CA2351348A1

CA2351348A1 - Substituted benzo[de]isoquinoline-1,3-diones

Info

Publication number: CA2351348A1
Application number: CA002351348A
Authority: CA
Inventors: Werner Mederski; Ralf Devant; Gerhard Barnickel; Sabine Bernotat-Danielowski; Guido Melzer; Peter Raddatz; Zhengdong Wu; Daljit Dhanoa; Richard Soll; James Rinker; Todd Graybill
Original assignee: Individual
Current assignee: Merck Patent GmbH
Priority date: 1998-11-25
Filing date: 1999-11-09
Publication date: 2000-06-02
Also published as: BR9915611A; WO2000031039A1; CN1328549A; MXPA01005228A; SK7012001A3; NO20012543D0; AR029152A1; AU1504900A; HUP0104469A2; HUP0104469A3; PL347766A1; NO20012543L; CZ20011792A3; EP1133475A1; JP2002530379A; ID29425A

Abstract

Novel compounds of formula (I), in which R, R1, R2 and i have the meaning indicated in Patent Claim 1, and their salts or solvates as glycoprotein IbIX
antagonists.

Description

Substituted beazo[de~isoquinoliae-1,3-diones This application is a continuation-in-part of Serial No. 09/199,409, the entirety of which is incorporated by reference herein.
The invention relates to substituted benzo[de]-isoquinoline-1,3-diones of the formula I
i ~ R1 I
i O~N/''~O [
(CI R)i in which R is H, A or CH2-Ph, Rl i s -Het, -N- [ ( CH2 ) s-OH ] 2, -N- [ ( CH2 ) g-OA] 2, -NA- ( CH2 ) s-Ar, -NA- ( CH2 ) ,n R5, -Y- ( CH2 ) m-R5, -Y- ( CH2 ) 2-NHA, -Y- ( CH2 ) 2-NH- ( CH2 ) s-OH, -Y- ( CH2 ) 2-NA2, -Y- ( CH2 ) m OH, -Y- ( CHz ) n- ( CHR4 ) -R3, -Y- ( CH2 ) n-R9 r R4 , -Y- ( CH2 ) n-Het- ( CHZ ) o-R6 r -Y- ( CH2 ) n-Ar' - ( CH2 ) o-R6 r -Het- ( CHZ ) n-Ar, -Het-Het, -Y- ( CH2 ) g-Ar' - ( CHZ ) o-Rll, -Y- [ X-O ] t- [ X1-0 ] u-XZ-RS or -Y- ( CH2 ) n-NA- ( CH2 ) o-R5 r R2 is H, OH, OA, COOH, COOA, CH (Ph) -Ph, Ar, Hetl, R5, R' or Re R3 is CH3, R9 is -CH=CH2, -Ar, COOA, COOH
O HaC
H H N H H 'N
-N-C ~S or -N-C i , p N ~ ~Ar RS is NH2, NHA, NA2, NHAr, -NH- (CH2) n-OH or -NH- ( CH2 ) n-OA, R6 is H or R5 R' i s -Ar' - ( CH2 ) n-RB or -Ar' - ( CH2 ) n-R5 R$ is CONH2, CONHA, CONA2, CONH- (CH2) o-Ar, CONH- ( CHz ) o-Het , CONH- ( CHZ ) o-R5, CONH- ( CH2 ) o-CH (Arl ) -Ar2, CONH- (CH2) o-CH (A) -Ph, CONH- (CHZ) o-Ar' -NH-CO-Ar, CONH-Ar'-Het or CHA-CONHZ, R11 i s -NH- ( C=NH ) -NH2, -NH- ( C=NH ) -NHA, -NH- ( C=NH ) -NA2, -NA- ( C=NH ) -NHZ, -NA- ( C=NH ) -NHA er -NA- ( C=NH ) -NAZ, Ar' is phenylene, cycloalkylene or biphenylene, which is unsubstituted or mono- or disubstituted by A, OH, OA, Hal, CN, NH2, NHA, NA2, N02, CF3, CO-A, S02NH2, S02NAH, S02NA2, Ar is phenyl, cycloalkyl, naphthyl, cyclohex-1-enyl, biphenyl, bicyclohexyl, 4-cyclohexyl-phenyl, benzo[1,3]dioxol-5-yl, or indanyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, 0-Ph, O-CH2-Ph, O-Ph-CH3, 0 (cycloalkyl) , Hal, CN, NH2, NHA, NA2, NH-C (0) A, (CHZ) n-NH2, (CHZ) n-NHA, (CH2)n-NA2, N02, CF3, C(0)A, SOZ-Ph, SOzNHz, SOZNAH, SOzNA2 or SOZNA-Ph, Arl and Ar2 are each independently phenyl, Het is a saturated, partially or complete ly unsatura-ted mono- or bicyclic heterocyclic ra dical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by CN, Hal, OH, OA, CF3, A, NO2, C0, CO-A or R5, Hetl 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 and/or can be mono- or disubstituted by Hal, OH, OA, A is unbranched or branched alkyl h aving 1-6 C

atoms, Hal is F, C1, 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

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, l, 2, 3 or 4, s is 1, 2, 3 or 9, t is 0, 1 or 2, a is 1 or 2, where if Rz is Ar or H, R1 is not H
~C~
-N~C~ (CH2)1-5 Hi and their pharmaceutically tolerable salts and 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.
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 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 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 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 tolerability. They act especially as GPIbIX inhibitors, in particular inhibiting the interaction of this 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
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 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, 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, 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).
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 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, Q832, 927-929) using botrocetin or 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 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 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 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 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 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 solvolysing or hydrogenolysing agent, or b) a compound of the formula II

i w ~ II
OwOiwO
in which R9 is C1, Br, N02 or R1, and R1 has the meaning indicated in Claim 1 is reacted with a compound of the formula III
H2N-(CHR) i RZ III

in which R, RZ and i have the meanings indicated in Claim 1, and, if necessary, the radical R9 is converted into a radical R1, or (c) a compound of the formula IV

IV
O NCO
I
H
in which R9 is C1, Br, NOZ or R1, where R1 has the meaning indicated in Claim 1 is reacted with a compound of the formula V
L (CHR)~ RZ V
in which L is C1, 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 R9 is converted into a radical Rl, or (d) a radical R and/or R2 and/or R9 is converted into another radical R and/or R2 and/or Rg 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 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
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, -- or carrying out a nucleophilic or electrophilic substitution, and/or (e) a base or acid of the formula I is converted intc 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 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 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.
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 dehydrates or alcoholates.
The abbreviations used have the following meanings:

BOC tert-butoxycarbonyl CBZ benzyloxycarbonyl DCC dicyclohexylcarbodiimide DMF dimethylformamide Et ethyl Fmoc fluorenylmethoxycarbonyl Me methyl Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl OBut tert-butyl ester OMe methyl ester OEt ethyl ester POA phenoxyacetyl _ g -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 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, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 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 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 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, o-, m- or p-(trifluoromethyl)phenyl, o-, m- or p-(trifluoromethoxy)phenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-iodophenyl, 9-benzenesulfonyl-phenyl, 4-(4-chloro-phenoxy)-phenyl, furthermore preferentially 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 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, 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-- g _ 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-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-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-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-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-9-methyl-, 3-fluoro-5-methyl-, 4-fluoro-3-methylphenyl, 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, 5-chloro-2,4-dimethoxy-phenyl, 2-cyano-3,9-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.
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, 4'-methylbiphenyl-4-yl, 2'-methylbiphenyl-3-yl, 3'-methylbiphenyl-3-yl, 4'-methylbiphenyl-3-yl, 2-methylbiphenyl-4-yl, 3-methylbiphenyl-4-yl, 2-methylbiphenyl-3-yl, 4-methylbiphenyl-3-yl, 2'-tert-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-butylbiphenyl-3-yl, 2-tert-butylbiphenyl-4-yl, 3-tert-butylbiphenyl-4-yl, 2-tertbutylbiphenyl-3-yl, 4-tert-butylbiphenyl-3-yl, 2'-isopropylbiphenyl-4-yl, 3'-isopropylbiphenyl-4-yl, 4'-isopropylbiphenyl-4-yl, 2'-isopropylbiphenyl-3-yl, 3'-isopropylbiphenyl-3-yl, 4'-isopropylbiphenyl-3-yl, 2-isopropylbiphenyl-4-yl, 3-isopropylbiphenyl-4-yl, 2-isopropylbiphenyl), 4-isopropylbiphenyl-3-yl, 2'-fluorobiphenyl-4-yl, 3'-fluorobiphenyl-4-yl, 9'-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, 2'-methoxybiphenyl-4-yl, 3'-methoxybiphenyl-4-yl, 4'-methoxybiphenyl-4-yl, 2'-methoxybiphenyl-3-yl, 3'-methoxybiphenyl-3-yl, '-methoxybiphenyl-3-yl, 2-methoxybiphenyl-4-yl, 3-methoxybiphenyl-4-yl, 2-methoxybiphenyl-3-yl, 4-methoxybiphenyl-3-yl, 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-9-yl, 2-nitro-biphenyl-3-yl, 4-nitrobiphenyl-3-yl, 2'-trifluoromethylbiphenyl- 9-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-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, 3'-trifluoromethoxybiphenyl-3-yl, 4'-tri-fluoromethoxybiphenyl-3-yl, 2-trifluoromethoxybiphenyl-4-yl, 3-trifluoromethoxybiphenyl-4-yl, 2-trifluoromethoxybiphenyl-3-yl, 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'-nitrobiphenyl-4-yl, 3'-methyl-4'-nitrobiphenyl-4-yl, 3'-methyl-5'-nitrobiphenyl-9-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, 2'-methyl-5'-nitrobiphenyl-3-yl, 2'-methyl-6'-nitro-biphenyl-3-yl, 3'-methyl-2'-nitrobiphenyl-3-yl, 3'-methyl-9'-nitrobiphenyl-3-yl, 3'-methyl-5'-nitrobiphenyl-3-yl, 3'-methyl-6'-nitrobiphenyl-3-yl, 4'-methyl-2'-nitrobiphenyl-3-yl, 4'-methyl-3'-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-9-yl, 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'-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, 9'-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, (3',4'-dimethoxy)biphenyl-9-yl, WO 00/31039 PCT/EP99/085b0 (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, (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, (3',4'-di(trifluoromethyl))biphenyl-4-yl, (3',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, (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, (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.
Arl and Ar2 are each independently phenyl.
Ar' preferentially is phenylene, cyclohexylene or biphenylene, which is unsubstituted or monosubstituted by Hal or CN.
In -Ar' - (CH2) n_R5, Ar' is preferentially unsubstituted or substituted phenylene or cycloalkylene, where RS is preferentially an amino, alkylamino or dialkylamino group and where n can be 0, 1, 2, 3 or 4.

or is particularly preferred for -Ar' - (CH2) n-R5.

In -Ar' - (CHZ) n-R8, Ar' is preferably unsubstituted or substituted phenylene or cycloalkylene, where R8 is preferentially an amido, an alkylamido or dialkylamido group or -CONH-(CH2)o-Ar, -CONH- ( CH2 ) o-Het , -CONH- ( CH2 ) a-CH (Arl ) -Ar2, -CONH- ( CH2 ) o-CH (A) -Ph or -CONH- (CHZ) o-R5 and where n is 0, 1, 2, 3 or 4.

CONH2 , CONH(C3H~) , CONH(C3H~) CONH-(CH2)2-C(CH3)s , CONH(C5H~~) or CONH(C5H») is particularly preferred for -Ar' - (CHZ) n-R8.

CONH
CONH (CH2)z CONH

CONH-(CH2)2 , CONH-(CH2)3 CONH-(CH2)a CONH
Br r CONH
CN
CONH-(CH2)2 ~ ~ N02 , r - CH
CONH-CH2 ~ ~ N~ 3 r - CH
CONH ~ ~ N~ CH r ~ C2H5 CONH ~ ~ N~
C2Hs CONH-CH2 ~ ~ S02-NHZ
CONH-(CH2)2 ~ ~ CH3 CONH ~ ~ CH3 CONH

CONH-CHZ

CONH

, CONH

C2H5 , CONH
.
CONH ~ \ CH

CONH

.
CONH-(CHz)2 CI
CONH
CI

l0 CI
CONH-(CH2)2 CI

CONH ~ ~ CI
, CONH-(CH2)2 ~ ~ CI
CONH CH2 ~ ~ CI
C!

CI
CI CI

, CI
CONH-CH2 ~ ~ CI
CI
CONH-(CH2)2 ~ ~ CI
Ci CI
CI
CONH
CI
CI
CONH ~ ~ CI
, CONH-CH2 ~ ~ F
CI

/ CONH / ~ F
CI
/ CONH-CH2 / ~ F
CI
.
CONH-(CH2)2 / ~ F
/
/ CONH-CHZ
F
/ CONH
F, CON
/ ~ ~._/
F
.
CONH-(CH2)z /

/ CON / ~

, / CONH / ~ OCH3 , / CONH-(CH2)2 / ~ OCH3 CONH-CH2 ~ ~ OCF3 F
CONH ~ ~ OCH3 F
CONH ~ ~ H3 CONH

tert-butyl CONH
tert-butyl CONH-(CH2)2 OC
CONH
OC

CONH-(CHZ)2 ~ ~ OCH3 OPh CONH
CONH ~ ~ OPh CONH ~ ~ O ~ ~ CH3 CONH
O
~--Ph CONH
CONH-CHz CONH /
, O\
CONH-CH2 ~ ~ O
CONH ~ ~ OCH3 CI
CONH ~ ~ CI

.
CONH-(CH2)2 CONH-(CH2)z CI

CONH-CH2 ~ ~ C!
.
CONH ~ ~ CI
CI

CI
CI CI

CONH-(CHZ)2 ~ ~ F
, CONH-(CHz)Z ~ ~ OCH3 CONH
CONH
CONH ~ ~ OPh CONH ~ ~ (~CH

CONH-CH2 ~ ~ f~CH

O\
CONH-CH2 ~ ~ ,O
CONH- ~
or CONH-(CH2)s are furthermore particularly preferred for -Ar' - ( CH2 ) n-R8 where R8 is -CONH- ( CHZ ) o-Ar .

-N
CONH
-N
, CONH-CH2 ~ ~N
CONH ~ ~N
N
CONH-(CH2)2 CONH-(CH2)2-N
CONH-(CH2)2-N O
O
CONH-(CH2)3-N
, CONH-(CH2)2-N' CONH-(CH2)3 -N
=N
S
CONH-CHz .
O

CONH-(CH2)2-N O
O

CONH-(CH2)3 -N
=N
CONH-CH2 ~ ~N
CONH ~ ~N
CONH
-N
or -N
is particularly preferred for -Ar' - (CHZ) "-R8 where R$ is -CONH- ( CH2 ) o-Het .
~I
CONH-(CH2)2-CH /
\I

CONH-(CH2)2-CH /
or is particularly preferred for -Ar'-(CH2)n-Re where Re is -CONH- ( CH2 ) o-CH (Arl ) -Ar2 .
,CH3 is particularly preferred for -Ar' - (CH2) n-R8 where RB is -CONH- (CH2) o-CH (A) -Ph.
Furthermore, CONH-(CHZ)4 -NHZ , CONH (CH2)a - NH2 CONH-(CH2)2-NH2 or / \ CONH (CH2)2 -NH2 is particularly preferred for -Ar' - (CH2) n-R8 where R8 is -CONH- ( CHZ ) o-RS .
Cycloalkyl having 3 to 8 carbon atoms is preferentially cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; particularly preferred cyclohexyl or cyclopentyl.
Cycloalkylene having 3 to 8 carbon atoms is preferentially cyclobutylene, cyclopentylene, cyclohexylene, or cycloheptylene; particularly preferred cyclohexylene.
0(cycloalkyl) having 3 to 8 carbon atoms is preferentially cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy; particularly preferred cyclopentyloxy.
Hal is preferably F, C1, Br or iodine.
Hetl is preferentially substituted or unsubstituted 2-, 3-, or 4-pyridyl, 2- or 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-IH-indol-3-yl, 4-, 5-, 6-, methoxy-1H-indol-2-yl or 4-, 5-, 6-, 7-methoxy-1H-indol-3-yl, 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 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-, 9- 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 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,9-triazol-1-, -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, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-9- or -5-yl, 2-, 3-, 4-, 5 - or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 9-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, 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-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-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 1,1-dioxo-1H-1~,6-benzo[b]thiophen-5-yl or 2,~-dioxo-2,3-dihydro-1H-2~,6-benzo[c]thiophen-5-yl.
The heterocyclic radicals can also be partially or completely hydrogenated. Het can thus also be 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-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, pyrrolidine-2-on-1-yl, tetrahydro-1-, -2- or -3-pyrrolyl, tetrahydro-1-, -2- or 4-imidazolyl, 2, 3-dihydro-1-, -2-, -3-, -4-, -5-, -6-, -7-1H-indolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -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, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolinyl.
2-, 3- or 4-pyridyl, 1-imidazolyl, 2-methyl-1-imidazolyl, 2-pyrimidinyl, 5-fluoro-1H-indol-2-yl, 2, 3-dihydro-1-, -2-, -3-, -4-, -5-, -6-, -7-1H-indolyl, 1-quinolinyl, 1-isoquinolinyl, 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-piperazin-1-yl or 4-phenylmethylpiperazin-1-yl is particularly preferred.
In -Het-(CHz)"-Ar, Het and Ar have one of the preferred meanings indicated above, where Het is preferably piperidine-1,4-diyl or piperazine-1,4-diyl and n can be 0, 1, 2, 3, or 4.

-NON-CH2 ~ ~ O
U
or -NON-CH2 is particularly preferred for -Het-(CHZ)n-Ar.
In -Het-Het, Het has one of the preferred meanings indicated above, where in -Het-Het the first heterocycle is preferably piperidine-1,4-diyl or piperazine-1,4-diyl.
N-- NON --~~
U N
~--\ N -or - N N
U
is particularly preferred for -Het-Het.
In -Y- (CHz) n-Het- (CHZ) o-R6, Y is preferably O, S
or NH, where Het has one of the preferred meanings indicated above and R6 is preferentially H, amino or alkylamino. Furthermore, n and o independently of one another are preferably 0, 1, 2, 3 or 4.
-NH-(CH2)2-N . -NH-(CH2)3-N N-CH3 , 2 0 ~ ~--/
N~ N--NH-(CH2)2 \ / . -NH-CH2 \ / ' -NH-(CH2)2 \ > , -NH-(CH2)3-N~N
N
-NH-(CH2)3- ~ -(CH2)3 NHZ

_ 27 _ or _ NH N
are particularly preferred for -Y- (CH2) n-Het (CH2) o-R6.
Furthermore, in -Y- (CH2) n-Ar' - (CHZ) o-R6, Y is preferentially 0, S, or NH, where Ar' has a preferred meaning indicated beforehand and R6 is preferably H, amino or alkylamino and n and o independently of one another are 0, 1, 2, 3 or 4.
-NH~ , -NH , -NH
- NH-(CH2)2 ~ ~ OH . - NH-CH2 -NH-CH2 ~ ~ 02-NH2 .
-NH-CH2 ~ ~ NH2 . -NH_(CH2)2 ~ ~ .
_ NH-CHZ ~ ~ CH2- NH2 _NH-CH2 CH2- NH2 _ NH-CH2 or _ NH-CH2 is particularly preferred for -Y- (CH2) n-Ar' - (CHZ) o-R6.
Furthermore, in -Y- (CHZ) s-Ar' - (CHZ) o-Rll, Y is preferentially 0, S, or NH, where Ar' has a preferred meaning indicated beforehand and R11 is preferably -NH
(C=NH) -NH2 and s and o independently of one another are 0, 1, 2, 3 or 4.

H
CHZ ~ ~NH2 _ NH-CH2 is particularly preferred for -Y- (CHz) s-Ar' - (CH2) o-R11.
X and/or X1 and/or X2 is alkylene and is preferably methylene, ethylene, propylene, butylene, furthermore also pentylene or hexylene.
In -Y- [X-0] t- [X1-0] u-XZ-R5, Y is preferentially 0, S or NH, where X, X1 and X2 have a preferred meaning indicated beforehand. Furthermore, R5 is preferably amino, alkylamino or dialkylamino, t is 0, 1 or 2 and a i s 1 or 2 . -NH- ( CH2 ) 3-0- ( CHZ ) 4-O- ( CH2 ) 3-NHZ i s particularly preferred for -Y- [X-0] t- [X1-O] "-XZ-R5.
Y is preferentially O, S or NH, particularly preferentially NH.
R is preferably H, A, or CH2-Ph, where A has a preferred meaning indicated above. H, sec-butyl or CHZ-Ph is particularly preferred.
R1 is preferably -Het, -N- [ (CH2) S-OH] 2.
-N- [ ( CH2 ) s-OA ] 2 i -NA- ( CHZ ) s-Ar, -NA- ( CH2 ) m-R5 i 2 0 -Y- ( CH2 ) m-R5 r -Y- ( CH2 ) z-NHA, -Y- ( CH2 ) 2-NA2 i -Y- ( CH2 ) 2-NH- ( CH2 ) s-OH, -Y- ( CHz ) m-OH, -Y- ( CH2 ) n- ( CHR4 ) -R3.
-Y- ( CH2 ) n-R4 i R4 ~ -Y- ( CHZ ) n-Het- ( CH2 ) o-R6 i -Y- (CH2) n-Ar' - (CH2) o-R6, -Het- (CHZ) n-Ar, -Het-Het, -Y- [ X-0 ] t- [ X1-0 ] "-X2-RS or -Y- ( CH2 ) n-NA- ( CHZ ) o-R5. where 2 5 -Het , -Y- ( CH2 ) n-Het- ( CH2 ) o-R6, -Y- ( CH2 ) n-Ar' - ( CH2 ) o-R6, -Y- ( CH2 ) s-Ar' - ( CH2 ) o-R11, -Het- ( CH2 ) n-Ar, -Het-Het and -Y- [X-O] t- [X1-O] "-XZ-R5 in particular have the preferred meanings indicated beforehand. Furthermore, s in -N- [ (CH2) s-OH] 2 and -N- [ (CH2) S-OA] 2 is preferably 1, 2, 3 30 or 4 and A has the preferred meaning indicated beforehand. -N-[(CHZ)2-OH]2 is particularly preferred for -N- [ (CH2) s-OH] 2.

In -NA-(CH2)s-Ar, A and Ar have a preferred meaning indicated beforehand and s is preferably l, 2, 3 or 4.
OH
-N(CH3)-(CH )2 / ~ OH
is particularly preferred for -NA-(CH2)g-Ar.
Furthermore, A in -NA- (CH2) S-RS as a substituent for R1 has a preferred meaning indicated beforehand, where R5 is preferably amino, alkylamino or dialkylamino and s is 1, 2, 3 or 4 . -N (CH3) - (CH2) 3-NH (CH3) and -N (CH3) - (CH2) 2-N (C2H5) 2 are particularly preferred for -NA- ( CH2 ) s-RS .
In -Y- (CHZ) m-R5 Y is preferentially 0, S or NH, where RS
is preferably amino, alkylamino or dialkylamino and m is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. -NH- (CHZ) 3-NHZ, -NH- ( CH2 ) 3-NH ( CH3 ) , -NH- ( CHZ ) 3-N ( CH3 ) 2.
-NH- ( CHZ ) 3-NH [ CH ( CH3 ) 2 ] . -NH- ( CH2 ) 3-NH ( C6Hli ) , -NH- ( CHZ ) 4-NH2, -NH- ( CH2 ) 5-NH2, -NH- ( CH2 ) ~-NH2 and -NH-(CH2)e-NHZ are particularly preferred for -Y- ( CHZ ) m-R5 .
In -Y- (CH2) Z-NHA and -Y- (CH2) 2-NA2, Y is preferably O, S
or NH, where A has a preferred meaning indicated beforehand. -NH- (CH2) 2-NH (CZHS) , -NH- (CHZ) 2-NH (C3H~) and -NH- (CHZ) 2-NH [CH (CH3) 2] are particularly preferred for -Y- ( CH2 ) 2-NHA .
In -Y- (CH2) 2-NH- (CH2) g-OH, Y is preferably 0, S or NH, where s is 1, 2, 3 or 4 . -NH- (CH2) 2-NH (CH2) 2-OH is particularly preferred for -Y- (CHZ) 2-NH- (CHZ) S-OH.
In -Y-(CHZ)m-OH, Y is preferably O, S or NH, where m is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. -NH-(CH2)5-OH is particularly preferred for -Y-(CHZ)m-OH.
In -Y- (CHZ) n- (CHR9) -R3, Y is preferably 0, S or NH, where R3 is preferably methyl, R4 is preferentially Ar and n is 0, l, 2, 3 or 4. -NH-(CHPh)-CH3 is particularly preferred for -Y- (CH2) n- (CHR4) -R3.
In -Y- (CH2) ~-R4, Y is preferentially 0, S or NH, where in this formula R4 is preferably COOH or CODA, A has a preferred meaning indicated beforehand and n is 0, 1, 2, 3 or 4. -NH-(CH2)z-COOMe is particularly preferred .
In -Y- (CH2) n_NA- (CH2) o-R5, Y is preferentially 0, S, NH, where A has a preferred meaning indicated beforehand, R' 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- (CHZ) 3-N (CH3) - (CH2) 3-NH2 is particularly preferred for -Y- (CH2) n-NA- (CH2) o-R5.
i is preferentially 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, particularly preferentially l, 2, 3, 5, 7, 10 or 11.
Rz is preferably H, OH, OA, COOH, CODA, Ar, CH (Ph) -Ph, Hetl, R5, R' or Re, where A, Ar and Hetl have a preferred meaning indicated beforehand.
R3 is preferentially CH3.
R4 is preferably -CH=CH2, Ar, COOA, COOH
p H3C
H H N H H \N
-N-C ~S or -N-C i 'Ar O O
where Ar and A have a preferred meaning indicated beforehand.

H H
~N
-N C i O ~ \

is particularly preferred for H H
i i ~N
-N C i O 'Ar R5 is preferentially amino, alkylamino, dialkylamino, NHAr, -NH-(CH2)n-OH or -NH-(CH2)n-OA, where A and Ar have a preferred meaning indicated beforehand and n is 0, 1, 2, 3, or 4. -NH-(CHZ)2-OH is particularly preferred for -NH- (CHZ) n-OH.
R6 ~is H or R5, where R5 has a preferred meaning indicated beforehand.
R' is preferentially -Ar' - (CH2) n-RB or -Ar' - ( CH2 ) n-R5, where -Ar' - ( CHZ ) n-Re and -Ar' - ( CH2 ) "-R5 have a preferred or particularly preferred meaning indicated beforehand.
R8 is preferably CONHZ, CONHA, CONA2, CONH- (CH2) o-Ar, CONH- (CH2) o-Het, CONH- (CHZ) o-CH (Arl) -Ar2, CONH-Ar'-NH-CO-Ar, CONH-Ar'-Het, CONH-(CHZ)o-RS or CHA-CONH2, where A, CONH- (CHZ) o-Ar, CONH- (CHZ) o-Het, CONH- ( CHZ ) o-CH (Arl ) -Ar2, and CONH- ( CH2 ) o-R5 have a preferred or particularly preferred meaning indicated beforehand in -Ar' - (CHz) n-Re. CH (CH3) -CONH2 is particularly preferred for CHA-CONHz.
~CH3 O
O
CONH ~ ~ N

is particularly preferred for CONH-Ar'-NH-CO-Ar.
CONH ~ N
CI
CONH ~ ~ N, Ji CN
CONH
S
CONH

-._ CONH
S
CONH ~ \ CH3 S
O
CONH
S CI
or -N
CONH
is particularly preferred for CONH-Ar'-Het.
R11 i s -NH- ( C=NH ) -NHZ, -NH- ( C=NH ) -NHA, -NH- ( C=NH ) -NA2, -NA- ( C=NH ) -NH2, -NA- ( C=NH ) -NHA or -NA-(C=NH)-NA2, where A has a meaning indicated beforehand. -NH-(C=NH)-NHZ 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 G.
m is preferably 3, 4, 5, 6, 7, 8, 9, 10, 11 or 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 9.
s is preferably 1, 2, 3 or 4.
t is preferably 0, 1 or 2.
a 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

i i O~N/'O I
(CI R)i and in which the radicals not designated in greater detail have the meanings indicated in formula I, but in which:
in Ia R is H, RZ is H, Rl is -Het, -N- [ (CH2) s-OHJ 2, -Y- (CH2) n-R4 or R4 and i is 1, 2, 3, 9, 5, 6, 7, 8, 9, 10, 11 or 12;
in Ib R is H, RZ i s OH
R1 is -Het or -Y- (CHZ) n- (CHR4) -R3 and i is 2;
in Ic R is H, R2 is COOA, R1 1 s -Het, -Y- ( CH2 ) n- ( CHR4 ) -R3, -Y- ( CH2 ) n-Ar' - ( CHZ ) o-R6, -Het- ( CH2 ) n-Ar or -NA- ( CHZ ) $-Ar and i is 2;
in Id R is H, RZ i s Ar, Rl i s -Het, -NA- ( CH2 ) S-Ar, -Y- ( CH2 ) m-Rs, -Y- ( CH2 ) m-OH, -Y- ( CH2 ) n- ( CHR4 ) -R3 r 3 0 -Y- ( CH2 ) n-R9 r -Y- ( CH2 ) n-Het- ( CH2 ) o-R6 r -Y- ( CH2 ) n-Ar' ( CH2 ) o-R6 or -Het- ( CH2 ) n-Ar and i is 1 or 2;

in Ie R is H, R2 is Hetl, Rl i s -Het , -NA- ( CH2 ) s-Ar, -Y- ( CH2 ) m-R5, -Y- ( CH2 ) m-OH, -Y- ( CH2 ) n- ( CHR4 ) -R3.
-Y- ( CH2 ) n-R4. -Y- ( CH2 ) n-Ar' ( CHZ ) o-R6 or -Het- ( CHZ ) n-Ar and i is 1 or 2;
in If R is H, R2 i s R5 , R1 i S -Het, -Y- ( CH2 ) m-R5, -Y- ( CH2 ) m-OH, -Y- ( CHZ ) n- ( CHR4 ) -R3, -Y- ( CHZ ) n-R4.
-Y- ( CHZ ) n-Het- ( CHZ ) o-R6, -Y- ( CH2 ) n-Ar' - ( CH2 ) o-R6 or -Het- ( CHZ ) n-Ar and i is 3 or 5;
in Ig R is H, R2 is Re, R1 1 s -Het, -NA- ( CH2 ) m-R5, -Y- ( CHZ ) m-R5, 2 O -Y- ( CH2 ) 2-NH- ( CHZ ) S-OH, -Y- ( CHZ ) m-OH, -Y- ( CH2 ) n- ( CHR4 ) -R3, -Y- ( CH2 ) n-R4.
-Y- ( CHZ ) n-Het- ( CHZ ) o-R6.
-Y- ( CH2 ) n-Ar' - ( CHz ) o-R6. -Het- ( CHZ ) n-Ar, -Het-Het, -Y- [X-0] t- [X1-O] "-XZ-R5 or 2 5 -Y- ( CHZ ) n-NA- ( CH2 ) o-RS and i is 1, 2, 7, 10 or 11;
in Ih R is H, R2 is R', 30 Rl is -Het, -NA- ( CH2 ) m R5, -Y- ( CH2 ) m-R5, -Y- ( CH2 ) 2-NHA, -Y- ( CH2 ) 2-NH- ( CHz ) S-OH, -Y- ( CHZ ) m-OH, -Y- ( CH2 ) n- ( CHR4 ) -R3.
-Y- ( CHZ ) n-R4. -Y- ( CH2 ) n-Het- ( CH2 ) o-R6 r -Y- ( CH2 ) n-Ar' - ( CH2 ) o-R6.
35 -Y- (CH2) s-Ar' - (CH2) o-Rll, -Het- (CH2) n-Ar, -Het-Het, -Y- [X-O] t- [X1-O] "-X2-R5 or -Y- ( CHZ ) n-NA- ( CH2 ) o-R5 and i is 1 or 2:

in I k R is A or CH2-Ph, R2 is Re, R1 1 s -Het, -Y- ( CHZ ) m-R5, -Y- ( CH2 ) n-Het- ( CHz ) o-R6 or -Y- ( CHZ ) n-Ar' - ( CH2 ) o-R6 and i is 1;
in Im R is H, RZ is CONH2, R1 1 S -Het, -NA- ( CH2 ) m-R5, -Y- ( CH2 ) m-R5 r 1 O -Y- ( CH2 ) 2-NH- ( CH2 ) s-OH, -Y- ( CHZ ) m-OH, -Y- ( CH2 ) n- ( CHR4 ) -R3, -Y- ( CH2 ) n-R4 r -Y- ( CHZ ) n-Het- ( CH2 ) o-R6, -Y- ( CHZ ) n-Ar' - ( CHZ ) o-R6 i -Het- ( CH2 ) n-Ar , -Het-Het, -Y- [X-O] t- [X1-O] u-X2-RS Or -Y- ( CHZ ) n-NA- ( CHZ ) o-RS and i is 1, 2, 7, 10 or 11;
in In R is H, R2 is CONHA, 2 0 R1 i s -Y- ( CH2 ) m RS or -Y- ( CH2 ) n-Ar' - ( CH2 ) o-R6 and i is 2;
in Io R is H, RZ is CONH- (CHZ) o-Ar, Rl 1 s -Y- ( CHZ ) m-Rs r -Y- ( CH2 ) n-Het- ( CHZ ) o-R6 or -Y- ( CHZ ) n-Ar' - ( CHz ) o-R6 and i is 1 or 2;
in Ip R is H, Rz is CONH- (CH2) o-Het, R1 i s -Y- ( CH2 ) m-R5, or -Y- ( CHZ ) n-Ar' - ( CH2 ) o-R6 and i is 2;
in Iq R is H, RZ is CONH- (CH2) o-CH (Arl) -Ar2, R1 i s -Y- ( CH2 ) n-Ar' - ( CHZ ) o-R6 and i is 2;

in Ir R is H, R2 is CONH-Ar'-NH-CO-Ar, R1 i s -Y- ( CHZ ) n-Ar' - ( CHZ ) o-R6 and i is 2;
in Is R is H, R2 is CONH-Ar'-Het, R1 i s -Y- ( CHZ ) n-Ar' - ( CHz ) o-R6 and i is 2;
in It R is H, R2 is CH (Ph) -Ph, R1 i s -Y- ( CH2 ) m-R5. or -Y- ( CHz ) n-Ar' - ( CH2 ) o-R6 and i is 2;
in Iu R is H, RZ is Ar' - (CHZ) "-Re, R1 i s -Y- ( CH2 ) m-R5. -Y- ( CHz ) a-Ar' - ( CHZ ) o-R6 or -Y- ( CH2 ) n-Ar' - ( CH2 ) o-Ri1 and i is 1 or 2;
in Iv R is H, R2 is Ar, Re or Ar' - (CHZ) n-Re, R1 i s -Y- ( CH2 ) m-R5. or -Y- ( CHZ ) ~-Ar' - ( CH2 ) o-R6 and 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 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 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 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 solvolysis, in particular hydrolysis or by hydrogen olysis.
Preferred starting substances for the solvolysis or hydrogenolysis axe those which otherwise correspond to the formula I, but instead of one or more 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 carry a hydroxyl protective group, e.g. those which correspond to the formula I, but instead of a group -COOH carry a group -COOK", in which R" is a hydroxyl protective group.
A number of - identical or different 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 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 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;
however, those having I-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 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, 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
("carbobenzoxy"), 9-methoxybenzyloxycarbonyl, Fmoc;
arylsulfonyl such as Mtr. Preferred amino protective groups are BOC, furthermore CBZ, Fmoc, benzyl and acetyl.
The expression "hydroxyl protective group" is 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 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 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 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 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 solvent is possible, but not always necessary. Suitable inert solvents axe preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, 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 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 50°C; the reaction is preferably carried out between 15 and 30°C (room temperature).
The groups BOC and Obutyl can preferably be removed, for example, using TFA in dichloromethane or using approximately 3 to 5N HC1 in dioxane at 15-30°C, the Fmoc group using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°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 (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 hydrogenolysis is carried out at temperatures between approximately 0 and 100°C 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 methanol or ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°C.
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 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-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 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 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 days, the reaction temperature between approximately 0°
and 150°C, normally between 20° and 130°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.
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 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 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 (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.
For the preparation of compounds of the formula I in which R11 is H2N-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 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 between 0° and 150°C, preferably between 60° and 120°C.
For the preparation of compounds of the formula I in which RZ is unsubstituted or substituted biphenyl, -Ar'-Het and/or -CONH-(CHZ)o-Ar, an appropriate compound of the formula I in which RZ is 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 ( PPh3 ) 4, in the presence of a . base such as potassium carbonate in an inert solvent or solvent mixture, e.g. DMF at temperatures between 0° and 150°, preferably between 60° and 120°. Depending on the conditions used, the reaction time is between a few minutes and a number of days. The boronic acid 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, 111, 314ff. and Suzuki et al., Chem. Rev. 1995, 95, 2457ff.
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 available. The substituent R1 can preferably be introduced into the aromatic by substitution. In many cases, it is expedient to introduce this substituent before the reaction with ammonia.
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.
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 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, 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 employed in protected form. Possible protective groups are those mentioned beforehand.
For the esterification, an acid of the formula I (R1 - COOH or -Y- (CHZ) n-COOH and/or Rz - COOH) can be treated with an excess of an alcohol, expediently in the presence of a strong acid such as hydrochloric acid or sulfuric acid at temperatures between 0° and 100°C, preferably between 20° and 50°C.
Conversely, an ester of the formula I (R1 - COOA or -Y-(CHZ)n-CODA and/or R2 - COOA) can be converted into the corresponding acid of th,e 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 0° and 40°C, preferably between 10° and 30°C.

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 such as triethylamine or pyridine at temperatures between -60°C and +30°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 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 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.
formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malefic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, 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 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 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 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, 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 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, 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 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 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, 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 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 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 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 syndromes, angina pectoris, myocardial infarct, peripheral circulatory disorders, stroke, transient ischaemic attacks, arteriosclerosis and reocclusion/restenosis after angioplasty/stent implantation.
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 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, 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 in °C. 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 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.

In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.
The entire disclosure of all applications, patents and publications, cited above and below, is hereby incorporated by reference.

EXAMpI,ES
Example 1 A suspension of 4 g of 6-chlorobenzo[de]iso chromene-1,3-dione in 100 ml of toluene is treated with 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 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 methylbenzo[de]isoquinoline-1,3-dione with R1-H, the following compounds of the formula Ia are obtained:

i i ~ la O ' 'O
N

R in R -H and Ia -N [ (CH2) 2-OH] Z
N
O
H H N
-N C ~S
N
O

H H
~N
-N C i O ~ \
HsC CHs Example 2 A suspension of 4 g of 6-chlorobenzo[de)iso chromene-1,3-dione in 100 ml of dichloromethane is 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 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-9-yl-benzo[de]isoquinoline-1,3-dione is obtained.
Analogously, by reaction of 6-chloro 2-(2-hydroxyethyl)benzo[de]isoquinoline-1,3-dione with R1-H, the following compounds of the formula Ib are obtained i Ib O ~O
N
OH
R1 in R -H and in Ib -N N
U
-N
-N

R in R -H and in Ib - G~ --N~N
U
-N
i H
Example 3 Analogously to Example 2, 6-chloro benzo[de]isochromene-1,3-dione is reacted with methyl 3-aminopropionate and then with R1-H. The following compounds of the formula Ic are obtained:

i i ~ is O ' '-O
N
COOMe R~ in R -H and in Ic MS

calculated found U

-N, I 352 353 - N ~ ~ 443 444 U

~n R in R -H and in Ic MS
calculated found Ph -N~CH3 H
-N CHZ / \ 388 389 H
-N (CH2)2 / \ 402 403 H
-N-CH2 / \ Sp2NH2 H
--N (CH )2 / \ OH
H

-N (CH )2 / \ pH

H

H
i / \ 419 415 -N
Example 4 Analogously to Example 2, 6-chloro benzo[de]isochromene-1,3-dione is reacted with benzylamine and then with R1-H. The following compounds of the formula Ida are obtained:

R' i i Ida O ~O
N
~Ph Rl in R1-H and in Ida MS

calculated found Q

~

,.

-/

Ph 406 407 -NH- (CHa) 5-OH 38$ 389 -NH- ( CH2 ) Z-COOMe 3 8 8 3 g g -NH- ( CH2 ) 3-N ( CH3 ) 2 / ~

H

/ ~

-N (CH2)2 406 407 H

-. N -- CH2 / ~ g02NH2 H

_ ~~ _ R in R -H and in Ida MS
calculated found -N -(CH2)2 / \ pH 422 H
-N - CH2 / \ NHZ
H

H
N
-N-(CH2)2 / \ 407 408 H
-N (CH2)2 ~ \ 407 408 H
N
-N CH2 ~ \ 393 394 H
-N (CH2)2-N p 415 416 i U
H
-N (CH2)3-N N-CH3 H \--/
-N (CH2)3-N~N 410 411 H
i H ~h -N -(CH2)2 / \ pH

H

i H

R in R -H and in Ida i MS
calculated found I
H

-N
Example 5 Analogously to Example 2, 6-chlorobenzo [de]isochromene-1,3-dione is reacted with phenylethylamine and then with R1-H. The following compounds of the formula Idb are obtained:

i w i ~ Idb O ~O
N
Ph R in R -H and in Idb MS

calculated found -N~ 370 371 ~ ~ ~

Ph 420 421 -N ~

H

-NH- ( CHZ ) 5-OH 4 0 2 4 0 3 Ra in R''-H and in Idb MS
calculated found -NH- (CH2) 2-COOMe 402 403 -NH- (CH2) 3-N (CH3) 2 401 402 -N CH2 / \ 406 407 H
-N (CH2)2 / \ 420 421 H
-N - CH2 / \ Sp2NH2 H
-N (CH2)2 / \ pH
H
CH2 / \ NH2 421 422 H

-N - CH2 / \
H
N
-N -(CH2)2 / ~ 421 422 H
N
-N (CH2)2 / \ 421 422 H
-N CHZ / \ 407 408 H
-N (CH2)2-N p 429 430 U
H

R1 in R1-H and in Idb MS
calculated found -N -(CH2)3-N N-CH3 I ~J
H
-N -(CH2)3- ~N 424 H
H3 vn -N (CH2)2 / \ pH
-N 398 3gg H

I
H
i H
/ \
-N
Example 6 A suspension of 4 g of 6-chlorobenzo[de]iso quinoline-1,3-dione and 7 g of KZC03 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 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.

Example 7 Analogously to Example 2, 6-chlorobenzo-[de]isochromene-1,3-dione is reacted with C-cyclohexylmethylamine and then with R1-H. The following compounds of the formula Idc are obtained:

i I
i Idc O ' 'O
N
R in R -H and in Idc MS

calculated found - ~O 378 379 -N~ 362 363 /

H

-NH- (CH2) 5-OH 394 395 -NH- ( CH2 ) 2-COOMe 3 94 3 95 -NH- (CH2) 3-N (CH3) 2 393 394 / ~

H

_ 57 _ R in R -H and in Idc ~ MS
calculated found -N -(CH2)2 / \ 412 913 H
-N -CH / \ SOZNH2 H
-N (CH2)2 / \ OH 428 429 H
-N CH2 / \ NH2 H

-N-CH / \
H
-N
-N (CH2)2 / ~ 413 414 H
N--N (CHZ)2 ~ \ 413 414 H
-N CH2 ~ \ 399 400 H
-N (CH2)2-N p 421 422 I
H
-N -(CH2)3-N N-CH3 I U
H
-N
I (CH2)3- ~ 416 417 H
H3 vn -N (CH2)2 / ~ OH

R in R -H and in Idc MS
calculated found H
'- 376 377 H
i I
H

-N
Example 8 Analogously to Example 2, 6-chlorobenzo-[de]isochromene-1,3-dione is reacted with (3-chlorophenyl)methylamine and then with R1-H. The following compounds of the formula Idd are obtained:

i i Idd O ' 'O
N
~ CI
Rl in R1-H and in Idd MS
calculated found -NH- ( CH2 ) 3-N ( CH3 ) 2 4 21 4 22 _ 5 c~ _ R1 in R -H~ and in Idd MS
calculated found -N (CH2)2 ~ ~ 441 442 H
N
-N-(CH2)2 ~ ~ 441 442 H
-N CH2 ~ ~ 427 428 H
-N-(CH2)2-N p 449 450 H ~--/
-N -(CH2)3- N-CH3 476 -- 477 i H
-N - CH2)3 ~N 444 445 H
-NH- (CHZ) 5-OH 422 423 -N-CH / \
H
Example 9 Analogously to Example 2, 6-chlorobenzo [de]isochromene-1,3-dione is reacted with 4-(2 aminoethyl)benzenesulfonamide and then with R1-H. The following compounds of the formula Ide are obtained:

i i Ide O " O
N

R1 in R -H and in Ide MS
calculated found -NH- (CHz) 7-NH2 508 509 -NH- ( CHZ ) S-NHZ 4 8 0 . 4 81 -NH- ( CH2 ) 3-NHZ 4 52 4 53 H
Example 10 Analogously to Example 2, 6-chlorobenzo-[de]isochromene-1,3-dione is reacted with C-pyridin-4-ylmethylamine and then with R1-H. The following compounds of the formula Iea are obtained:

i i ~ lea O ' '_O
N
i ~ N

R1 in Rr-H and in Iea MS
calculated found -N p 373 374 U

-N, I 357 358 \ / 448 449 -NH- ( CH2 ) 2-COOMe -N CH2 / \ 393 394 H
-N (CH )2 / \ 407 408 H
-N,CHZ / \ S02NH2 472 473 H
--N (CH )2 / \ OH
H
i H3 OI-f --N (CH )2 / \ OH

I
H

-R1 in Rl-H and in Iea MS
calculated found H
i I
H
/ \
-N
Example 11 Analogously to Example 2, 6-chlorobenzo [de]isochromene-1,3-dione is reacted with C
benzo[b]thiophen-3-ylmethylamine and then with R1-H. The following compounds of the formula Ieb are obtained:

i i leb O ~O
N
~ ~S
\ /
R in R -H and in Ieb MS
calculated found -NH- ( CH2 ) 5-NHZ 4 4 3 9 4 4 -NH- (CHZ) ~-NH2 471 472 _N,CH / \
H

Example 12 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 H2N-(CHZ)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: 915; found: 416.
Example 13 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with H2N-(CH2)2-Hetl and then with R1-H. The following compounds of the formula Iec are obtained:

i i ~ lec O "O
N
Het1 Het R in R -H and in Iec -NH- ( CH2 ) s-NH2 / -NH- ( CH2 ) s-NHZ
/ ' 1 -NH- ( CHZ ) ~-NHZ

-N-CH2 /-\
H

Fd -Hetl Rl in R -H and in Iec -NH- ( CH2 ) 3-NHZ
-NH- ( CH2 ) s-NHZ
-NH- ( CH2 ) ~-NH2 -N-CH2 /-\
H
-NH- ( CH2 ) 3-NH2 CH3 -NH- ( CH2 ) s-NH2 -NH- ( CH2 ) ~-NHz -N-CHZ /-\
H
-NH- ( CHz ) 3-NH2 CH3 -NH- ( CHz ) s-NHZ
/ ' -NH- ( CHz ) ~-NH2 H
-NH- ( CH2 ) 3-NH2 -NH- ( CH2 ) s-NH2 OCH -NH- ( CH2 ) ~-NH2 -N-CH2 /-\
H
Example 14 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with 1,3-propanediamine and then with R1-H. The following compounds of the formula If are obtained:

R' i i O~N~O

R in R -H and in If - ~O
-N
N _ - \-/N \ /
Ph -N ~CH3 H
-NH- ( CHZ ) 2-COOMe -N CH2 / \
H
( / \
-N CH2)2 H
-N-CH2 / \ Sp2NH2 H
-N -(CH2)2 / \ pH
H
-NH- ( CHZ ) s-OH _ -NH- ( CH2 ) 3-N ( CH3 ) 2 _ Rl in Rl-H and in If -N CH2 ~ ~ NH2 H

H
-N (CH2)2 H
-N -(CH2)2 i H

i H
-N -(CH2)2-N p H
-N -(CH2)3-N N-CH3 i U
H
-N (CH2)3-H
-NH- ( CH2 ) 5-NHZ
-NH- C CH2 ) ~-NH2 Example 15 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with 3-amino-2 methylpropionamide and then with R1-H. The following compounds of the formula Iga are obtained:

i i ~ Iga O ' 'O
N
O
HsC NH~
R1 in R -H and in Iga --NH- ( CHZ ) 3-N~( CHs ) 2 -N-(CH2)2-N--C
H H
w -N - (CH2)2 / \
i H
-N -(CH2)3- ~N
i H
-NH- ( CH2 ) 9-NH2 -NH- ( CH2 ) ~-NH2 -NH- ( CH2 ) e-NHZ

--N -. CH / \
H
Example 16 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with 2-aminoacetamide and then with R1-H. The following compounds of the formula Igb are obtained:

i i Igb p ' 'O
N
O
NHS
R1 in R -H and in Igb MS
calculated found -N O
U

-N~ 323 324 ~N \ /
.-N~CH3 'H
-NH- ( CHZ ) 2-COOMe CH2 / \
H
-N -(CH2)2 / \
i H
-N - CH / \ S02NH2 H
-N '(CH2)2 / \ OH
H
-NH- (CH2) 5-OH

R1 in R -H and i MS
calculated found -NH- (CH2) 3-N (CH3) 2 354 355 -N CH2 / \ NH2 H

-N -- CH2 / \
H
/ ~\
-N (CH2)z t H
N
-N (CH2)2 / \ 374 375 H
N

H
N (CH2)2 Nip i U
H
-N -(CH2)3-N N-CH3 i H
N (CH2)3-N~ N 37 9 -NH- ( CH2 ) s-NHZ
-NH- ( CH2 ) ~-NHZ
Example 17 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with 3-aminopropionamide and then with R1-H. The following compounds of the formula Igc are obtained:

R' i i ~ Igc O ~O
N

R1 in R1-H and in Igc MS
calculated found -' ~O

-N~ 337 338 ~N \ /
Ph -N~CH3 H
-NH- ( CH2 ) Z-COOMe -N CH2 / \
H
-N -(CH2)2 / \
i H
,N -CH2 / \ g02NH2 H
--N (CH )2 / \ OH
H

R~ in R -H and in Igc MS
calculated found -NH- (CHZ) 5-OH 369 370 -NH- ( CHZ ) 3-N ( CH3 ) 2 -N-CH / \ HZ
H

-N - CH2 / \
H
-N -(CH2)2 / N.
i H
-N (CH2)2 \
H

H
-N (CH2)2-N O
H
-N -(CH2)3- N-CH3 U
H
-N (CH2)3 N~
i H
-NH- ( CHZ ) s-NH2 -NH- (CHZ) ~-NHZ 396 397 Example 18 Analogously to Example 2, 6-chlorobenzo[de]iso-chromene-1,3-dione is reacted with 6-amino-hexanoamide WO 00/31039 PCT/EP99l08560 and then with R1-H. The following compounds of the formula Igd are obtained:

i I
w i ~ Igd O ~O
N
t IH2)5 R1 in R -H and in Ms R in R -H and in Igd Ms Igd talc. talc fnd.

fnd.

- ~ -NH- (CHZ) 3-NH (CH3) 396 -N -N (CH3) - (CHZ) 3-NH 410 (CH3) -N 379 -N (CH3) - (CH2) 2-N 938 (CZHS) 2 - N - 470 -N-(CH2)2-N---~ 910 U \ / 971 H H 411 Ph N~

\~

-NH- ( CH2 ) Z-COOMe / \ 4 8 _ _ -N -CH / \ -N N- 471 H
./ \ ~ 472 N--N -(CH2)2 / \ -N N--~\

H ~--/ N

R in R -H and in MS R in Rr-H and in Igd Ms Igd calc. calc fnd.
fnd.
-N - CH2 ~-~ SOZNH2 -NH-(CH2)3- ~ -(CH2)3--NH2 5 0 $
H

-N (CH2) / \
H -NH N
-NH- { CHZ ) 5-OH -NH- ( CHZ ) 2-NH- ( CH2 ) 2-OH 412 -NH- ( CH2 ) 3-N ( CH3 ) 2 -NH- ( CHZ ) Z-NH ( C3H~ ) 410 -N - CH2 ~-~ NH2 -NH- ( CHz ) 3-O- ( CHz ) a-O- ( CHz ) 3-NHz 512 H

-tV-CH2~ -NH-(CH2)3 N 464 " H 465 CHzNH2 -N -(CH2)2 --~~ 450 -N -(CH2)2 ~ ~ 430 -NH- (CHz) 3-N (CH3) - (CHZ) 3-NHz 453 -N CH2 N \ 416 -NH- 396 ( CH2 ) 2-NH ( CZHS ) H 417 3g7 -H -(CH2)2- ~O -NH- (CHZ) s-NHZ
-N -(CH2)3- N-CH3 4 62 H ~ -NH- ( CHZ ) ~-NHZ

- 7a -R in R -H and in Ms R in R -H and in Igd Ms Igd calc. calc fnd.

fnd.

(CH2)3- -N-CHZ /
\ CH2._NH2 ~ -H H

Exam lp a 19 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1, 3-dione is reacted with HZN- (CH2) i-CONHZ and then with R1-H. The following compounds of the formula Ige are obtained:

i i Ige O ' 'O
N
~ ~H2~i R~ in R -H and in Ige i MS

calculated found -N-(CH2)2 ~ \ 7 458 _ 459 'H--(CH2)2-H-C 7 4 52 4 53 -NH- (CH2) 4-NH2 _ ~5 _ R in R -H and in Ige i MS

calculated found -NH- ( CHZ ) 3-N ( CH3 ) 2 -NH- { CHZ ) ~-NHz -NH- (CH2) 8-NH2 -N -(CH2)3- ~ N 7 9 63 4 64 H

Example 20 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1, 3-dione is reacted with H2N- (CH2) 2-CONH (Rlo) and then with R1-H. The following compounds of the formula Igf are obtained:

i i Igf O ' '-O
N
( ~H2~2 CONH(R10) Rj in Rl-H and in Igf R MS
calculated found CsH~ 438 439 -NH- ( CH2 ) ~-NH2 C5H11 4 6 6 4 67 CH2-NHZ C3H~ 444 445 -N -CH
CsHii 472 473 Example 21 Analogously to Example 2, 6-chlorobenzo[deJiso chromene-1, 3-dione is reacted with HZN- (CHZ) 2-CONH
(CH2)o-Ar and then with R1-H. The following compounds of the formula Iha are obtained:

i i Iha O ' 'O
N
CONH-(CH2)o Ar CONH- (CH2) o-Ar R in R -H and in Iha MS
calc. fnd.
-NH- ( CH2 ) ~-NH2 CONH-CH2----( ) / \ CH2-NH2 499 500 ~J -N - CH2 H
-N-(CH2)3-N~N 489 490 H

Example 20 Analogo _ 77 -CONH- (CH2) o-Ar R in R -H and in Iha MS
calc. fnd.
-NH- ( CH2 ) ~-NH2 515 516 ~CH3 -N - / \

H
-N -(CH2)3-N
i H
-NH- ( CH2 ) ~-NHZ 52 0 521 CONH-CH2 ~ ~ C~ CH2- NH2 52 6 52 7 -N-CHZ / \
H
-N (CH2)3-NON
i H
-NH- (CH2) ~-NHZ 548 549 CONH ~ ~ ~ CH2- NHZ 517 518 -N-CH2 / \
H
-NH- ( CH2 ) ~-NH2 514 515 CONH--(CH2)3 -N - CH2 / \
H
-N -(CHZ)3-N~N 511 512 H
Example 22 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1, 3-dione is reacted with HZN- (CHZ) Z-CONH
(CH2) o-R5 and then with Rl-H. The following compounds of the formula Ihb are obtained:

_ 78 _ I
i Ihb O ' 'O
N
CONH-(CH2)o-R5 CONH- (CH2) o-R R in R -H and in Ihb MS
calc. fnd.
-NH- ( CH2 ) ~-NH2 4 67 4 68 CONH- ( CH2 ) 4-NHz CHZ- NH2 H
-NH- ( CH2 ) ~-NH2 5 3 9 5 4 0 CONH- (CH2) 2-NHZ CH2-NH2 H
Example 23 Analogously to Example 2, 6-chlorobenzo[de]iso-chromene-1,3-dione is reacted with H2N-(CHZ)2-CONH-(CH2)o-Het and then with R1-H. The following compounds of the formula Ihc are obtained:

i ( i Ihc O " O
N
CONH-(CH2)o Het _ 79 -CONH- (CH2) o-Het R in R -H and in Ihc MS
calc. fnd.
-NH- ( CH2 ) ~-NH2 4 8 7 4 g g CONH-CH2 ~ ~ -N-CH2 ~ ~ 493 494 H
Example 24 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1,3-dione is reacted with 3 aminomethylbenzylamine and then with R1-H. The following compounds of the formula Iia are obtained:

i w i lia O N O

i R1 in R -H and in Iia '- ~O
-N
N
\ /

R in R -H and in Iia h -N ~CH3 H
-NH- ( CH2 ) Z-COOMe -N CH2 / \
H
-N (CHZ)2 / \
i H
-N - CH2 / \ Sp2NH2 H
-N (CH2)2 / \ pH
H
-NH- ( CHz ) 5-OH
-NH- ( CH2 ) 3-N ( CH3 ) z -N - CH / \ NH
H

-N -CH2 / \
H
~\
-N (CH2)2 i H
-N (CH2)2 ~ \
H

H
-N (CH2)2-N O
WJ
H

Rl in R -H and in Iia -N -(CH2)3-N N-CH

N (CH )3 N~
i H
-NH- ( CHZ ) s-NH2 -NH- ( CH2 ) ~-NH2 Example 25 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1, 3-dione is reacted with H2N-CHZ-Ar' - (CH2) n CONH2 and then with Rl-H. The following compounds of the formula Iib are obtained:

i l i ~ lib O "_O
N
~H2 Ar'-(CH2)n-CONH2 Ar' - (CH2) n-CONHZ R in R -H and in Iib MS
calc. fnd.
CONH2 - p 415 416 / \

Ar' - (CH2) n-CONHZ R in R -H and in Iib MS
calc. fnd.
CONH2 -N, / \ 413 414 / \ 399 400 \ /

/ \ 490 491 CONH2 Ph 449 450 -N~CH3 H

/ \

Ar' - (CHZ) n-CONH2 R in R -H and in Iib MS
calc. fnd.
CONH2 -NH- (CHZ) 2-COOMe 431 432 / \
CONH2 -N - CH2 / \
H

/ \
CONH2 -N-(CH2)2 / \ 449 450 H

/ \

Ar'-(CH2)n-CONH2 Ri in R -H and in Iib MS
calc. fnd.
CONH2 -N '-CH2 /-\ SO2NH~
H

/ \
CONH2 -N -(CH2)2 / \ O~ 9 65 4 66 H

CO - NHz / \
CONH2 -N-(CH2)2 / f~ 450 451 H

/ \ 450 451 CONHZ -N-(CH2)2 ~ \ 450 H 4s1 Ar' - (CH2) n-CONH2 R in R -H and in Iib MS
calc. fnd.
CONH2 -N -CH2 / \ 436 437 H

/ \ 436 CONH2 -N (CH2)2-N p 458 459 H

/ \ 458 459 CONH2 /~ 485 986 -H -(CH2)3- ~N-CH;

/ \ 485 486 CONH2 -N-(CH2)3-N~N 455 456 H

/ \

Ar' - (CH2) n-CONH2 R in R -H and in Iib MS
calc. fnd.
CONH2 -NH- ( CH2 ) 5-NH2 / \ 430 431 CONH2 -NH- ( CHZ ) ~-NH2 4 5 8 4 5 9 / \
CONH2 -NH- ( CH2 ) 3-N ( CH3 ) z 9 3 0 4 31 / \ 930 931 CONH2 -NH- ( CH2 ) 5-OH 4 31 4 32 _ 87 _ Ar' - (CH2) n-CONH2 R in R -H and in Iib MS
calc. fnd.
CO - NH2 -NH- ( CHZ ) 5-OH
CONH2 -N -CH2 ~ ~ NH2 H

CO ' NH2 / \

-N -CH2 ~ \
H

/ \
CONH2 -NH- ( CH2 ) 3-NH ( CH3 ) 416 417 CONH2 -N (CH3) - (CH2) 3-NH (CH3) 430 431 - RR -Ar' - (CH2) n-CONHZ R in R -H and in Iib MS
calc. fnd.
CONHZ -N (CH3) - (CHZ) z-N (C2H5) 2 458 459 CONH2 N-(CH2)2-N--~ 4 30 4 31 H H

CONH2 -N N-CH ~ ~ p 548 549 U z CONH2 - ~ -CHZ ~-~ 504 505 CONH2 -N N ~ ~ 4 91 4 92 U

CONHZ -N N--C~ ~ 4 92 4 93 N

CONH 'NH-(CH2)3- ~ -(CH2)3--NH2 528 529 _ 8g _ Ar' - (CH2 ) n-CONHZ R in R -H and in Iib MS
calc. fnd.

-NH N

CONH2 -NH- ( CH2 ) 2-NH- ( CHZ ) z-OH 4 32 4 3 3 CONH2 -NH- ( CHZ ) 2-NH ( C3H~ ) 9 3 0 4 31 CONHZ -NH- (CHz) 3-0- (CHz) a-0- (CH2) 3-NHZ

CONH2 -NH-(CH2)3 N 484 485 H

- An -Ar' - (CHZ) "-CONHZR in R -H and in Iib MS

calc. fnd.

-NH- (CH
) -N (CH

3) - (CH2) 3--NH- ( CH
) -NH ( C
H

Z
S ) CONH N-'CH2 ~-~ CHZ NHS

Example 26 Analogously to Example 2, 6-nitrobenzo[de]iso chromene-1, 3-dione is reacted with H2N-CH2-Ar' - (CH2) n CONH- (CH2) o-NH2 and then with R1-H. The following compounds of the formula Iic are obtained:

i i lic O ' 'O
N
~H2 Ar'-(CHZ)~-CONH-(CH2)o-NH2 a~
Ar' - (CH2) n-CONH- R in R -H and Iic MS

(CH2) o-NH2 calc. fnd.

~CONH-(CHZ)4 NHZ -NH- ( CHZ ) ~-NHZ

\

_ H

CONH-(CH2)4-NHZ
-NH- (CHZ) ~-NH2 529 530 CH2- NHz \

_ H

'-~-CONH-(CH2)Z NHZ -NH- ( CH2 ) ~-NH2 5 0 7 5 \

-H

~ CONH-(CHZ)z-NHi -NH- (CHz) ~-NH2 501 502 \

-H

Example 27 Analogously to Example 2, 6-chlorobenzo[de]iso-chromene-1, 3-dione is reacted with HZN-CHZ-Ar' - (CHZ) n-CONH- (CH2) o-Het and then with R1-H. The following compounds of the formula Iid are obtained:
i i lid O ' 'O
N
~H2 Ar'-(CH2)n-CONH-(CH2)o Het Ar' - (CHz) n-CONH- R in R -H and Iid MS
(CHz) o-Het calc. fnd.
--~-CONH-CH ~ -NH- ( CHz ) 3-N ( CH3 ) z 2~
1d -NH- (CHz) 7-NHz 555 556 -N-oHZ /-\ 561 562 H
~CONH-CH2~ -NH- (CHz) 3-N (CH3) z 521 522 -NH- ( CHz ) ~-NHz -N-CH2 ~_~ 555 556 H
Example 28 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1, 3-dione is reacted with H2N-CHz-Ar' - (CHz) n CONHA and then with Rl-H. The following compounds of the formula Iie are obtained:

i i ~ lie O ' \-O
N
~HZ
Ar'-{CH2)n-CONHA
Ar' - (CHz) n-CONHA R in R -H and Iie MS
calc. fnd.
-NH- ( CHz ) 7-NHz CONH(C3H~) CHp- NH2 -N-CH2 ~-~ 512 513 H
- -NH- (CHz) 3-N (CH3) z 472 473 CONH(C3H7) -NH- ( CHz ) ~-NHz -N---CH2 ~_~ 506 507 H

Ar'-(CHZ)n-CONHA R in R -H and Iie MS
calc. fnd.
-NH- ( CHZ ) ~-NHZ
CONH(CSH~ ~ ) -N-CH2 /_\ 540 541 H
-NH- (CH2) 3-N (CH3) 2 500 50 CONH(C5H~ ~ ) -NH- ( CHZ ) ~-NH2 -N ~ CH2 /-\
H
Example 29 Analogously to Example 2, 6-chlorobenzo[de]iso chromene-1, 3-dione is reacted with H2N-CH2-Ar' - (CH2) n CONH- (CH2) o-Ar and then with R1-H. The following compounds of the formula Iif are obtained:

i i lif O ~O
N
~H2 Ar'-(CH2)n-CONH-(CH2)o Ar Ar' - ( CH2 ) n-CONH- R in R -H and I i f MS
(CH2}o-Ar calc. fnd.
~CONH-CH2--( ) -NH- ( CH2 ) 3-N ( CH3 ) z -NH- ( CH2 ) ~-NH2 -H-CH2 ~_~ 566 567 --\ r-CONH-CH2-( ) -NH- (CH2) ~-NHZ 554 555 ~l CHZ NHZ
-H-CHZ ~_~ 560 561 Ar'-(CHZ)n-CONH- R in R -H and Iif MS

(CHZ) o-Ar calc. fnd.

-NH- ( CH2 ) 3-N
\-/ ( CH3 ) 2 CONH ~

-NH- (CHZ) ~-NH2 583 584 \ 589 590 -\ / CONH \-/ ~ -NH- (CH2) ~-NH2 577 578 \
-H -. CH2 /

-/ \ -NH- ( CH2 ) ~-NH2 ~CONH

\ /

\

-/ -NH- ( CH2 ) 3-N
\ ( CH3 ) 2 CONH

-\ /

-NH- ( CH2 ) 7-NH2 -CH / \
-H

~CONH-CH2 ~ / CI -NH- (CHZ) 3-N (CH3}560 561 Z

-NH- (CHz) ~-NH2 588 589 \

_ ~CONH-CH2 \ / CI WNH- (CHZ) ~-NHZ 582 583 \ 9 _ H

~CONH-(CH2)3 \ / -NH- (CH2) 3-N (CH3)554 555 -NH- (CH2) ~-NH2 582 583 - -CHZ / \

CONH-(CHZ)3 \~/ -NH- ( CHZ ) ~-NHZ 57 6 577 \
_N-CH2 /

-H

Example 30 Analogously to Example 2, 6-chlorobenzo[de)iso chromene-1,3-dione is reacted with HZN-CH(R)-CONH2 and then with R1-H. The following compounds of the formula 5 Ik are obtained:

i i Ik O N' ' O
~H(R) R in R -H and Ik R MS

calc. fnd.

CH2-NH2 CH2-Ph ~N-eH2 /-\ CH2-CH (CH3) 2 H

-NH- (CH2) 3-N (CH3) CH2-Ph CHZ-CH ( CH3 } 2 -NH- ( CHZ ) 4-NH2 CH2-Ph CH2-CH ( CH3 ) 2 -NH- ( CHZ ) ~-NHZ CHZ-Ph CHZ-CH (CH3) 2 -NH- ( CH2 ) g-NH2 CH2-Ph CH2-CH ( CH3 ) z -N -(CH -N~N CHz-Ph 4 69 4 70 CH2-CH ( CH3 ) 2 4 3 5 4 3 6 CH2-Ph CH2-CH ( CH3 ) z -N-(CH2)2-N--C CH2-Ph H H CH2-CH ( CH3 ) 2 Example 31:
Analogously to Example 2, 6-chlorobenzo [de]isochromene-1,3-dione is reacted with H2N-Ar and then with R1-H. The following compounds of the formula I1 are obtained:
R~

C N ~O
~CH2);
IAr Ar R1 in R1-H and in I1 O-CHz-Ph -NH- ( CH2 ) s-NH2 _ / O CHz_Ph -NH- ( CH2 ) s-NHz -NH- ( CHz ) 7-NHZ

\

-H

CHz - NHz -N-CHz--( ) HH

-N-CHz-( r-CHz-NHz ~
/H

.

-NH- ( CH2 ) 3-NHZ

/ O-Ph -NH- ( CHz ) s-NHZ

-NH- ( CH2 ) ~-NHz \

-H

CHz - NHz -N-CHz--( ) ~J

H

-N-.CHz~CHz-NHz H

1~

Ar R1 in R1-H and in I1 1 -NH- ( CH2 ) 3-NH2 -NH- ( CHZ ) s-NHZ

-NH- (CHZ) ~-NHZ

\

-H

CHz - NHZ
-N-CH2-( ) ~/

H

-N-CHZ-( r--CHz-NHZ
\
/H

~

1 ""' -NH- ( CHZ ) 3-NH2 oCH, -NH- ( CH2 ) 5-NH2 oCH -NH- ( CHz ) ~-NH2 \

-H

CHi - NHZ
-N-CHz--( ) ~
/

..
H

-N-CHZ--( r-CHz-NHz \
/H

~

Example 32:
Equimolar amounts of 6-(3-amino-propylamino)-2-(3,9,5-trimethoxy-benzyl)-benzo[de]isoquinoline-1,3-dione (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.
1H-nmr (DMSO-d6) 8.74 (dd, J - 0.8 and J - 8.5 Hz, 1H), 8.46 (dd, J -0.$ 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 (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).

Abbreviations of the nmr-signals (nmr - nuclear magnetic resonance):
s singlet, d doublet, dd double doublet, t triplet, sbr broad singlet, m multiplet, q quadruplet, J coupling constant J in Hz Example 33:
Analogously to Example 2, 6-chlorobenzo [de]isochromene-1,3-dione is reacted with H2N-CHZ-Ar' (CH2) n-CONH- (CH2) o-Ar and then with R1-H. The following compounds of the formula Iif are obtained:
R~
I if O N" O

Ar'-(CH2)~-CONH-(CH2)o Ar Ar' - ( CHZ ) "-CONH- R1 1n R1-H and I
( CHZ ) o-Ar i. f H
CONH-CH2 ~ N
~

NHi -N -~H~

H

CONH ~ -N-CH

H

NH
N

NHZ
-N_CH=

H

_ 99 _ Ar' - (CHZ ) "-CONH- (CH2 ) o-Ar Rl in Rl-H and I i f ~ CH =
~ CONH-(CH2)Z-(' ) 2 2 ~.J -N-CHZ ~-~ ' H
NH
N NHs -N -CHZ
H

CONH ~ ~ -N-CH2 H
jJ H
N NH=
-N -CHZ
H

~ CONH-CHZ ~ ~ -N-CHz H
JJH
N NHi -N-CHZ
H
CONH-(CHz)2 ~ ~ / \ CH2- 2 H
JJH
~//N
NHz -N -CHZ
H
H
CONH-(CHZ)~ ~ ~
NHz -N -CHz H

CONH-(CHZ)a _ H
JJH
N NHz -N -CHZ
H

CONH ~ ~ -N-CH

JJH
N NHa -N-CH=
H

Ar~-(CHz)~-CONH-(CHZ)o-Ar R1 in R1-H and Iif CONH ~ ~ -N-CH2 /-\
H
CN H
N NHz -N -CHz H
CH -CONH-(CH2)z ~ ~ NOz / \ 2 2 -N CH2 '-/
H
NH
N NHz -N -CHz H

CONH-CHZ ~ ~ -N-CH2 /-\
O H
f,IH
N NHz -N -CHi H
~CH~ CH2-CONH-CHz ~ ~ N~CH~ -N-CH2 / \
H
~H
N NHz -N -CHz H
~CH3 H
CONH
CHI ~ N NHz '_ ~ -CHz H
CONH ~ / N\ CZHS C -C2H3 ~N-CH2 /-\
H
NH
N NHz -N -CHZ
H
CONH-CHz ~ ~ SOz-NHz CH2 2 -N-CH2 /-\
H
JJH
N NHz -N -CHz H

Ar~-(CHZ)"-CONH-(CHZ)o-Ar R1 in R1-H and Iif / CONH-(CHz)z / ~ CH3 CH2- 2 -N-CH2 /-\
H
/JH
N NH:
-N -CHZ
H

CONH ~ ~ CH3 -N-CH2 /-\
H
~H
N NHS

H
CH3 CH2- ~
CONH ~ ~ -N-cH2 /-\
H
CH3 ~H
N NHz - N - CHI
H
CH2- NH2 _ ~ CONH-CHZ / \
-~ -CH2 fIH
N NHz -N -CHZ
H

CONH -N-CH / \
i 2 H

NJ~NH:

H
Lh3 CHZ- NH2-CONH ~ ~ -N-CH2 /-\
H
CF3 rH
N NHS
-N -CHz H
1:2r15 CHZ-NH2 -N-CH2 /-\
~ CONH
TI H
N NHi -N-CHz H

Ar ~- (CH2) ~-CONH- (CHZ)R1 in R1-H arid o-Ar Iif CH2= 2 CONH / ~ CH / \

I -N-CH

H

flH
N

NH=

-N-CHz H

CH2 N z CONH -N- / \

i H

r1H
N

NHS
-N-CHZ

H

CONH / ~ CH3 / \ CH2- 2 -N-i 2 H

JJH
N

NHz -N -CHI

H

CH2-NHz CONH-(CHz)2 -N-CHZ / \

H

CI H
N~

NH~

-N -~HZ
H

CHZ-NHZ
CONH ~ ~ -N-cH /
\

-H

CI H
N

NHi -N -CHI
H

CONH-CH2 -N-CH / \

i H

CI H
N~

NH~

-N -CHZ
H

CONH-(CHz)Z / \
' --N - CHZ

H

CI H
N~

NH~

-N -CHi H

Ar' - (CHz) "-CONH- (CHZ) o-Ar R1 lri R1-H drid Ilf n CONH ~ ~ CI -N-CH

JJH
N NHz -N -CHz H

CONH-(CHz)z / ~ CI / \
-~ - CH2 H
TlH
N NHz -N -CHz H
CONH -CHz ~ ~ CI N H
~NHz - N - CHz H

CONH-CHz ~ ~ -N-CHZ
H
CI H
N NH=
-N -CHz H

CONH-CH2 ~ ~ -N-CHZ
H
Tl H
N NHZ
-N -CHz H
CI CHy- 2 CONH-CHz / ~ CI -N-CHz H
H
N~NHx - N -CHz H

CONH-(CHz)z ~ ~ CI -N-CH2 H
H
N~NH=
-N-CHz H

Ar ~ - ( CHZ ) ~-CONH- ( CHZ ) o-Ar R1 in R1-H and T i f CONH-CHZ ~ ~ -N-CH2 H
CI H
N
NHi -N -CHZ
H

CONH ~ ~ -N-cH2 H
CI
N NHz -N -CHI
H
CI CH2=R
CONH ~ ~ CI N-cH2 H
NH
N
NHz -N -CHI
H

CONH-CHZ ~ ~ F

CI H
rIH
N NH?
-N-CHZ
H

~ CONH ~ \ F -N-CH

CI ,,,H
N NH:
-N -CHz H
H -CONH-CH2 ~ ~ F

CI H
H
N NHZ

H

CONH-(CHZ)2 ~ ~ F

H
JJ H
N NHz -N-CHi H

Ar'- (CHz) "-CONH- (CHZ) o-Ar R1 lri R1-H and Ilf ~ CONH-CH2 -N-CH / \
i 2~
F H
f1H
N NHz -N -CHz H

/ CONH / ~ -N-CH2 /-\
H
F H
N NHz -N -CHs H
CHZ- NHZ -/ CON / ~ -N-CHZ /-\
H
F H
N NHz -N -CHZ
H

CONH-(CH2)z / \ -N-CH2 / \
OCH~ H
JJ H
N NHi -N -CHz H

CON ~ ~ -N-CHZ / \
H
OCH3 ~H
N NHZ
-N-CHz H

CONH-CH2 / \

NH
N NH=
-N -CHz H

CON ~ ~ OCH3 / \
-N -CHZ
H
JJ H
N NHz H

Ar~-(CHZ)n-CONH-(CHZ)o-Ar R1 in_ R1-H and Iif CONH-(CHZ)i ~_~ OCH~ / \

H
JJH
N NH=
-N -CHZ
H
-N-CH2 /-\
CH2= 2 CONH-CHi ~ ~ OCF~
H
rI H
N N H:
- N - CHZ
H
F -CONH ~ ~ OCH3 -N-CHZ /-\
H
fJH
N NHz -N -CHj H

CONH ~ ~ H3 -N-CH2 /-\
H
NH
N NHz -N-CHs H

CONH ~ ~ -N-CH2 /-\
H
NH
OCH3 ''//\N

-N-CHz H
tert-butyl CH2- 2 -N-CHZ /-\
CONH
H
tert-butyl H
N NHz - N - CHz H

-N-CH /-\
CONH-(CHz)z ~ p H
OCH~ H
N NHS
-N-CHz H

Ar'-(CHz)"-CONH-(CHz)o-Ar R1 in R1-H and Iif C~tig CH2- NH2 CONH ~ ~ -N -CH2 /-\
H
jJH
OCH3 ~//N
NHi -N -CHz H
v.n~ CH2-N 2 CONH-(CHI Z ~ ~ OCH~ -N-CHZ /-\
H
NH
N NHz -N -CHi H

-N-CH2 /-\ , ~ CONH H
fIH
N NH=
-N -CHz H

CONH ~ ~ OPh -N-CH / \
2~
H
JJH
N~l/ NH:

H
/ \ ~ CH2-NH2 _ \ / CONH O ~ ~ CHI
-N-CH2 /-\
H
H
N' \NHI
-N -CHZ
H
CHZ- NHZ
CONH /-\

O
~--Ph H
N NHz -N -CHi H
CH2- NH2 _ CONH-CHZ -N- H~ / \
C z \.-/
H
TIH
~//N
NHS
-N -CHZ
H

Ar'-(CHZ)~-CONH-(CHZ)o-ArR1 i.ri R1-H arid Iif ~ \
~
-C
-/ -N
H

NH
N

NHi H

CONH-CH

2 ~ ~ H

H
N~

NH~
-N-MHz I ~

H

CONH ~ ~ OCH3 CI H

~H
N NHZ
-N -CHZ

H

CH2-NHZ _ _ CONH ~ ~ CI -N-CHZ

H

CF3 ~H
N NHs -N -CHZ
H

CHp- NH2 CONH-(CH2)2 -N -cH

H

H

CONH-(CHz)z ~ ~ ,.

-N -CH

CI H

CHZ- NHZ _ CONH ~ ~ CI \
-N -cH2 ~

-H

CI _ _ _ cH - 2 CONH-CH2 ~ ~ -N-CH2 ~-\
H

CI

CI CI cH2- 2 CONH-CHZ ~ ~ -N -cH2 ~-\
H

/~
---( r-CONH-(CHz)2 /-\ ,.
F CH2- y ~/ ~ \
N

H

Ar~-(CHZ)~-CONH-(CHZ)o-Ar R1 in R1-H and Iif CONH-(CHz)z ~ ~ OCH~ C 2 2 H

CONH ~ ~ -N-cH2 /~\ ~
H
CONH ~ ~ cH2 2 -N-CH2 /-\
H

CONH ~ ~ OPh / \

H

CONH ~ ~ t~ , -N-CH? / \ CHz-NHz CHI
CHI CH
CONH-CHI
~CH3 -N -CH2 /-\
H

-N-CH2 /-\
H
CONH-CHZ
~~ CH2 2 1~f1 CONH-CH2 ~ ~ 0 -N -CH2 /_\
H

Example 34:
Analogously to Example 2, 6-chlorobenzo-[de]isochromene-1,3-dione is reacted with HZN-CHZ-Ar'-(CH2) n-CONH- (CH2) o-Het and then with R1-H. The following compounds of the formula Iid are obtained:
R~
/ \
\ I /
lid O ~O
N

Ar'-(CH2)~ CONH-{CH2)o Het Ar' - ( CHZ ) ~-CONH- (CHZ ) o-Het R1 in R1-_H and I id H
CONH-CH2 ~ ~ N 'NHz N
-N -CHZ
H

CONH ~-~ -N-CHZ
N H
rIH
N NHS
-N -CHz H

CONH-CH2 ~ \ -N-CH2 H
TI H
N NHi H

CONH ~ ~N -N-CH ~-~
i 2 H
H
N~NHz -N -CHZ
H

Ar'-(CHZ)n-CONH-(CH2),o-HetR1 iri R1-H arid Iid CONH-(CHZ)Z ~-~ -N-CH / \
2~ , i H

f,IH
N

NH=
-N -CHZ

H

CONH-(CH2)Z -N-CH / \

i 2 H

NH
N'//\

NH~
-N -CHz H

CONH-(CH2)2-N~ / \

H

/ \
CONH-(CHZ)3-N -N-CHZ--d H

CH2- NH2.
CONH-(CHZ)z N / \
CH

H

JJH
N

NHz -N-CHI

H

CONH-(CHZ)3 -N~ / \
~ H-CH

H

S
H
CONH-CH2 \ I CHZ--N-CH / \
2~

H

f! H
N

NHz -N -CHz H

CONH-CHz \ ( --N-CH / \

i H

fiH
N

NHZ

-N-CHI
H

/~ /~ CH2-NHZ ---C r--CONH-(CHZ)2-~O -N-cH /
~/ \

~/ -Ar'- (CHZ) ~-CONH- (CHz) o-Het R1 in R1-H and Iid /~ O ~ CH2- 2 --( r--CONH-CH2 ~ I -N-cH ~-~ H
~/ H

CONH-(CHZ)3 -~~ -N -cH2 N ' H
/'~ CH2-NHZ -~CONH-CH2 ~ ~N -N-CH
H
CHZ NHZ
CONH ~ ~N -N-cH2 i-\
H

CONH ~ ~ -H -cH2 -N
Example 35:
Analogously to Example 2, 6-chlorobenzo [de]isochromene-1,3-dione is reacted with HZN-CH2-Ar' (CH2) n-CONH- (CHZ) o-CH (Arl) -Ar2 and then with R1-H. The following compounds of the formula I2 are obtained:
R~
/

O " O
N

Ar'-(CH2)~-CONH-(CH2)o CH(Ar~)-Ar2 Ar ~ - (CHZ ) "-CONH- R1 in R1-H and (cH2 ) o- I2 CH;ArI ) -Arz -N - CH

CONH=
(CHZ)z-CH H

J H

\ J
N

NHz -N -CHi H

Ar' - (CHZ ) ~-CONH- (CHz ) o- R1 in R1-H and I2 CH (Arl ) -Arz -N-CH2 / \
CONH- CH -CH
( z)z / H
NH
NN
NHS
-N-CHz H

-N -CH2 / \ -CONH-CHz-CH , H
N'\H
NH=
~N-CHz H
Example 36:
Analogously to Example 2, 6-chlorobenzo [de]isochromene-1,3-dione is reacted with H2N-CH2-Ar' (CH2) n-CONH- (CH2) o-CH (A) -Ph and then with R1-H. The following compounds of the formula I3 are obtained:
R~
~ 13 O " O
N
I

Ar'-(CH2)~-CONH-(CHZ)o CH(A).Ph Ar ~ - ( CHz ) n-CONH- (CHZ ) o- R1 in R1-H and I 3 CH(A)-Ph h CONH-CHz-CH , _N-CH2 / \
H
,CH3 H
CONH-CHz-CH / N~NH
-N-CHz H

Example 37:
Analogously to Example 2, 6-chlorobenzo-[deJisochromene-1,3-dione is reacted with HZN-CH2-Ar'-(CH2)n-CONHA and then with R1-H. The following compounds of the formula Iie are obtained:
R~
/ \
\
~ lie O " O
N

Ar'-(CH2)~-CONHA
Ar' - (CHZ) "-CONHA R1 in R1-H and Iie CONH-(CH2)Z C(CH
) 3 ,N-CH
3 i 2 H

H

N"tNHx -N -CHZ

H

_ NH
N~

CONH-C3H~ NH, ~ ~
-N-CHZ

H

Example 38:
Analogously to Example 2, 6-nitrobenzo-[de]isochromene-1,3-dione is reacted with HZN-(CH2)z-CONH- (CH2) o-Ar and then with R1-H. The following compounds of the formula Iha are obtained:

R~
iha O N"O
CONH-(CH2)o Ar CONH- (CHZ) o-Ar R1 in R1-H and in IHa CONH-(CH2)2~ / \

_ H

-N-CHZ /-\ ~
CONH-(CH2)z H

CONH-(CHZ)z ~ ~ F / \

H

CONH-(CHz)z ~ ~ OCH3 H

CONH-CHz -N-GHZ /-\
H

/-\ ~
CONH-CH2 ~ ~ -H-CH2 CI

CONH-CH2 -N-CHZ /-\
H
CI CI

CONH-CHZ ~ ~ N, ' CH3 -N -, GH2 /-\
H

-N-CHZ /-\

/ \
CONH-CH ~ ~ O -N-GH2--H

CONH- (CHz) o-Ar R1 in R1-H and in IHa \
CONH ~ ~ -N-cH2 H

CONH ~ ~ -N-CH

CONH ~ ~ OPh -N-CH2 H

CONH ~ ~ C~ -N-CH2 H

CONH ~ ~ -N-cH
H
CHs CONH ~ ~ -N -cH
i 2 H

CHs _ cH -CONH ~ \ CHs -N-CH
CHs CONH ~ ~ OH -N -cH2 H
N
CZHS ~C2H5 CONH ~ ~ CH3 SOz-N, H
CzHS
\ ,CH3 CH2- 2 CONH N'CH
SOz \ / CH3 H CHZ
CH2- NH2 _ CONH ~ ~ OCH3 CH2- NH2 _ CONH-CHZ ~ ~ B~ -N-cH
i 2 H

CONH ~ ~ -N-CH

CONH- (CH2 ) o-Ar R1 in R1-H and in IHa CONH

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 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-1H,3H-benzo[de]isoquinolin-2-yl)-acetamide is obtained. 1.2 Equivalents of KZC03, 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°C until conversion is complete.
After filtering off the catalyst and customary working up, N-biphenyl-4-yl-2-(6-nitro-1,3-dioxo-1H,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-dioxo-1H,3H-benzo[de]isoquinolin-2-yl]-N-biphenyl-4-yl-acetamide is obtained.
Analogously, by reaction of N-(4-iodo-3-methoxyphenyl)-2-(6-nitro-1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-propionamide with Ph-B-(OH)Z
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.
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-dioxo-1H,3H-benzo[de]isoquinolin-2-yl]-N-biphenyl-4-ylmethyl-propionamide is obtained.

Example 40:
Analogously to example 39, by reaction of 6-nitro-2-{4-iodophenyl)benzo[de]isoquinoline-1,3-dione with R12-B-(OH)2 and 3-aminomethyl-benzylamine, the following compounds of the formula I4 are obtained:
N ~ / ~NHZ
O N" O

CONH ~ ~ R~z R12 in I4 F

R12 in I4 CH' O

,_O
-~N

Example 41:
Analogously to Example 2, 6-nitrobenzo [de]isochromene-1,3-dione is reacted with H2N-(CH2)2 CONH-(CHZ)o-Het and then with R1-H. The following compounds of the formula Ihc are obtained:
R~
/ \
Ihc O ' 'O
N
CONH-(CH2)o Het CONH- (CH2) o-Het R1 in R1-H and in Ihca CONH-(CH2)2-N ~
\

~ -N-CH2 _ H

/~ CH2-NH2_ CONH-(CH2)s -N ~ \
-N-CH

2 L.J
H

CONH-CHZ ~ \ -N-cH ~
\

_ H

CH2-NHz CONH-CH2 ~ \N \
~
-N-CH

-H
_ CONH-CH
\
-N-CH2 ~

-H

CONH ~ \ \
-N-cH ~

-i H

\ CH2- NH2 _ CONH~N -N-CH ~
\

_ H

,O \
~
-N - CH

CONH -Z

-N-CH2 ~
\

~ ~ -H

CONH

Example 42:
Analogously to example 2, by reaction of 6 nitro-benzo[de]isochromene-1,3-dione with 3-amino-N
(3,3-diphenyl-propyl)-propionamide and 3-aminomethyl benzylamine, 3-[6-(3-aminomethyl-benzylamino)-1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl]-N-(3,3-diphenyl-propyl)-propionamide is obtained.
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-Aminomethyl-benzylamino)-1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl]-propionylamino}-2-methoxy-phenyl)-2-methoxy-benzamide is obtained.
Example 44:
Analogously to example 2, 6-nitrobenzo-[de]isochromene-1,3-dione is reacted with H2N-(CH2)z-CONH-Ar'-Het and then with 3-aminomethyl-benzylamine.
The following compounds of the formula I5 are obtained:
N ~ / \NH2 \ I
O ' 'O
N
CONH-Ar'-Het CONH-Ar'-Het in I5 CONH ~ ~ p U
CI
CONH ~ ~ N
CN
CONH
S
CONH
\ S

CONH
S
CONH / \ CHs S
O

CONH-Ar'-Het in I5 CONH
CI

CONH

Example 45:
Analogously to example 2, 6-nitrobenzo [de]isochromene-1,3-dione is reacted with 3,3-diphenyl propylamine and then with R1-H. The following compounds of the formula I6 are obtained:
R~
~ 16 O " O
N
R1 in R1-H and I6 -NH- ( CH2 ) 3-NH2 -NH- ( CH2 ) 5-NHZ _ -NH- ( CHz ) ~-NHZ

-N-CHZ ~

H I

CHZ-NHi -N-CHz-( j ~H

-N-CHZ~CHZ-NHZ

~/H

The following examples relate to pharmaceutical preparations:
Example A: Injection vials 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 conditions and aseptically sealed. Each injection vial contains 5 mg of active compound.
Example 8: Suppositories A mixture of 20 g of an active compound of the 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.
Example C: Solution A solution is prepared from 1 g of an active compound of the formula I, 9.38 g of NaH2P04.2H20, 28.48 g of Na2HP04.12Hz0 and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The 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 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 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.

Example F: Coated tablets Analogously to Example E, tablets are pressed which are then coated with a coating of sucrose, potato starch, talc, tragacanth and colourant in a customary manner.
Example G: Capsules 2 kg of active compound of the formula I are dispensed into hard gelatin capsules in a customary manner such that each capsule contains 20 mg of the active compound.
Example H: Ampoules 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.
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 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 various changes and modifications of the invention to adapt it to various usages and conditions.

Claims

What is claimed is:

1. Compounds of the formula I

in which R is H, A or CH2-Ph, R1 is -Het, -N-[(CH2)s-OH]2, -N-[(CH2)s-OA]2.
-NA-(CH2)s-Ar, -NA-(CH2)m-R5, -Y-(CH2)m-R5, -Y-(CH2)2-NHA, -Y-(CH2)z-NH-(CH2)s-OH, -Y-(CH2)2-NA2, -Y-(CH2)m-OH, -Y-(CH2)n-(CHR4)-R3, -Y-(CH2)n-R4, R4, -Y-(CH2)n-Het-(CH2)o-R6, -Y-(CH2)n-Ar'-(CH2)o-R6, -Het-(CH2)n-Ar, -Het-Het, -Y-(CH2)s-Ar -(CH2)o-R11, -Y-[ X-O ]t-[X1-O]u-X2-R5, -Y-(CH2)n-NA-(CH2)o-R5, R2 is H, OH, OA, COON, COOA, CH(Ph)-Ph, Ar, Het1, R5, R7 or R8 R3 is CH3, R4 is -CH=CH2, -Ar, COOA, COOH

R5 is NH2, NHA, NA2, NHAr, -NH-(CH2)n-OH or -NH-(CH2)n-OA, R6 is H or R5 R7 is -Ar'-(CH2)n-R8 or -Ar'-(CH2)n-R5 R8 is CONH2, CONHA, CONA2, CONH-(CH2)o-Ar, CONH-(CH2)o-Het, CONH-(CH2)o-R5, CONH-(CH2)o-CH(Ar1)-Ar2, CONH-(CH2)o-CH(A)-Ph, CONH-(CH2)o-Ar'-NH-CO-Ar, CONH-Ar'-Het or CHA-CONH2, R11 is -NH- (C=NH) -NH2, -NH-(C=NH)-NHA, -NH-(C=NH)-NA2, -NA-(C=NH)-NH2, -NA-(C=NH)-NHA or -NA-(C=NH)-NA2, Ar' is phenylene, cycloalkylene or biphenylene, which is unsubstituted or mono- or disubstituted by A, OH, OA, Hal, CN, NH2, NHA, NA2, NO2, CF3, CO-A, SO2NH2, SO2NAH or SO2NA2, Ar is phenyl, cycloalkyl, naphthyl, cyclohex-1-enyl, biphenyl, bicyclohexyl, 9-cyclohexyl-phenyl, benzo[1,3]dioxol-5-yl or indanyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, O-Ph, O-CH2-Ph, O-PH-CH3, O(cycloalkyl), Hal, CN, NH2, NHA, NA2, NH-C(O)A, (CH2)n -NH2, (CH2)n -NHA, (CH2)n -NA2, NO2, CF3, C(O)A, SO2-Ph, SO2NH2, SO2NAH, SO2NA2 or SO2NA-Ph, Ar1 and Ar2 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 O atoms can be present and the heterocyclic radical can be mono- or disubstituted by CN, Hal, OH, OA, CF3, A, NO2, CO, CO-A or R5, Het1 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 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, X, X1,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, 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, t is 0, 1 or 2, a is 1 or 2, where if R2 is Ar or H, R1 is not 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-1H-3H-benzo[de]isoquinolin-2-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 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, or b) a compound of the formula II

in which R9 is Cl, Br, NO3 or R1, where R1 has the meaning indicated in Claim 1 is reacted with a compound of the formula III

H2N~(CHR)i~R2 III

in which R, R2 and i have the meanings indicated in Claim 1, and, if necessary, the radical R9 is converted into a radical R1, or (c) a compound of the formula IV

in which R9 is Cl, Br, NO2 or R1, where R1 has the meaning indicated in Claim 1 is reacted with a compound of the formula V

L~(CHR)i ~R2 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 Claim 1 and, if appropriate, the radical R9 is converted into a radical R1, or (d) a radical R and/or R2 and/or R9 is converted into another radical R and/or R2 and/or R9 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 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
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, - or carrying out a nucleophilic or electrophilic substitution, and/or (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 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, 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 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 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 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 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.