yl, 2-trifluoromethoxybiphenyl-3-yl, 5 4-trifluoromethoxybiphenyl-3-yl, furthermore preferentially disubstituted biphenyls, such as 2'-methyl-3'-nitrobiphenyl-4-yl, 2'-methyl-4'-nitro biphenyl-4-yl, 2'-methyl-5'-nitrobiphenyl-4-yl, 2' methyl-6'-nitrobiphenyl-4-yl, 3'-methyl-2' 10 nitrobiphenyl-4-yl, 3'-methyl-4'-nitrobiphenyl-4-yl, 3'-methyl-5'-nitrobiphenyl-4-yl, 3'-methyl-6' nitrobiphenyl-4-yl, 4'-methyl-2'-nitrobiphenyl-4-yl, 4'-methyl-3'-nitrobiphenyl-4-yl, 2'-methyl-3' nitrobiphenyl-3-yl, 2'-methyl-4'-nitrobiphenyl-3-yl, 15 2'-methyl-5'-nitrobiphenyl-3-yl, 2'-methyl-6'-nitro biphenyl-3-yl, 3'-methyl-2'-nitrobiphenyl-3-yl, 3'-methyl-4'-nitrobiphenyl-3-yl, 3'-methyl-5' nitrobiphenyl-3-yl, 3'-methyl-6'-nitrobiphenyl-3-yl, 4'-methyl-2'-nitrobiphenyl-3-yl, 4'-methyl-3' 20 nitrobiphenyl-3-yl, 2'-methoxy-2-methylbiphenyl-4-yl, 3'-methoxy-2-methylbiphenyl-4-yl, 4'-methoxy-2 methylbiphenyl-4-yl, 4'-methoxy-3-nitrobiphenyl-4-yl, 2'-chloro-3'-fluorobiphenyl-4-yl, 2'-chloro-4' fluorobiphenyl-4-yl, 2'-chloro-5'-fluorobiphenyl-4-yl, 25 2'-chloro-6'-fluorobiphenyl-4-yl, 3'-chloro-2' fluorobiphenyl-4-yl, 3'-chloro-4'-fluorobiphenyl-4-yl, 3'-chloro-5'-fluorobiphenyl-4-yl, 3'-chloro-6' fluorobiphenyl-4-yl, 4'-chloro-2'-fluorobiphenyl-4-yl, 4'-chloro-3'-fluorobiphenyl-4-yl, 2'-chloro-3' 30 fluorobiphenyl-3-yl, 2'-chloro-4'-fluorobiphenyl-3-yl, 2'-chloro-5'-fluorobiphenyl-3-yl, 2'-chloro-6' fluorobiphenyl-3-yl, 3'-chloro-2'-fluorobiphenyl-3-yl, 3'-chloro-4'-fluorobiphenyl-3-yl, 3'-chloro-5' fluorobiphenyl-3-yl, 3'-chloro-6'-fluorobiphenyl-3-yl, 35 4'-chloro-2'-fluorobiphenyl-3-yl, 4'-chloro-3' fluorobiphenyl-3-yl, (2',3'-dimethoxy)biphenyl-4-yl, 2',4'-dimethoxy)biphenyl-4-yl, (2',5'-dimethoxy)biphenyl-4-yl, (2',6'-dimethoxy) biphenyl-4-yl, (31,4'-dimethoxy)biphenyl-4-yl, WO 00/31039 PCT/EP99/08560 - 12 (3',5'-dimethoxy)biphenyl-4-yl, (2',3'-dimethoxy) biphenyl-3-yl, (2',4'-dimethoxy)biphenyl-3-yl, (2',5'-dimethoxy)biphenyl-3-yl, (2',6'-dimethoxy) biphenyl-3-yl, (3',4'-dimethoxy)biphenyl)-3-yl, 5 (3',5'-dimethoxy)biphenyl-3-yl, (2',3'-di(trifluoromethyl))biphenyl-4-yl, (2',4'-di(trifluoromethyl))biphenyl-4-yl, (2',5'-di(trifluoromethyl))biphenyl-4-yl, (2',6'-di(trifluoromethyl))biphenyl-4-yl, 10 (3',4'-di(trifluoromethyl))biphenyl-4-yl, (31,5' di(trifluoromethyl))biphenyl-4-yl, (2',3'-di(trifluoromethyl))biphenyl-3-yl, (2',4'-di(trifluoromethyl))biphenyl-3-yl, (2',5' di(trifluoromethyl))biphenyl-3-yl, 15 (2',6'-di(trifluoromethyl))biphenyl-3-yl, (3',4'-di(trifluoromethyl))biphenyl-3-yl, (3',5' di(trifluoromethyl)biphenyl-3-yl, (2,2'-dimethyl)biphenyl-4-yl, (2,'3-dimethyl)biphenyl 4-yl, (2,4'-dimethyl)biphenyl-4-yl, 20 (2,2'-dimethyl)biphenyl-3-yl, (2,3'-dimethyl)biphenyl 3-yl or (2,4'-dimethyl)biphenyl-3-yl. Furthermore, Ar is preferably cycloalkyl, particularly preferred cyclohexyl or cyclopentyl. Ar 1 and Ar 2 are each independently phenyl. 25 Ar' preferentially is phenylene, cyclohexylene or biphenylene, which is unsubstituted or monosubstituted by Hal or CN. In -Ar' - (CH 2 ) n-R 5 , Ar' is preferentially unsubstituted or substituted phenylene or 30 cycloalkylene, where R 5 is preferentially an amino, alkylamino or dialkylamino group and where n can be 0, 1, 2, 3 or 4.
CH
2
NH
2
CH
2
NH
2 / \ CH 2
NH
2 or 35 is particularly preferred for -Ar'-(CH 2 )n-R 5 WO 00/31039 PCT/EP99/08560 - 13 In -Ar'- (CH 2 )n-R', Ar' is preferably unsubstituted or substituted phenylene or cycloalkylene, where R 8 is preferentially an amido, an alkylamido or dialkylamido group or -CONH-(CH 2 )o-Ar, 5 -CONH- (CH 2 ) o-Het, -CONH- (CH 2 ) o-CH (Ar ) -Ar 2, -CONH- (CH 2 ) o CH (A) -Ph or -CONH- (CH 2 ) -R 5 and where n is 0, 1, 2, 3 or 4.
CONH
2
CONH
2 -0 - CONH 2 I (,_C
CONH(C
3
H
7 ) ,
CONH(C
3
H
7 ) 10
CONH-(CH
2
)
2 -C(CH 3
)
3
CONH(C
5
H
1 ) or CONH(C 5
H
1 ) is particularly preferred for -Ar'-(CH2)n-R. 15
-CONH-CH
2 CONH
CONH-(CH
2
)
2 / CONH / \ CONH-CH 2 2 / CONH-(CH 2
)
2 WO 00/31039 PCT/EP99/08560 - 14 CONH-(CH 2
)
3 \ / CONH-(CH 2
)
4 CONH Br CONH CN /5\ CONH-(CH 2
)
2 / NO 2 / O CONH-CH 2 \ /
NO
2
CONH-CH
2 N CONH N C3 - ~ . OH 3 CONH \& < CH 3 CONH N C2H \ / CONH-CH 2 / \ SO 2
-NH
2 \ / CONH-(CH 2
)
2 / CH 3 CONH
CH
3
CH
3 CONH
CH
3 WO 00/31039 PCT/EP99/08560 - 15 CONH-CH 2 / \
CF
3 CONH CF
CF
3
CF
3 CONH CH -- -CONH--<2 CH3 CONH CONH-H
CH
3 C3 CONH CI CONH-CH2 10 c \ / CONH-(CH 2
)
2 / Cl WO 00/31039 PCT/EP99/08560 - 16 CONH Cl
CONH-(CH
2
)
2 cI CONH -CH 2 /a Cl
CONH-CH
2 CI CI CI \ / CONH-CH 2 / 5 CI \ / CONH-CH 2 /\CI CII \ / CONH-(CH 2
)
2 " cI Cl \ / CONH-CH 2 / c Cl CI CONH CI Cl 10 0CONH Cl \ / CONH-CH 2 /Q - F
CI
WO 00/31039 PCT/EP99/08560 - 17 CONH F Cl \ / CONH-CH 2 F \ / CONH-(CH 2
)
2 F
CONH-CH
2 F CONH 5 F CONH F
CONH-(CH
2
)
2 /H
OCH
3 CONH
OCH
3 \ / CONH-CH 2 / O
OCH
3 10 / CONH / OCH 3 \ / CONH-(CH 2
)
2 / OCH 3 WO 00/31039 PCT/EP99/08560 - 18 \ / CONH-CH 2 / OCF 3 F CONH OCH3 F CONH
H
3
CF
3 CONH CF
OCH
3 tert-butyl CONH 5 tert-butyl
CH
3 \ / CONH-(CH 2
)
2 / \
OCH
3 CONH-4 OH
OCH
3
OCH
3
CONH-(CH
2
)
2 OCH 3 OPh CONH-O< CONH OPh WO 00/31039 PCT/EP99/08560 - 19 CONH - &j
CH
3 CONH 0 Ph CONH
CONH-CH
2 CONH 0
CONH-CH
2 \ / CONH
OCH
3 Cl CONH CI
CF
3
CONH-(CH
2
)
2
CONH-CH
2
CONH-(CH
2
)
2
CI
WO 00/31039 PCT/EP99/08560 - 20 -0 -CONH-0H 2 / \ cl O0-ONH -0 cI
CONH-OH
2 / CA
CONH-CH
2 / 0 CONH
-
& < / \
--
CONH-CH 2 ) / '
CH
3 CONH3
CONH-CH
2 WO 00/31039 PCT/EP99/08560 - 21 0
CONH-CH
2 O CONH or
CONH-(CH
2
)
3 5 are furthermore particularly preferred for -Ar'- (CH 2 ) -R 8 where R' is -CONH- (CH 2 ) o-Ar.
CONH-CH
2 CONH
CONH-CH
2 N 10 CONH N N
CONH-(CH
2
)
2
CONH-(CH
2
)
2 -N
CONH-(CH
2
)
2 -N 0 0 15/ CONH-(CH 2
)
3 -N \ / CONH-(CH 2
)
2
-N
WO 00/31039 PCT/EP99/08560 - 22 CONH-(CH 2
)
3 -N N S
CONH-CH
2 \ I 0 \ / CONH-CH 2
CONH-(CH
2
)
2 -N 0 0 5
CONH-CH
2 \
CONH-(CH
2
)
3 -N
CONH-CH
2 N CONH / N CONH 10 or
CONH-CH
2 / is particularly preferred for -Ar'-(CH 2 )n-RB where R 8 is -CONH- (CH 2 ) o-Het.
CONH-(CH
2
)
2
-CH
WO 00/31039 PCT/EP99/08560 - 23 CONH-(CH 2
)
2 -CH or
CONH-CH
2 -CH is particularly preferred for -Ar'-(CH 2 )n-R 8 where R 8 is 5 -CONH- (CH 2 ) o-CH (Ar ) -Ar2 I-- CH 3
CONH-CH
2 -CH CH3 is particularly preferred for -Ar'-(CH 2 )n-R where R, is -CONH- (CH 2 ) o-CH (A) -Ph. Furthermore,
CONH-(CH
2
)
4 - NH 2 10\ CONH -(CH 2
)
4
-NH
2 10
CONH-(CH
2
)
2
-NH
2 or / 0 -CONH -(CH 2
)
2
-NH
2 is particularly preferred for -Ar'-(CH 2 )n-R 8 where R, is 15 -CONH- (CH 2 ) o-R. Cycloalkyl having 3 to 8 carbon atoms is preferentially cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; particularly preferred cyclohexyl or cyclopentyl. 20 Cycloalkylene having 3 to 8 carbon atoms is preferentially cyclobutylene, cyclopentylene, WO 00/31039 PCT/EP99/08560 - 24 cyclohexylene, or cycloheptylene; particularly preferred cyclohexylene. O(cycloalkyl) having 3 to 8 carbon atoms is preferentially cyclobutyloxy, cyclopentyloxy, 5 cyclohexyloxy or cycloheptyloxy; particularly preferred cyclopentyloxy. Hal is preferably F, Cl, Br or iodine. Het is preferentially substituted or unsubstituted 2-, 3-, or 4-pyridyl, 2- or 10 3-benzo[b]thiophenyl, 1H-indol-2-yl, 1H-indol-3-yl, 4-, 5-, 6-, 7-fluoro-1H-indol-2-yl, 4-, 5-, 6-, 7-fluoro 1H-indol-3-yl, 4-, 5-, 6-, 7-methyl-1H-indo-2-yl, 4-, 5-, 6-, 7-methyl-lH-indol-3-yl, 4-, 5-, 6-, methoxy-1H indol-2-yl or 4-, 5-, 6-, 7-methoxy-1H-indol-3-yl, 15 4-Pyridyl, 3-benzo[b]thiophenyl, 1H-indol-3-yl, 5 fluoro-1H-indol-3-yl, 5-methyl-1H-indol-3-yl, 5- or 6 methoxy-1H-indol-3-yl are furthermore particularly preferred. Het is preferably substituted or unsubstituted 20 2- or 3-furyl, 2- or 3-thienyl, 2-chloro-thienyl-5-yl, 2-acetyl-thienyl-5-yl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4 or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 25 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-l-, -4- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 30 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-1H-indolyl, 35 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3- WO 00/31039 PCT/EP99/08560 - 25 oxadiazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 5 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 1, 1-dioxo-1H-1X 6 -benzo[blthiophen-5-yl or 2,2-dioxo-2,3-dihydro-1H-2k 6 -benzo[c]thiophen-5-yl. The heterocyclic radicals can also be partially or completely hydrogenated. Het can thus also be 10 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 15 3-pyrrolidinyl, pyrrolidine-2-on-1-yl, tetrahydro-1-, -2- or -3-pyrrolyl, tetrahydro-l-, -2- or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4-, -5-, -6-, -7-1H-indolyl, 2,3-dihydro-l-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-l-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, 20 -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-l-, -2-, -3-, -4-, -5- or -6-pyridyl, 1,2,3,6-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 1-, 2-, 3- or 4-azepanyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 25 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro 1-, -3- or -4-pyridazinyl, hexahydro-l-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-l-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolinyl, 1,2,3,4-tetrahydro-l-, -2-, -3-, -4-, 30 -5-, -6-, -7- or -8-isoquinolinyl. 2-, 3- or 4-pyridyl, 1-imidazolyl, 2-methyl-l-imidazolyl, 2-pyrimidinyl, 5-fluoro-lH indol-2-yl, 2, 3-dihydro-l-, -2-, -3-, -4-, -5-, -6-, -7-1H-indolyl, 1-quinolinyl, 1-isoquinolinyl, 35 1,2,3,4-tetrahydroisoquinoline-1-yl, tetrahydro 1-pyrrolyl, 1-piperidinyl, 2,6-tetramethyl piperidine-4-yl, 1-azepanyl, 4-morpholinyl, 1 piperazinyl, 4-methyl-piperazin-1-yl, 4-phenyl- WO 00/31039 PCT/EP99/08560 - 26 piperazin-1-yl or 4-phenylmethylpiperazin-1-yl is particularly preferred. In -Het-(CH 2 )n-Ar, Het and Ar have one of the preferred meanings indicated above, where Het is 5 preferably piperidine-1,4-diyl or piperazine-1,4-diyl and n can be 0, 1, 2, 3, or 4. 0
/
or -N N-CH 2 / \ is particularly preferred for -Het-(CH 2 )n-Ar. In -Het-Het, Het has one of the preferred 10 meanings indicated above, where in -Het-Het the first heterocycle is preferably piperidine-1,4-diyl or piperazine-1,4-diyl. N --N N N or -N N is particularly preferred for -Het-Het. 15 In -Y-(CH 2 )n-Het-(CH 2 )o-R 6 , Y is preferably 0, S or NH, where Het has one of the preferred meanings indicated above and R is preferentially H, amino or alkylamino. Furthermore, n and o independently of one another are preferably 0, 1, 2, 3 or 4.
-NH-(CH
2
)
2 -- NvO . -NH-(CH 2
)
3 -N N-CH 3 20 - N-
N
-NH-(CH
2
)
2 . -NH-CH 2 -NH-(CH 2
)
2 - ~NH-(CH 2
)
3 -N N -H(H3 N - NH-(H 2
)
3
-N-N-(H
2 )a-NH 2 WO 00/31039 PCT/EP99/08560 - 27 or -. NH N are particularly preferred for -Y-(CH 2 )n-Het(CH 2 )o-R 6 . Furthermore, in -Y- (CH 2 ) -Ar' - (CH 2 ) o-R 6 f Y is preferentially 0, S, or NH, where Ar' has a preferred 5 meaning indicated beforehand and R 6 is preferably H, amino or alkylamino and n and o independently of one another are 0, 1, 2, 3 or 4. -NH -NH , -NH I
-NH-(CH
2
)
2 -0/ OH-
-NH-CH
2 10 -NH-CH 2 \X/ 0 2 -NH 2
-NH-CH
2 -O/
NH
2 ' -NH-(CH 2
)
2 \ /
-NH-CH
2 / \ CH 2 - NH 2
-NH-CH
2 CH 2 - NH 2 NH-CH2
CH
2
-
NH 2
OH
2 - NH 2 or .NH-CH 2 15 is particularly preferred for -Y-(CH 2 )n-Ar'-(CH 2
)
0 o-R 6 Furthermore, in -Y- (CH 2 ) s-Ar'- (CH 2 )o-R, Y is preferentially 0, S, or NH, where Ar' has a preferred meaning indicated beforehand and R" is preferably -NH (C=NH) -NH 2 and s and o independently of one another are 20 0, 1, 2, 3 or 4.
WO 00/31039 PCT/EP99/08560 - 28 NH CH2~-
NH
2
.NH-CH
2 is particularly preferred for -Y- (CH 2 ) 3-Ar'- (CH 2
)
0 -R". X and/or X 1 and/or X 2 is alkylene and is 5 preferably methylene, ethylene, propylene, butylene, furthermore also pentylene or hexylene. In -Y-[X-O]t-[X 1 -0]u-X 2
-R
5 , Y is preferentially 0, S or NH, where X, X 1 and X 2 have a preferred meaning indicated beforehand. Furthermore, R 5 is preferably 10 amino, alkylamino or dialkylamino, t is 0, 1 or 2 and u is 1 or 2. -NH- (CH 2 ) 3 -0- (CH 2 ) 4 -0- (CH 2 ) 3
-NH
2 is particularly preferred for -Y-[X-O]t-[X'-O]u-X 2 -R'. Y is preferentially 0, S or NH, particularly preferentially NH. 15 R is preferably H, A, or CH 2 -Ph, where A has a preferred meaning indicated above. H, sec-butyl or
CH
2 -Ph is particularly preferred. R is preferably -Het, -N-[ (CH 2 ) s-OH] 2 . -N- [ (CH 2 ) s-OA] 2 , -NA- (CH 2 ) s-Ar, -NA- (CH 2 )m-R , 20 -Y- (CH 2 ) m-R, Y- (CH 2 ) 2-NHA, -Y- (CH 2 ) 2-NA 2 , -Y- (CH 2 ) 2 -NH- (CH 2 ) s-OH, -Y- (CH 2 ) m-OH, -Y- (CH 2 ) n- (CHR 4 ) -R , -Y- (CH 2 ) n-R 4 , R 4 , -Y- (CH 2 ) n-Het- (CH2) o-R , -Y- (CH 2 ) n-Ar' - (CH 2 ) o-R 6 , -Het- (CH 2 ) n-Ar, -Het-Het, -Y- [X-0] t- [X1-0] u-X 2
-R
5 or -Y- (CH 2 ) n-NA- (CH 2 ) o-R 5 , where 25 -Het, -Y- (CH 2 ) -Het- (CH 2 ) o-R 6 , -Y- (CH 2 ) -Ar' - (CH 2 ) o-R 6 -Y- (CH 2 ) s-Ar' - (CH 2 ) o-R 11 , -Het- (CH 2 ) n-Ar, -Het-Het and -Y-[X-O]t-[X 1 -O]u-X 2
-R
5 in particular have the preferred meanings indicated beforehand. Furthermore, s in
-N-[(CH
2 )s-OH] 2 and -N-[(CH 2 )s-OA] 2 is preferably 1, 2, 3 30 or 4 and A has the preferred meaning indicated beforehand. -N-[(CH 2
)
2
-OH]
2 is particularly preferred for -N-[(CH 2 )s-OH]2- WO 00/31039 PCT/EP99/08560 - 29 In -NA-(CH 2 )s-Ar, A and Ar have a preferred meaning indicated beforehand and s is preferably 1, 2, 3 or 4. OH
-N(CH
3
)-(CH
2
)
2 / -OH 5 is particularly preferred for -NA-(CH 2 )s-Ar. Furthermore, A in -NA-(CH 2 )s-R 5 as a substituent for R 1 has a preferred meaning indicated beforehand, where R 5 is preferably amino, alkylamino or dialkylamino and s is 1, 2, 3 or 4. -N (CH 3 ) - (CH 2 ) 3 -NH (CH 3 ) and 10 -N(CH 3
)-(CH
2
)
2
-N(C
2
H
5
)
2 are particularly preferred for -NA- (CH 2 ) 3-R 5 . In -Y-(CH 2 )m-R 5 Y is preferentially 0, S or NH, where R 5 is preferably amino, alkylamino or dialkylamino and m is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. -NH- (CH 2 ) 3
-NH
2 , 15 -NH- (CH 2 ) 3 -NH (CH 3 ) , -NH- (CH 2 ) 3 -N (CH 3 ) 2, -NH- (CH 2 ) 3 -NH [CH (CH 3 ) 2], -NH- (CH 2 ) 3 -NH (C 6
H
1 1 ) , -NH- (CH 2 ) 4
-NH
2 , -NH- (CH 2 ) 5
-NH
2 , -NH- (CH 2 ) 7
-NH
2 and -NH- (CH 2 ) 8
-NH
2 are particularly preferred for -Y- (CH 2 ) m-R 20 In -Y-(CH 2
)
2 -NHA and -Y-(CH 2
)
2
-NA
2 , Y is preferably 0, S or NH, where A has a preferred meaning indicated beforehand. -NH- (CH 2 ) 2 -NH (C 2
H
5 ) , -NH- (CH 2 ) 2 -NH (C 3
H
7 ) and -NH- (CH 2 ) 2 -NH [CH (CH 3 ) 2 ] are particularly preferred for -Y- (CH 2 ) 2 -NHA. 25 In -Y-(CH 2
)
2
-NH-(CH
2 )s-OH, Y is preferably 0, S or NH, where s is 1, 2, 3 or 4. -NH- (CH 2 ) 2 -NH (CH 2 ) 2 -OH is particularly preferred for -Y- (CH 2
)
2
-NH-(CH
2 )s-OH. In -Y-(CH 2 )m-OH, Y is preferably 0, S or NH, where m is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. -NH- (CH 2 ) 5 -OH is 30 particularly preferred for -Y-(CH 2 )m-OH. In -Y-(CH 2 )n-(CHR 4
)-R
3 , Y is preferably 0, S or NH, where
R
3 is preferably methyl, R 4 is preferentially Ar and n is 0, 1, 2, 3 or 4. -NH-(CHPh)-CH 3 is particularly preferred for -Y-(CH 2 )n-(CHR 4
)-R
3 . 35 In -Y-(CH 2 )n-R 4 , Y is preferentially 0, S or NH, where in this formula R4 is preferably COOH or COOA, A has a WO 00/31039 PCT/EP99/08560 - 30 preferred meaning indicated beforehand and n is 0, 1, 2, 3 or 4. -NH-(CH 2
)
2 -COOMe is particularly preferred . In -Y-(CH 2 )n.-NA-(CH 2 )o-R 5 , Y is preferentially 0, S, NH, where A has a preferred meaning indicated beforehand, R 5 5 is preferably amino, alkylamino or dialkylamino and n and o in each case independently of one another are 0, 1, 2, 3 or 4. -NH- (CH 2 ) 3 -N (CH 3 ) - (CH 2 ) 3
-NH
2 is particularly preferred for -Y- (CH2) -NA- (CH 2 ) o-R 5 . i is preferentially 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 10, 11 or 12, particularly preferentially 1, 2, 3, 5, 7, 10 or 11.
R
2 is preferably H, OH, OA, COOH, COOA, Ar, CH(Ph)-Ph, Het 1 , R , R 7 or R , where A, Ar and Het' have a preferred meaning indicated beforehand. 15 R 3 is preferentially
CH
3 .
R
4 is preferably -CH=CH 2 , Ar, COOA, COOH o H 3 C H H N H H -N-CS or -N--C, N O Ar o 0 where Ar and A have a preferred meaning indicated beforehand. H H H 3 C N -N--C HCOH 200 20 H3e CH3 is particularly preferred for H H H 3 C -N-C 0 Ar R is preferentially amino, alkylamino, dialkylamino, NHAr, -NH-(CH 2 ) n-OH or -NH-(CH 2 )n-OA, where 25 A and Ar have a preferred meaning indicated beforehand WO 00/31039 PCT/EP99/08560 - 31 and n is 0, 1, 2, 3, or 4. -NH-(CH 2
)
2 -OH is particularly preferred for -NH-(CH 2 )n-OH. R6 is H or R 5 , where R5 has a preferred meaning indicated beforehand. 5 R 7 is preferentially -Ar'-(CH 2 )n-R' or -Ar'- (CH 2 ) n-R 5 , where -Ar'-(CH 2 )n-R 8 and -Ar'- (CH 2 ) n-R 5 have a preferred or particularly preferred meaning indicated beforehand. R 8 is preferably CONH 2 , CONHA, CONA 2 , 10 CONH- (CH 2 ) o-Ar, CONH- (CH 2 ) o-Het, CONH- (CH 2 ) o-CH (Ar 1 ) -Ar 2 , CONH-Ar' -NH-CO-Ar, CONH-Ar' -Het, CONH- (CH 2 ) o-R 5 or
CHA-CONH
2 , where A, CONH- (CH 2 ) o-Ar, CONH- (CH 2 )o 0 -Het, CONH- (CH 2 ),o-CH (Ar) -Ar 2 , and CONH- (CH2) o-R 5 have a preferred or particularly preferred meaning indicated 15 beforehand in -Ar'-(CH 2 )n-R 8 . CH(CH 3
)-CONH
2 is particularly preferred for CHA-CONH 2 ,CH 3 0 0 CONH N 0-CH 3 is particularly preferred for CONH-Ar'-NH-CO-Ar. CONH N 0 CI CONH / N 20 CN CONH S CONH
S
WO 00/31039 PCT/EP99/08560 - 32 CONH O / s SZ CONH - CFH3 0 CONH/ CI or CONH 5 is particularly preferred for CONH-Ar'-Het. R11 is -NH-(C=NH)-NH 2 , -NH-(C=NH)-NHA, -NH- (C=NH) -NA 2 , -NA-(C=NH)-NH 2 , -NA-(C=NH)-NHA or
-NA-(C=NH)-NA
2 , where A has a meaning indicated 10 beforehand. -NH-(C=NH)-NH 2 is particularly preferred for Ril i is preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, particularly preferred 1, 2, 3, 4, 5 or 6. m is preferably 3, 4, 5, 6, 7, 8, 9, 10, 11 or 15 12, particularly preffered 3, 4, 5, 6, 7 or 8. n and o are in each case independently of one another preferably 0, 1, 2, 3 or 4. s is preferably 1, 2, 3 or 4. t is preferably 0, 1 or 2. 20 u is preferably 1 or 2. Some preferred groups of compounds can be expressed by the following subformulae Ia to Iv, which correspond to the formula I WO 00/31039 PCT/EP99/08560 - 33 R1 0 N O (CHR)i R2 and in which the radicals not designated in greater detail have the meanings indicated in formula I, but in 5 which: in Ia R is H, R2 is H,
R
1 is -Het, -N- [ (CH 2
)
3
-OH]
2 , -Y-(CH 2 )n-R 4 or R 4 10 and i is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; in Ib R is H, R2 is OH 15 R 1 is -Het or -Y- (CH 2 ) n- (CHR 4 ) -R 3 and i is 2; in Ic R is H, 20 R2 is COOA, RI is -Het, -Y- (CH 2 ) - (CHR 4 ) -R 3 , -Y- (CH 2 ) n-Ar' - (CH 2 ) o-R , -Het- (CH 2 ) n-Ar or -NA- (CH 2 )s-Ar and i is 2; 25 in Id R is H, R2 is Ar, R is -Het, -NA-(CH 2 )s-Ar, -Y-(CH 2 )m-R, -Y- (CH 2 ) m-OH, -Y- (CH 2 ) n- (CHR 4 ) -R 3 , 30 -Y- (CH 2 ) n-R 4, -Y- (CH 2 ) n-Het- (CH 2 ) o-R6, -Y- (CH 2 ) n-Ar' (CH 2 ) o-R 6 or -Het- (CH 2 ) n-Ar and i is 1 or 2; WO 00/31039 PCT/EP99/08560 - 34 in Ie R is H, R2 is Het', R is -Het, -NA- (CH 2 ) s-Ar, -Y- (CH 2 )m-R 5 , -Y- (CH 2 ) m-OH, -Y- (CH2) n- (CHR 4 ) -R 3 , 5 -Y- (CH 2 )n-R 4 , -Y- (CH2) n-Ar' (CH2) o-R 6 or -Het- (CH 2 )na-Ar and i is 1 or 2; in If R is H, 2 5 10 R is R R' is -Het, -Y-(CH 2 ),m-R 5 , -Y- (CH 2 ).-OH, -Y- (CH2) n- (CHR') -R3, -Y- (CH2) n-R, -Y- (CH 2 ) n-Het- (CH 2 ) o-R 6 , -Y- (CH 2 ) n-Ar' - (CH 2 ) o-R 6 or -Het- (CH 2 ) n-Ar and 15 i is 3 or 5; in Ig R is H, R2 is R,
R
1 is -Het, -NA-(CH 2 )m-R 5 , -Y- (CH 2 ) m-R 5 20 -Y- (CH 2 ) 2-NH- (CH 2 ) s-OH, -Y- (CH 2 ) m-OH, -Y- (CH2) n- (CHR') -R3, -Y- ( CH2) n-R, -Y- (CH 2 ) n-Het- (CH 2 ) o-R 6 , -Y- (CH 2 ) n-Ar' - (CH 2 ) o-R 6 , -Het- (CH 2 ) n-Ar, -Het-Het, -Y-[X-O]t-[X 1 -0] u-X 2
-R
5 or 25 -Y- (CH 2 )n-NA- (CH 2 ) o-R 5 and i is 1, 2, 7, 10 or 11; in Ih R is H, 2 7 R is R, 30 R 1 is -Het, -NA-(CH 2 )m-R 5 , -Y-(CH 2 )m-R 5 , -Y- (CH 2 ) 2 -NHA, -Y- (CH 2 ) 2 -NH- (CH 2 ) s-OH, -Y- (CH 2 ) m-OH, -Y- (CH 2 ) n- (CHR 4 ) -R 3 , -Y- (CH 2 ) n-R 4 , -Y- (CH 2 ) -Het- (CH 2 ) o-R 6 , -Y- (CH2) n-Ar' (CH2) o-R 6 35 -Y- (CH2) s-Ar' - (CH2) o-Ri , -Het- (CH2) n-Ar, -Het-Het, -Y-[X-O]t-[X -0] -X 2
-R
5 or -Y- (CH 2 ) n-NA- (CH 2 ) o-R 5 and i is 1 or 2; WO 00/31039 PCT/EP99/08560 - 35 in Ik R is A or CH 2 -Ph, R2 is R8,
R
1 is -Het, -Y- (CH 2 ) m-R 5 , -Y- (CH 2 ) n-Het- (CH 2 ) o-R 6 or -Y- (CH 2 )n-Ar' - (CH 2 ) o-R 6 and 5 i is 1; in Im R is H,
R
2 is CONH 2 , R is -Het, -NA-(CH 2 )m-R, -Y-(CH 2 )m-R, 10 -Y-(CH 2 )2-NH-(CH 2 ) s-OH, -Y-(CH 2 )m-OH, -Y- (CH2) n- (CHR') -R3, -Y- (CH2) .- R, -Y- (CH 2 ) n-Het- (CH 2 ) o-R 6 , -Y- (CH 2 )n-Ar' - (CH 2 ) o-R 6 , -Het- (CH 2 )n-Ar, -Het-Het, -Y-[X-O]t-[Xl-O]u-X 2
-R
5 or 15 -Y- (CH 2 )n-NA- (CH 2 ) o-R 5 and i is 1, 2, 7, 10 or 11; in In R is H, R2 is CONHA, 20 R 1 is -Y-(CH 2 )m-R 5 or -Y- (CH 2 ) -Ar' - (CH 2 ) o-R 6 and i is 2; in Io R is H, 25 R2 is CONH- (CH 2 ) -Ar,
R
1 is -Y- (CH 2 ) m-R 5 , -Y- (CH 2 ) n-Het- (CH 2 ) o-R 6 or -Y- (CH 2 ) n-Ar'- (CH 2 ) o-R6 and i is 1 or 2; 30 in Ip R is H, R2 is CONH- (CH 2 )o-Het, Rl is -Y- (CH 2 ) m-R 5 , or -Y- (CH 2 ) -Ar' - (CH 2 ) o-R 6 and i is 2; 35 in Iq R is H, 2 1 2 R is CONH- (CH 2 ) -CH (Ar ) -Ar
R
1 is -Y- (CH 2 ) n-Ar'- (CH 2 ) -R 6 and i is 2; WO 00/31039 PCT/EP99/08560 - 36 in Ir R is H, R2 is CONH-Ar'-NH-CO-Ar, R is -Y- (CH 2 ) -Ar' -(CH2) o-R6 and i is 2; 5 in Is R is H, R2 is CONH-Ar'-Het,
R
1 is -Y- (CH 2 ) n-Ar' - (CH 2 ) o-R 6 and i is 2; 10 in It R is H, R2 is CH(Ph)-Ph,
R
1 is -Y- (CH 2 ) m-R 5 , or -Y- (CH 2 ) n-Ar' -(CH 2 ) o-R 6 and i is 2; 15 in Iu R is H, 2 8 R is Ar'-(CH 2 )n-R R is -Y- (CH 2 ) m-R , -Y- (CH 2 ) n-Ar'- (CH 2 ) o-R 6 or
-Y-(CH
2 ),n-Ar'-(CH2)o-R 1 ' and 20 i is 1 or 2; in Iv R is H, R2 is Ar, R or Ar'- (CH 2 ) n-R8,
R
1 is -Y- (CH 2 ) m-R 5 , or -Y- (CH 2 ) n-Ar' - (CH 2 ) o-R 6 and 25 i is 1 or 2. The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described 30 in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), namely under reaction conditions which are known and suitable for the reactions mentioned. In this case, use 35 can also be made of variants which are known per se, but not mentioned here in greater detail. The starting substances, if desired, can also be formed in situ such that they are not isolated from WO 00/31039 PCT/EP99/08560 - 37 the reaction mixture, but immediately reacted further to give the compounds of the formula I. The compounds of the formula I can be obtained by liberating them from their functional derivatives by 5 solvolysis, in particular hydrolysis or by hydrogen olysis. Preferred starting substances for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more 10 free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxyl groups, in particular those which instead of an H-N- group carry an R'-N group, in which R' is an amino protective group and/or those which instead of the H atom of a hydroxyl group 15 carry a hydroxyl protective group, e.g. those which correspond to the formula I, but instead of a group COOH carry a group -COOR", in which R" is a hydroxyl protective group. A number of - identical or different 20 protected amino and/or hydroxyl groups can also be present in the molecule of the starting substance. If the protective groups present are different from one another, in many cases they can be removed selectively. The expression "amino protective group" is 25 generally known and relates to groups which are suitable for protecting (for blocking) an amino group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. Typical 30 groups of this type are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size is otherwise not critical; 35 however, those having 1-20, in particular 1-8, C atoms are preferred. The expression "acyl group" is to be interpreted in the widest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic WO 00/31039 PCT/EP99/08560 - 38 carboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl groups, aryloxycarbonyl groups and especially aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl such as acetyl, 5 propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ 10 ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, Fmoc; arylsulfonyl such as Mtr. Preferred amino protective groups are BOC, furthermore CBZ, Fmoc, benzyl and acetyl. The expression "hydroxyl protective group" is 15 also generally known and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. Typical groups 20 of this type are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups. The nature and size of the hydroxyl protective groups is not critical, since they are removed again after the desired chemical reaction or 25 reaction sequence; groups having 1-20, in particular 1-10 C atoms, are preferred. Examples of hydroxyl protective groups are, inter alia, benzyl, p-nitrobenzoyl, p-toluolsulfonyl, tert-butyl and acetyl, benzyl and tert-butyl being particularly 30 preferred. The liberation of the compounds of the formula I from their functional derivatives is carried out - depending on the protective group used - for example using strong acids, expediently using TFA or 35 perchloric acid, but also using other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene- or p-toluene sulfonic acid. The presence of an additional inert WO 00/31039 PCT/EP99/08560 - 39 solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, 5 halogenated hydrocarbons such as dichloromethane, furthermore also alcohols such as methanol, ethanol or isopropanol, and also water. Furthermore, mixtures of the abovementioned solvents are possible. TFA is preferably used in an excess without addition of a 10 further solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures for the cleavage are expediently between approximately 0 and approximately 500C; the reaction is preferably carried 15 out between 15 and 300C (room temperature). The groups BOC and Obutyl can preferably be removed, for example, using TFA in dichloromethane or using approximately 3 to 5N HCl in dioxane at 15-30 0 C, the Fmoc group using an approximately 5 to 50% solution 20 of dimethylamine, diethylamine or piperidine in DMF at 15-30 0 C. Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst 25 (e.g. of a noble metal catalyst such as palladium, expediently on a support such as carbon). Suitable solvents in this case are those indicated above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. As a rule, the 30 hydrogenolysis is carried out at temperatures between approximately 0 and 1000C and pressures between approximately 1 and 200 bar, preferentially at 20-30*C and 1-10 bar. Hydrogenolysis of the CBZ group takes place readily, for example, on 5 to 10% Pd/C in 35 methanol or ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-300C. Compounds of the formula I can also preferably be obtained by reacting compounds of the formula II with compounds of the formula III. As a rule, the WO 00/31039 PCT/EP99/08560 - 40 starting compounds of the formulae II and III are known or commercially available. The unknown compounds, however, can be prepared by methods known per se. The compounds of the formula II are naphthalene 5 1,8-dicarboxylic anhydride derivatives. They can be prepared in a conventional manner from appropriately substituted 1,8-naphthalenedicarboxylic acids or corresponding derivatives. It is furthermore possible to introduce appropriate substituents into the aromatic 10 by conventional electrophilic or alternatively nucleophilic substitutions. The compounds of the formula III are primary amines, which, as a rule, are also commercially available. Furthermore, syntheses for the preparation 15 of primary amines, such as, for example, the Gabriel synthesis, can be used. As a rule, the reaction is carried out in an inert solvent. Depending on the conditions used, the reaction time is between a few minutes and a number of 20 days, the reaction temperature between approximately 00 and 150'C, normally between 200 and 130 0 C. The reactions can be carried out in analogy to the methods indicated in Eur. J. Chem. Chim. Ther. 1981, 16, 207 212 and in J. Med. Chem. 1982, 25, 714-719. 25 Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols 30 such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl 35 glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, N-methylpyrrolidone (NMP), dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide WO 00/31039 PCT/EP99/08560 - 41 (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or mixtures of the solvents mentioned. 5 For the preparation of compounds of the formula I in which R" 1 is H 2 N-C(=NH)-NH-, an appropriate amino-substituted compound can be treated with an amidinating agent. The preferred amidinating agent is 1-amidino-3,5-dimethylpyrazole (DPFN), which is 10 employed, in particular, in the form of its nitrate, or pyrazole-1-carboxamidine. The reaction is expediently carried out with addition of a base such as triethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, e.g. DMF at temperatures 15 between 00 and 150 0 C, preferably between 60* and 120'C. For the preparation of compounds of the formula I in which R 2 is unsubstituted or substituted biphenyl, -Ar' -Het and/or -CONH- (CH 2 ) o-Ar, an appropriate compound of the formula I in which R 2 is 20 aryl bromide or aryl iodide can be reacted with the appropriate boronic acid derivatives in a Suzuki reaction. The Suzuki reaction is expediently carried out in palladium-mediated form, preferably by addition of Pd (PPh 3 ) 4 , in the presence of a base such as 25 potassium carbonate in an inert solvent or solvent mixture, e.g. DMF at temperatures between 00 and 1500, preferably between 600 and 1200. Depending on the conditions used, the reaction time is between a few minutes and a number of days. The boronic acid 30 derivatives can be prepared by conventional methods or are commercially available. The reactions can be carried out in analogy to the methods indicated in Suzuki et al., J. Am. Chem. Soc. 1989, 11, 314ff. and Suzuki et al., Chem. Rev. 1995, 95, 2457ff. 35 The compounds of the formula IV are derived from the anhydrides of the formula II and can be prepared from these by reaction with ammonia under conditions known per se. As a rule, the imides of the formula IV, however, are known and commercially WO 00/31039 PCT/EP99/08560 - 42 available. The substituent R' can preferably be introduced into the aromatic by substitution. In many cases, it is expedient to introduce this substituent before the reaction with ammonia. 5 As a rule, the alcohols, activated alcohols or halides of the formula V are known and their preparation is familiar to the person skilled in the art, so that a description of the syntheses is unnecessary here. 10 The reaction of the compounds of the formula IV with compounds of the formula V is preferably carried out in an inert solvent, with addition of a base and at temperatures and with reaction times as indicated beforehand. Suitable acid-binding agents are preferably 15 alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates or other salts of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium, calcium or caesium. The addition of an organic base such as triethylamine, 20 dimethylaniline, pyridine or quinoline or an excess of the amine component of the formula IV may also be favourable. Derivatives having a free primary or an additional secondary amino group are expediently 25 employed in protected form. Possible protective groups are those mentioned beforehand. For the esterification, an acid of the formula I (R1 = COOH or -Y-(CH 2 )n-COOH and/or R 2 = COOH) can be treated with an excess of an alcohol, 30 expediently in the presence of a strong acid such as hydrochloric acid or sulfuric acid at temperatures between 00 and 1000C, preferably between 200 and 500C. Conversely, an ester of the formula I (R1 = COOA or
-Y-(CH
2 )n-COOA and/or R 2 = COOA) can be converted into 35 the corresponding acid of the formula I, expediently by solvolysis according to one of the methods indicated above, e.g. using NaOH or KOH in water-dioxane at temperatures between 00 and 400C, preferably between 100 and 300C.
WO 00/31039 PCT/EP99/08560 - 43 Furthermore, free amino groups can be acylated in a customary manner using an acid chloride or anhydride, expediently in an inert solvent such as dichloromethane or THF and/or in the presence of a base 5 such as triethylamine or pyridine at temperatures between -60*C and +30 0 C. A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base 10 and of the acid in an inert solvent such as ethanol and subsequent evaporation. Acids which give physiolo gically acceptable salts are particularly suitable for this reaction. Thus inorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as 15 hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, further more organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. 20 formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, 25 methane- or ethanesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and disulfonic acids or laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. picrates, can be used for the isolation and/or purification of the compounds of the 30 formula I. On the other hand, compounds of the formula I with bases (e.g sodium or potassium hydroxide or carbonate) can be converted into the corresponding metal salts, in particular alkali metal or alkaline 35 earth metal salts, or into the corresponding ammonium salts. All synthesis methods indicated here and all other suitable processes for the preparation of compounds of the formula I can also be carried out by WO 00/31039 PCT/EP99/08560 - 44 means of the novel methods of combinatorial chemistry, i.e. by robot- and computer-assisted syntheses, and subjected to mass screening (for this see: US 5,463,564; M. A. Gallop et al., J. Med. Chem. 1994, 37, 5 1233-1251 and 1385-1401 and M.J. Sofia, Drugs Discovery Today 1996, 1, 27-34). The invention furthermore relates to pharmaceutical preparations comprising at least one compound of the formula I and/or one of its 10 physiologically acceptable salts, which are prepared, in particular, in an non-chemical way. In this case, the compounds of the formula I can be brought into a suitable dose form together with at least one solid, liquid and/or semi-liquid excipient or auxiliary and, 15 if appropriate, in combination with one or more other active compounds. These preparations can be used as medicaments in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable 20 for enteral (e.g. oral) or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceryl triacetate, gelatin, carbohydrates such as 25 lactose or starch, magnesium stearate, talc and petroleum jelly. Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used, in particular, for oral administration, suppositories are used for rectal administration, 30 solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, are used for parenteral administration, and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the 35 lyophilizates obtained used, for example, for the production of injection preparations. The preparations indicated can be sterilized and/or can contain auxiliaries such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts WO 00/31039 PCT/EP99/08560 - 45 for affecting the osmotic pressure, buffer substances, colourants, flavourings and/or one or more other active compounds, e.g. one or more vitamins. The compounds of the formula I and their 5 physiologically acceptable salts act as adhesion receptor antagonists, in particular glycoprotein IbIX antagonists, and can be employed for the prophylaxis and/or therapy of thrombotic disorders and sequelae deriving therefrom. The disorders are acute coronary 10 syndromes, angina pectoris, myocardial infarct, peripheral circulatory disorders, stroke, transient ischaemic attacks, arteriosclerosis and reocclusion/restenosis after angioplasty/stent implantation. 15 In this case, the substances according to the invention are as a rule administered in the dose of the glycoprotein IIbIIIa antagonist ReoPro@ of preferably between approximately 1 and 500 mg, in particular between 5 and 100 mg, per dose unit. The daily dose is 20 preferably between approximately 0.02 and 10 mg/kg of body weight. The specific dose for each patient depends, however, on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health and sex, 25 on the diet, on the time and route of administration, and on the excretion rate, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Oral administration is preferred. Above and below, all temperatures are indicated 30 in 0C. In the following examples, "customary working up" means: if necessary, water is added, if necessary, depending on the constitution of the final product, the mixture is adjusted to pHs between 2 and 10 and extracted with ethyl acetate or dichloromethane, the 35 organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallization. Mass spectrometry (MS) apparatuses Kratos Maldi III and Finnigan LCQ. (M+H)* values are determined.
WO 00/31039 PCT/EP99/08560 - 46 In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and 5 percentages are by weight. The entire disclosure of all applications, patents and publications, cited above and below, is hereby incorporated by reference.
WO 00/31039 PCT/EP99/08560 - 47 EXAMPLES Example 1 A suspension of 4 g of 6-chlorobenzo[de]iso chromene-1,3-dione in 100 ml of toluene is treated with 5 0.8 g of methylamine and heated under reflux. After reaction is complete, the reaction mixture is allowed to cool and is worked up as is customary. 6-Chloro 2-methylbenzo [de ]isoquinoline-1, 3-dione is obtained. This compound is then heated in morpholine until 10 conversion is complete. After cooling the reaction mixture, it is worked up as is customary and 2-methyl 6-morpholin-4-ylbenzo[de]isoquinoline-1,3-dione is obtained. Analogously, by reaction of 6-chloro-2 15 methylbenzo[de]isoquinoline-1,3-dione with R 1 -H, the following compounds of the formula Ia are obtained: R1 la o N 0
CH
3 R- in R'-H and Ia -N [ (CH 2 ) 2
-OHI]
2 H H N -N -CS N 0 HO HH H 3 C I I -N -N-C 0 H 3 C OH 3 WO 00/31039 PCT/EP99/08560 - 48 Example 2 A suspension of 4 g of 6-chlorobenzo[de]iso chromene-1,3-dione in 100 ml of dichloromethane is 5 treated with 3.2 g of 2-aminoethanol and heated under reflux. After reaction is complete, the reaction mixture is allowed to cool and is worked up as is customary. 6-Chloro-2-(2-hydroxyethyl)benzo[de]iso quinoline-1,3-dione is obtained. This compound is then 10 heated in morpholine until conversion is complete. After cooling the reaction mixture, it is worked up as is customary and 2-(2-hydroxyethyl)-6-morpholin-4-yl benzo[de]isoquinoline-1,3-dione is obtained. Analogously, by reaction of 6-chloro 15 2-(2-hydroxyethyl)benzo[de]isoquinoline-1,3-dione with Ri-H, the following compounds of the formula Ib are obtained R1 lb O N 0 OH R in R 1 -H and in Ib -N N -N -N 20 WO 00/31039 PCT/EP99/08560 - 49 R- in R--H and in Ib
CH
3 -N N \--/ Ph -N I CH3 H 3 Example 3 Analogously to Example 2, 6-chloro 5 benzo[de]isochromene-1,3-dione is reacted with methyl 3-aminopropionate and then with Ri-H. The following compounds of the formula Ic are obtained: R1 Ic o N 0 COOMe R in R-H and in Ic MS calculated found -N 0 368 369 -N 366 367 -N 352 353 -N N 443 444 10 WO 00/31039 PCT/EP99/08560 - 50 R 1 in R 1 -H and in Ic MS calculated found Ph -N I CH3 H 3
-N-CH
2 388 389 H -N-(CH 402 403 H -N-
CH
2 SO 2
NH
2 H -N -(CH 2 2 / OH H
OH
3 OH - (OH 2
)
2 / OH -N 380 381 H 366 367 H H 414 415 -N Example 4 Analogously to Example 2, 6-chloro benzo[de]isochromene-1,3-dione is reacted with 5 benzylamine and then with R 1 -H. The following compounds of the formula Ida are obtained: WO 00/31039 PCT/EP99/08560 - 51 R1 Ida o N 0 Ph R' in R 1 -H and in Ida MS calculated found -N 0 372 373 -N 370 371 N 356 357 -N N 447 448 Ph 406 407 . CH 3 H -NH- (CH 2 ) 5 -OH 388 389 -NH- (CH 2 ) 2 -COOMe 388 389 -NH- (CH 2 ) 3 -N (CH 3 ) 2 -N-CH 392 393 H -N-(CH 406 407 H -N-
CH
2 /
SO
2
NH
2
H
WO 00/31039 PCT/EP99/08560 - 52 R' in R'-H and in Ida MS calculated found -N -(CH OH 422 423 H -N-CH
NH
2 H
CH
2 - NH 2 421 422 -N - OH 2 H N N -(CH 407 408 H N -N -(CH 2
)
2 407 408 H N
-N-CH
2 393 394 H -N -- (CH -N 0 415 416 H -N -(H 2 3 -N N-CH -- - -2)3 - N 4131 H - H (CH2O
-
410 411 H
OH
3 OH -N -(H 2
)
2 /- -"OH -N 384 385 H rO370 371
H
WO 00/31039 PCT/EP99/08560 - 53 R- in R--H and in Ida MS calculated found 418 419 H 418 419 -N Example 5 Analogously to Example 2, 6-chlorobenzo 5 [de]isochromene-1,3-dione is reacted with phenylethylamine and then with R 1 -H. The following compounds of the formula Idb are obtained: R1 Idb o N 0 Ph R' in R 1 -H and in Idb MS calculated found -N 384 385 -N 370 371 -N N 461 462 Ph 420 421 H 3 -NH- (CH 2 ) 5 -OH 402 403 WO 00/31039 PCT/EP99/08560 - 54 R' in R'-H and in Idb MS calculated found -NH- (CH 2
)
2 -COOMe 402 403 -NH- (CH 2 ) 3 -N (CH 3 ) 2 401 402 -N - CH 406 407 H -N -(CH 2
)
2 420 421 H
-N-CH
2 / " SO 2
NH
2 H -N -- (CH 2
)
2 / "' OH H -N-CH2 NH 421 422 H
OH
2 - NH 2 435 436 -N -- CH2 N -N -- (CH 2
)
2 421 422 H N -- N -(CH 2 / 421 422 H -- N--CH2 0 1407 408 H -N -(CH 2
)
2 -N 0 429 430
H
WO 00/31039 PCT/EP99/08560 - 55 R' in R 1 -H and in Idb MS calculated found -N -(CH2-N N-CH 3 H -N -(CH 2
)
3 -N N 424 425 H
CH
3 OH -N -(CH 2
)
2 / -OH -N 398 399 H - 384 385 H -/ \ --N Example 6 A suspension of 4 g of 6-chlorobenzo[de]iso 5 quinoline-1,3-dione and 7 g of K2CO3 in 100 ml of DMF is heated under reflux with 6 g of phenylethyl chloride. After conversion is complete, the mixture is allowed to cool, and is filtered and worked up as is customary. 6-Chloro-2-(2-phenylethyl)benzo[de]isoquinoline-1,3-dione 10 is then heated in morpholine until conversion is complete. After cooling of the reaction mixture, it is worked up as is customary and 2-(2-phenylethyl 6-morpholin-4-ylbenzo[de]isoquinoline-1,3-dione is obtained. MS: calculated: 386; found: 387. 15 WO 00/31039 PCT/EP99/08560 - 56 Example 7 Analogously to Example 2, 6-chlorobenzo [de]isochromene-1,3-dione is reacted with C cyclohexylmethylamine and then with R'-H. The following 5 compounds of the formula Idc are obtained: R1 Idc 0 N 0 R' in R 1 -H and in Idc MS calculated found -N 0 378 379 -N 376 377 -N3 362 363 -N N \ / 453 454 Ph 330 331 H 3 -NH- (CH 2 ) 5 -OH 394 395 -NH- (CH 2 ) 2 -COOMe 394 395 -NH- (CH 2 ) 3 -N (CH 3 ) 2 393 394
-N-CH
2 398 399
H
WO 00/31039 PCT/EP99/08560 - 57 R in R -H and in Idc MS calculated found -N -(CH 2
)
2 412 413 H -N-
CH
2 SO 2
NH
2 H -N -(CH 2
)
2 OH 428 429 H -N CH 2
/NH
2 H
CH
2 - NH 2
--N-H
2 __ H -N /N-(CH2)2 413 414 H N -N -(CH 2
)
2 413 414 H N
-N--CH
2 399 400 H -N -- (CH -N 0 421 422 H
-N-(CH
2
)
3 -N
N-CH
3 H N-C23N N416 417 H
OH
3 OH -N - -(O 2
)
2 /C -"OH WO 00/31039 PCT/EP99/08560 - 58 R' in R'-H and in Idc MS calculated found -N 390 391 H -- 376 377 H H I 424 425 424 425 -N Example 8 5 Analogously to Example 2, 6-chlorobenzo [de]isochromene-1,3-dione is reacted with (3 chlorophenyl)methylamine and then with Ri-H. The following compounds of the formula Idd are obtained: R1 Idd o N 0 / 0 -CI 10
R
1 in R--H and in Idd MS calculated found
-NH-(CH
2
)
3
-N(CH
3
)
2 421 422 WO 00/31039 PCT/EP99/08560 - 59 R' in R 1 -H and in Idd MS calculated found N N - (CH2)2 441 442 H N -N -(CH 441 442 H -N -CH 2 427 428 H -N -- (CH -N 0 449 450 H -N -(CH 2
)
3 -N N-CH 3 476 477 H -N -( 2)3-N N 444 445 H \= -NH- (CH 2 ) 5 -OH 422 423
CH
2
-
NH
2 -N - CH 2 __ H Example 9 Analogously to Example 2, 6-chlorobenzo 5 [de]isochromene-1,3-dione is reacted with 4-(2 aminoethyl)benzenesulfonamide and then with R 1 -H. The following compounds of the formula Ide are obtained: WO 00/31039 PCT/EP99/08560 - 60 R1 Ide 0 N 0
SO
2
NH
2 R- in R--H and in Ide MS calculated found -NH- (CH 2 ) 7
-NH
2 508 509 -NH- (CH 2 ) 5
-NH
2 480 481
-NH-(CH
2
)
3
-NH
2 452 453
CH
2
-
NH
2 514 515 -N-- OH 2 H Example 10 5 Analogously to Example 2, 6-chlorobenzo [de]isochromene-1,3-dione is reacted with C-pyridin-4 ylmethylamine and then with R 1 -H. The following compounds of the formula Iea are obtained: R1 lea 0 N 0 N 10 WO 00/31039 PCT/EP99/08560 - 61 R' in R 1 -H and in Iea MS calculated found -N 0 373 374 -N 371 372 -N 357 358 -N N \ / 448 449 -N 407 408 H 3 -NH- (CH 2 ) 2 -COOMe -N - CH 2 393 394 H -N-(CH 407 408 H -N- CH 2
SO
2
NH
2 472 473 H -N -(CH 2
)
2 OH H H3OH - -(H 2
)
2 / OH -N 385 386
H
WO 00/31039 PCT/EP99/08560 - 62 R1 in R--H and in Iea MS calculated found 371 372 H 419 420 H -N Example 11 Analogously to Example 2, 6-chlorobenzo 5 [de]isochromene-1,3-dione is reacted with C benzo[b]thiophen-3-ylmethylamine and then with Ri-H. The following compounds of the formula Ieb are obtained: R1 leb o N 0 S R' in R'-H and in Ieb MS calculated found -NH- (CH 2 ) 5
-NH
2 443 444 -NH- (CH 2 ) 7
-NH
2 471 472
CH
2 - NH 2 477 478
-N--H
2 _
H
WO 00/31039 PCT/EP99/08560 - 63 Example 12 10 ml of TFA are added at room temperature to a 5 solution of 2 g of tert-butyl [3-(2-benzo[b]thiophen 3-ylmethyl-1,3-dioxo-2,3-dihydro-1H-benzo[de]iso quinolin-6-ylamino)propyl]carbamate in 40 ml of dichloromethane [obtainable by reaction of 6-chlorobenzo[de]isochromene-1, 3-dione with C-benzo[b] 10 thiophen-3-ylmethylamine and H 2
N-(CH
2
)
3 -NH-BOC] and the reaction mixture is stirred until removal is complete. After customary work-up 6-(3-aminopropylamino) 2-benzo[b]thiophen-3-ylmethylbenzo[de]isoquinoline 1,3-dione is obtained. MS: calculated: 415; found: 416. 15 Example 13 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with H 2
N-(CH
2
)
2 -Het 1 and then with Ri-H. The following compounds of the formula 20 Iec are obtained: R1 lec o N 0 Hetl Het 1
R
1 in R 1 -H and in Iec -NH- (CH 2 ) 3
-NH
2 -NH- (CH 2 ) 5
-NH
2 -NH- (CH 2 ) 7
-NH
2 N CH 2 -- NH 2
--N-CH
2 _
H
WO 00/31039 PCT/EP99/08560 - 64 Het- R- in R 1 -H and in Iec -NH- (CH 2 ) 3
-NH
2 F -NH- (CH 2 ) 5
-NH
2 -NH- (CH 2 ) 7
-NH
2 N
-H
2 - NH 2 -N- -CH 2 H -NH- (CH 2 ) 3
-NH
2
CH
3 -NH- (CH 2 ) 5
-NH
2 -NH- (CH 2 ) 7
-NH
2 N
OH
2 -- NH 2
-N-CH
2 H -NH- (CH 2 ) 3
-NH
2
CH
3 -NH- (CH 2 ) 5
-NH
2 -NH- (CH2) 7
-NH
2
CH
2 - NH 2 N N- CH 2 / H -NH- (CH 2 ) 3
-NH
2 -NH- (CH 2 ) 5
-NH
2 -NH- (CH 2 ) 7
-NH
2 3 CH 2 - NH 2 -N- CH 2 H Example 14 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with 1,3-propanediamine 5 and then with R 1 -H. The following compounds of the formula If are obtained: WO 00/31039 PCT/EP99/08560 - 65 R1 If O N 0
NH
2
R
1 in R--H and in If -N 0 -N -NO -NN -N N \- / Ph -N H CH 3 -NH- (CH 2 ) 2 -COOMe -N -CH 2 H .- N -- (CH2) H
-N-CH
2 SO 2
NH
2 H -N -- (CH 2
)
2 OH H -NH- (CH 2 ) 5 -OH -NH- (CH 2 ) 3 -N (CH 3 ) 2 WO 00/31039 PCT/EP99/08560 - 66 R- in R--H and in If -N -CH 2 NH 2 H
CH
2 - NH 2 -N - CH 2 -2 H N -N -(CH2 H N -N -(CH2 H N -N -CH 2 / CH H -N -(CH 2 )-N 0 H -N-(CH2 -N-N H N-(OH H -NH- (CH 2 ) 7-NH 2 Example 15 Analogously to Example 2, 6-chlorobenzo[de]iso 5 chromene-1,3-dione is reacted with 3-amino-2 methylpropionamide and then with R 1 -H. The following compounds of the formula Iga are obtained: WO 00/31039 PCT/EP99/08560 - 67 R1 Iga o N 0 0 H3C
NH
2 R' in R--H and in Iga -NH- (CH 2 ) 3 -N (CH 3 ) 2 -- N-(CH2 -N H H N -N
-(CH
2
)
2 H -N -(CH23 I
H
2
)
3 -N' N H -NH- (CH 2 ) 4
-NH
2 -NH- (CH 2 ) 7
-NH
2 -NH- (CH 2 ) 8
-NH
2
CH
2 - NH 2 -N - CH 2 / 2 H Example 16 Analogously to Example 2, 6-chlorobenzo[de]iso 5 chromene-1,3-dione is reacted with 2-aminoacetamide and then with R 1 -H. The following compounds of the formula Igb are obtained: WO 00/31039 PCT/EP99/08560 - 68 R1 Igb O N O 0
NH
2 R' in R--H and in Igb MS calculated found -N 0 -N 337 338 -N 323 324 -N \"- N Ph -N I
CH
3 H -NH- (CH 2 ) 2 -COOMe
-N-CH
2 H -N -- (CH2 H -N--
H
2 SO 2
NH
2 H -N -(CH 2
)
2 OH H -NH- (CH 2 ) 5
-OH
WO 00/31039 PCT/EP99/08560 - 69 R- in R--H and in Igb MS calculated found -NH- (CH 2 ) 3 -N (CH 3 ) 2 354 355 -N--CH2 NH 2 H
CH
2
-
NH
2 -N-
CH
2 H N -N--(CH2 H N -N -- (CH2) 37 4 375 H N -N -CH 2 / H -N -(CH2 -N O H -N -(CH 2 3 -N N-CH H
-N--(CH
2
)
3 -N N 379 380 H -NH- (CH 2 ) 5
-NH
2 -NH- (CH 2 ) 7
-NH
2 Example 17 Analogously to Example 2, 6-chlorobenzo[de]iso 5 chromene-1,3-dione is reacted with 3-aminopropionamide and then with R 1 -H. The following compounds of the formula Igc are obtained: WO 00/31039 PCT/EP99/08560 - 70 R1 Igc O N 0
H
2 N 0 R' in R'-H and in Igc MS calculated found -N 0 -N 351 352 -N 337 338 -N N Ph -N H 3 -NH- (CH 2 ) 2 -COOMe
----
H
2 /' H -N - (CH 2 2 H -N- /CHSO 2
NH
2 H -N -(CH 2
)
2 OH
H
WO 00/31039 PCT/EP99/08560 - 71 R' in R 1 -H and in Igc MS calculated found -NH- (CH 2 ) 5 -OH 369 370 -NH- (CH 2 ) 3 -N (CH 3 ) 2 -N-CH NH 2 H
CH
2 - NH 2 -N
-
CH
2 H N -N -- (CH2 H N
-N-(OH
2
)
2 H N
-N-CH
2 1 2 H -- N -(CH2)-N O H -N -(CH 2
)
3 -N N-CH 3 H -N -- (CH2 -- NN -N(O 2
)
3 - NN H -NH- (CH 2 ) 5
-NH
2 -NH- (CH 2 ) 7
-NH
2 396 397 Example 18 5 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with 6-amino-hexanoamide WO 00/31039 PCT/EP99/08560 - 72 and then with R 1 -H. The following compounds of the formula Igd are obtained: R1 Igd 0 N O
(CH
2
)
5
CONH
2 R in R -H and in MS R' in R'-H und in Igd MS Igd calc. calc fnd. fnd. -N O
-NH-(CH
2 ) 3
-NH(CH
3 ) 396 397 -N
-N(CH
3 ) -(CH 2 ) 3
-NH(CH
3 ) 410 411 -N 379 -N (CH 3 ) -(CH 2 ) 2 -N (C 2
H
5 ) 2 438 380 439 -N N - 470 -N-(CH 2
)
2 -N 410 471 H H 411 Ph 0 H CH 3 -N N-CH 2 / -NH- (CH 2 ) 2 -COOMe 4 4 -N N-CH 2 /"' 44 2 485 SN- 471
-N-CH
2 -N N / H 472
-N-(CH
2
)
2 -N N H N 5 WO 00/31039 PCT/EP99/08560 - 73 R- in R--H and in MS R- in R-H and in Igd MS Igd calc. calc fnd. fnd. -- N - CH2-SO 2
NH
2
-NH-(CH
2 3 -N \/N-(CH 2
)
3 --- NH 2 508 H 509 -N -- (CH2) H -NH N -NH- (CH 2 ) 5 -OH -NH- (CH 2 ) 2 -NH- (CH 2 ) 2 -OH 412 413 -NH- (CH 2 ) 3 -N (CH 3 ) 2 -NH- (CH 2 ) 2 -NH (C 3
H
7 ) 410 411 -N- CH 2 / o NH 2 -NH- (CH 2 ) 3-0- (CH 2 ) 4-0- (CH 2 ) 3
-NH
2 512 H 513
CH
2 - NH 2
-N--CH
2 /2
-NH-(CH
2
)
3 -- N 464 H H 465 N CH 2
NH
2 -N - (CH) H -NH-CH 2 451 N -N -(CH 2
)
2 430 -NH- (CH 2 ) 3 -N (CH 3 ) - (CH 2 ) 3
-NH
2 453 H 431 454 N S CH 2 416 -NH- (CH 2 ) 2 -NH (C 2
H
5 ) H 417 397 S- 2)2- -NH- (CH 2 ) 5
-NH
2 H -N -(CH 2
)
3 -N
N-CH
3 462 H -NH- (CH 2 ) 7
-NH
2 463 WO 00/31039 PCT/EP99/08560 - 74 R' in R--H and in MS R 1 in R--H und in Igd MS Igd calc. calc fnd. fnd. -N -(CH 2
)
3 -N N -N-CH 2
CH
2 -- NH 2 H H H Example 19 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with H 2
N-(CH
2 )i-CONH 2 and 5 then with R'-H. The following compounds of the formula Ige are obtained: R1 Ige o N O
(CH
2 )i
CONH
2 R' in R'-H and in Ige i MS calculated found N -N -(CH 7 458 459 H 10 500 501 11 -N-(CH 2-N 7 452 453 H H 10 494 495 11 508 509 7 -NH- (CH 2 ) 4
-NH
2 10 466 467 11 10 WO 00/31039 PCT/EP99/08560 - 75 R' in R 1 -H and in Ige i MS calculated found 7 438 439 -NH-
(CH
2 ) 3 -N (CH 3 ) 2 10 11 494 495 7 -NH-
(CH
2 ) 7
-NH
2 10 11 7 480 481 -NH- (CH 2 ) 8
-NH
2 10 522 523 11 536 537 7 472 473
CH
2 - NH 2 10 H 11 528 529 -N -(CH2)3-N N 7 463 464 H 10 505 506 11 519 520 Example 20 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with H 2
N-(CH
2
)
2
-CONH(R
1 0 ) 5 and then with R 1 -H. The following compounds of the formula Igf are obtained: R1 Igf o N 0
(CH
2
)
2
CONH(R
1 0) 10 WO 00/31039 PCT/EP99/08560 - 76 R- in R--H and in Igf RIu MS calculated found
C
3
H
7 438 439 -NH- (CH 2 ) 7
-NH
2 C 5
H
11 466 467
CH
2 -- NH 2
C
3
H
7 444 445 /N-C2C 5
H
11 472 473 H Example 21 Analogously to Example 2, 6-chlorobenzo[de]iso 5 chromene-1,3-dione is reacted with H 2
N-(CH
2
)
2
-CONH
(CH
2 )o-Ar and then with R 1 -H. The following compounds of the formula Iha are obtained: R1 Iha o N 0
CONH-(CH
2
)
0 -Ar 10 CONH- (CH 2 ) o-Ar R in R-H and in Iha MS calc. fnd. -NH- (CH 2 ) 7
-NH
2
CONH-CH
2 -N-CH2 CH 2
-NH
2 499 500 H -N--(CH 489 490
H
WO 00/31039 PCT/EP99/08560 - 77 CONH- (CH 2 ) -Ar R 1 in R'-H and in Iha MS calc. fnd.
-NH-(CH
2
)
7
-NH
2 515 516 CONH CH 3
CH
2 - NH 2 521 522
S-N-CH
2 H -N -(CH 2 3 -N'1N H -NH- (CH 2 ) 7
-NH
2 520 521
CONH-CH
2 &/ -N /- CH2 CH 2 - NH 2 526 527 H -N -(CH 2 3 -N N H -NH- (CH 2 ) 7
-NH
2 548 549 CONH - / C CH 2 - NH 2 517 518
-N---OH
2 H
-NH-(CH
2
)
7
-NH
2 514 515
CONH-(CH
2
)
3
CH
2 - NH 2 -N--CH2 H N--(CH2 511 512 H Example 22 Analogously to Example 2, 6-chlorobenzo[de]iso 5 chromene-1,3-dione is reacted with H 2 N- (CH 2 ) 2
-CONH
(CH
2 )o-R 5 and then with Ri-H. The following compounds of the formula Ihb are obtained: WO 00/31039 PCT/EP99/08560 - 78 R1 lhb o N 0
CONH-(CH
2 )o-R 5 CONH- (CH 2 ) o-Ra R' in R--H and in Ihb MS calc. fnd. -NH- (CH 2 ) 7
-NH
2 467 468 CONH- (CH 2 ) 4
-NH
2 CH 2 - NH 2
-~J-CH
2 4/3 474 H
-NH-(CH
2
)
7
-NH
2 539 540 CONH- (CH 2 ) 2
-NH
2 CH 2 - NH 2 445 446 -- N - CH2d H Example 23 5 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with H 2
N-(CH
2
)
2
-CONH
(CH
2 )o-Het and then with R 1 -H. The following compounds of the formula Ihc are obtained: R1 lhc o N 0
CONH-(CH
2
)
0 -Het 10 WO 00/31039 PCT/EP99/08560 - 79 CONH- (CH 2 ) o-Het R' in Ri-H and in Ihc MS calc. fnd.
-NH-(CH
2
)
7
-NH
2 487 488
CH
2 - NI
CONH-CH
2 \
-N-CH
2 -494 H Example 24 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with 3 5 aminomethylbenzylamine and then with R 1 -H. The following compounds of the formula Iia are obtained: R1 Iia o N 0
NH
2 R- in Ri-H and in Iia -N O -N -NO -N N -- / 10 WO 00/31039 PCT/EP99/08560 - 80 R" in R 1 -H and in Iia Ph -N H 3 -NH- (CH 2 ) 2 -COOMe -N
-
CH
2 H -N
--
(CH
2
)
2 H
-N-CH
2
SO
2
NH
2 H -N -(CH 2
)
2 OH H -NH- (CH 2 ) 5 -OH -NH- (CH 2 ) 3 -N (CH 3 ) 2
-N-CH
2 NH 2 H
CH
2 - NH 2 -N
-H
2 / __ H
N
-N -- (CH2) H N -N -(CH 2
)
2 / 0 H N -N -CH 2 / 0 H -N -(CH2)2 -N 0
H
WO 00/31039 PCT/EP99/08560 - 81 R in R--H and in Iia -N -- (CH N N-CH 3 H -N -- (C H2N3--NN H -NH- (CH 2 ) 5
-NH
2 -NH- (CH 2 ) 7
-NH
2 Example 25 Analogously to Example 2, 6-chlorobenzo[de]iso 5 chromene-1,3-dione is reacted with H 2
N-CH
2 -Ar'-(CH2)n
CONH
2 and then with R 1 -H. The following compounds of the formula Iib are obtained: R1 lib o N 0 H2 Ar'-(CH 2 )n-CONH 2 Ar'- (CH 2 ) -CONH 2 R- in R--H and in Iib MS calc. fnd.
CONH
2 -N 0 415 416
CONH
2
CO-NH
2 10 WO 00/31039 PCT/EP99/08560 - 82 Ar'- (CH 2 ) n-CONH 2 R' in R 1 -H and in Iib MS calc. fnd. CONH2 -N
CONH
2 419 420 Co -NH 2 C - N 413 414
CONH
2 -N 399 400
CONH
2 405 406 Co -NH 2 399 400
CONH
2 -N N
CONH
2 Co -NH 2 490 491
CONH
2 Ph 449 450 - CH 3 H
CONH
2
CO-NH
2 WO 00/31039 PCT/EP99/08560 - 83 Ar'-(CH 2 )n-CONH 2 R- in R--H and in Iib MS calc. fnd.
CONH
2 -NH- (CH 2 ) 2 -COOMe 431 432
CONH
2
CO-NH
2
CONH
2
-N-CH
2 / H CONH 2 441 442
CO--NH
2
CONH
2 -N -(CH 2 2 449 450 H
CONH
2 455 456
CO-NH
2 5 WO 00/31039 PCT/EP99/08560 - 84 Ar'-(CH 2 )n-CONH 2 R" in R--H and in Iib MS calc. fnd.
CONH
2 H2 SO 2
NH
2 H
CONH
2 520 521
CO--NH
2
CONH
2 - -(CH 2 2 OF 465 466 H
CONH
2 471 472
CO-NH
2
CONH
2 -N -(CH 2
)
2 450 451 H
CONH
2 457 458 450 451 N
CONH
2 -N -(CH 2
)
2 450 H 451
CONH
2 456 Co - NH 2 WO 00/31039 PCT/EP99/08560 - 85 Ar '-(CH 2 ) n-CONH 2 Rl in R 1 -H and in Iib MS calc. fnd. N
CONH
2 -N -CH 2 436 437 H
CONH
2 442 443
CO-NH
2 436 437
CONH
2 -N -(CH 2
)
2 -N 0 458 459 H
CONH
2 464 465 CO -NH2 458 459 CN2485 486
CONH
2 -N-(CH 2 3 ~-N
N-CH
H
CONH
2 491 492 Co - NH 2 CO - NH2485 486 CONH2 (CH 2
)
3 -N N 455 456 2 H
CONH
2 461 462
CO-NH
2 WO 00/31039 PCT/EP99/08560 - 86 Ar-(CH 2 )n-CONH 2
R
1 in R--H and in Iib MS calc. fnd.
CONH
2 -NH- (CH 2 ) 5
-NH
2
CONH
2 436 437 Co -NH 2 430 431
CONH
2
-NH-(CH
2
)
7
-NH
2 458 459
CONH
2 464 465
CO-NH
2
CONH
2 -NH- (CH 2 ) 3 -N (CH 3 ) 2 430 431
CONH
2 436 437 Co -NH 2 430 431
CONH
2 -NH- (CH 2 ) 5 -OH 431 432
CONH
2 437 438 WO 00/31039 PCT/EP99/08560 - 87 Ar '-(CH 2 ) n-CONH 2 R- in R 1 -H and in Iib MS calc. fnd. CO - NH 2 -NH- (CH 2 ) 5 -OH
CONH
2 - CH 2
NH
2 CONH2 - 20 H
CONH
2 CO -NH 2
CONH
2 -N-CH2
CH
2 - NH 2 464 465 H
CONH
2
CO-NH
2
CONH
2 -NH- (CH 2 ) 3 -NH (CH 3 ) 416 417
CONH
2 422 423
CONH
2 -N (CH 3 ) - (CH 2 ) 3 -NH (CH 3 ) 430 431
CONH
2 436 437 WO 00/31039 PCT/EP99/08560 - 88 Ar' (CH 2 )n-CONH 2 Ri Ri-H and in Iib MS calc. fnd.
CONH
2 -N (CH 3 ) - (CH 2 ) 2 -N (C 2
H
5 ) 2 458 459
CONH
2 464 465
CONH
2 - H 2
)
2 - 430 431 -H H
CONH
2 436 437
CONH
2 -N N-CH2 548 549
CONH
2 554 555 CONH 2 -N \ N-CH 2 504 505
CONH
2
N
CONH
2 -N N 491 492
CONH
2 CONH2 -N /-\N 492 493
CONH
2
-NH-(CH
2
)
3 -N \N-(CH 2
)
3 --- NH 2 528 529
CONH
2 WO 00/31039 PCT/EP99/08560 - 89 Ar'- (CH 2 ) -CONH 2 R in R -H and in Iib MS calc. fnd.
CONH
2 -NH N 484 485
CONH
2 490 491
CONH
2 -NH- (CH 2 ) 2 -NH- (CH2) 2 -OH 432 433
CONH
2 438 439
CONH
2 -NH-(CH 2
)
2
-NH(C
3 H7) 430 431
CONH
2 436 437
CONH
2 -NH- (CH 2 ) 3-0- (CH 2 ) 4-0- (CH 2 ) 3
NH
2
CONH
2 538 539
CONH
2
-NH-(CH
2
)
3 -N 484 485 H
CONH
2 490 491
CONH
2
CH
2
NH
2 -N H-CH 2
CONH
2 476 477 5 WO 00/31039 PCT/EP99/08560 - 90 Ar'- (CH 2 ) -CONH 2 R in R--H and in Iib MS calc. fnd.
CONH
2 -NH- (CH 2 ) 3 -N (CH 3 ) - (CH 2 ) 3 NH 2
CONH
2 479 480
CONH
2 -NH- (CH 2 ) 2 -NH (C 2
H
5 ) 416 417
CONH
2 422 423
CONH
2 -- CH CH 2
-NH
2 2 H
CONH
2 Example 26 Analogously to Example 2, 6-nitrobenzo[de]iso 5 chromene-1,3-dione is reacted with H 2
N-CH
2 -Ar'-(CH 2 )n
CONH-(CH
2 )o-NH 2 and then with R 1 -H. The following compounds of the formula Iic are obtained: R1 lic o N 0 H2 10 Ar'-(CH 2 )n-CONH-(CH 2
)
0
-NH
2 WO 00/31039 PCT/EP99/08560 91 Ar'-(CH 2 )n-CONH- R- in R--H and Iic MS
(CH
2 ) o-NH 2 calc. fnd.
CONH-(CH
2
)
4
-NH
2 -NH- (CH 2 ) 7
-NH
2
CH
2 -- NH 2
-N-CH
2 _\ 541 542 H
CONH-(CH
2
)
4
-NH
2 -NH- (CH 2 ) 7
-NH
2 529 530
CH
2 -- NH 2
-N-C
H / "' 535 536 H
CONH-(CH
2
)
2
-NH
2 -NH- (CH 2 ) 7
-NH
2 507 508
CH
2 - NH 2
-N-CH
2 _\ 513 514 H /0 \CONH--(CH 2
)
2
-NH
2 -NH- (CH 2 ) 7-NH 2 501 502
CH
2 - NH 2
--N-H
2 /_" H Example 27 5 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with H 2
N-CH
2 -Ar'-(CH 2 )n CONH- (CH 2 ) -Het and then with R 1 -H. The following compounds of the formula Iid are obtained: R1 lid o N 0 H2 10 Ar'-(CH 2 )n-CONH-(CH 2
)
0 -Het WO 00/31039 PCT/EP99/08560 92 Ar'- (CH 2 ) n-CONH- R in R-H and Iid MS
(CH
2 ) -Het calc. fnd.
CONH-CH
2 -NH- (CH 2 ) 3 -N (CH 3 ) 2 -NH- (CH 2 ) 7
-NH
2 555 556
CH
2 - NH 2 -y-CH 2 C2N 561 562 H
CONH-CH
2 -NH- (CH 2 ) 3 -N (CH 3 ) 2 521 522 -NH- (CH 2 ) 7
-NH
2
CH
2 - NH 2
-N-CH
2 555 556 H Example 28 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with H 2
N-CH
2 -Ar'-(CH 2 )n 5 CONHA and then with R'-H. The following compounds of the formula Iie are obtained: R1 lie o N 0 H2 Ar'-(CH 2 )n-CONHA Ar'-(CH 2 )n-CONHA R 1 in R 1 -H and Iie MS calc. fnd. -NH- (CH 2 ) 7
-NH
2
CONH(C
3
H
7 )
CH
2 - NH 2 -N --CH 2 /\ 512 513 H -NH- (CH 2 ) 3 -N (CH 3 ) 2 472 473
CONH(C
3
H
7 ) -NH- (CR 2 ) 7
-NH
2
-H
2 - NH 2 - - CH2 506 507
H
WO 00/31039 PCT/EP99/08560 93 Ar'-(CH 2 )n-CONHA R- in R 1 -H and Iie MS calc. fnd. -NH- (CH 2 ) 7-NH 2
CONH(C
5
HI
1 i) CH2- NH 2 / \CH 540 541 H -NH- (CH 2 ) 3 -N (CH 3 ) 2 500 501
CONH(C
5
H
1 1 ) -NH- (OH 2 ) 7
-NH
2
CH
2 - NH 2 - - -CH 2 / 2N H Example 29 Analogously to Example 2, 6-chlorobenzo[de]iso 5 chromene-1,3-dione is reacted with H 2
N-CH
2 -Ar'-(CH 2
).
CONH- (CH 2 ) -Ar and then with R 1 -H. The following compounds of the formula Iif are obtained: R1 lif o N O H2 Ar'-(CH 2 )n-CONH-(CH 2
)
0 -Ar 10 Ar'-(CH 2 )n-CONH- R" in Ri-H and Iif MS
(CH
2 )o 0 -Ar calc. fnd.
CONH-CH
2 -NH- (CH 2 ) 3 -N (CH 3 ) 2 -NH- (CH 2 ) 7
-NH
2
CH
2 - NH 2 - --CH 2 H 2 566 567 H /0 \CONH-CH 2 -NH- (CH 2 ) 7
-NH
2 554 555
CH
2 - NH 2 -N -CH 2 / ' 560 561
H
WO 00/31039 PCT/EP99/08560 94 Ar'- (CH 2 ) n-CONH- R 1 in R--H and Iif MS
(CH
2 ) o-Ar calc. fnd. CONH N- -NH- (CH 2 ) 3 -N (CH 3 ) 2
-NH-(CH
2
)
7
-NH
2 583 584 -N-H H-H 2 2 58 9 59 0 C ONH N" NH- (CH 2 ) 7
-NH
2 577 578
CH
2
-NH
2
-N-CH
2 / 59 H CONH -O/ / -NH- (CH 2 ) 7
-NH
2
CH
2 - NH 2
-N--H
2 / H / C ONH _ \ -NH- (CH 2 ) 3 -N (CH 3 ) 2 -NH- (CH 2 ) 7
-NH
2
CH
2 - NH 2
-N-H
2 / H C ONHH -NH- (CH 2 ) 3 -N (CH 3
)
2 560 561
-NH-(CH
2
)
7
-NH
2 588 589
-N-CH
2 /CH- 594 595 H / N-H - -NH- (CH 2
)
7
-NH
2 582 583 - -CN H C 2 588 589 H
CONH-(H
2 3 -- ) -NH- (OH 2 ) 3 -N (OH 3 ) 2 554 555
-NH-(CH
2
)
7
-NH
2 582 583 - -- CH2- CH 2 - NH 2 H S CON(CH2)3- -NH-(CH 2
)
7
-NH
2 576 577 -N-- CH CH2 N 2
OH
2 - NH 2 .- N-CH 2 /'
H
WO 00/31039 PCT/EP99/08560 95 Example 30 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with H 2
N-CH(R)-CONH
2 and then with Ri-H. The following compounds of the formula 5 Ik are obtained: Rk Ik o N 0 SH(R)
CONH
2 RH in R--H and Ik R MS calc. fnd. C-) NH 2 CH 2 -Ph -- N -- CH2 _
CH
2 -CH (CH 3 ) 2 H -NH- (CH 2 ) 3-N(CH3) 2
CH
2 -Ph
CH
2 -CH (CH 3 ) 2 -NH- (CH 2 ) 4-NH 2
CH
2 -Ph
CH
2 -CH (CH 3 ) 2
-NH-(CH
2 )7-NH2 CH 2 -Ph
CH
2 -CH (CH 3 ) 2 -NH- (CH2) 8-NH2 CH2-Ph CH2-CH (CH3) 2 -N -(CH2-N NH 2 -Ph 469 470 1 2)3CH2-CH (CH3) 2 4 35 4 36
CH
2 -Ph -- N NCH2-CH (CH3) 2
-N-(CH
2
)
2 -N CH2-Ph H H CH 2
-CH(CH
3
)
2 WO 00/31039 PCT/EP99/08560 - 96 Example 31: Analogously to Example 2, 6-chlorobenzo [de]isochromene-1,3-dione is reacted with H 2 N-Ar and then with R 1 -H. The following compounds of the formula 5 Il are obtained: R1 o N 0
(CH
2 ) Ar i Ar R' in R'-H and in Il 2 O-CH 2 -Ph -NH- (CH 2 ) 3
-NH
2
\/O--CH
2 -Ph -NH- (CH 2 ) 5
-NH
2 -NH- (CH 2 ) 7
-NH
2
CH
2 - NH 2 -N -CH 2 /" H
CH
2 -- NH 2
-N-OH
2 H
-N--H
2
CH
2 -- NH 2 2 ~ O-Ph -NH- (CH2)3-NH2 -NH- (CH 2 ) s-NH 2 -NH- (CH 2 ) 7
-NH
2
CH
2
-NH
2 -N - CH 2 / H
CH
2
-NH
2
-N-CH
2 H
-N-OH
2 CH 2
-NH
2 10 WO 00/31039 PCT/EP99/08560 - 97 i Ar R 1 in R 1 -H and in Il 1-NH- (CH 2
)
3
-NH
2 -NH- (CH 2 ) 5
-NH
2 -NH- (CH2) 7
-NH
2
CH
2 - NH 2
--N-H
2 _ H
-
--
CH2
-
CH2
--
NH2 CH2 - CH 2 - NH 2 -NH- (CH2) 3-NH2 -NH- (CH2) 5-NH 2 -NH- (CH2 7-NH2 4 0CH2-- H2 -N -CH 2__ H
CH
2 - NH 2 H
-N-CH
2
CH
2
-NH
2 H Example 32: Equimolar amounts of 6-(3-amino-propylamino)-2-(3,4,5 trimethoxy-benzyl)-benzo[de]isoquinoline-1,3-dione 5 (according to example 31, page 96, table line 4) and methanesulfonic acid are reacted according to known procedures to give the acid addition salt 6-(3-amino propylamino)-2-(3,4,5-trimethoxy-benzyl) benzo[de]isoquinoline-1,3-dione, methane sulfonate. 10 1 H-nmr (DMSO-d 6 ): 8.74 (dd, J = 0.8 and J = 8.5 Hz, 1H), 8.46 (dd, J = 0.8 and J = 7.3 Hz, 1H), 8.29 (d, J = 8.5 Hz, 1H), 7.81 (t, J = 5.5 Hz, 1H(NH)), 7.77-7.68 (m, 4H (3xNH)), 6.86 15 (d, J = 8.7 Hz, 1H), 6.66 (s, 2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.53-3.47 (m, 2H), 3.02-2.94 (m, 2H), 2.31 (s, 3H), 2.04-1.96 (m, 2H).
WO 00/31039 PCT/EP99/08560 - 98 Abbreviations of the nmr-signals (nr nuclear magnetic resonance): s singlet, d doublet, 5 dd double doublet, t triplet, sbr broad singlet, m multiplet, q quadruplet, 10 J coupling constant J in Hz Example 33: Analogously to Example 2, 6-chlorobenzo [delisochromene-1,3-dione is reacted with H 2
N-CH
2 -Ar' 15 (CH 2 )n-CONH-(CH 2 )o-Ar and then with Ri-H. The following compounds of the formula Iif are obtained: R1 lif o N 0
CH
2 Ar'-(CH 2 )n-CONH-(CH 2 )o-Ar Ar'- (CH 2 ) n-CONH- (CH 2 ) o-Ar R 1 in R -H and Iif CONH- CH 2 - HH -N-H /_ CH NH 2 H CONH -N-CH 2 __/ "' NH H NH N2
-N--H
2 / N H 20 WO 00/31039 PCT/EP99/08560 - 99 Ar '-(CH 2 ) n-CONH- (CH 2 ) o-Ar R 1 in R 1 -H and hf
CONH-(CH
2 )2 /
OH
2 - NH 2 H CONH-CH2 NH H
OH
2 -- NH 2
-N-CH
2 H H -- N-CH2 / NH HH
OH
2 - NH 2
N-CH
2 H H
-N-H
2 / N H
-
-CH2 CH-NH2 H CONH-(CH 2
)
2 - -CH2
CH
2 - NH 2 H
NH
2
-N-OCH
2 /H2 H NH
CONH--(CH
2
)
3 -- CH2 N NH2 CONH-CH2)4-N-OH 2 / H2-NH H --HH / --2 2 - NH 2 CONH-
-N-CH
2 CH2-NH H
CHNH
2 H CONHN-CH-C
H
2 - NH 2 -H Br H
NH
2
H
WO 00/31039 PCT/EP99/08560 - 100 Ar'-(CH 2 )n-CONH-(CH 2 )o-Ar R 1 in R-H and Iif CH- NH 2 T C O N H - -- CN- O H 2 /2 -H CN NH
NH
2
-CH
2 / H H
OH
2 - NH 2
CONH-(CH
2 ) _ __OCH2 C H NH
-N-OH
2 N/2 - -CH2, H H - -- CH2 N NH2
CONH-CH
2 N
CH
2 NH 2 H N - 2 NH - N
-
H 2 /
-
N H / -~.OHCH 2 -NH 2 OONH-0H 2 Nl / H -N - OH 2 H NH NNH, 22 < CH3 - H 2 / A NH H OONH N CH 2-NH2 NHN N2 H OONH O 2
H
5
H
2 - NH 2 CON -CH - -S ,-N 2 - N - OH 2 -C H -CHH
H
WO 00/31039 PCT/EP99/08560 - 101 Ar '-(CH 2 )n-CONH- (CH 2 ) o-Ar R 1 in R 1 and hf
O
2 - NH 2 \ / CONH-(CH 2
)
2
CH
3
_-CH
2 _ H CNH -N-OH 2 /_ : N H H OH-NH 2
S/CONH-H
2 HHC
-N-OH
2 H CONH CH 3 H N_ H 2 HN F
CF
3 - -CH 2 / H2-NH 2 H \/ CONH-CH 2 -- / -N -H 2 - _ OH 2 - NH 2
CF
3 H P N NH 2 -N -CH 2 / H" H H - -CH2 2 N NH 2 CONH -- CH 2 CH2-NH2 H
CF
3
--
H
2 / N
NH
2 -- 3 - CH 2_ CH2- NH2 HN H CF 3 OH N_ H - -CH2NH2
NH-N-OCH
2 C H 5CH2 N NH 2
---
CH
2 / H2 NH HN -- CH2 ON- NH 2 -N-CH2 C CONH C2H NH
---
H
2
NNH
WO 00/31039 PCT/EP99/08560 - 102 Ar '-(CH 2 ) -CONH- (CH 2 )o-Ar R 1 in R 1 and hf CONH / ' CH3
OH
2 - H H
NH
2
-H
2 / H CONH-CH2 -N-H 2 / 2 H NHC
-N-CH
2
/C
H C HH OH - NH 2 CO-- O H C-N-H 2 H
NH
2
-N-OCH
2 H NH2 H-- NH 2 \ / ONH(CH 2 2 / '~' -N--CH 2 _ H COH-Q -N-OH 2 -- / 2- N 2 H - CH2 N NH 2 \ / CON
-
-N-H 2 CH-H H -- H NH2
-
-
H 2 /
-
NH 2 HNH
--
CH2 N
NH
2 \ / CO H-C 2 -\-N - CH / H - H OH c- H NH -H 2 /C -N NH2
H
WO 00/31039 PCT/EP99/08560 - 103 Ar'- (CH 2 ) n-CONH- (CH 2
)
0 o-Ar R 1 in R 1 -H and Iif CONH Cl -N- -CH 2
OH
2
-NH
2 H NH -- CH2 6 NA NH2 Cl-CH2HNH2 H
H
2 - NH 2
CONH-(CH
2
)
2 / oCH2 H - H 2 N NH 2 NH2 /\ CONH-CH 2 C/ -1 -- CH2 2 -N -CH 2 NH H CI
CH
2 - N 2
CONH-CH
2 / I - -- H 2 NH -NNH
-NH
2 / H Ci-C C-C OH 2 -NH
CONH-CH
2 /\ N-O 2 HN I -N-H 2__ CN2-NH2
-N-OH
2 / HI HN 01 OH 2
-NH
2 - H H HH CN-H l-N-OH 2 _ 2/
N
2 H 01 CH 2 NH,
-
H H NH
-N-OH
2 N/2
H
WO 00/31039 PCT/EP99/08560 - 104 Ar'-(CH 2 )n-CONH-(CH 2 )o--Ar R 1 in R 1 -H and Iif CI CH 2 -- NH 2
CONH-CH
2 -2 CIH
NH
2 C1CHN -- CH 2 NH2 HH CI CH 2 - NH 2 -l -N-CH2 6 N - NH2 CONH F - H 2 H CI H
NH
2
N-OH
2 2 H -C -CHH 2 - NH 2 CONH-CH2 F -N-
CH
2 C2N Cl H NH - -CH2 b N
NH
2 CONH(CH22 F-N--CH 2 / H2NH H
OH
2 - NH 2
CONH-
2 F -N-C
OH
2 2 CI H 2 HN CH 2
CO-N-OH
2 /F N-H
OH-NH
2 CONH F -~C -NOH 2 H N H
OH-NH
2 NI H WO 00/31039 PCT/EP99/08560 - 105 Ar'- (CH 2 ) -CONH- (CH 2 ) o-Ar R 1 in R 1 and hf
CONH-CH
2 / F H 2 F H
NH
2
-NH
2 / H CONH2)2C2
.
H2 H OC'
CHNH
2 -CH H -- H 2 / NH 2 HA
OH
2 - NH 2 -N-
CH
2 H
--
CH2 NH2
-
--
CH
2 / 2 H -H -C2NHH
-N--OCH
2 C NH 2 OC~a CNH *H
OH
2 - NH 2 CON -N- CH 2 / 2 H - -CH 2 / H H
-CONH-CH
2
-N-CH
2 N
OCH
3 HPH -Nl-H 2 / b-N
NH
2 H CONH-- ) OCH 3 -N- H- 2 2 H -N-OH 2 N/ NH 2
H
WO 00/31039 PCT/EP99/08560 - 106 Ar '-(CH 2 ) n-CONH- (CH 2 ) o-Ar R 1 in R -H and Iif
OH
2 - NH 2
CONH-(CH
2
)
2 OCH -- COH 2 CH2N H NH, - CH 2 N H H
OH
2 - NH 2 \ / CONH-H 2 OOF, -N-CH 2 C2-N H
NH
2
-N-OH
2 2-N H F OH 2 -- NH 2 CONH -- CH2 H HN H - OCH2 NH 2 H-CH2 - -- CH 2 N NH 2 CONH-H22--H 2 CH2 - H NH
OCH
3 CH H ter-bty OH 2 - NH 2 - ONH / - -N-H 2 -C_ - HH -N-O
H
2 / \-N
NH
2 H
CH
3 -bty OH 2 - NH 2 OONH0N 2
-
H
2 -/ " - H 00H 2 2 NH CONH(CH,, 3 -N -OH 2 -C / -- qf2
H
WO 00/31039 PCT/EP99/08560 - 107 Ar'-(CH 2 )n-CONH-(CH 2 )o--Ar R' in R 1 -H and Iif
OCH
3
CH
2
NH
2 -N- C CONH
OH
2 NH - HH
-N-CH
2
NH
2 H CH, 2 H 2 - NH 2 C O NH -(0H 2
)
2 C H2HH 3 - -2OH 2 H
-N-H
2 N\ NH 2 CONH O C~ - -CH C2- H H Ph CH 2 - NH 2 -CONH
-N-H
2 '.AO'd1H PhH CN NH HH
OH
2
-NH
2 ~ / CONH -CH2 - - J- CH 2 H H
-N-OH
2 H/- NH 2 H HH
-N-OH
2 / NH 2 H C ONH--J
-N-OH
2 - _H 0/ H \-P H -N-OH / \ NH 2 H O_
H
2 - N 2
\/CONH-CH
2 / -N-H 2 _ H -CH2 C -NNH 2
H
WO 00/31039 PCT/EP99/08560 - 108 Ar'-(CH 2 )n-CONH- (CH2)o-Ar R 1 in R 1 -H and Iif CONHCH 2__ CH2--N2 OH-C-
NH
2 OCH C CONHH H - -H
NH
2 H - -H 2 - NH 2
CONH-CH
2 O-N - OH 2 / NH2 H NH N- NH2 CONH-Q OC3 -N-CH 2 CH2- NH2 CF, H HN --- CH2- NH 2 CONH-H -/-C2 CH-NH CO ) -- CH 2 CI CH2-NH2 -C CONHCH2 -N-CH 2_C HN
NH
2 H
CH
2
-NH
2 CONH-CH2 -N-CH 2 _ H -OHC 2N-OH 2 /C
NH
2 -0 -N- O 2 _ H
OH
2 - N 2
CONH-CH
2 / -N -H 2 _ H CONH-(H) /N C \d / H 2
-NH
2 -C2 -O 2 H I -NCH2-C OH 2 - NH 2 CONH """ CHNOH -0 - H CI CH -NH 2 CONH-CH) / F H CI-C - H WO 00/31039 PCT/EP99/08560 - 109 Ar'-(CH 2 )n-CONH-(CH 2 )o-Ar R 1 in R 1 -H and Iif
CONH-(CH
2
)
2 / \ OCH - CH2--NH2 CONH
-
-- CH2
-
-
CH
2 -- NH 2 CONH Oh --- CH 2 CH2H 2 CONH - -CH2H 2
-NH
2 CON-C2 - a -- -CH 2 CH-N2 H
CH
2 - NH 2 CONH -C2 OPh OHH_ - CH 3 -- , CH , H OONH CH 1 / 0- NH
H
3 H OH CH 2
-NH
2 C O N H - CH 2 0 -/C H
OH
3 -N -C/H
O
2 _ /N \C2C
H
2 - NH 2
CONH-CH
2 / H
CONH-CH
2 / ~ NO 2
~O
2 H - H WO 00/31039 PCT/EP99/08560 - 110 Example 34: Analogously to Example 2, 6-chlorobenzo [de]isochromene-1,3-dione is reacted with H 2
N-CH
2 -Ar'
(CH
2 )n-CONH-(CH 2
)
0 -Het and then with R 1 -H. The following 5 compounds of the formula Iid are obtained: R1 lid o N 0
CH
2 Ar'-(CH 2
),-CONH-(CH
2
)
0 -Het Ar'- (CH 2 ) -CONH- (CH 2 ) o-Het R1 in R 1 -H and Iid NH
CONH-CH
2 /N - -- NH2 HH CONH N -N-CH 2 /d CH 2 - NH 2 - H NH H / \ CNH-CH / ~N -- CH 2 / H- 2 H
--
CH 2 N
NH
2 10H H 10 WO 00/31039 PCT/EP99/08560 - 111 Ar'- (CH 2 ) -CONH- (CH 2 ) o-Het R 1 in R 1 -H and Iid
CONH-(CH
2
)
2 / - -- CH 2 C H 2 -- NH 2 N H 2
-N-CH
2 NH2 HA OHC2 NH 2
CONH-(CH
2
)
2 -N -- CH 2 C -N - 2 H
N-CH
2 / NH 2 CONH-(CH2)3-No N -CH2-C CH2 -NH 2 H O N- NH 2 / CONH-CH 2 - -0 -CH2 CH2 H --- HH 2 - NH 2 CONH-(CH2)2-N O---CH 2 /
-NOH
2 - NH 2 \/ CONH-(CH 2 )-N J -IJC 2 H HN NNH
-N-OH
2 /A H
OH
2 - NH 2 \/ CONH-(CH 2
)
3 -N N-CH H S OH 2 - NH 2
CONH-CH
2 <\ OH 2 /N -C H NH NNH2 H 0 O_.d H 2 - NH 2 -0 CONH-CH 2 \3 N OCH 2 H
NH
2 H
OH
2 - NH 2
CONH-(CH
2
)
2 -N -N /CH
H
WO 00/31039 PCT/EP99/08560 - 112 Ar'- (CH 2 ) n-CONH- (CH 2 ) o-Het R' in R 1 -H and Iid 0 CH 2 -- WH 2
CONH-CH
2
-N-CH
2 C2N H_
CH
2
-NH
2
CONH-(CH
2 ) N - -CH2CH CONH /N -N-CH
CH
2 - NH 2 CONH- N -N- CH 2 C2 H -N H Example 35: Analogously to Example 2, 6-chlorobenzo 5 [de]isochromene-1,3-dione is reacted with H 2
N-CH
2 -Ar'
(CH
2 ) -CONH- (CH 2 ) o-CH (Ar') -Ar2 and then with R -H. The following compounds of the formula 12 are obtained: R1 12 o N 0
OH
2 Ar'-(CH 2 )n-CONH-(CH 2 )o-CH(Arl)-Ar 2 Ar'- (CH 2 ) n-CONH- (CH 2 ) o- R 1 in R 1 -H and 12 CH (Ar' ) -Ar 2
CH
2 - NH 2 --N - CH2-C2 \ CONH-(CH 2
)
2 -CH HH -N-
CH
2 /
NH
2 H 10 WO 00/31039 PCT/EP99/08560 - 113 Ar '-(CH 2 ) n-CONH- (CH 2 )o- R 1 in R 1 -H and 12 CH (Ar 1 ) -Ar 2
OH
2 - NH 2 / 2 -N -O CH 2 2
CONH-(CH
2 )r-CH H NH
-N--CH
2 N
NH
2 H _N -CH2-C
H
2
NH
2
OH
2 /2~
CONH-CH
2 -CH H
-
N-
CH
2 /
NH
2 H Example 36: Analogously to Example 2, 6-chlorobenzo [de]isochromene-1,3-dione is reacted with H 2
N-CH
2 -Ar' 5 (CH 2 ) -CONH- (CH 2 ) o-CH (A) -Ph and then with Ri-H. The following compounds of the formula 13 are obtained:
R
1 13 o N 0
OH
2 Ar'-(CH 2 )n-CONH-(CH 2 )o-CH(A).Ph Ar'-(CH 2 )n-CONH-(CH 2 )o- R1 in R 1 -H and 13 CH (A) -Ph
CONH-CH
2 -CH - -CH2 C ~CH'
CONH-CH
2 -CH CH3 N H 2 I -N- H 2 N/ CH2 10 WO 00/31039 PCT/EP99/08560 - 114 Example 37: Analogously to Example 2, 6-chlorobenzo [de]isochromene-1,3-dione is reacted with H 2
N-CH
2 -Ar'
(CH
2 )n-CONHA and then with R 1 -H. The following compounds 5 of the formula Iie are obtained: R1 lie o N 0
CH
2 Ar'-(CH 2 )n-CONHA Ar'-(CH 2 )n-CONHA R 1 in R'-H and Iie CH- NH 2
CONH-(CH
2
)
2
-C(CH
3
)
3
-N-CH
2 C H
-
--
H
2 /
-
NH
2 H NH \/ CONH-0 3
H
7 N-C,-S N H Example 38: 10 Analogously to Example 2, 6-nitrobenzo [delisochromene-1,3-dione is reacted with H 2 N-(CH2) 2 CONH-(CH2)o-Ar and then with Ri-H. The following compounds of the formula Iha are obtained: WO 00/31039 PCT/EP99/08560 - 115 R1 Iha o N 0
CONH-(CH
2 )o-Ar CONH- (CH 2 )o-Ar R 1 in R 1 -H and in IHa
CONH-(CH
2
)
2 - C2H 2
-N
2
-
-y-H /I H
OH
2 - NH 2
CONH-(CH
2
)
2 -N-CH2 H CONH-(CH 2
)
2 /\F -- C2
CH
2
-NH
2
OH
2 - N 2
CONH-(CH
2
)
2 / OCHa -N -CH 2 CH 2 H CONH-CH 2 - -CH 2
CH
2 -NH 2 H CI
CH
2 - NH 2
CONH-CH
2 H 2 Cl CONH-CH 2 /
--
H
2 \CH2-NH2 CI CC
CONH-CH
2 N CH -H 2 -- NH 2 SCH 2 -- NH 2 H
CONH-CH
2 H 0 CH 2 - NH 2
CONH-CH
2 O --- H 2 WO 00/31039 PCT/EP99/08560 - 116 CONH- (CH 2 ) o-Ar R 1 in RI-H and in IHa
C
2 H CH 2 - NH 2 CONH H 2 CONH
--
CH2-C CH2-N2 H CONH -OPh -N-CH 2_
CH
2 -- NH 2 CONH CI N-H /' H CHH
O
2 - NH 2 CONH /N - OC ~-H 2 'C H CONH N-CH-C
H
2 - NH 2 H CONH H CONH N - -y-H 2 -C / H2 N H NO2 C2H NH 2 - NH 2 CONH C Ha
-P-CH
2 h/ CONH NH N0 2
CH
2
-NH
2 CONH - OH 3
-N-CH
2 H
-
--
H CH 25 CH2-NH2 Ph -N-CH
CH
2 -- NH 2 CONH /- Q\ OH 3 -N--CH2 H SHCH 2 - NH 2 ,P I~-H 2 / , H0H /-0-CCH2 OH 2 - NH 2 OONH N..- CH CH2 - NH2 2 & H -N--CH2 H
-
--
CH 2
CH
2
-
NH 2
-<--HH
2
-
NH 2 ONH H -- -CH2H 2 -- NH 2 WO 00/31039 PCT/EP99/08560 - 117 CONH- (CH 2 ) o-Ar R 1 in R 1 -H and in IHa CH -NH- CONH -N -CH 2 2 2 H Example 39: A suspension of 4 g of 6-nitrobenzo[de]iso chromene-1,3-dione in 100 ml of toluene is treated with 5 3.1 g of 2-amino-N-(4-iodo-phenyl)-acetamide and the mixture is heated under reflux. After reaction is complete, the reaction mixture is allowed to cool and is worked up as is customary. N-(4-Iodo-phenyl)-2-(6 nitro-1,3-dioxo-lH,3H-benzo[delisoquinolin-2-yl) 10 acetamide is obtained. 1.2 Equivalents of K 2
CO
3 , 1.2 equivalents of Ph-B-(OH) 2 and 10 mol% of Pd((PPh) 3
)
4 are added to a solution of this compound in 80 ml of DMF and it is heated at 80 0 C until conversion is complete. After filtering off the catalyst and customary working 15 up, N-biphenyl-4-yl-2-(6-nitro-1,3-dioxo-lH,3H benzo[de]isoquinolin-2-yl)-acetamide is heated with 3 aminomethyl-benzylamine until conversion is complete. After cooling the reaction mixture, it is worked up as is customary and 2-[6-(3-aminomethyl-benzylamino)-1,3 20 dioxo-lH,3H-benzo[delisoquinolin-2-yl]-N-biphenyl-4-yl acetamide is obtained. Analogously, by reaction of N-(4-iodo-3 methoxyphenyl)-2-(6-nitro-1,3-dioxo-lH,3H 25 benzo[de]isoquinolin-2-yl)-propionamide with Ph-B-(OH) 2 and 3-aminomethyl-benzylamine, 3-[6-(3-aminomethyl benzylamino)-1,3-dioxo-1H,3H-benzo[de]isoquinolin-2 yl]-N-(2-methoxy-biphenyl-4-yl)-propionamide is obtained. 30 Analogously, by reaction of N-(4-iodo-benzyl) 3-(6-nitro-1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl) propionamide with Ph-B-(OH) 2 and 3-aminomethyl benzylamine, 3-[6-(3-aminomethyl-benzylamino)-1,3 35 dioxo-lH,3H-benzo[de]isoquinolin-2-yl]-N-biphenyl-4 ylmethyl-propionamide is obtained.
WO 00/31039 PCT/EP99/08560 - 118 Example 40: Analogously to example 39, by reaction of 6 nitro-2- (4-iodophenyl) benzo [de] isoquinoline-1, 3-dione 5 with R -B-(OH) 2 and 3-aminomethyl-benzylamine, the following compounds of the formula 14 are obtained: N
NH
2 o N O 14 CONH R12 R12 in 4 F \/ OCH 3
CF
3
CF
3
H
3 C
CF
3
-&CF
3
SCH
3
NO
2 WO 00/31039 PCT/EP99/08560 - 119 R" in 14 - CH 3
CH
3 -G -CH 3 0
CH
3
CH
3 a
CH
3 Example 41: Analogously to Example 2, 6-nitrobenzo [delisochromene-l,3-dione is reacted with H 2 N- (CH- 2
)
2 5 CONH- (CH 2 ) -Het and then with R 1 -H. The following compounds of the formula Iho are obtained: \hc o N 0
CONH-(CH
2
)
0 -Het 10 WO 00/31039 PCT/EP99/08560 - 120 CONH- (CH 2 ) o-Het R 1 in R 1 -H and in Ihca
CH
2 - NH 2
CONH-(CH
2
)
2 -N 0 / H
CONH-(CH
2
)
3 -N N CH2-NH2 - -CH 2 _ H CONHN-H
-
OCH2 CH 2 - NH 2
CONH-CH
2 N __ _H 2 / H-H
CH
2 -- NH 2
CONH-CH
2 N -N -CH 2 / 2 0 CH 2
-NH
2
CONH-CH
2 C\/ -N2-NH 2 H2 H N OH 2 - NH 2 2 CONH O - -CH2 C2
O-N-OH
2 N/2 H O-H
-
C H 2 2 CONHH 0 C0H 2 - NH 2 -1 0 N-H CONH / 'j Example 42: Analogously to example 2, by reaction of 6 nitro-benzo [de] isochromene-1, 3-dione with 3-amino-N 5 (3, 3-diphenyl-propyl) -propionamide and 3-aminomethyl benzylamine, 3- [6- (3-aminomethyl-benzylamino) -1,3 dioxo-lH, 3H-benzo [de ]isoquinolin-2-yl] -N- (3, 3-diphenyl propyl)-propionamide is obtained. 10 Example 43: Analogously to example 2, by reaction of 6 nitro-benzo[de]isochromene-1,3-dione with N-[4-(3 amino-propionylamino) -2-methoxy-phenyl] -2-methoxy benzamide and 3-aminomethyl-benzylamine, N- (4-{3-[6- (3 15 Aminomethyl-benzylamino) -1, 3-dioxo-lH, 3H- WO 00/31039 PCT/EP99/08560 - 121 benzo[de]isoquinolin-2-yl]-propionylamino}-2-methoxy phenyl)-2-methoxy-benzamide is obtained. Example 44: 5 Analogously to example 2, 6-nitrobenzo [de]isochromene-1,3-dione is reacted with H 2
N-(CH
2
)
2 CONH-Ar'-Het and then with 3-aminomethyl-benzylamine. The following compounds of the formula 15 are obtained: N
NH
2 15 O N 0 CONH-Ar'-Het CONH-Ar'-Het in 15 CONH N 0 CI CONH \ / N CN CONH CONH \/ \s CONH CONH CH 3 0 WO 00/31039 PCT/EP99/08560 - 122 CONH-Ar'-Het in 15 CONH Cl CONH___\ Example 45: Analogously to example 2, 6-nitrobenzo 5 [delisochromene-1,3-dione is reacted with 3,3-diphenyl propylamine and then with R'-H. The following compounds of the formula 16 are obtained: R1 16 o N O
R
1 in R 1 -H and 16 -NH- (CH 2 ) 3
-NH
2 -NH- (CH 2 ) 5
-NH
2 -NH- (CH 2 ) 7
-NH
2
CH
2 - NH 2 -N-CH2 H
-N-CH
2 CH2-NH2
-N-CH
2
CH
2
-NH
2 10 WO 00/31039 PCT/EP99/08560 - 123 The following examples relate to pharmaceutical preparations: Example A: Injection vials 5 A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 1 of double-distilled water using 2N hydrochloric acid, sterile-filtered, dispensed into injection vials, lyophilized under sterile 10 conditions and aseptically sealed. Each injection vial contains 5 mg of active compound. Example B: Suppositories A mixture of 20 g of an active compound of the 15 formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 20 mg of active compound. 20 Example C: Solution A solution is prepared from 1 g of an active compound of the formula I, 9.38 g of NaH 2
PO
4 .2H 2 0, 28.48 g of Na 2
HPO
4 .12H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The 25 mixture is adjusted to pH 6.8, made up to 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops. Example D: Ointment 30 500 mg of an active compound of the formula I is mixed with 99.5 g of petroleum jelly under aseptic conditions. Example E: Tablets 35 A mixture of 1 kg of active compound of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 g of talc and 0.1 kg of magnesium stearate is compressed in a customary manner to give tablets such that each tablet contains 10 mg of active compound.
WO 00/31039 PCT/EP99/08560 - 124 Example F: Coated tablets Analogously to Example E, tablets are pressed which are then coated with a coating of sucrose, potato 5 starch, talc, tragacanth and colourant in a customary manner. Example G: Capsules 2 kg of active compound of the formula I are 10 dispensed into hard gelatin capsules in a customary manner such that each capsule contains 20 mg of the active compound. Example H: Ampoules 15 A solution of 1 kg of active compound of the formula I in 60 ml of double-distilled water is sterile-filtered, dispensed into ampoules, lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 10 mg of active compound. 20 The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the 25 preceding examples. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make 30 various changes and modifications of the invention to adapt it to various usages and conditions.

Claims (10)

1. Compounds of the formula I R1 O N 0 (CHR)i 5 R2 in which R is H, A or CH 2 -Ph, Ri is -Het, -N- [ (CH 2 ) s-OH] 2 , -N- (CH2) s-OA]2, 10 -NA- (CH 2 ) -Ar, -NA- (CH 2 ) m-R, Y (CH 2 ) m-R, -Y- (CH 2 ) 2 -NHA, -Y- (CH 2 ) 2 -NH- (CH 2 ) s-OH, -Y- (CH 2 ) 2 -NA 2 , -Y- (CH 2 ) m-OH, -Y- (CH 2 )- (CHR 4 ) -R, -Y- (CH2) n-R 4 , R 4 , -Y- (CH 2 ) n-Het- (CH 2 ) o-R 6 , -Y- (CH 2 ) n-Ar' - (CH 2 ) o-R 6 -Het- (CH 2 ) n-Ar, -Het-Het, -Y- (CH 2 ) s-Ar' - (CH 2 ) o-R", 15 -Y- [X-0] t- [X 1 -O] u-X 2 _Rs or -Y- (CH 2 ) n-NA- (CH 2 ) o-R , R2 is H, OH, OA, COOH, COOA, CH(Ph)-Ph, Ar, Het', R', R or R8 R 3 is CH 3 , R 4 is -CH=CH 2 , -Ar, COOA, COOH OH3O H H N H H -N-C S or -N-C = N Ar 20 0 0 r R is NH 2 , NHA, NA 2 , NHAr, -NH- (CH 2 ) -OH or -NH- (CH 2 ) n-OA, R is H or R5 R is -Ar' - (CH 2 ),n-R or -Ar' - (CH2) n-R5 25 R' is CONH 2 , CONHA, CONA 2 , CONH- (CH 2 ) o-Ar, CONH- (CH 2 ) o-Het, CONH- (CH 2 ) o-R 5 , CONH- (CH 2 ) o-CH (Ar') Ar 2, CONH- (CH 2 ) o-CH (A) -Ph, CONH- (CH 2 ) -Ar'-NH-CO-Ar, CONH-Ar'-Het or CHA-CONH 2 , WO 00/31039 PCT/EP99/08560 - 126 R11 is -NH- (C=NH) -NH 2 , -NH- (C=NH) -NHA, -NH- (C=NH) -NA 2 , -NA- (C=NH) -NH 2 , -NA- (C=NH) -NHA or -NA- (C=NH) -NA 2 , Ar' is phenylene, cycloalkylene or biphenylene, which is unsubstituted or mono- or disubstituted by A, OH, OA, 5 Hal, CN, NH 2 , NHA, NA 2 , NO 2 , CF 3 , CO-A, SO 2 NH 2 , SO 2 NAH or SO 2 NA 2 , Ar is phenyl, cycloalkyl, naphthyl, cyclohex-1-enyl, biphenyl, bicyclohexyl, 4-cyclohexyl-phenyl, benzo[1,3]dioxol-5-yl or indanyl, which is 10 unsubstituted or mono-, di- or trisubstituted by A, OH, OA, 0-Ph, 0-CH 2 -Ph, 0-PH-CH 3 , O(cycloalkyl), Hal, CN, NH 2 , NHA, NA 2 , NH-C(O)A, (CH 2 )n-NH 2 , (CH 2 ) n-NHA, (CH 2 )n-NA 2 , NO 2 , CF 3 , C(O)A, S0 2 -Ph, SO 2 NH 2 , SO 2 NAH, SO 2 NA 2 or SO 2 NA-Ph, 15 Ar 1 and Ar 2 are each independently phenyl, Het is a saturated, partially or completely unsatura ted mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 20 2 S or 0 atoms can be present and the heterocyclic radical can be mono- or disubstituted by CN, Hal, OH, OA, CF 3 , A, NO 2 , CO, CO-A or R 5 , Het' is an unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 25 2 N and/or 1 or 2 S or 0 atoms can be present and/or can be mono- or disubstituted by Hal, OH, OA, A is unbranched or branched alkyl having 1-6 C atoms, 30 Hal is F, Cl, Br or I, X, X1, X2 in each case independently of one another are alkylene having 1 to 12 C atoms, Y is 0, S or NH, 35 i is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, m is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, n,o in each case independently of one another are 0, 1, 2, 3 or 4, s is 1, 2, 3 or 4, WO 00/31039 PCT/EP99/08560 - 127 t is 0, 1 or 2, u is 1 or 2, where if R2 is Ar or H, R1 is not H 2 C H 2 5 and their pharmaceutically tolerable salts and solvates.
2. Compound of the formula I according to Claim 1 a) methyl 3-(1,3-dioxo-6-piperidin-1-yl-3a,9b dihydro-lH-3H-benzo[de]isoquinolin-2 10 yl)propionate; b) 6-(3-amino-propylamino)-2-(3,4,5-trimethoxy benzyl)-benzo[de]isoquinoline-1,3-dione; and its physiologically acceptable salts and solvates.
3. Process for the preparation of the compounds of 15 the formula I according to Claim 1 and their salts or solvates, characterized in that a) a compound of the formula I is liberated from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent, 20 or b) a compound of the formula II R9 0 0 0 25 in which R 9 is Cl, Br, NO 2 or R 1 , where R1 has the meaning indicated in Claim 1 is reacted with a compound of the formula III H 2 N-(CHR)i R 2 111 30 in which R, R 2 and i have the meanings indicated in Claim 1, and, if necessary, the radical R 9 is converted into a radical Ri, WO 00/31039 PCT/EP99/08560 - 128 or (c) a compound of the formula IV R9 IV 0 H 5 in which R 9 is Cl, Br, NO 2 or R 1 , where R 1 has the meaning indicated in Claim 1 is reacted with a compound of the formula V L- (CHR)i-R 2 v 10 in which L is Cl, Br, or I, OH or a reactive esterified OH group and R, R2 and i have the meanings indicated in Claim 1 and, if appropriate, the radical R 9 is converted into a radical R 1 , 15 or (d) a radical R and/or R 2 and/or R 9 is converted into another radical R and/or R 2 and/or R 9 by, for example - converting an amino group into a guanidino group 20 by reaction with an amidinating agent, - reacting an aryl bromide or iodide to give the corresponding coupling products by means of a Suzuki coupling with boronic acids, - reducing a nitro group, sulfonyl group or 25 sulfoxyl group, - etherifying an OH group or subjecting an OA group to ether cleavage, - alkylating a primary or secondary amino group, - partially or completely hydrolysing a CN group, 30 - cleaving an ester group or esterifying a carboxylic acid radical, - or carrying out a nucleophilic or electrophilic substitution, and/or WO 00/31039 PCT/EP99/08560 - 129 (e) a base or acid of the formula I is converted into one of its salts or solvates.
4. A pharmaceutical composition comprising an effective amount of a compound of formula I of claim 1 5 or a physiologically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
5. A pharmaceutical composition of claim 4 which is effective as a glycoprotein IbIX antagonist.
6. A pharmaceutical composition of claim 5, 10 wherein said glycoprotein IbIX antagonist is effective for the control of thrombotic disorders and sequelae deriving therefrom.
7. A compound of formula I of claim 1, or a physiologically acceptable salt or solvate thereof as 15 pharmaceutical active compound.
8. A compound of formula I of claim 1, or a physiologically acceptable salt or solvate thereof as a glycoprotein IbIX antagonist.
9. Use of compounds of the formula I according to 20 Claim 1 and/or their physiologically acceptable salts or solvates for the production of a medicament for the control of thrombotic disorders and sequelae deriving therefrom or for use as anti-adhesive substances.
10. Use of compounds of the formula I according to 25 Claim 1 and/or their physiologically acceptable salts or solvates in the treatment of illnesses, such as for the prophylaxis and/or therapy of thrombotic disorders, as well as sequelae such as, for example, myocardial infarct, arteriosclerosis, angina pectoris, acute 30 coronary syndromes, peripheral circulatory disorders, stroke, transient ischaemic attacks, reocclusion/restenosis after angioplasty/stent implantations or as anti-adhesive substances for implants, catheters or heart pacemakers. 35
AU15049/00A 1998-11-25 1999-11-09 Substituted benzo(de)isoquinoline-1,3-diones Abandoned AU1504900A (en)

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GB0104240D0 (en) 2001-02-21 2001-04-11 Clariant Int Ltd Copolymer composition having pigment like properties
GB0419850D0 (en) * 2004-09-07 2004-10-13 Angeletti P Ist Richerche Bio Therapeutic agents
US8097725B2 (en) * 2004-12-03 2012-01-17 Roche Diagnostics Operations, Inc. Luminescent indicator dye and optical sensor
WO2012115945A1 (en) * 2011-02-21 2012-08-30 The Board Of Regents Of The University Of Texas System Viral inhibitors
CN103848787A (en) * 2012-12-06 2014-06-11 中国科学院大连化学物理研究所 Fluorescence probe and application thereof in reversible detection of hypochlorous acid
WO2014149198A1 (en) * 2013-03-15 2014-09-25 Alumend, Llc Compositions and methods of using the compositions for plaque softening
CN105492428A (en) * 2013-05-01 2016-04-13 中央研究院 Methods and compositions for treating beta-thalassemia and sickle cell disease
US20200172489A1 (en) * 2017-05-19 2020-06-04 Dojindo Laboratories Fluorescent compound and autophagy detection reagent using same
CN111253368B (en) * 2018-11-30 2020-12-25 沈阳药科大学 Stable nitroxide radical modified naphthalimide compound and application thereof
CN111777557B (en) * 2020-07-28 2022-11-22 中国科学院上海有机化学研究所 Novel anti-tumor lead compound with aromatic biphenyl alkene as framework and application thereof
CN113087702B (en) * 2021-03-29 2022-07-12 苏州大学 Multifunctional perchloroethylene derivative and preparation method and application thereof
WO2023166531A1 (en) * 2022-03-04 2023-09-07 Jawaharlal Nehru Centre For Advanced Scientific Research Amyloid and associated pathology modulators and methods thereof
WO2024042539A1 (en) * 2022-08-22 2024-02-29 Jawaharlal Nehru Centre For Advanced Scientific Research Modulators of tau liquid-liquid phase separation and methods thereof

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SK7012001A3 (en) 2001-11-06
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CA2351348A1 (en) 2000-06-02
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AR029152A1 (en) 2003-06-18
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CZ20011792A3 (en) 2001-09-12

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