SK7022001A3 - Derivative of benzo[de]isoquinoline-1,3-dione, process for the preparation thereof, use thereof and pharmaceutical composition comprising the same - Google Patents

Abstract

Novel compounds of formula (I) in which R, R<1> and R<2> have the meaning indicated, and their salts or solvates as glycoprotein IbIX antagonists.

Description

Benzo [de] isoquinoline-1,3-dione derivative, process for its preparation, use thereof and pharmaceutical composition containing it

This application follows the application of the invention number 09/199413.

Technical field

The present invention relates to substituted benzo [de] isoquinoline-1,3-dione derivatives of formula (I)

R.

(I)

N

where it means

R is hydrogen, NO ₂ ,

R ¹ Het, Het-SO 2 -Ar, Het-R ⁵ , -Het- (CH 2) _n -Ar, NO ₂ , -N = CH-Ar,

-NHAlk, NAAlk, NHA ', NA' ₂ , a group

NH

-YDH, -Y-Ar'-R ³ , -Y- (CH 2) QR ³ , -Y- (CH 2) _n - (CHR ⁴ ) R ⁵ -, -YC - [(CH 2) 0-0H] 3, -Y- (CH 2) m -NA 2, -Y- (CH 2) m -NHA ', -Y- (CH 2) 0 -OH, -Y' (CH 2) k R ⁶ , -Y- (CH 2) _i -R ⁸ Y- _{(CH2) n} Het, -Y- (CH _{2) n} -Ar,

Y- _{(CH2) n-Ar} '- _(CH2) ⁶ _± R, Y- _{(CH2) n-D- (CH2)} -R ^6,

Y- _{(CH2) n} -Het- (CH ₂₎ -R ^6, Y- _{(CH2) n} -NA- _(CH2) j R ^6,

Y- _{(CH2) n} "-NH- (CH ₂₎ j R ^6, Y- (CH 2) n ^- D (CH 2) -R ^8,

-Y- (CH ₂ ) _n -Ar '- (CH ₂ ) 3 R ⁸ , Y "(CH ₂ ) _n -NH- (CH ₂ ) 4 R ⁸ ,

-Y- (CH ₂ ) _n ^- NA ^- (CH ₂ ) p -R ⁸ , a group of formula

NH

-Y- [XO] _t - [X ¹ -O] uX ² -R ⁶ or -Y- [X-NH] UX ¹ -OH,

R ^{2 is} -Ar, -Ar'-DH, -Het ¹ , -Het ¹ -Ar, -Ar'-Het ¹ , -Ar '- (CH 2) n R ³ , -Ar'-Y- (CH 2) _n - R ³ , -Ar'-YC (A) 2 -R ³ , Het ¹ -R ³ , -Ar'-Het ¹ -R ³ , -Ar '- (CH 2) _n -R ⁶ , -Ar'-SO 2 - Het, -Ar'-NH-SO 2 -Het, -Ar'-SO 2 -R ⁷ , -Ar '- (CH 2) _n - (CO-NH) - (CH ₂ ) _i -R ⁶ , -Ar' - ( CH ₂ ) _n - (CO-NH) - (CH ₂ ) i R ¹¹ ,

-Ar '- (CH ₂ ) _n -CO-Het,

-Ar '- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) —DH,

-Ar '- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) —Ar, -Ar' - (CH ₂ ) _n - (CO-NH) - (CH ₂ ) —Het ¹ , -Ar ' - (CH 2) n - (CH (CN)) - (CH 2) 1 -Ar, -Ar '- (CH 2) n - (CONH) - (CH 2) —CH- (Ar ¹ ) -Ar ² , -Ar' -S- (CH 2) _n - (CO-NH) - (CH ₂ ) —Ar, -Ar'-S- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) i R ¹¹ , -Ar'- S- (CH 2) n - (CO-NH) - (CH 2) —Het ¹ , -Ar 1 -S- (CH 2) - (CO-NH) - (CH ₂ ) 4 - CH (Ar ¹ ) Ar ^2, or -Ar'-S- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) —DH,

R ³ is C (O) A, CONH _2, CONHA, CONA _2, COOH or COOA,

R ⁴ = Ph, or OH,

R ^{5 is} CH ₃ , CH ₂ Cl, CF ₃ or Ph,

R ^{6 is} NH ₂ , HNA, NA ₂ , NH (DH) or NH-C (O) A,

R ^{7 is} NA (DH), NHA, NH (DH) or NA ₂ ;

R ⁸ -NH- (C = NH) -NH ₂ , -NH- (C = NH) -NHA, -NH- (C = NH) NA ₂ , -NA- (C = NH) -NH ₂ , - NA- (C = NH) NHA, -NA- (C = NH) NA _2,

R ¹¹ -CH (A) -Ph

Ar 1 is a phenylene, biphenylene, naphthylene or pyrazol-4-yl group which is unsubstituted or has one, two or three substituents from the group consisting of A, OH, OA, OCF ₃ , Hal, CN, NH ₂ , NHA, NA _2, N0 _2, CF _3, SO ₂ NH _2, SO ₂ Ph, _SO2 preview, having _{from 2} to _2,

Ar, Ar ¹ , Ar ² independently of one another are phenyl, biphenyl, stilbyl, pyridyl, pyrimidyl, quinolyl, 1-imidazolylpyrazolyl, indanyl, benzo [1,3] dioxol-5-yl or dibenzofuranyl, 9H-fluorenyl, 9H-fluorenyl, 9H-fluorenyl, 9H-fluorenyl; , [1,1 ', 4', 1 ''] Phenyl, anthracenyl, naphthalen-1-yl, naphthalen-2-yl or fluoren-9-one-2-yl, which is unsubstituted or has one, two or three substituents A, OH, OA, OCF ₃ , O-Ph, O-Ph-CH ₃ , CH ₂ -Ph, OCH ₂ -Ph, Hal, CN, NH ₂ , NHA, NA ₂ , NO ₂ , CF ₃ , SO ₂ NH ₂ , SO ₂ ~ Ph, SO ₂ NAH, SO ₂ NA ₂ and R ⁸ ,

A Het saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or tricyclic heterocyclic group having 5 to 13 ring members containing one or two nitrogen atoms and / or one or two sulfur or oxygen atoms in the heterocyclic moiety, the heterocyclic moiety being monosubstituted or disubstituted by CN, Hal,

The

OH, OA, CF ₃ , A, NO ₂ , oxo and R, wherein the pyrazole group is not bonded via a nitrogen atom, ····

A Het ¹ saturated, monocyclic, bicyclic or tricyclic heterocyclic group of 5 to 13 ring members containing one or two nitrogen atoms and / or one or two sulfur or oxygen atoms in the heterocyclic moiety, wherein the heterocyclic moiety is monosubstituted or disubstituted by a group selected from the group including the group Hal, A, OH, OA, oxo and CF ₃ , or is piperidine, morpholine, pyrrolidine or pyrrolidine-

2-one,

A branched or unbranched alkyl group having 1 to 8 carbon atoms,

A 'branched or unbranched alkyl group having 2 to 6 carbon atoms,

Alk a straight-chain alkyl group having 4 to 8 carbon atoms,

C 4 -C 7 cycloalkylene or cyclohexen-1-yl,

Hal is fluorine, chlorine, bromine or iodine,

X, X ¹ , X ² are independently C 1 -C 12 alkylene,

Y is O or S or NH or NA,

and about, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 to 3 4, 5, 6, 7, 8, 9, 10, 11, or 12 m 0 1 or 2,

n 0 1, 2, 3 or 4. about 1 2 3 4 5 6 7, 8, 9 or 10 T about, 1 or 2, at 1 or 2,

provided that when R ^{2 is} 4-chlorophenyl, R ^{1 is} not -NH-CH ₂ -CH ₂ -OH and pharmaceutically acceptable salts and solvates thereof.

Similar compounds having a benzo [de] isoquinoline-1,3-dione-like structure are described as dyes in U.S. Patent Nos. 4,200,752, FR 2,272,215, Fr 2,272,216 A and in the journal Chemical Abstracts, Vol. 73, no. 2, July 13, 1970, Chemical Abstracts, Vol. 57, no. 13, December 24, 1962 and Chemical Abstracts, Vol. 111, no. 20, 13 October 1989.

SUMMARY OF THE INVENTION It is an object of the present invention to provide novel compounds which have valuable properties and are particularly suitable for the manufacture of pharmaceutical compositions.

SUMMARY OF THE INVENTION

The present invention provides compounds of the formula I as defined above and salts or solvates thereof which have valuable properties and are particularly suitable for the manufacture 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. In particular, they act as inhibitors of GPlblX, in particular by inhibiting the interaction of this receptor with the ligand

Willebrand factor (vWF). This action can be documented

6, for example, by the method of S. Meyer et al. (J. Biol. Chem. 268: 20555-20562, 1993). The compounds may also be blocked by the GPIblX α-thrombin receptor (N.J. Greco, Biochemistry 35, 915-921, 1996).

The importance of GPIb1X as an adhesion receptor on platelets that causes primary platelet interaction with an arteriosclerotic modified vascular wall by binding expressed vWF has been described by many authors (e.g. Z.M. Ruggeri, Thromb. Hemost. 1997, 78, 611-616). Activation of another platelet adhesion receptor, GPIIblIIa, following GPIblX-vWF interaction leads to platelet aggregation and thus to thrombotic vascular occlusion.

The GPIblX antagonist may therefore prevent the onset of thrombus formation and thus also release the active substances from the platelets, which, for example, promote thrombus growth and have an additional trophic effect on the vascular wall. This has been demonstrated with inhibitory peptides or antibodies in various experimental models, for example, H. Yamamoto et al. Thromb. Hemos. 79, p. 202-210, 1998).

In the case of higher shear forces, the blocking action of GPIblX inhibitors exerts its maximum effect (J.J. Sixma et al., Arteriosclerosis, Thrombosis and Vascular Biology 16: 64-71 (1996)). According to the flow cell method described herein, compounds of Formula I may be characterized as GPIblX inhibitors in the blood as a whole.

Inhibition of thrombus formation by GPIblX inhibitors can be measured by the modified method described by Born (Nature 4832, 927-929, 1962) using botrocetin or ristocetin as aggregation stimulators.

The compounds of the formula I according to the invention can therefore be used as pharmaceutical active substances in human and veterinary medicine. They act as antagonists of adhesion re · · · ·

Ceptor, particularly as antagonists of the Ib1X glycoprotein, and are useful in the prophylaxis and / or therapy of thromotic diseases and conditions associated therewith. The most advantageous effect can be expected in the case of thrombotic disorders in the arterial vascular system, but GPIblX inhibitors also act in the case of thrombotic disorders in the vascular bed. The disorders are acute coronary symptoms, angina pectoris, myocardial infarction, peripheral circulatory disorders, stroke, transient ischemic events, arteriosclerosis, reocclusion / restenosis after angioplastic stent implantation. Furthermore, the compounds may be used as anti-adhesive agents when the body comes into contact with foreign surfaces such as implants, catheters or pacemakers.

Comparable, commercially available drugs include aspirin and GPIIbIIa antagonists.

According to the invention, the process for the preparation of the compounds of the formula I, in which the individual symbols are as defined above, is characterized in that:

(a) released from their functional derivatives by treatment with a solvolysing or hydrogenolysing agent; or

b) a compound of formula II

(II) wherein R ⁹ is chloro, bromo, nitro or R and R is as defined above, reacts with a compound of formula III

H ₂ N - R ² (III) · φ φ φ φ φ

- 8 η, where R is as defined above and optionally a group

R ⁹ is changed to R ¹ , or

c) in a compound of formula I, the group R and / or R ² and / or R ⁹ is changed to another R and / or R ² and / or R ⁹ such that, for example, the amino group is converted to guanidino by reaction with an amidating agent; arylbromide or aryl iodide to the corresponding coupling products by Suzuka coupling with boric acid, nitro, sulphonyl or sulphoxyl group is reduced, the hydroxyl group is etherified or the OA group undergoes ether cleavage, the primary or secondary amino group is alkylated, the cyano group is partially or completely hydrolysed, the ester group or the carboxyl group is esterified, the nucleophilic or electrophilic substitution is carried out and / or

d) the base or acid of formula I is converted into its salt or solvate.

The compounds of formula I may have a chiral center and may therefore be in different stereoisomeric forms. The invention includes all such forms (e.g., R and S forms) and mixtures thereof (e.g., RS forms).

The invention also includes so-called prodrug derivatives, i.e., compounds of formula I modified with, for example, alkyl or acyl groups, sugars or oligopeptides that rapidly cleave in the body to provide the active compounds of the invention.

Free amino groups as substituents of the compounds of formula I may be protected by conventional protecting groups.

Solvates of the compounds of the formula I are understood to be addition products of the compounds of the formula I with inert solvent molecules, which are formed because of their attraction to one another. Solvates are, for example, monohydrates, dihydrates or alcoholates.

Abbreviations used have the following meanings:

BOC tert-butoxycarbonyl CBZ benzyloxycarbonyl DCC dicyclohexylcarbodiimide DMF dimethylformamide et ethyl Fmoc fluórenylmetoxykarbony1 Me methyl Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl OBu tert-butyl OMe methyl ester OEt ethyl ph phenyl POA phenoxyacetyl tert tert-butyl TFA trifluoroacetic acid

In formula I, the symbols have the following meanings:

A represents an alkyl group having 1 to 8 carbon atoms, preferably 1, 2,3, 4 or 5 carbon atoms. Alkyl is especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and also pentyl, 1-, 2 or 3-methylbutyl, 1,1-, 1,2- or 2,2-methyl. -dimetylpropylová.

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, heptyl,

1-, 2-, 3-, 4- or 5-methylhexyl, 1,1-, 1,2-, 1,3-, 1,4-,

2,2-, 2,3-, 2,4-, or 3,3-dimethylpentyl, 1-, 2-, 3-, 4-ethylpentyl, 1,1,2-, 1,1,3-, 1 , 1,4-, 1,2,2-, 1,2,3-, 1,2,4-,

1,3,3-, 1,3,4-, 1,4,4- or 2,2,3-trimethylbutyl or octyl.

A 'represents an alkyl group of 2 to 6 carbon atoms, preferably 1, 2, 3 or 4 carbon atoms. Preferred groups A 'are ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

Alk represents a straight-chain alkyl group having 4 to 8 carbon atoms. Preferred Alk groups are n-butyl, n-pentyl, n-hexyl, n-heptyl or n-octyl.

Ar is preferably a phenyl group, especially as mentioned a monosubstituted phenyl group, preferably a phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl group, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-aminophenyl, o-, m- or p- (N, N-dimethylaminophenyl, 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- (phenylmethoxy) phenyl 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, 4-benzenesulfonylphenyl, 4- (4-chlorophenoxy) phenyl, b) further preferably, 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 o 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-methylphenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl, 2-chloro-6-methylphenyl, 3-chloro-2-methylphenyl, 4-chloro-2-methylphenyl 5-chloro -2-methylphenyl, 3-chloro-4-methylphenyl, 3-chloro-5-methylphenyl, 4-chloro-3-methylphenyl, 2-bromo-3-methylphenyl, 2-bromo-4-methylphenyl, 2-bromo -5-methylphenyl, 2-bromo-6-methylphenyl,

3-bromo-2-methylphenyl, 4-bromo-2-methylphenyl, 5-bromo-2-methylphenyl, 3-bromo-4-methylphenyl, 3-bromo-5-methylphenyl, 4-bromo-3-methylphenyl, 2- iodo-3-methylphenyl, 2-iodo-4-methylphenyl, 2-iodo-5-methylphenyl, 2-iodo-6-methylphenyl, 3-iodo-2-methylphenyl, 4-iodo-2-methylphenyl, 5-iodo- 2-methylphenyl, 3-iodo-4-methylphenyl, 3-iodo-5-methylphenyl, 4-iodo-3-methylphenyl, 2-chloro-3-methoxyphenyl, 2-chloro-4-methoxyphenyl, 2-chloro- 5-methoxyphenyl, 2-chloro-6-methoxyphenyl, 3-chloro-2-methoxyphenyl,

4-chloro-2-methoxyphenyl, 5-chloro-2-methoxyphenyl, 3-chloro-4-methoxyphenyl, 3-chloro-5-methoxyphenyl 4-chloro-3-methoxyphenyl, 2-chloro-3-hydroxyphenyl 2-chloro- 4

-hydroxyphenyl, -hydroxyphenyl, -hydroxyphenyl, -hydroxyphenyl, -hydroxyphenyl, -methoxyphenyl,

2-chloro-5-hydroxyphenyl,

3-chloro-2-hydroxyphenyl,

5-chloro-2-hydroxyphenyl,

3-chloro-5-hydroxyphenyl,

3-fluoro-4-methoxyphenyl, 4-fluoro-3-

2-chloro-3-fluorophenyl, 2-chloro-4-fluoro

2-chloro-6-

4-chloro-2-

3-chloro-4-

4-chloro-3-phenyl, 2-chloro-5-fluorophenyl, 2-chloro-6-fluorophenyl,

3-chloro-2-fluorophenyl, 4-chloro-2-fluorophenyl, 5-chloro

-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 4-chloro-3-fluorophenyl, 2-fluoro-3-methylphenyl,

2-fluoro-4-methylphenyl, 2-fluoro-5-methylphenyl, 2-fluoro

6-methylphenyl, 3-fluoro-2-methylphenyl, 4-fluoro-2-methylphenyl, 5-fluoro-2-methylphenyl, 3-fluoro-4-methylphenyl,

3-fluoro-5-methylphenyl, 4-fluoro-3-methylphenyl, 2,5- or

3,4-dimethoxyphenyl, 2-cyano-4,5-dimethoxyphenyl, 5-chloro12

-2,4-dimethoxyphenyl, 2-cyano-3,4-dimethoxyphenyl or 3,45-trimethoxyphenyl.

In addition, Ar is preferably unsubstituted biphenyl as mentioned above or monosubstituted biphenyl, particularly preferably 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 2-tert-butylbiphenyl-3-yl, 2'-iso-propylbiphenyl-4-yl, 3'-isopropylbiphenyl-4-yl, 4'-isopropylbiphenyl-4-yl, 2-tert-butylbiphenyl-3-yl; 1'-isopropylbiphenyl-3-yl, 3'-isopropylbiphenyl-3-yl, 4'-isopropylbiphenyl-3-yl, 2-iso-propylbiphenyl-4-yl, 3-isopropylbiphenyl-4 -yl, 2-isopropylbiphenyl-3-yl, 4-isopropylbiphenyl-3-yl, 2'-fluorobiphenyl-4-yl, 3'-fluorobiphenyl-4-yl, 4'-fluorobiphenyl-4

-yl, 2'-fluorobiphenyl-3-yl, 3'-fluorobiphenyl-3-yl 4'-fluorobiphenyl-3-yl, 2-fluorobiphenyl-4-yl, 3-fluorobiphenyl-4-yl, 2-fluorobiphenyl- 3-yl, 4-fluorobiphenyl-3-yl, 2'-methoxybiphenyl-4-yl, 3'-methoxybiphenyl-4-yl, 4'-methoxybiphenyl-4-yl, 2'-methoxybiphenyl-3-yl 3'- methoxybiphenyl-3-yl, 4'-methoxybiphenyl-3-yl, 2-methoxybiphenyl-4-yl, 3-methoxybiphenyl-4-yl, 2-methoxybiphenyl-3-yl,

4-methoxybiphenyl-3-yl, 2'-nitrobiphenyl-4-yl, 3'-nitrobiphenyl-4-yl, 4'-nitrobiphenyl-4-yl 2'-nitrobiphenyl-3-yl, 3'-nitrobiphenyl-3- yl, 4'-nitrobiphenyl-3-yl,

2-nitrobiphenyl-4-yl, 3-nitrobiphenyl-4-yl, 2-nitrobiphenyl-3-yl, 4-nitrobiphenyl-3-yl, 2'-trifluoromethylbiphenyl-4-yl, 3'-trifluoromethylbiphenyl-4-yl, 4'-trifluoromethylbiphenyl-4-yl, 2'-trifluoromethylbiphenyl-3-yl, 3 '· · · · · · · · · · · · · · · · · · · · · ·

-trifluoromethylbiphenyl-3-yl, 4'-trifluoromethylbiphenyl-3-yl, 2-trifluoromethylbiphenyl-4-yl 3-trifluoromethylbiphenyl-4-yl, 2-trifluoromethylbiphenyl-3-yl, 4-trifluoromethylbiphenyl-3-yl, trifluoromethoxybiphenyl-4-yl, 3'-trifluoromethoxybiphenyl-4-yl, 4'-trifluoromethoxybiphenyl-4-yl, 2'-trifluoromethoxybiphenyl-3-yl 3'-trifluoromethoxybiphenyl-3-yl, 4'-trifluoromethoxybiphenyl-3-yl, 2-trifluoromethoxybiphenyl-4-yl, 3-trifluoromethoxybiphenyl-4-yl,

2-trifluoromethoxybiphenyl-3-yl, 4-trifluoromethoxybiphenyl-3-yl, further Ar represents partially substituted biphenyl groups such as 2'-methyl-3'-nitrobiphenyl-4-yl, 2'-methyl-4'- nitrobiphenyl-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-4-yl,3'-methyl-6'-nitrobiphenyl-4-yl,4'-methyl-2'-nitrobiphenyl- 4-yl, 4'-methyl-3'-nitrobiphenyl-4-yl, 2'-methyl-3'-nitrobiphenyl-3-yl, 2'-methyl-4'-nitrobiphenyl-3-yl, 2'-methyl 5'-nitrobiphenyl-3-yl, 2'-methyl-6'-nitrobiphenyl-3-yl, 3'-methyl-2'-nitrobiphenyl-3-yl, 3'-methyl-4'-nitrobiphenyl-3- yl, 3'-methyl-5'-nitrobiphenyl-3-yl, 3'-methyl-6'-nitrobiphenyl-3-yl, 4'-methyl-2'-nitrobiphenyl-3-yl, 4'-methyl-3 1'-nitrobiphenyl-3-yl, 2'-methoxy-2-methylbiphenyl-4-yl, 3'-methoxy-2-methylbiphenyl-4-yl, 4'-methoxy-2-methylbiphenyl-4-yl, 4'- methoxy-3-nitro-biphenyl-4-yl 2'-chloro-3'-fluorobiphenyl-4-yl, 2'-chloro-4'-fluorobiphenyl-4-yl, 2'-chloro-5'-fluorobiphenyl-4-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 1'-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'-fluoro-biphenyl-3-yl, 2'-chloro-5'-fluoro-biphenyl-3-yl, ¹ 2-chloro-6'-fluoro-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, 4'-chloro-2'-fluorobiphenyl · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

3-yl, 4'-chloro-3'-fluorobiphenyl-3-yl, (23'-dimethoxy) biphenyl-4-yl, (24'-dimethoxy) biphenyl-4-yl, (2 ', 5'- dimethoxy) biphenyl-4-yl, (2 ', 6'-dimethoxy) biphenyl-4-yl, (3', 4'-dimethoxy) biphenyl-4-yl, (3 ', 5'-dimethoxy) biphenyl-4 yl, (2 ^1, 3 ' dimethoxy) biphenyl-3-yl, (24'-dimethoxy) biphenyl-3-yl, (2 ', 5'-dimethoxy) biphenyl-3-yl, (2', 6 1'-dimethoxy) biphenyl-3-yl, (3 ', 4'-dimethoxy) biphenyl-3-yl, (3', 5'-dimethoxy) biphenyl-3-yl, (2 ', 3'-di (trifluoromethyl) (2 ', 4'-di (trifluoromethyl)) biphenyl-4-yl, (2', 5'-di (trifluoromethyl)) biphenyl-4-yl, (2 ', 6) 1'-di (trifluoromethyl) biphenyl-4-yl, (3 ', 4'-di (trifluoromethyl)) biphenyl-4-yl, (35'-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)) biphene yl-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.

In addition, Ar is also preferably benzo [1,3] dioxol-5-yl, 9H-carbazolyl, quinolyl, dibenzofuranyl, 9H-fluorenyl, 7-bromo-9H-fluoren-2-yl, 9H-fluoren-9- ol-1-yl, fluoren-9-one-2-yl, imidazolyl indanyl, 1-imidazolyl, pyrazolyl, 9H-carbazolyl [1,1 ', 4', 1 ''] terphenyl, anthracenyl, naphthalen-1-yl , naphthalen-2-yl, 4-bromonaphthalen-1-yl, 4-cyanaphthalen-1-yl, 4-chloronaphthalen-1-yl, 4-nitronaphthalen-1-yl, 4-methoxynaphthalen-2-yl, 6-hydroxynaphthalene a 1-yl 7-hydroxynaphthalen-1-yl, 8-hydroxynaphthalen-1-yl, or a stilbyl group.

Particularly preferably, Ar is pyridyl-2-yl, pyridyl-3-yl, pyridyl-4-yl, pyrazol-3-yl, pyrazol-4-yl or pyrazol-5-yl, pyrimidin-2-yl, pyrimidine 15

-4-yl or pyrimidin-5-yl which is unsubstituted or substituted by A or Hal and particularly preferably represents pyridyl-2-yl, pyridyl-3-yl,

4-chloropyridyl-2-yl, 1-methylpyrazol-4-yl or pyrimidin-2-yl.

Ar 'is preferably phenylene, biphenylene

A 1-naphthylene or pyrazol-4-yl group which is unsubstituted or monosubstituted by A, OH, OA, CF ₃ , OCF ₃ , and Hal. Unsubstituted phenylene or 1-naphthylene, 2-methoxyphenylene,

2-methylphenylene, 3-biphenylene, 4-biphenylene or 1-methylpyrazol-4-yl are particularly preferred.

Ί 9

Ar and Ar are, independently of one another, an Ar group having the preferred meanings indicated above. Phenyl is especially preferred for Ar and Ar, which are independent of one another.

In the group -Ar'-D-H, Ar 'is preferably an unsubstituted or substituted phenylene group and D has the preferred or particularly preferred meanings given below.

-Ar'-D-H is particularly preferred.

In the group -Ar'-Het ¹ , Ar 'is preferably an unsubstituted or substituted phenylene group and Het ¹ has the following preferred or particularly preferred meanings.

-Ar'-Het ¹ groups are particularly preferred.

Q

In the -Ar'-YC (A) ₂ -R group, Ar ¹ is preferably an unsubstituted or substituted biphenylene group, R ³ is preferably an alkyloxycarbonyl group, and A has the following preferred meanings.

It is particularly preferred for -N'-YC (A) ₂ N-R ³

In the group -Ar '- (CH ₂ ) _n -R, Ar' is preferably an unsubstituted or substituted phenylene, naphthylene, biphenylene or pyrazol-4-yl group, R preferably an amido group, an alkylamido group or a dialkylamido group, a carboxyl group, an alkyloxycarbonyl group or an alkyloxycarbonyl group 0, 1, 2, 3 or 4.

“€ ^ ° ^Η2 Λη,. ^{-CH2 (ch2)} 3 ^

-Ar '- (CH ₂ ) _n -R ³ are particularly preferred.

In the group -Ar'-Y- (CH ₂ ) _n -R ³ , Ar 'is preferably an unsubstituted or substituted phenylene group, Y preferably a sulfur or oxygen atom, R ³ preferably an amido group, an alkylamido group or a dialkylamido group, an alkyloxycarbonyl group or an alkylcarbonyl group 0, 1, 2, 3 or 4.

S - CH _{2 -} CONH (CH ₂ ) ₂ -C (CH ₃ ) ₃

S-CH ₂ CONH-C ₃ H ₇

-Ar'-Y- (CH ₂ ) _n -R ³ are particularly preferred.

Ί

In the group -Ar'-Het-R- *, Ar 'is preferably an unsubstituted or substituted phenylene group, Het ¹ has the further preferred meanings indicated, and R is preferably an alkylcarbonyl group.

-Ar'-Het ¹ -R 6 'are particularly preferred. -Ar '- (CH ₂ ) _n -R ⁶ is preferably Ar' unsubstituted or substituted phenylene or biphenylene, R ⁶ preferably amino, alkylamino or dialkylamino or alkyloxycarbonylamino and n 0, 1, 2, 3 or 4.

-Ar '- (CH ₂ ) _n -R ⁶ are particularly preferred.

The _Ar'-SO2- Het is Ar is preferably unsubstituted or substituted naphthylene or phenylene radical, and Het have the preferred meanings indicated below.

It is particularly preferred _-N'-SO2- Het.

In the group -Ar'-NH-SO ₂ -Het, Ar * is preferably an unsubstituted or substituted phenylene group and Het particularly preferably a 3-methoxy-pyrimidin-2-yl group.

is a particularly preferred group -Ar'-NH-SO ₂ -Het.

In the group -Ar'-SO ₂ -R ⁷ , Ar 'is preferably an unsubstituted or substituted naphthylene group and R is preferably an alkylamino group, a dialkylamino group, a cycloalkylamino group or an alkylcycloalkylamino group.

····

-Ar '-SO ₂ -R ⁷ are particularly preferred In -Ar' - (CH 2) _n - (CONH) - (CH ₂ ) 1 - R ⁶ is preferably Ar 'unsubstituted or substituted phenylene, R ⁶ preferably amino, alkylamino or dialkylamino or cycloalkylamino, n 0, 1, 2, 3 or 4; and 10, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

-Ar 1 - (CH ₂ ) _n - (CONH) - (CH ₂ ) 4 - R ⁶ are particularly preferred.

In the group -Ar '- (Η Η ₂ ) _η - (ΟΟΝΗ) “(Η Η ₂ ) Ο -Η-Η, Ar' is preferably an unsubstituted or substituted phenylene group, D has the following preferred meaning, n is 0, 1 , 2, 3 or 4 and 10, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

/ • · · · ·

-Ar 1 - (CH ₂ ) _n - (CONH) - (CH ₂ ) 4 -DH are particularly preferred.

In the group -Ar'-S- (CH ₂ ) _n - (CONH) - (CH ₂ ) 4 -DH, Ar 'is preferably an unsubstituted or substituted phenylene group, D has the following preferred meanings, n is 0, 1, 2 , 3 or 4 and 10, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

or

S-CH ₂ -CONH- (CH _{2) 2} is particularly preferred for ^Ar, -S- (CH _{2) n} - (CONH) - (CH ₂₎ -DH.

In the group -Ar '- (CH ₂ ) _n - (CONH) - (CH ₂ ) _i -R ¹¹ , Ar' is preferably an unsubstituted or substituted phenylene group, R ¹¹ represents a group -CH (A) -Ph, where A has the top said preferred meaning, Ph represents a phenyl group, n 0, 1, 2, 3 or 4 and i 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

or especially -Ar '- (CH ₂ ) _n - (CONH) - (CH ₂ ) _i -R ¹¹ are particularly preferred.

In the group -Ar 1 -S- (CH ₂ ) _n - (CONH) - (CH ₂ ) 4 - R ¹¹ , -Ar ¹ is preferably unsubstituted or substituted phenylene, R ^{11 is} -CH (A) -Ph, wherein A is as defined above, Ph is phenyl, n 0, 1, 2, 3 or 4 and 10, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

S — CH _{2 —} CONH-CH ₂ f

is a particularly preferred group -Ar 1 -S- (CH ₂ ) _n - (CONH) - (CH ₂ ) 4 -R ¹¹ .

In the group -Ar '- (CH ₂ ) _n - (CO) -Het, Ar' is preferably an unsubstituted or substituted phenylene group, Het has the following preferred meanings, n is 0, 1, 2, 3 or 4 and i 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

• · • ·

is a particularly preferred group -Ar '- (CH ₂ ) _n - (CO) -Het.

In the group -Ar '- (CH ₂ ) _n - (CONH) - (CH ₂ ) 4 - Ar is preferably Ar' unsubstituted or substituted phenylene, Ar is as defined above, n is 0, 1, 2, 3 or 4 and 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

CN ·>'· · · Β'.Β' · · · · _r - _e --- B • · · · • BBBB BB

B · · ♦ ·

BB ·· ···

4.01 at ₄

. · · · · · ·. · '· • · ·· · • • · · ' • • • · • · • • ..... in • · · • • · · · • · • • · · • • • • • ··· ·· «· «· • · • · e

- 24b-

(CH ₂ ) ₂ -CONH-CH ₂

- 24 _C \ ₄

Cl • ·

Cl

··· ·· ··

Cl

Cl Cl

, (CH ₂₎ 2 -CONH-CH ₂

29 Cl

Cl

Cl

Cl

Cl

, (CH ₂ ) ₂ -CONH-CH ₂

··· '

-Ο

ch ₃ ch ₃

k \ //

• · · · · ··. · · • · · . · «· ·.  - · · ·· 9 · ··. '··· · · • · · • · · · · ·· ·· ·· ··

, (ch ₂ ) ₂ -conh

• · · · · · · · · · ·

-v ³³ -

• · · · · •. · • in . r -....... * · - · - • · · · · • · ·· ···· · · • · · · · -r ··· · · · ·. · • · • r · '· • · • · · · • · • · • · • · ·

-.34 -

_(CH2) 2-CONH- (CH2) 2 \ '

F

-, .35 -.

\\ //

-.36 -

λ //

9 '···. ·. ··. ·· 99 9 ·· ..... ♦ ··. .. ·. 9 9 9 9 9 9 9 9 Í 9 9 '9 ··· 9 '9 9' 9 9 9 · · « 9 9 9 ··· ·· ·· 99 99 99 9

T

_r 38 -

is particularly preferred N '- _{(CH2) n} - (CONH) - (CH ₂₎ Ar.

• · · ··· A- ... · *. ·· .. · ··. ·. · • J ». · 9 .. .. ·. · · · • · · · · · • ··· · · · · ····· · · · · ····· ·· ·· ·· ·· in

c ³⁹ In the group -Ar'-S- (CH ₂ ) _n - (CONH) - (CH ₂ ) p -Ar, Ar 'is preferably unsubstituted or substituted phenylene, Ar is as defined above, n is 0, 1, 2, 3 or 4; and 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

br

CH ₂ --- CONH- (CH ₂ ) ₂

· · · · · · ·

·. - · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Cl

Cl

• · · · · φ

· '.2..41 -

···· é · · · ··. · · · · · · · · · · · · · · · · · · · ·

^; 4 3 -

Cl

Φ Φ Φ Φ Φ φ Φ Φ Φ φ φ .φ · • * Φ Φ  · -Φ 'Φ. ·. '· • φ - -i 2 .. * ', Φ. ·. .. · Κ. / .φ φ • 9 • · • ··· φ • φ Φ Φ Φ Φ Φ Φ · φ φ φ φ φ

·. ··· - · ··. ·· · · ·. · · '. ·. ··. · · · ··. '• / ... ‘' •• '• r ·'. ··. ···· '9. 9'9. ··· · ··

-. . ·. · · -. *. -. ....... φ · '* ·.......... 999 · 999 · · · · · · · · · · · · · ·

• · ·

♦ ·

V- 45 -

In the group -Ar '- (CH ₂ ) _n - (CONH) - (CH ₂ ) 4 - Het ¹ , Ar' is preferably an unsubstituted or substituted phenylene group, Het ¹ is as defined below, n is 0, 1, 2, 3 or 4 and 10, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

• ···· · · ♦♦ ··· · 4>. . · · · · .. ·.

•. ·. · ·. * · '.

----_. _w ..φ · ·, φ .. ·. ¢. <·· '· · · · · · · · φ «·

(CH ₂ ) ₂ -CONH- (CH ₂ ) ₂

(CH ₂ ) ₂ -CONH- (CH ₂ ) ₃ -

-Ar '- (CH ₂ ) _n - (CONH) - (CH ₂ ) ---Het ¹ are particularly preferred

In the group -Ar'- S- (CH ₂ ) _n - (CONH) - (CH ₂ ) 4 - Het ¹ , Ar 'is preferably an unsubstituted or substituted phenylene group, Het ¹ is as defined below, n is 0, 1, 2, 3 or 4 and 10, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

or ··

are particularly preferred -Ar 1 -S- (CH ₂ ) _n - (CONH) - (CH ₂ ) 4 - Het ¹ groups.

In the group -Ar '- (CH ₂ ) _n - (CH (CN)) - (CH ₂ ) p -Ar, Ar' is preferably unsubstituted or substituted phenylene, Ar is as defined above, n is 0, 1, 2 , 3 or

N

N are particularly preferred groups -Ar 1 - (CH ₂ ) _n - (CH (CN)) - (CH ₂ ) 4 -Ar.

In the group -Ar ^, - (CH ₂ ) _n - (CONH) - (CH ₂ ) p -CH (Ar ¹ ) -Ar ² , Ar ¹ is preferably unsubstituted or substituted phenylene, Ar ¹ and Ar ² independently of one another have n is 0, 1, 2, 3 or 4 and 10, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··

or are particularly preferred groups

-Ar 1 - (CH ₂ ) _n - (CONH) - (CH ₂ ) 1 -CH (Ar ¹ ) -Ar ² .

In the group -Ar 1 -S- (CH ₂ ) _n - (CONH) - (CH ₂ ) 4 - CH (Ar ¹ ) -Ar ² , Ar ¹ is preferably an unsubstituted or substituted phenylene group, Ar 1 · a and Ar independently of one another has the above-mentioned preferred meaning, n is 0, 1, 2, 3 or 4 and i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

or

are particularly preferred groups

-Ar 1 -S- (CH ₂ ) _n - (CONH) - (CH ₂ ) 1 -CH (Ar ¹ ) -Ar ² .

In the above formulas, D is a cycloalkylene group having 4 to 7, preferably 5 or 6 carbon atoms. The cycloalkylene group is preferably a cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene group, particularly preferably a cyclopentylene group or a cyclopentylene group, or more preferably a cyclopentylene group or a cyclopentylene group. Cyclohexylene. In addition, D is preferably a cyclohex-1-ylene group.

Hal is preferably a fluorine, chlorine, bromine or iodine atom.

Het ¹ is preferably a substituted or unsubstituted furan-2-yl, furan-3-yl, carbazol-9-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl [1,3,4] ] thiadiazol-2-yl, 1,2-dihydropyrazol-3-one-4-yl, 1,2-dihydropyrazol-3-one-5-yl, benzothiophen-2-yl, benzothiophen-3-yl, 3H-benzotriazole 5-yl, benzothiazol-2-yl, benzofuran-2-yl, benzofuran-3-yl, imidazol-1-yl, benzo [1,3] dioxol-5-yl, piperidin-1-yl, pyrrolidin- 1-yl or pyrrolidin-2-one-1-yl. Further particularly preferred is furan-2-yl, carbazol-9-yl, 3,6-di-tert-butylcarbazol-9-yl, thiazol-2-yl, thiazol-3-yl, 5-methyl [1, 3,4] thiadiazol-2-yl, 5-trifluoromethyl [1,3,4] thiadiazol-2-yl, 1,5-dimethyl-1,2-dihydropyrazol-3-one-4-yl, benzofuran-2- 6-methylbenzothiazol-2-yl,

2,3-dihydro-1H-indol-6-yl, 3H-benzotriazol-5-yl, benzothiophen-2-yl, imidazol-1-yl, benzo [1,3] dioxol-5-yl, piperidin-1-yl- yl, morpholin-4-yl, pyrrolidin-1-yl or pyrrolidin-2-one-1-yl.

In the -Het ¹ -Ar group, Het ¹ and Ar have the preferred meanings given above, wherein Ar is preferably a phenyl group. Particularly preferred groups -Het ¹ -Ar are 4-phenylthiazol-2-yl, 5-phenyl [1,3,4] thiazol-2-yl or 1,5-dimethyl-2-phenyl-1,2-dihydropyrazole- 3-on-4-yl.

In the group -Het ¹ - ^1-3 , Het ¹ is preferably 2,3-dihydro-1H-indol-6-yl and R ³ is preferably CO (A). A particularly preferred group -Het ¹ -R ³ is a group of the formula

Het is preferably a substituted or unsubstituted 2- or 3-furyl, 2- or 3-thienyl group,

1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl,

1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl,

3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-,

4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-,

5- or 6-pyrimidinyl, further preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, 4- or -5- 1-, 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-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-,

3-, 4-, 5-, 6- or 7-1H-indolyl, 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-cinolinyl, 2-, 4-, 5-, 6- , 7- or 8-quinazolinyl.

The heterocyclic groups may also be partially or fully hydrogenated. Het therefore also means 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, tetrahydro-1-, -2- or -3-pyrrolyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4-, -5-, -6- or -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-piperidinyl;

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.

Particularly preferably, Het is tetrahydro-1-pyrrolyl, 2,3-dihydro-1H-indol-1-yl, 1-piperidinyl, 2,6-tetramethylpiperidin-4-yl, 4-morpholinyl, 1-piperazinyl, 4- methylpiperazin-1-yl, 4-phenylpiperazin-1-yl,

1,2.3.4-tetrahydroquinolin-1-yl or 1,2,3,4-tetrahydroisoquinolin-1-yl.

In the group -Het-SO ₂ -Ar, Het and Ar have one of the above preferred meanings, wherein Het is preferably piperazine-1,4-diyl.

is a particularly preferred group of the formula -Het-SO ₂ -Ar.

In the group of formula Het-R ⁵ is Het preferably a piperazin-1,4-diyl and R @ ⁵ is preferably phenyl, methyl, chloromethyl or trifluoromethyl.

C is a particularly preferred group of the formula -Het-R.

In the group -Het- (CH ₂ ) _n -Ar, Het and Ar have one of the preferred meanings above, wherein Het is preferably piperazine-1,4-diyl and n is 0, 1, 2, 3 or 4.

or

particularly preferred are groups of formula -Het- (CH _{2) n} -Ar

The X and / or ^X1 and / or ^X2 is alkylene and especially methylene, ethylene, propylene, butylene, furthermore also pentylene or hexylene group.

Y is preferably oxygen, sulfur, NH or NA.

In the group -Y- (CH ₂ ) _n -Het, Y is preferably oxygen, sulfur, NH or NA, Het has one of the above preferred meanings and n is 0, 1, 2, 3 or.

and is particularly preferred formula Y- (CH _{2) n} Het.

In the group -Y-Ar'-R ³ , Y is preferably oxygen, sulfur, NH or NA, Ar 'has one of the preferred meanings mentioned above, and R ³ is preferably alkylcarbonyl.

is a particularly preferred group of the formula -Y-Ar'-R ³ .

In the group of the formula -Y- (CH ₂ ) _n -Ar, Y is preferably oxygen, sulfur, NH or NA, Ar has one of the preferred meanings mentioned above and n is 0, 1, 2, 3 or 4.

, -NH-CH ₂

-NH- _{(CH2) 2}

-NH- _{(CH2) 2}

NH

nh ₂

-NH- _{(CH2) 2}

-NH-GH ₂ .nh-ch ₂

is particularly preferred formula Y- (CH _{2) n} -Ar.

In the group of the formula -Y- (CH ₂ ) _n -Ar 1 - (CH ₂ ) p -R ⁶ is -. preferably Y, oxygen, sulfur, NH or NA, Ar 'has one of the preferred meanings indicated above, R ⁶ is amino-

a group or an alkylamino group, n represents ai means 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, ΌΗ ₂ - nh ₂ 0, 1, 2, 3 or 4 10, 11 or 12. _nh-ch ₂ - In l or .nh-ch ₂ - CH ₂ NH ₂

is particularly preferred formula Y- _{(CH2) n-Ar} '- _(CH2) - [- R ⁶ ·

In the group -Y- (CH ₂ ) _n -D- (CH ₂ ) - R ⁶ , Y is preferably oxygen, sulfur, NH or NA, D has one of the above preferred meanings, R ⁶ is preferably amino or alkylamino, n is 0, 1,

2, 3 or 4 and i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

CH. MH.

are particularly preferred groups of the formula -Y- (CH 2) _n -D- (CH ₂ ) i -L ⁶

In the group -Y- (CH ₂ ) _n -Het- (CH ₂ ) 4 -R ⁶ , Y is preferably O, S, NH or NA, Het has one of the preferred meanings above, R ⁶ is s preferably amino or alkylamino, n is 0, 1, 2, 3 or 4 and i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. y-. NH- (CH ₂ ) ₃ -NN - (CH ₂ ) ₃ -NH ₂ is a particularly preferred group of the formula -Y- (CH 2) _n -Het- (CH ₂ ) _i R ⁶

In the group -Y- (CH ₂ ) _n -NNA- (CH ₂ ) p -R ⁶ , Y is preferably O, S, NH or NA, A has one of the above preferred meanings, R ⁶ is s preferably amino or alkylamino, n is 0, 1, 2, or 4 and i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. -NH- (CH ₂₎ ) ₃ -N (CH ₃₎ - (CH _{2) 3} NH ₂ is particularly preferred group of formula -Y- (CH _{2) n} -NA- _(CH2) ^ - R ^6th

In the group of the formula -Y- (CH ₂ ) _n -D- (CH ₂ ) 4 -R ⁸ , Y is preferably oxygen, sulfur, NH or NA, D has one of the above preferred meanings, R ⁸ is s preferably guanidino or alkylaguanidino, n is 0, 1, 2, 3 or 4 and i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or

12th

Q are particularly preferred groups -Y- (CH ₂ ) _n -D- (CH ₂ ) p -R.

Q

In the group of the formula -Y- (CH ₂ ) _n -Ar '- (CH ₂ ) 4 -R, Y is preferably oxygen, sulfur, NH or NA, Ar' has one of the preferred meanings mentioned above, R ⁸ is preferably guanidino or alkylaguanidino, n is 0, 1, 2, 3 or 4 and i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

N

is particularly preferred Y- _{(CH2) n-Ar} '- (CH ₂₎ j -R ⁸ ·

Q

In the group of the formula -Y- (CH ₂ ) _n -NNA- (CH ₂ ) j, Y is preferably oxygen, sulfur, NH or NA, A has O one of the preferred meanings mentioned above, R is preferably guanidino or n is 0, 1, 2, 3 or 4 and i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. -NH- (CH ₂ ) ₃ -N (CH ₃ ) - (CH ₂ ) ₃ -NH-C (= NH) -NH ₂ is a particularly preferred group of the formula -Y- (CH ₂ ) _n -NNA- (CH ₂ ) n R ⁸ .

In the group of the formula -Y- [XO] _t - [X ¹ -O] _U -X ² -R 1, Y is preferably oxygen, sulfur, NH or NA, X, X ¹ and X ² have one of the above the preferred meanings, ^R6 is preferably amino, alkylamino or dialkylamino, t is 0, 1 or 2 and in is 1, or

2. The group -NH- (CH ₂ ) ₃ -O- (CH ₂ ) ₄ -O- (CH ₂ ) ₃ -NH ₂ is a particularly preferred group of the formula -Y- [XO] _t - [X ¹ -O] _u -X ² -R ⁶ .

q

In the group -Y- [X-NH) _U -X -OH, Y is preferably oxygen, sulfur, NH or NA, X and X ¹ have one of the above preferred meanings and u is 1 or

2-NH- _{(CH2) 2} -NH- (CH _{2) 2} OH is particularly preferred for the formula Y- [X-NHJ _U-X ¹ -OH.

R is preferably hydrogen or nitro.

The symbol ^R1 is preferably Het, _Het-SO2 -Ar,

Het-R ⁵ , -Het- (CH ₂ ) _n -Ar, NO ₂ , -N = CH-Ar, -NHAlk, NAAlk, NHA ',

NA ' ₂ , a group of formula

-YDH, -Y-Ar'-R ³ , -Y- (CH 2) OR ³ , -Y- (CH 2) _n - (CHR ⁴ ) R ⁵ -, -YC - [(CH 2) 0-0H] 3, Y- (CH2) n-NA2, Y- (CH2) mNHA ', Y- (CH2) θ-ΟΗ, Y- (CH 2) r R ^6, Y- (CH 2) _i -R ^8, - Y- (CH 2) n -Het, -Y- (CH 2) n -Ar, -Y- (CH 2) n -Ar '- (CH 2) -R ⁶ , -Y- (CH 2) _n -D- (CH ₂₎ R ⁶ , -Y- (CH 2) n -Het- (CH 2) —R ⁶ , -Y- (CH 2) _n -NA- (CH ₂ ) ₁ -R ⁶ , -Y- (CH 2) n -NH- (CH 2) R ⁶ , -Y- (CH 2) _n -D- (CH ₂ ). R ⁸ , -Y- (CH 2) n -Ar - (CH ₂ ) i R ⁸ , -Y- (CH 2) _n -NH - (CH ₂ ) _i -R ⁸ , -Y- (CH ₂ ) _n -NNA- (CH ₂ ) 4 - R ⁸ , a group of the formula

ΛΛ ” ⁶ -Y- (CH ₂ ) _n - _y N

-Y- [XO] _t - [X ¹ -O] uX ² -R ⁶ or -Y- [X-NH] UX ¹ -OH, particularly preferably Het, Het-SO 2 -Ar, Het-R ⁵ , -Het- (CH 2) _n -Ar, -Y-Ar'-R ³ , -Y- (CH 2) n -Het, -Y- (CH 2) n -Ar, -Y- (CH 2) n -Ar ' - (CH 2) -R ^6, Y- (CH 2) _n -D- (CH ₂₎ j R ^6, Y- (CH2) n-Het- (CH2) and ^6, Y- (CH2) _n -NA - (CH ₂ ) _± -R ⁶ , -Y- (CH 2) n D- (CH ₂ ) _n R ⁸ , -Y- (CH 2) _n -Ar '- (CH ₂ ) n R ⁸ , -Y- (CH 2) n-NA- (CH 2) 1 -R ⁸ , -Y- [XO] 1 - [X ¹ -O] uX ² -R ⁶ or -Y- [X-NH] UX ¹ -OH.

Ar in the -N = CH-Ar group is preferably a 2-hydroxyphenyl group.

In the NHAlk group, Alk is preferably as defined above. More preferably, NHAlk is NH- (nC ₅ H 4).

In the NAAlk group, A and Alk are preferably as defined above. Is particularly preferably NAAlk N (CH ₃₎ - (n-C ₄ H _g).

• 4 44 4 · 4 · 4 · 4 · 4 · 4 · 44 4 · 444 · 44

In the NHA 'group, A' is preferably as defined above. More preferably, NHA 'is NH- (nC ₃ H ₇ ).

In the group NA ' ₂ , A' is preferably as defined above. Particularly preferably, NA ' _{2 is} N (C ₂ H ₅ ) ₂ .

The -YDH group as substituent R ^1, Y is preferably O, S, NH or NA, and D is as defined above. The group -NHC ₆ H _{1; L} or -NH-C ₅ H ₉ is a particularly preferred group -YDH.

In the group -Y- (CH ₂ ) _O -R ³ , Y is preferably oxygen, sulfur, NH or NA, R ³ is preferably alkyloxycarbonyl aol, 2, 3, 4, 5, 6, 7, 8, 9 10, or by -NH (CH _{2) 2} C00Me is particularly preferred for-Y- _{(CH2) O} ~ R ^3rd

In the group -Y- (CH ₂ ) _n - (CHR ⁴ ) -R ⁵ , Y is preferably oxygen, sulfur, NH or NA, R ⁴ is preferably phenyl or hydroxyl, R ⁵ is preferably methyl chloromethyl or trifluoromethyl nor, 2, 3 or 4.

OH or -NH-CH ₂ H

CH ₂ Cl are particularly preferred groups -Y- (CH ₂ ) _n - (CHR ⁴ ) -R ⁵ .

The group -YC _{[(CH2) o} ~ 0H] _3, Y is preferably O, S, NH or NA, AOL, 2, 3, 4, 5, 6, 7, 8, 9, or

10. -NH-YC _[(CH2) -0H _{Q] 3} is particularly preferred for -YC _[(CH2) -0H] _3rd

In the group -Y- (CH ₂ ) _m -NNA ₂ , Y is preferably oxygen, sulfur, NH or NA, A has the above-mentioned preferred meaning and _m is 0, 1 or 2. -NH- (CH ₂ ) ₂ ^_N ( ^C 2 ^H 5 ^ 2 ^a l ^e ^ ° ······································· ··· · · · · ··· ··· ···········

- 60 -N (CH ₃ ) - (CH ₂ ) 2 ^N "( ^c 2 ^h 5) 2 ^with particularly preferred groups

- * - (ch ₂ ) '- to ₂ .

In the group -Y- (CH ₂ ) _m -NHA ', Y is preferably oxygen, sulfur, NH or NA, A' has the above-mentioned preferred meaning and _m is 0, 1 or 2. -NH- (CH ₂ ) ₂ -NH- (C ₃ H ₇ ) is a particularly preferred group -Y- (CH ₂ ) _m -NHA '.

W-Y- _{(CH2) q-OH,} Y is preferably O, S, NH or NA, and is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, -NH - (CH ₂ ) ₂ -OH or -NH- (CH ₂ ) ie -OH is a particularly preferred group -Y- (CH ₂ ) _o -H.

In the group -Y- (CH ₂ ) -R ⁶ , Y is preferably O, S, NH or NA, R ⁶ is preferably amino, alkylamino, dialkylamino or cycloalkylamino when 3, 4, 5, 6, 7 , 8, 9, 10, 11 or 12. Group

-nh- (ch ₂ ) ₃ -nh ₂ , -nh- (ch ₂ ) ₄ -nh ₂ , -nh- (ch ₂ ) ₅ -nh ₂ , -nh- (ch ₂ ) ₇ -nh ₂ ,

-nh- (ch ₂ ) ₈ -nh ₂ , -nh- (ch ₂ ) ₃ -nh (ch ₃ ), -NH- (CH ₃ ) - (CH ₂ ) ₃ -NH (CH ₃ ) or the formula

-NH (CH ₂ ) ₃ -N

H

particularly preferred are -Y- (CH ₂ ) 4 -R.

In the group -Y- (CH ₂ ) 4 - R ⁸ , Y is preferably oxygen, sulfur, NH or NA, R ⁸ is preferably -NH- (C = NH) -NH ₂ , -NH- (C = NH) -NHA, -NH- (C = NH) -NA ₂ , -na- (c = nh) -nh ₂ , -NA- (C = NH) -NHA, -NA- (C = NH) - NA ₂ and i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. -NH- (CH ₂ ) ₂ -NH-C (= NH) -NH _{2 group} , -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ , -NH- (CH ₂ ) ₄ -NH-C (= NH) -NH ₂ , -NH- (CH ₂ ) ₅ - NH-C (= NH) -NH ₂ , -NH- (CH ₂ ) g -NH-C (= NH) -NH ₂ , -NH- (CH ₂ ) ₇ -NH-C (= NH) -NH ₂ or formula N (CH _{2) 3} -

H

CH ₃ are particularly preferred -Y- (CH ₂ ) 4 -R ⁸ groups.

In a group of formula

Y is preferably O, S, NH or NA, R ⁶ is preferably an amino, alkylamino or dialkylamino and n is 0, 1, 2, 3 or 4 groups of formula

and

are particularly preferred groups of the general formula

R6

-Y- (CH ₂ ) _n

about

R is preferably a group -N, -N'-DH, Het ^1, Het ¹ -N, -N'-Het ^1, N '- (CH 2) n R ^3, -Ar-Y- (CH 2 ) _n -R ³ , -Ar 1 -YC (A) 2-R ³ , Het ^x -R ³ , -Ar 1 -He 2 -R ³ , -Ar 1 - (CH 2) _n -R ⁶ , -Ar 1 -SO 2 -Het, -Ar'-NH-SO 2 -Het, -Ar'-SO 2 -R ⁷ , -Ar '- (CH 2) _n - (CO-NH) - (CH ₂ ) j' R ⁶ , -Ar '- (CH 2) n - (CO-NH) - (CH 2) i R ¹¹ , -Ar' - (CH 2) _n -CO-Het,

-Ar '- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) _± -O-Η,

-Ar '- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) _± -Ar,

-Ar '- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) j -Het ¹ , ····. · · · · · ·

- 61 - .........

-Ar '- (CH ₂ ) _n - (CH (CN)) - (CH ₂ ) _i -Ar,

-Ar '- (CH ₂ ) _n - (CONH) - (CH ₂ ) i -CH- (Ar ¹ ) -Ar ² ,

-Ar 1 -S- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) 1 - Ar,

-Ar'-S- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) —R ¹¹ ,

-Ar'-S- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) —Het ¹ ,

-Ar 1 -S- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) _i -CH (Ar ¹ ) Ar ² or -Ar 1 -S- (CH ₂ ) _n - (CO-NH) - _(CH2) -DH, and Ar, Ar ', Ar ^1, Ar ^2, a, D, Het, Het ^1, R ^3, R ^6, R ^11, Y, nai preferably have one of the abovementioned preferred meanings.

Preferably, R ^{3 is} C (O) A, CONH ₂ , CONHA, CONA ₂ , COOH or COOA, wherein A has one of the above preferred meanings.

Preferably, R ^{4 is} phenyl or hydroxyl.

Preferably R ⁵ is methyl, chloromethyl, trifluoromethyl or phenyl.

Preferably, R ⁶ is NH _2, NHA, NA _2, NH (DH) or NHC (O) A wherein A and D have one of the above preferred meanings.

Preferably R ^{7 is} NA (DH), NHA, NH (DH) or NA ₂ , wherein A and D have one of the preferred meanings listed above.

Preferably R ^{8 is} -NH- (C = NH) -NH ₂ , -NH- (C = NH) -NHA, -NH- (C = NH) -NA ₂ , -NA- (C = NH) - NH ₂ , -NA- (C = NH) -NHA, -NA- (C = NH) -NA ₂ , wherein A has one of the above preferred meanings.

Ί -1

Preferably R is -CH (A) -Ph wherein A has one of the preferred meanings listed above.

Accordingly, the invention relates in particular to a compound of the formula I in which at least one of the symbols has the above-mentioned preferred meaning. Some preferred groups of compounds of formula I are the following compounds of formulas Ia to Iz and 1+ to I5i, which correspond to formula I

R ² wherein the symbols not specifically mentioned have the meaning given in formula (I) and in the formula

la R R ¹ R ² no ₂ , NO ₂ a. Ar; lb R H, R ² Ar a R ¹ -Het, -Het-SO ₂ -Ar, -Het-R ⁵ , NO ₂ , NHAlk, NAAlk, NHA ', NA' ₂ , -YDH, -Y-Ar'-R ³ , -Y- (CH ₂ ) _o -R ³ , -Y- (CH ₂ ) _n - (CHR ⁴ ) -R ⁵ , -YC _((CH2) -0H] _3, Y- _{(CH2) n} -NA ₂ -Y- (CH _{2) n} NHA ', Y- _(CH2) -0H, Y - (CH ₂ ) x R ⁶ ,

ic

4.-Y- (CH ₂ ) _n -Het, · -Y- (CH ₂ ) _n -Ar,

-Y '(CH ₂ ) _n -Ar' - (CH ₂ ) _i R ⁶ _z

-Ϊ- (CH ₂ ) _n -Ar '- (CH ₂ ) 1 -R ⁸ ,

Y- (CH _{2) n} -D- (CH ₂₎ and ^6, Y- _{(CH2) n} _Het- (CH ₂₎ ⁶ i_r,

Y- _{(CH2) n} -NA- _(CH2) and ⁶ and "y" (CH _{2) n} _NH- (CH ₂₎ and ^6;

RH,

R ² -Het ¹ a

R ¹ NO

Id R

R ²

R ¹ 'H,

-Het ¹ -Ar a: Z-NO ₂ ;

Ie R H

R ² -N '- _{(CH2) n} ^-R3, and. '

R ¹ -Het, -Het-SO ₂ -Ar, -Het-R ⁵ ,

-Het- (CH ₂ ) _n -Ar, NO ₂ , NHAlk, NAAlk, NHA ', NA' ₂ , -YDH, -Y-Ar'-R ³ , -Y- (CH ₂ ) ₀ -R ³ ,

-Y- (CH ₂ ) _n - (CHR ⁴ ) -R ⁵ , -YC [(CH ₂ ) _o -0H] 3,

Y- _{(CH2) n} -NA ₂ -Y- (CH _{2) n} NHA ', Y- _(CH2) -0H.

Y- (CH ₂₎ a 'R ^S, Y- (CH2) n-Het, -Y- (CH2) n-Ar-Y- (CH2) n-t - (CH 2) -R ^6, Y- (CH 2) _n -D- (CH ₂₎ and ^6, Y- (CH2) n-Het- (CH2) ^R6, -Y- _(CH2) -NA- _(CH2) i- R ⁶ , -Y- (CH ₂ ) _n -NH- (CH ₂ ) 1 -R ⁶ ,

Y- [X 0] T [X ^1_ 0] _of -X ² -R ^6, or-Y- [X-NH] '^ -Χ ΟΗ;

If

R

R ²

R ¹

Ig R 'R ²

R ¹

H,

-Ar 1 -Y- (CH ₂ ) _n -R ³ a.

i. .-Y- (CH ₂₎ k R ^6, Y- _{(CH2) n-Ar} '- _(CH2) and ^6, or

-Y- (CH ₂ ) _n -Ar;

H, · -Ar'-SO ₂ -Het and:

-Y- _(CH2) k ⁶ or Y- _{(CH2) n-Ar} '- _(CH2) and ^6;

.. .φ · _β -.

vr- 64 ^ Ih R Η,

R ² -Ar'-SO ₂ -R ⁷ a.

R ¹ • -Y- (CH 2) k R ⁶ or -Y- (CH 2) _n -Ar '- (CH ₂ ) _i R ⁶ ;

Ii R. H,

R ² -Ar 1 - (CH ₂ ) _n - (CONH) - (CH ₂ ) 1 -R ^6a .

R ¹ -Y- (CH ₂ ) x R 6 or -Y- (CH ₂ ) _n -Ar 1 - (CH ₂ ) 1 -R ⁶ ;

Ik R

R ²

R ¹ . II R

R ²

R ¹

H,> N '- _{(CH2) n} - (CONH) - (CH ₂₎ and the IDH'

-Y- (CH ₂ ) _k -R ⁶ , -Y- (CH ₂ ) _n -Ar '- (CH ₂ ) _i R ⁶ ,.

-Y- (CH ₂ ) 1 -R ⁸ , -Y- (CH ₂ ) _n -D- (CH ₂ ) 1 -R ⁸ ,

Y- _{(CH2) n-Ar} '- _(CH2) ⁸ iR _and i will _e

-Y- (CH ₂ ) _n -N (CH ₂ ) 1 -R ⁸ ;

H,

-Ar 1 - (CH ₂ ) _n - (CONH) - (CH ₂ ) 1 -Ar

Y- (CH _{2) a} -R ^6, Y- (CH _{2) n} -N '- (CH ₂₎ j R ^6,

Y- _{(CH2) n} -Ar-Y- _(CH2) iR ^8,

Y- _(CH2) Nd- _(CH2) iR ^8,

-Y- (CH ₂ ) n -Ar - (CH ₂ ) 1 -R ⁸ ,. .

Y- _{(CH2) n} -NA- _(CH2) iR ⁸ _of

-Y- (CH ₂ ) n - (Qy 1/1 Im RH,

R ² -Ar'- (CH ₂₎ n "(CONH) -i (CH ₂₎ a -Het ^1. .

R ¹ -Y- (CH 2) _n -R ⁸ , -Y- (CH 2) _n -D- (CH 2) _i R ⁸ ,

Y- _{(CH2) n-Ar} '- _{(CH2) ^8, or} IR

-Y- (CH ₂ ) _n -N (CH ₂ ) 1 -R ⁸ ;

: :::. : · ·:: ··: ·: ·· ·· - 64b- in R H, i R ² -Ar '- (CH ₂ j _n - (CH (CN)) - (CH ₂ ) i -Ar) · R ¹ . · "Y- (CH ₂₎ k R ⁶ '-Y (CH 2) ND-- (CH 2) and ^6, or -Y (CH2) n-Ar' - (CH ₂₎ and ^6; ·. ·. Ιο R 'H, R ² . , -Ar 1 - (CH ₂ ) _n - (CO-NH) - (CH ₂ ) 1 -CH (Ar ¹ ) -Ar ² a. R ¹ -Y- (CH ₂ ) _n -R ⁸ , -Y- (CH ₂ ) _n -D- (CH ₂ ) ⁱ R ^e , Y- _{(CH2) n-Ar} '- _(CH2) iR ⁸ -Y- (CH _{2) n} -NA- _(CH2) iR ^8;  Ip R • H, R ² -Ar'-Het ¹ and: R ¹ Y- (CH _{2) a} -R ^6, Y- _{(CH2) n-Ar} '- _{(CH2) A-R} ^6, -Y- (CH ₂ ) _n -Ar ^z - (CHa) _i R ⁸ -Y- (CH ₂ ) _n -D- (GH ₂ ) 1 -R ⁶ ; Iq R • H, R ² • -At-Het ^ -R ³ and: R ¹ -Y- (CH ₂ ) _k -R ⁶ or -Y- (CH ₂ ) _n -D- (CH ₂ ) _i R ⁶ ; / . Irishman R H R ² -Ar '- (CH ₂ ) _n -R ^6a . R ¹ Y- (CH _{2) k} -R ⁶ or -Y- (CH _{2) n} -D- (CH ₂₎ -R ⁶ _A: ... Is R H, R ² -Ar 1 -YC (A) 2 -R ³ a R ¹ -Y- (CH ₂ ) k -R ⁶ ; lt • R H, R ² -Ar'-NH-SO ₂ -Het a R ¹ -Y- (CH ₂ ) _k -R ⁶ ; Iu R H, R ² -Het ^x -R ³ a. R ¹ Y- (CH ₂₎ k R ^6; / λ Iv R . · ’· H, R ² ; -Ar'-D-H and. '

«····

ABOUT ·· • ·

9 · • ···································· 9 · 9

t 64c-.

R ¹ : -Y- (CH ₂ ) k-Ŕ ⁶ ;

Iw R; H,

R ² . , -Ar '- (CH ₂ ) _n - (CONH) - (CH ₂ ) i R ^a and.

R ¹ -Y- (CH ₂ ) _n -Ar '- (CH ₂ ) _i R ⁶ ;

1x R, H,

R ² '-Ar'- (CH ₂ ) _n -CO-Het a

R ¹ -Y- (CH ₂ ) _n -D- (CH ₂ ) _i R ⁶ ;

iy

RH,

R ² -Ar'-S- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) i -Ar and

R ¹ -Y- (CH ₂ ) _n -Ar 1 - (CH ₂ ) 3 R ⁶ or

Y- _{(CH2) n-Ar} '- _(CH2) iR ^p;

Iz RH,

R ² -Ar 1 -S- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) i -Het ^1a .

R ¹ -Y- (CH ₂ ) _n -Ar 1 - (CH ₂ ) 1 -R ⁶ debe

-Y- (CH ₂ ) _n -Ar 1 - (CH ₂ ) 1 R ⁸ ;

II RH,

R ² -Ar'-S- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) i -DH and

R ¹ -Y- (CH _{2) n} -N '- _(CH2) and ^6, or

-Y- (CH ₂ ) _n -Ar 1 - (CH ₂ ) 1 R ⁸ ;

R H H,

R ² -Ar'-S- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) i R ¹¹ and

R ¹ -Y- (CH 2) n 'Ar ^f - (CH 2) 1 - R ⁶ or b

-Y- (CH ₂ ) _n -Ar 1 - (CH ₂ ) 1 R ⁸ ;

R H,

R ² -Ar'-S- (CH ₂ ) _n '(CO-NH) - (CH ₂ ) β-CH (Ar ¹ ) -Ar ²

R ¹ -Y- (CH ₂ ) _n -Ar 1 - (CH ₂ ) 1 -R ⁶ or

-Y- (CH ₂ ) _n -Ar 1 - (OH ₂ ) 1 R ⁸ ;

H,

-Ar, -Ar'-Het ¹ , -Ar'- (CH ₂ ) _n - (CO-NH) -

_(CH2) a-Ar · ♦ •

R ¹ -Y- (CH 2) k R ⁶ , -Y- (CH 2) 1 R ⁸ ;

Y- _(CH2) Nd- _(CH2) iR ^8, Y- _(CH2) n-NA- _(CH2) ^8, or IR

-Y- (CH ₂ ) _n -Ar 1 - (CH ₂ ) 1 R ⁸ ;

RH _from r ² -Ar, -Ar '- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) i -Ar,

-Ar '-S- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) i -Ar, -Ar' - (CH ₂ ) _n (CO-NH) - (CH ₂ ) i -Het ¹ , -Ar '-S- (CH 2) n - (CO-NH) (CH 2) i -Het ¹ , -Ar' - (CH 2) _n - (CO-NH) - (CH ₂ ) i D H,

-Ar '-S- (CH ₂ ) n' (CO-NH) - (CH ₂ ) iDH, -Ar '- (CH ₂ ) n - (CO-NH) - (CH ₂ ) i -CH (Ar ¹⁾ ) -Ar ² , -Ar '-S- (CH 2) n - (CO-NH) - (CH 2) i -CH (Ar ¹ ) -Ar ² , -Ar' - (CH 2) n '(CO-NH) - _(CH2) iR ¹¹ _and iebo -N'-S (CH _{2) n} - (CO-NH) - _(CH2) s-R ⁱⁿ a "'· _R and Y- _(CH2) n-Ar - (CH ₂ ) 1 -R ⁶ or ^,; Y- _(CH2) n-Ar '- _(CH2) iR ^eighth

Preferred compounds of formula I are the following:

3- (3- (6- (4-guanidinometylbenzylamino) -1,3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] phenyl} -N- [2- (4-sulfamoyl-phenyl] ethylpropionamide,

N- [2- (4-chlorophenyl) ethyl] -3- {3- [6- (4-guanidinomethylbenzylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} propionamide .

6- (3-amino-propylamino) -2- (3,4,5-trimethoxy-phenyl) -benzo [de] isoquinoline-1,3-dione,

6- (3-amino-propylamino) -2- (7-hydroxy-naphthalen-l-yl) -benzo [de] isoquinoline-1,3-dione,

- 66 6 - [(3-aminopropylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] -4,5-dimethoxybenzonitrile,

6- (3-amino-propylamino) -2- (2,3-dimethoxyphenyl) benzo [de] isoquinoline-1,3-dione,

N- [2- (3-chlorophenyl) ethyl] -3- {3- [6- (4-guanidinometylcyklohexylmetylamino) -1,3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] -phenyl} -propionamide .

N- [2- (4-chlorophenyl) ethyl] -3- {3- [6- (4-guanidinometylcyklohexylmetylamino) -l, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] -phenyl} -propionamide .

6- (3-Aminopropylamino) -2- (4'-methoxybiphenyl-4-yl) benzo [de] isoquinoline-1,3-dione,

6- (3-amino-propylamino) -2- (4-carbazol-9-yl-phenyl) -benzo [de] isoquinoline-1,3-dione,

6- (3-amino-propylamino) -2- (4'-hydroxy-2-methylbiphenyl-4-yl) -benzo [de] isoquinoline-1,3-dione,

N- (3 - {- [2- (4'-methoxybiphenyl-4-yl) -1,3-dioxo-2,3-dihydro-6-benzo [d] isoquinolin-6-ylamino] methyl} benzyl) guanidine,

3- {3- [6- (2guanidino-) -l, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] phenyl} -N- (4-phenyl-butyl) -propionamide,

N- [2- (4-chlorophenyl) ethyl] -3- {3- [6- (2guanidino-) -1,3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] -phenyl} -propionamide .

N- [2- (4-chlorophenyl) ethyl] -3- {3- [6- (3-guanidinopropylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} propionamide , • ·

N- [2- (4-chlorophenyl) ethyl] -3- [3- (6- {3 - [(3-guanidinopropyl) methylamino] propylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinoline 2-yl) -phenyl] -propionamide,

N- [2- (3-chlorophenyl) ethyl] -3- {3- [6- (3-guanidinopropylamino) -1,3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] fenyljpropiónamid,

6- (3-amino-propylamino) -2- (4'-methoxy-biphenyl-4-yl) -benzo [de] isoquinoline-1,3-dione,

N- [3 - ({2- [4- (3,6-di-tert-butylcarbazole-9-yl) phenyl] -1,3-dioxo-2,3-dihydro-benzo [de] isoquinolin-6 ylamino) methylbenzylguanidine a

6- (3-amino-propylamino) -2- (4-carbazol-9-yl-phenyl) -benzo [de] isoquinoline-1,3-dione.

The compounds of formula I and the starting materials for their preparation are prepared by known methods as described in the literature (for example, in standard publications such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme Verlag, Stuttgart), under the reaction conditions known and suitable for the above reactions. It is also possible to use known variants which are not described here in greater detail.

The starting materials may optionally be formed in situ, i.e. they are not isolated from the reaction mixture, but the reaction mixture is immediately used to prepare compounds of formula I.

The compounds of formula I may be prepared by liberating from their functional derivatives solvolysis, in particular hydrolyzing or hydrogenolyzing agents.

The starting materials for solvolysis or hydrogenolysis are compounds which otherwise correspond to the aforementioned ones. · · · · · ·

However, instead of free amino or hydroxyl groups, they have corresponding protected amino or hydroxy groups, preferably compounds which have an amino protecting group instead of a hydrogen atom which is bonded to a nitrogen atom, in particular compounds having an R 'group instead of HN -N, wherein R 'is an amino protecting group and / or compounds which have a hydroxyl protecting group instead of a hydrogen atom in a hydroxyl group, for example compounds having a -COOR group instead of -COOH, wherein R is a hydroxyl protecting group.

Several of the same or different amino protecting groups and / or hydroxyl groups may be present in the molecule of the starting material. If the protecting groups are different from each other, they can in many cases be selectively cleaved.

The term amino-protecting group is generally known and refers to groups which are suitable for protecting (blocking) the amino group from chemical reactions but which are readily removable when the desired reaction is carried out elsewhere in the molecule. Typically, such groups are unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protecting groups are removed after the desired reaction (or sequence of reactions), their type and size are not critical. However, groups having 1 to 20 and in particular 1 to 8 carbon atoms are preferred. The term acyl is always understood in the broadest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, such as, in particular, alkoxycarbonyl, aryloxycarbonyl and, in particular, aralkoxycarbonyl groups. Examples of such acyl groups include alkanoyl groups such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as phenoxyacetylo

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC) and arylsulfonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr, CBZ, Fmoc, benzyl and acetyl.

The term hydroxy protecting group is also generally known and refers to groups which are suitable for protecting (blocking) the hydroxy group from chemical reactions, but which are readily removable when the desired reaction is carried out elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups as well as alkyl groups. Since the hydroxyl protecting groups are removed after the desired reaction (or reaction sequence), their type and size are not critical. However, groups having 1 to 20 and in particular 1 to 10 carbon atoms are preferred. Examples of hydroxyl protecting groups are tert-butyl, benzyl, p-nitrobenzyl, p-toluenesulfonyl and acetyl, with benzyl, acetyl and tert-butyl being particularly preferred.

Depending on the protecting group used, the liberation of the compounds of the formula I from their functional derivatives is successful, for example with strong acids, preferably trifluoroacetic acid or perchloric acid, but also with other strong inorganic acids such as hydrochloric or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid such as benzenesulfonic acid or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary.

• ·

Suitable inert solvents are, for example, organic carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol as well as water. Mixtures of these solvents may also be suitable. Trifluoroacetic acid is preferably used in excess without addition of additional solvents, perchloric acid in the form of a 9: 1 mixture of acetic acid and 70% perchloric acid. The reaction temperature for the cleavage is expediently about 0 to about 50'C, preferably 15 to 30'C (room temperature).

For example, the BOC and Obutyl groups can be conveniently cleaved with trifluoroacetic acid in dichloromethane or about 3-5% hydrochloric acid in dioxane at 15-30 ° C, the FMOC group with a 5-50% solution of dimethylamine, diethylamine or piperidine in dimethylformamide at 15-30 ° C. ° C

Hydrogenolytically removable protecting groups (e.g., CBZ or benzyl) can be removed, for example, by treatment with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, suitably supported, such as coal). Suitable solvents are the abovementioned solvents, in particular, for example, alcohols such as methanol or ethanol or amides such as dimethylformamide. The hydrogenolysis is generally carried out at a temperature of about 0 to 100'C, at a pressure of about 0.1 to 20 MPa, preferably at a temperature of 20 to 30'C, at a pressure of about 0.1 to 1 MPa. Hydrogenolysis of the CBZ group, for example, performs well on 5 to 10% palladium on carbon in methanol or ammonium formate (instead of hydrogen) in the presence of palladium on carbon as a catalyst in a methanol / dimethylformamide system at 20-30 ° C.

Preferably, the compounds of formula I can be prepared by reacting the oxazolidine of formula II with a compound of formula III. As a rule, the compounds of formula II and the compounds of formula III are known or commercially available. However, unknown compounds can be prepared by known methods. The compounds of formula II are naphthalene-1,8-dicarboxylic anhydride derivatives. They are prepared by known methods from suitably substituted naphthalene-1,8-dicarboxylic acids or their corresponding derivatives. Suitable substituents may be introduced into the aromatic compounds by known electrophilic or nucleophilic substitutions.

The compounds of formula III are primary amines which are generally commercially available. Gabriel synthesis may be used for their possible preparation.

The reaction is generally carried out in an inert solvent. Depending on the conditions used, the reaction may take from a few minutes to several days. The reaction temperature is about 0 to 150 ° C, typically 20 to 130 ° C. The reaction can be carried out similarly to that described in the literature (Eur. J. Chem. Chim. Ther. 16: 207-212, 1981 and J. Med. Chem. 25: 714-719, 1982).

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane or 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 ether or ethylene glycol 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, dimethylformamide (DMF); nitriles such as • · · ·

acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulphide; organic carboxylic acids such as formic or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; or mixtures of these solvents.

Derivatives having free primary amino groups or additional secondary amino groups are conveniently used in protected form. Possible protecting groups are listed above.

For the preparation of compounds of the general formula I, wherein

R ¹ and / or R ² H ₂ NC (= NH) -NH-, a suitably amino-substituted compound is treated with an amidating agent. Preferred amidating agents are 1-amidino-3,5-dimethylpyrazole (DPFN), which is mainly used in the form of its nitrate, or pyrazole-1-carboxamidine. The reaction is conveniently carried out with the addition of a base such as triethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, for example in dimethylformamide, at a temperature of 0 to 150 ° C, preferably 60 to 120 ° C.

For the preparation of compounds of formula I wherein R ^{2 is an} unsubstituted or substituted group a biphenyl group -Ar'-Het ¹ , -Ar'-Het ¹ -R ³ , -Ar '- (CH 2) n R ³ and / or -Ar'- (CH 2) _n -R ⁶ , a suitable compound of formula I wherein R ^{2 is an} aryl bromide or aryl iodide group can be reacted with suitable boronic acid derivatives by a Suzuka reaction. Suitably, the Suzuka reaction is carried out in a palladium-mediated form, preferably with the addition of a tetravalent palladium compound Pd (PPh ₃ ) ₄ in the presence of a base such as potassium carbonate, in an inert solvent or solvent mixture e.g. dimethylformamide at 0 to 150 ° C. preferably 60 to 120 ° C. Depending on the reaction conditions, the reaction may take several minutes to several days. Boric acid derivatives can be prepared by known methods or are commercially available. The reaction may be carried out in a similar manner to that described in the literature (Suzuki et al., J.

···· · · · · · · · · · · · · · · · · · ·

.. · · · · · · · · · · ·

Am. Chem. Soc. 11 from p. 314, 1989 and Suzuki et al., Chem. Rev. 95 from p. 2457, 1995).

For the esterification of the acid of formula I (R ¹ = COOH or -Y- (CH 2) n COOH and / or R ² = COOH) can be treated with excess of alcohol, preferably in the presence of a strong acid, such as hydrochloric acid or sulfuric acid, at a temperature 0 to 100 ° C, preferably 20 to 50 ° C. Conversely, an ester of formula I (R ¹ = COOA or -Y- (CH 2) _n -COOA and / or R ² = COOA) can be converted to the corresponding acid of formula I, suitably by solvolysis by any of the above methods, for example using hydroxide sodium or potassium in a water / dioxane system at a temperature of 0 to 40 ° C, preferably 10 to 30 ° C.

In addition, the free amino groups can be acylated in a known manner using acid chloride or anhydride, suitably in an inert solvent such as dichloromethane or tetrahydrofuran and / or in the presence of a base such as triethylamine or pyridine at a temperature of -60 to +30 ° C.

The base of formula (I) can be converted into the appropriate acid addition salt by acid, for example by reacting an equivalent amount of base and acid in an inert solvent such as ethanol and then evaporating the solvent. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Inorganic acids such as sulfuric, nitric, hydrohalic acids such as hydrochloric or hydrobromic acids, phosphoric acids such as orthophosphoric acid, sulfamic acid and organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic acids may be used or sulfuric acids such as formic, acetic, trifluoroacetic, propionic, pivalic, diethyl, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotonic, ·

- 74 ethanesulfonic acid, ethanedisulfonic acid, p-toluenesulfonic acid, naphthalene monosulfonic acid and naphthalenedisulfonic acid and lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of formula I.

Optionally, the free bases of the compounds of formula I can be liberated from their salts by treatment with strong bases such as sodium or potassium hydroxide, sodium or potassium carbonate to the corresponding metal salts, especially alkali metal or alkaline earth metal salts, or the corresponding ammonium salts .

All methods of preparation and all other methods of preparing compounds of formula I can also be carried out using novel methods of combinatorial chemistry, i.e., methods using robots and computers, and are screened (e.g., U.S. Patent No. 5,465,664; MA Gallop et al., J. Med. Chem., 37, 1233-1251 and 1385-1401 (1994) and MJ Sofia, Drugs Discovery Today 1, 27-34 (1996).

The compounds of formula I and their physiologically acceptable salts can be used for the production of pharmaceutical compositions, in particular by a non-chemical route. For this purpose, they can be converted into a suitable dosage form with at least one solid or liquid and / or semi-liquid carrier or excipient and optionally in admixture with one or more other active substances.

The compositions of the invention may be used as medicaments in human and veterinary medicine. Suitable carriers are inorganic or organic substances which are suitable for enteral (e.g., oral) or parenteral or topical administration and which do not react with the compounds all.

of the formula I, such as water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerin triacetate, gelatin, carbohydrates such as lactose or starches, magnesium stearate, talc and petrolatum. Especially suitable for oral use are tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops, suppositories for rectal use, solutions for parenteral use, in particular oily or aqueous solutions, further suspensions, emulsions or implants, for topical use ointments, creams or powders. The compounds of the invention may also be lyophilized and the lyophilizates obtained, for example, used for the preparation of injectables. The compositions may be sterilized and / or may contain adjuvants such as glidants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffers, coloring agents, flavoring agents and / or one or more more other active ingredients such as vitamins.

The compounds of the formula I and their physiologically acceptable salts act as antagonists of the adhesion receptor, in particular as antagonists of the glycoprotein Ib1X, and can be used for the prophylaxis and / or treatment of thrombotic diseases and the consequences thereof. Coronary syndromes, angina pectoris, myocardial infarction, peripheral circulatory disorders, stroke, transient ischemic problems, arteriosclerosis and reocclusion / restenosis after stent implantation are suitable diseases.

The compounds of the formula I according to the invention are generally used in dosages as the glycoprotein IIbIIa antagonist of ReoPro ^R , preferably in a dose of about 1 to 500 mg, in particular 5 to 100 mg per dosage unit. The daily dose is preferably about 0.02 to 10 mg / kg body weight. The particular dose for each individual depends on a variety of factors, such as the potency of the particular compound used, age, body weight, general health, sex, diet, the time and route of administration, the rate of excretion, the combination of drugs and the severity of the disease. Oral administration is preferred.

The invention is illustrated by the following non-limiting examples. Temperatures are always given in degrees Celsius. In the following examples, the expression conventional processing means:

Optionally, water is added or, depending on the constitution of the final product, the pH is adjusted to 2-10, the reaction mixture is extracted with ethyl acetate or dichloromethane, separated, dried over the organic phase with sodium sulfate, evaporated and purified by silica gel chromatography and / or crystallization. Mass spectrometry (MS) (Kratos Maldi III and Finnigan LCQ). (M + H) ⁺ values determined.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

A suspension of 6.6 g of 6,7-dinitrobenzo [de] isochromene-1,3-dione in 100 ml of toluene is treated with 3.3 g of 5-chloropyridin-2-ylamine and the reaction mixture is heated to reflux. After completion of the reaction, the reaction mixture was allowed to cool to room temperature and worked up in the usual manner. 2- (5-chloropyridin-2-yl) -6,7-dinitrobenzo [de] isoquinoline-1,3-dione is obtained.

Example 2

Suspension of 4 g of 6-chlorobenzo [de] isochromene-1,3-dione in 100

77 ml of toluene are treated with 4.6 g of 2,5-dichlorophenylamine and the reaction mixture is heated to reflux. After completion of the reaction, the reaction mixture is allowed to cool and worked up in the usual manner. There was thus obtained 6-chloro-2- (2,5-dichlorophenyl) benzo [de] isoquinoline-1,3-dione. This compound is heated in morpholine until conversion is complete. After completion of the reaction, the reaction mixture is allowed to cool and worked up in the usual manner. 2- (2,5-Dichlorophenyl) -6-morpholin-4-ylbenzo [de] isoquinoline-1,3-dione is obtained. MS: calcd 426, found 427.

Similarly, the reaction of 6-chloro-2- (2,5-dichlorophenyl) benzo [de] isoquinoline-1,3-dione with R 1 -H affords the following compounds of Formula Iba:

R ¹

Cl

Only · ♦ ·· •. · · · · · · · · · · · · · · · · · · ·

\

• ·

• · ·. · ·. ' ·. · '· ^· · ·. '·' ·

--------------- ·· * 4- _# · -> - ·· • ....... · · · · ··· ·

Example 3

Analogously to Example 2, 6-chlorobenzophenyl] isochromene-1,3-dione is reacted with 3-chlorophenylamine and then with R-H. The following compounds of formula Ibb are obtained:

Ibb

-.

F

 · · · · · · · · · · · -------------- • · • - · - · - - - ♦ • · ' • 9 • · • · • • « •. · · · * ··· · • · · ·· • · · • ‘· • · • • * 9 9 9 9 · • · • • • 9 9

-.

Example 4

Analogously to Example 2, 6-chloro benzo [de] isochromene-1,3-dione is reacted with phenylamine and then with R 1 -H. The following compounds of formula Ibb are obtained.

• B · · ·

- No. 83 -

····

R ¹ at 'R ^x -H a in Ibc MS -N- (CH ₂ ) ₂ -H \_FROM 401 402 N (CH _{2) 3} - H -N-CH-W ⁶ -N- (CH ₂ ) ₃ -H -N ^ N \ = / 396 397 -NH- (CH ₂ ) ₂ -COOCH ₃ 374 375 -NH (C ₅ H _u ) 358 359 -NH (C ₃ H ₇ ) 330 331 -N (CH ₃ ) -C ₄ H ₉ 358 359 -N (C ₂ H ₅ ) ₂ 344 345 -NH-CH ₂ -CH (CH ₂ Cl) -oh

HO

-NH- _{(CH2) 5-OH} 374 375 ΓΛ 358 359 N \ __ 0

Example 5

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with 3-nitrophenylamine and then _R1- H is reacted. The following compounds of formula Ibd are obtained:

• ···· * ·· ·· _{e β} ··. · ·································. · ·· _ <. «. ··. ' .

·· ·· ·· ·· ·· ·

R ¹

• ·

/

8 3 - / R in R ^x -H a. in Ibd MS -N- (CH ₂ ) ₃ - / - H ^Xf -ch ₃ -N— (CH ₂ ) ₃ -N ^ N H " 441 442 -NH- (CH ₂ ) ₂ -COOCH ₃ 419 420 -NH (C ₅ HH) 403 404 -NH (C ₃ H ₇ ) 375 376 -N (CH ₃ ) -C ₄ H ₉ 403 404 -N (C ₂ H ₅ ) 2 389 390 —R / \) 403 404

Example 6

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with 3-methoxyphenylamine and then with R ¹ -H. The following compounds of formula Ibe are obtained:

- W _

R ¹ in R ^x -H a. I · Ibe MS (_____ —N CH ₂ - £ Λ ~ ^ΝΗ 2 423 .424 -N- (CH ₂ ) ₂ H / -N 423 424 —N-CH ₂ - <3 409 410 H -N- (CH ₂ ) ₂ H r ~ \ —N 0 IN_/ 431 432 -N- (CH ₂ ) ₃ -H —NM — CHo v_ / ³ -NH- (CH ₂ ) ₂ -COOCH ₃ 404 405 -NH (C ₃ H ₇ ) 360 361 -N (CH ₃ ) -C ₄ H 9 388 389 -N (C ₂ H ₅ ) 2 374 375 -NH- _(CH2) p-OH 404 405 ^—N \ Z / ° 388 389

- 94, -

Example 7

Analogously to Example 2, 6-chloro-benzo [de] isochromene-1,3-dione is reacted with 4-styrylphenylamine and then with R 1 -H. The following compounds of formula Ibf are obtained

• ·

Analogously to Example 2, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with HN ₂ -Ar and then (optionally) with R 1 -H. The following compounds of formula Ibg are obtained.

Example 9

Analogously to Example 2, 6-chloro benzo [de] isochromene-1,3-dione is reacted with 3-chloro-4-methylphenylamine and then with R ¹ -H. The following compounds of formula Ibh are obtained:

9t-

Example 10

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with HN ₂ -Ar and then with R ¹ - R ² . The following compounds of formula Ibg are obtained:

Ar

R ¹ v · RH ai v. Ibg MS

-NH- (CH ₂ ) ₃ -NH ₂

435

436

-NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂

498

-NH- _{(CH2) 3 -NH2} -NH- _{(CH2) p-NH2}

-NH- (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂

433

434

-NH- (CH ₂ ) ₃ -NH ₂ 462 463 -NH- (CH ₂ ) ₅ -NH ₂ 490 491 -NH- (CH _{2) 7} -NH ₂

524

524

-NH- (CH ₂ ) ₃ -NH ₂ 395 396 -NH- _{(CH2) p-NH2} 423 424 -NH- (CH _{2) 7} -NH ₂ 451 452 / ^CH 2 ' - nh ₂ ..A 457 458

-NH- (CH ₂ ) ₃ -NH ₂ 396 397 -NH- _{(CH2) p-NH2} 424 425 -NH- (CH _{2) 7} -NH ₂ 452 453

-NH- (CH ₂ ) ₃ -NH ₂ 396 397 -NH- _{(CH2) p-NH2} 424 425 -NH- (CH _{2) 7} -NH ₂ 452 453 From ^CH 2 ~ - NH, M 458 459

Example 11

A suspension of 4 g of 6-nitrobenzo [de] isochromene-1,3-dione in 100 ml of toluene is treated with 3.1 g of 4-iodophenylylamine and the reaction mixture is heated to reflux. After completion of the reaction, the reaction mixture is allowed to cool and worked up in the usual manner. 6-Nitro-2- (4-iodophenyl) benzo [de] isoquinoline-1,3-dione is obtained. Add 1.2 equivalents of potassium carbonate, 1.2 equivalents of Ph-B- (OH) _2, and 10 mol% of a tetravalent palladium compound Pd (PPh) ₃ ) ₄ to a solution of this compound in 80 ml of dimethylformamide. 4 4 4 4 4 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 And the reaction mixture was heated to 80 ° C until the conversion was complete. After filtering off the catalyst after the usual work-up, 6-nitro-2-biphenyl-4-ylbenzo [de] isoquinoline-1,3-dione is heated with 1,3-diaminopropane until conversion is complete. After cooling, the reaction mixture was worked up in the usual manner to give 6- (3-aminopropylamino) -2-biphenyl-4-yl-benzo [de] isoquinoline-1,3-dione.

Similarly, reaction of 6-nitro-2- (4-iodophenyl) benzo [de] isoquinoline-1,3-dione with Ph-B (OH) ₂ and R ¹ -H affords the following compounds of formula Ibk:

R ¹

R ¹ v. R ¹ -Hi ' · .- · Ibk -NH- (CH ₂ ) 5 -NH 2 -NH- (CH ₂ ) 7 -NH ₂ ^x nh ₂ H

Example 12

Analogously to Example 11, 6-nitro-2- (4-iodophenyl) benzo [de] isoquinoline-1,3-dione is reacted with R ¹⁰ -B- (OH) _o as

Ί,

R = H. The following compounds of the general formula Ibl are obtained:

R ^{1 is} VR ^x -H and: Ibl

-NH- (CH ₂ ) ₃ -NH ₂

-nh- (ch ₂ ) ₅ -nh ₂

-NH- (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂

-NH- _{(CH2) p-NH2}

-NH- (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂

-NH- (CH ₂ ) ₅ -NH ₂

-NH- (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂

-NH- _{(CH2) p-NH2}

-NH- (CH _{2) 7} -NH ₂

- 99 .R ¹ -y. R 1 H a. . Ibl

-NH- (CH ₂ ) ₃ -NH ₂

-NH- (CH ₂ ) ₅ -NH ₂

-NH- (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂

-NH- (CH ₂ ) ₅ -NH ₂

-NH- (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂ '

-NH- (CH ₂ ) 5 -NH ₂

-NH- (CH ₂ ) 7 -NH ₂

-nh- (ch ₂ ) ₃ -nh ₂

-NH- _{(CH2) p-NH2}

-NH- (CH _{2) 7} -NH ₂

Example 13

Analogously to Example 11, 6-nitro-2- (3-iodophenyl) benzo [de] isoquinoline-1,3-dione was reacted with η ¹ θ-Β- (ΟΗ) ₂ and pI-H. The following compounds of formula Ibm are obtained.

R ¹ VR ^x -H to -I Ibm

-NH- (CH ₂ ) ₃ -NH ₂

-NH- (CH ₂ ) ₅ -NH ₂

-NH- (CH _{2) 7} -NH ₂

cf ₃ / ^Cr 3 ^x cf ₃ ocf ₃

-NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂

-NH- (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂

-NH- (CH ₂ ) ₅ -NH ₂

-NH- (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂

-NH- _{(CH2) p-NH2}

-NH- (CH _{2) 7} -NH ₂

<· - '·. '-> · ···. ·., 'Γ · · Λ';, “··· '·. · · · · · · · · · · · · '. · * ·'> · .. ·· ' ^: -.r. · · ·

..- vL-. ·. · e · <<.. #. · ·. é. ·. ·. · * <

,. · .. ·. · '· .. · · · - .. ·. · ".. ·' · ... ··. ···., · · · . ·. .. ·> ............ «> · - ·. · · ·

- 102 -

Ŕ ™ R ¹ y R ^x -H a. Ibm

H ₃ C _x -NH- (CH ₂ ) 3 -NH ₂

-NH- _{(CH2) 5-NH2} \ = / NH (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂

-nh- (ch ₂ ) ₅ -nh ₂

-NH- (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂

-nh- (ch ₂ ) ₃ -nh ₂

-NH- (CH ₂₎ a 'NH ₂

-NH- (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂

-nh- (ch ₂ ) ₅ -nh ₂

-NH- (CH _{2) 7} -NH ₂

-103 - ^-

Ŕ ¹ VR ⁱ -H a: d Ibm

-NH- (CH ₂ ) ₃ -NH ₂

-NH- (CH ₂ ) ₅ -NH ₂

-NH- (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂

-NH- (CH _{2) 7} -NH ₂

-nh- (ch ₂ ) ₃ -nh ₂ -nh- (ch ₂ ) ₅ -nh ₂ -NH- (CH ₂ ) ₇ -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂

-NH (CH ₂ ) ₃ -NH ₂

-NH- _{(CH2) p-NH2}

-NH- (CH _{2) 7} -NH ₂

Example 14

Analogously to Example 11, 6-nitro-2- (3-iodo-4-methylphenyl) benzo [de] isoquinoline-1,3-dione was reacted with R ¹⁰ -B- (OH) ₂ and R ¹ -H. The following compounds of the general formula are obtained

Ibn:

- 10Y -

Ibn

t «·· · · * ·’ ·. ; ·· ´ '·' - ·; *. · · · · · · · · · ·

...... ·> ·. ··· ♦ · ··.: · ·. . >.

Analogously to Example 11, it is reacted

-2- (4-iodo-3-methylphenyl) benzo [de] isoquinoline-1,3-dione with R 1 -H. The following compounds of general formula are obtained

Ibo:

•• y • · · · · ·;

Example 15

Ibo

- 10 S 6-nitroR ¹⁰ -B- (OH) _{2 of} formula

in/

- 106 / -

R ¹ in R ^x -H a Ibo / TA -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ h ₃ c -nh- (ch ₂ ) ₇ -nh ₂ -'í'YCY ^x nh ₂ H M

Example 16

Analogously to Example 2, 6-nitro-benzo [de] isochromene-1,3-dione is reacted with H ₂ N-Het ¹ . The following compounds of formula 1c are obtained:

to y Ύ Τι 1 k * ^c N ⁰ 1. Het ¹ Het ¹ R ^{@ 1} y IC -no ₂ - {N sA ch ₃ —N CF ₃ -no ₂

Example 17

Analogously to Example 2, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with H ₂ N-Het ¹ -Ar. The following compounds of formula Id are obtained:

Example 18 Analogously to Example 2, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 2- (3-aminophenylacetamide and then with R ¹ -H). Compounds of formula Iea are obtained.

Example 19

Analogously to Example 2, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 2- (4-aminophenylacetamide and then with R ¹ -H). Compounds of formula Ieb are obtained:

LEB

- ΙΟ ¹ '' - ·

R ¹ VR ^x -H and \ Z Ieb MS -N- -about 413 414 -Ό 399 400 -oo -NH- _(CH2) p-OH -NH- (CH ₂ ) ₃ -N (CH ₃ ) ₂ 430 431

—N 1 H - (CH ₂ ) ₂ 449 450 —N 1 H —Ch ₂ - about > _{-SO2 NH2} —N 1 H - (CH ₂ ) ₂ - -c OH 465 466 -N 0 NH (CH ₂ ) ₂ -COOCH ₃ 431 432 —N · 1 H —Ch ₂ - < D ch ₂ —nh ₂ 464 465

• · · ·

Example 20

Analogously to Example 2, 6-nitro benzo [de] isochromene-1,3-dione is reacted with 3-aminobenzamide and then with R 1 -H. Compounds of formula Iec are obtained:

Ŕ ¹ \ _A - 114'- 1 1 lec ⁰ N ' Λ í nh ₂

- ’· i i i <<<<<

- 113 - ·

Analogously to Example 2, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 4- (4-aminophenyl) butyramide and then with R 1 -H. Compounds of formula Ied are obtained:

ice

R ¹ in R ¹ -H a. ied MS -NH- (CH ₂ ) 4 -NH ₂ -NH- (CH ₂ ) 7 -NH ₂ 486 487 -NH- (CH ₂ ) ₈ -NH ₂ 500 501 —N— (CH ₂ ) ₂ - N < 458 459 H H

-NH- (CH ₂ ) ₃ -N (CH ₃ ) ₂

- 114

Example 22

Analogously to Example 2, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 3- (3-aminophenyl) propionamide and then with R ¹ -. Compounds of formula lee are obtained:

R ¹

conh ₂

R ¹ and _R V- and H :. '. -MS R ^x R ^x -H and:. lee «with lee. —3 429 430 -NH- (CH ₂ ) ₃ -NH (CH ₃ ) 430 431 - f / 427,428 --N - (CH _{2) 2} - N - <^ 444 HH 445 —413 414 Ck - ^{Γ θ |} - ° ^Η 2-0 '°' ⁿ \ Z / ⁿ Cy ^{504 505}

• .'IN

- 115 -

R ¹ .γ :. R ^x -H and Iee MS • A R ¹ .i? .''.- ^'and R H *, and' Iee MS - ^N - <u H ^{C 3} r ~ N / ^N -NH- (CH ₂ ) 2 -COOMe - N - CHo - C 7 -NH 2 CH ₂ ) 3 -R 2 - (CH ₂ ) ₃ -NH ₂ 542 i ² \ - / H 543 -N- (CH ₂ ) _{2 -} no 463 464 A 498 H -NH— (N 499 N - CH-C 7 -SO ₂ NH ₂ -NH- (CH ₂ ) ₂ -NH- (CH ₂ ) ₂ - 446 OH 447 N _{(CH2) 2-OH,} -C 7 H -NH- (CH ₂ ) ₂ -NH (C ₃ H ₇ ) -NH- (CH _{2) 5} OH -NH- (CH 3) 3 -O- (CH ₂ ) 1 -O- (CH ₂ ) 3 - 546 nh ₂ 547 -N (CH ₃ ) - (CH ₂ ) 3 - 444 445 -N (CH ₃ ) - (CH ₂ ) ₂ - 472 NH _(CH3) N (C ₂ H ₅ ) 2 473 -NH- (CH ₂ ) ₃ -N (CH ₃ ) 2 444 445 -NH- (CH ₂ ) ₃ -nV) H '-' 498 499 - N CH ₂ —I / - ^NH 2 CH ₂ NH ₂ tc 484 H '----' -nh-ch ₂ - / 485 . > CH ₂ --- NH 3 -Ν-ΟΗ, -θ -NH- (CH ₂ ) 3 -N (CH ₃ ) - (CH ₂ ) ₃ - 487 H N H 488

·: · Α, '; - ·· · ·

L:.

, ··.

• ···

UNTIL.

. , ··: •• .t ·· .- · »··· - * · ·· *

- 11 / -

R ¹ Λ - R ^{1 -} H ar L '- ms .a':. < _P , d. IEE R ¹ and R ^x -H a, "r" ms N-R-N (0Η ₂₎ 2 \ 464 465 H -NH- (CH ₂ ) 2 -NH (C ₂ H 5) 430 431 N-> —N— (CH ₂ ) ₂ - € 7 H ^λ - ' / λ ~ N _{(CH2) 2-N} 0 H ^{X f} N -> - N - CH _{2 -} 450 451 H -N- (CH ₂ ) ₃ -N (CH ₃ 499 ^H 500) N- (CHjla _{NA-469 "0} V -NH- (CH ₂ ) 5 -NH ₂ NH (C ₅ H N) -NH- (CH ₂ ) ₇ -NH ₂ 472 473 -NH (C ₃ H ₇ ) —N — ch ₂ —C p — ch _{2 —} NH ₂

Example 23

In analogy to Example 2, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 3-amino-4-methoxybenzamide and then with R ¹ -R ¹ . Compounds of formula Ief are obtained:

Example 24

Analogously to Example 2, 6-nitro is reacted;

113, -.

benzo [de] isochromene-1,3-dione with H ₂ N-Ar 1 - (CH ₂ ) _n -R ³ and then (at η falls) with R -H. Compounds of formula Ieg are obtained:

R ¹

N 6 - (CH ₂ ) _n -R ³

Example 25

6-Nitro-2- (3-iodophenyl) benzo [de] isoquinoline-1,3-dione or 6-nitro-2- (4-iodophenyl) benzo [de] isoquinoline-1 is reacted analogously to Example 11. 3-dione with R ³ - (CH ₂ ) _n -Pb-B- (OH) ₂ and with R 3 -H. Compounds of formula Ieh (Ph-Ph = Ar ') are obtained:

IEH

N 1 - (CH ₂ ) _n -R ³

- 120'-Ar '- (CH ₂ ) _n -R ^J

R ^x VR ^x -H a'S Ieh

-NH- (CH ₂ ) ₃ -NH ₂

-NH- (CH ₂ ) ₅ -NH ₂

-NH- (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂

-NH- (CH ₂ ) ₅ -NH ₂

-NH- (CH _{2) 7} -NH ₂

Example 26

Analogously to Example 2, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 2- (4-aminophenylsulfanyl) acetamide and then with R 1 -H. Compounds of general formula Ifa are obtained:

ifa

S — ch ₂ -conh ₂

••, ···. ·. ··. · ..- ··. ·· ··. ·>. ·· ·· '·· ·. · ·· -  . <·· · \ · 7. · '. · -. . · · ·. · .. ·. ·. ♦ ····. · * · · · · · ... • · ♦ . . ♦ ·> ·. ♦ '. • ·; · ^; , ν ·· _Λ ·. X »>> · <; ·· ..-? ·.? ./. ♦. · ·:> - · <• ν '···> - ·. · - - /.>. ··· <·:' · .._ ·· ŕ <--- - ·· - '·''ΛJ''Τ. * ·' · · * (f. <. ·. ·· ,: fr • · · ·· · · · · • · * · ·. ... .t. * -... ’ .'c '* ·' · N

Analogously to Example 2, 6-nitro-benzo [d] isochromene-1,3-dione is reacted with 2- (4-aminophenoxy) acetamide and then with R 1 -H. Compounds of general formula Ifb are obtained.

o — ch ₂ -conh ₂

- 122- ·

R ¹ VR ^£ -H and · IFB MS -NH- (CH ₂ ) ₄ -NH ₂ -NH- (CH _{2) 7} -NH ₂ 474 475 -NH- (CH ₂ ) ₈ -NH ₂ 488 489 N (CH _{2) 2} - n < 460 461 H H -NH- (CH ₂ ) ₃ -N (CH ₃ ) ₂ 446 447 -n- (CH ₂ ) ₃ -H -N ^ N \ = / 471 472 _; N x -N- (CH ₂ ) ₂ - H / CHN- 480 481 —N — CH, —é 7 H

Example 28

Analogously to Example 2, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 5- (piperidine-1-sulfonyl) naphthalen-1-ylamine and then with R 1 -H. Compounds of the general formula Ig are obtained:

in,

- 123 - ·

R ¹ VR ^ H a. · ig MS -NH- (CH ₂ ) ₃ -NH ₂ 542 543 -NH- _{(CH2) p-NH2} 570 571 -NH- (CH ₂ ) 7 -NH ₂ H / CH ₂ - -nh ₂

Example 29

Analogously to Example 2, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with H ₂ N-Ar'-SO ₂ -R 4 and then with R 4 -H. The following compounds of formula Ih are obtained:

ABOUT

R ¹ y. Ι ^ -Η a: '' Ih J4S

·: ·

Ar'-SO ₂ -R '

-NH- (CH ₂ ) ₃ -NH ₂ 'NH- (CH ₂ ) ₅ -NH ₂

-NH- (CH _{2) 7} -NH ₂

584

612

585

613

647

-NH- _{(CH2) 3} -NH ₂ 544 545 -NH- _(CH2) 5-NH2 572 573 -NH- _{(CH2) 7} -NH ₂ 600 601 / CH ₂ —NH ₂ N - CH ₂ - -d 606 607

-NH- (CH ₂ ) ₃ -NH ₂

-NH- _{(CH2) p-NH2}

-NH- (CH _{2) 7} -NH ₂

516

544

517

545

579

Example 30

Analogously to Example 2 is reacted 6-nitro-benzo [de] isochromene-1,3-dione with H 2 ^{N c} 6 ^H 4 ^"(CI1 2 ^ 2" ^{CONH "(CH2} ^ i" ^NH 2 then the R ¹ - H. Compounds of formula Ii are obtained:

- 125, -

Example 31

Analogously to Example 2, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with H ₂ NC ₆ H ₄ - (CH ₂ ) ₂ -CONH-CH ₂ -C ₆ H- _L1 and then with R ^X -H. Compounds of formula Ika are obtained:

Ika

(CH ₂ ) ₂ -CONH-CH ₂

, ..------------------------------- - K in R-H a. · 1 Ika Kindergarten: ‘----- -NH- (CH ₂ ) 7 -NH ₂ 568 564 __y , čh ₂ - Ήίζ-- -N - CH ₂ - 574 575 H

Example 32

Analogously to Example 2 is reacted 6-nitro-benzo [de] isochromene-l, 3-dione with H ₂ NC ₆ H ₄ - (CH _{2) 2} CONH _{(CH2) 2-} -CgH _g, and H ₂ N - (CH ₂ ) 5 -NH ₂ . One equivalent of tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate is added to a solution of 3- (3- (6- (5-aminopentylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinoline-2-). yl] phenyl) -N- (2-cyclohex-1-enylethyl) propionamide in 60 mL of DMF and after completion of the reaction, the BOC protecting group is removed by addition of TFA in 1,2-dichloroethane to give N- (2-cyclohex-1- enylethyl) -3- {3- [6- (5-guanidinopentylamino) -1,3-dioxol-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} propionamide.

The following compounds of formula Ikb are similarly obtained by reacting H ₂ NC ₆ H ₄ - (CH ₂ ) ₂ -CONH- (CH ₂ ) ₂ -C ₆ H ₉ with a suitable diamine and tert-butyl- (tert-butoxycarbonyliminopyrazol-1-ylmethyl) in each case ) carbamate and deprotection:

IKB

(CH ₂ ) ₂ -CONH- (CH ₂ ) 2

- 12?, -.

Example 33

Analogously to Example 2, 6-nitro benzo [de] isochromene-1,3-dione is reacted with H ₂ NC ₆ H ₄ - (CH ₂ ) ₂ -C ° NH- (CH ₂ ) _± Ar and then with R ¹ -H. Compounds of formula IIIa are obtained:

ha

(CH ₂ ) ₂ -CONH- (CH ₂ ) _r Ar -

- 128. -C ₆ H ₂ - (CH ₂ ) ₂ -CONH (CH ₂ ) i -Ar

R ¹¹ ; R ^x -H ai '. Hä mš

-NH- (CH _{2) 7} -NH ₂

569 570

560 561

_n x CH, -NH- (CH ₂ ) ₇ -NH ₂ ^x ch ₃

59Γ 592 N - _CH2

_CH2 -NH _2597598

624

630

621

625

631

622

596 597

-NH- (CH _{2) 7} -NH ₂

Example 34

In analogy to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 1 N, N-C 6 ^H 5 -Cl 2 ^- CONH- (CH 2) 3 - ^c 6 ^H 5 'in each case with with a suitable diamine and (optionally with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate.) After deprotection, compounds of formula IIb are obtained:

j.-2 ·. ·. <

- 127 -

R ¹

R ¹ M Ilb MS -NH- (CH _{2) 7} -NH ₂ y CH ₂ N ₂ --NH ₂ -θ -ΟΗ 596 597 -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 604.8 605.3 -NH- (CH ₂ ) ₂ -NH-C (= NH) -NH ₂ 562.7 563, 6 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 632.8 633.4

—N — CH, ^iĹ

H

² 644,8

638.8

CH ₂ - * N

H

645.5

639.5 N - _CH2 H

-NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ '576.7 577.5 -NH- (CH ₂ ) JN (CH 3) - (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 647.8 648.4 ------------------------- NR N - _CH2-CH--ΛΛ N ^ NH, HH 644.8 645.7 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ 590.7 591.7

Example 35

In analogy to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with H ₂ NC ₆ H ₄ - (CH ₂ ) ₂ -CONH- (CH ₂ ) ₂ ^-c 6 ^h 4 ^s 2 ^Nh 2 ' ⁱⁿ each case with a suitable diamine and tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. The following compounds of formula IIc are obtained after deprotection:

R ¹

♦ · »»

'· ·· »·

.....in

‘..: i in λ ·: · \ ... am *. ·. · *». ·· <·

Example 36

In analogy to Example 32, 6-nitrobenzo [de] iso-chromene-1,3-dione is reacted with H 2 N-C 8 H 4 - (C 1 H 3 - CONH-C 4 H 4), in each case with a suitable diamine and tert-butyl- (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate After deprotection, compounds of formula

ild:

(ch ₂ ) ₂ -conh

- 132, -

R ¹ γ Ild MS -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 562.7 563.3 -NH- (CH ₂ ) ₂ -NH-C (= NH) -NH ₂ 520.6 .521,3 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 590.7 591.4 NH Λ CH ₂ —N NH ₂ -V-ch ₂ -O ^H H - 602.7 603.4 N - _CH2 - (f ~ _W-CH2-N ^ NH ^ ₂ = H ⁷ H 596.7 597.3 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 534.6 535.3 -NH- (CH ₂ ) 3 -N (CH 3) - (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 605.7 606.4 -NH-N - CH ₂ - \ - CH ₂ -N ^ N H HH 602.7 603.4 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 576.7 577.3 -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ 548.6 549.3 11 —N— (CH ₂ ) ₃ -N NH ₂ H CH ₃ 548.6 549.5 - Z-h-N - (CH ₂ ) ₂ - (7-N NH ₂ AH) 596.7 597.0 Γ \ 7 ^ 2 —N N — 4 \ __ / NH 546.6 547,7 W - N - CH ₂ - (N-4 ¢, ² V NH NH) 574.7 575.5

Example 37

In analogy to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with a compound of the formula

with a suitable diamine and with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After deprotection, the following compounds of formulas (Ile) to (Ilef) are obtained:

R ¹

R ¹ In Ilea MS -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 625.2 625.3 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 583.1 583.2 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 653.2 653.3 Λ _z ch ₂ -n nh ₂ / - \ H 665.2 665.4 -n — ch ₂ -H N - CH ₂ --CH ₂ -N ^ _NH2 ^{in the} HH 659.2 659.3 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 597.1 597.3 -NH- _(CH2) jN (CH) - (CH ₂₎ j NHC ( »NH) _-NH-; 668.2 668.3

.... X · ·;

Cl

R ¹ in Ileb

-NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂

625.2

625.3

-NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ -NH- (CH ₂ ) ₇ -NH-C (= NH) -NH ₂ '

T

583.3

653? 4

653.

in,

-135 -

-136 - ·

R ¹ V <Ilec MS • -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 625.2 625.4 -NH- (CH ₂ ) ₂ -NH-C (= NH) -NH ₂ 583.1 583.4 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 653.2 653.5 For zCH ₂ —n NH ₂ Λ ~ H 665.2 665.4 -N - CH ₂ - <) H NR N - CH ₂ --CH ₂ N HH 659.2 659.4 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 597.1 597.3 -NH- (CH ₂ ) 3 -N (CH ₃ ) - (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 668.2 668.4 NH N - CH ₂ CH ₂ NH ₂ N 665.2 665.4 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 639.2 639.5 -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ 611.1 611.4 NH ₁ - N - (CH ₂ ) ₃ -N NH ₂ 611.1 612.4 H CH ₃

'f.:·;··-;'·,<·?Λ·ί'· i', · i · ,. '

- 13 7 -

R ¹ V. Kll MS MS NH (CH _Z) 5-NH-C (= NH) -NH ₂ -NH- (CH ₂ ) ₂ -NH-C (= NH) -NH ₂ 555.0 555.4 -NH- (CH ₂ ) ₇ -NH-C (= NH) -NH ₂ 625.2 625.3 Λ / ^CH 2 ^—NH 2,637.2 637.4 -N-CH ₂ - H - NR: _ _ _{N C} H ₂ -CH ₂ _Zy _-NAH! 631.1 631.3 HH -NH- (CH ₂ ) ₃ -NH-C (= NH) -NH ₂ 569, 1 569.3 NH _{(CH) 3} -N _(CH3) - _{(CH2) 3} -NH- 640.2 640.3 C (= NH) -NH ₂

, '·.; · ..' · _ ·· ·· ... .. ·· .. ··. ·. : .. ‘ • .Λ, .- ·. '• and A - ·. ·. .. __ · .-- ··. · ‘I. ·., · • • W * · · «• s • Φ r. . ..i i ·: • · · · · · • · · · · · · • ···

- 138 -.

······

R ¹ y Ilee MS -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 611.1 611.4 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 569.1 569.4 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 639.2 639.3 NH _ζ οη ₂ —n ^ nh ₂ / - \ ^H 651.2 651.5 N CH ₂ - ^) H N H II - N - CH ₂ - —CH ₂ N NH ₂ H 4 = ⁷ H 645.2 645.4 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 583.1 583.5 -NH- (CH ₂ ) j N (CH 3) - (CH ₂ ) 3 —NH — C (= NH) -NH _Z 654.2 654.2 --NR / - \ JL N - CH ₂ - () _-CH2 - ₂ N NH HH 651.2 651.6 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 625.2 625.3 -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ 597.1 597.4

. ·. ·.

• ··· · ···. F. in. - ₉ <...... · _φ φ · --é · «' _{4 4}

R ¹ ; y? · Ile f MS -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 597.1 597.2 -NH- (CH ₂ ) ₂ -NH-C (= NH) -NH ₂ 555.0 555.3 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 625.2 625.3 ---- NH U / 0Η ₂ - N _NH2 ^H 637.2 637.2. N _CH2 - <) H '-' -------------------; _NH-N-CH-CH2 -7b - HH 631.1 631.3 -NH- (CH 2) 3 -NH-C (= NH) -NH ₂ 569.1 569.3 -NH- (CH ₂ ) j N (CH 3) - (CH ₂ ) j -NH- 640.2 640.2 C (= NH) -NH ₂ -

144 -

R ¹ V Ilef ¹ MS -------------------------------: ------------------ --------------------------- with NH N CH ₂ - _(2-CH2 - Ah ₂ H '- H 637.2 637.5 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 611.1 611.3 -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ 583.1 583.3

Example 38

Analogously to Example 32, 6-nitrobenzo [de] isochromen-1,3-dione is reacted with H ₂ NC ₆ H ₄ - (CH ₂ ) ₂ -CONH-CH ₂ -Ar, with a suitable diamine and tert-butyl (t-butoxykarbonyliminopyrazol-l-ylmethyl) carbamate. After deprotection, the following compounds of formula (Ufa) are obtained: h ₂ nc ₆ h ₄ - (ch ₂ ) ₂ -conh-ch ₂ -c ₁₀ h ₇ :

R ¹

R ¹ ; .v \ Ufa MS -NH- (CH ₂ ) ₅ -NH-C (= NH) -NH ₂ 626.8 627.3 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 584.7 585.3 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 654.8 655.4

······

661.0

611.6

639.6

Removal of the protective groups gives the following combined Ufa Nina formula is H ₂ N-CGH ₄ - (CH ₂₎ 2 ^CH 2 ^{_C _CONH} 9 ^H 9 '

- 143 -

R ¹ V 11 fb MS -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 602.7 603.3 -NH- (CH ₂ ) ₂ -NH-C (= NH) -NH ₂ 560.7 561.4 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 630.8 631.3 --NR II '/ N-CH 2 NH ₂ R \ ^H 642.8 643.5 N CH ₂ - () NH II N CH _2-CN NH H H ^ = ⁷ 636.8 637.3 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 574.7 575.6 -NH- (CH,) NOS (CH) - (CH _{2) 3} NHC (= NH) -NH, 645.8 646.5 -; NR / - \ JL - N-CH ₂ - (/ _-CH2 ^- ₂ N NH HH 642.8 643.5 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 616.8 617.4 -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ 588.7 589.4

φ · φ · φ · · · ·

’· · · · · · · · · · · · · · · · · ·

Example 39

Analogously to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 3-amino- (3-aminophenyl) -N- (3-chloro-4-methoxyphenyl) propionamide, with a suitable diamine and with tertiary butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After deprotection, the following compounds of formula IIg are obtained:

R ¹

Cl

r ¹ . in Hg MS -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 627.1 627.3

and

R ¹ y Ilg MS -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 585.1 585.2 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 655.2 655,3 - NH, CH ₂ -n '4' nh ₂ 667.2 667.3 _N-CH2 -hQJ H NH -N-CH ₂ —CH ₂ -N 4 NH ₂ H 4 = ⁷ H 661.2 661.2 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 599.1 599.2 -NH- (CH ₂ ) 3 -N (CH ₃ ) - (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 670.2 670.3 NH - N - CH ₂ - / - CH ₂ N 4 NH ₂ H ^W H 667.2 667.3 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 641.2 641,3 ' -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ 613.1 613.3

_N1 H - ( ^ch ₂ ) 2 — yu ^{nh 2661/2} ^ = ⁷ h 661.2 -N N - 4,611.1 - / NH 611.4 —N1 H / ~ \ / ^NH 2 ^CH ₂ ^N v3 Ah ^639.2 639.4

Example 40

- 14í

Analogously to Example 32, 6-nitro-benzo [de] isochromene-1,3-dione is reacted with 3-amino- (3-aminophenyl) -N- (4-phenylbutyl) propionamide, with a suitable diamine and tert-butyl- ( butoxykarbonyliminopyrazol tert-l-ylmethyl) carbamate.

After deprotection, the following compounds of formula IIh are obtained:

R ¹

R ¹ V Ilh MS -NH- (CH ₂ ) s -NH-C (= NH) -NH ₂ 618.8 619.4 -NH- (CH ₂ ) 2 -NH-G (= NH) -NH ₂ 576.7. 577.3 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 646.8 647.4 RFI J _from CH ₂ -NH 3 / - 658.8 659.4 -N - ^ch _{2 -} no H NH -N - CH _{2 -} ΟΗ ₂ -Ν ^Λ ΝΗ ₂ H 4 = ⁷ H 652.8 653.4 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 590.7 591.3 -NH- _(CH2) jN (CH) - (CH) j NHC (= NH ^) -NHj 661,8 662.4 RH-N - CH ₂ - () _-CH2-N ^ _NH2 HH 658.8 659.5 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 632.8 633.4

- 14 7 -

Example 41

Analogously to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with a compound of formula

with a suitable diamine and with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After deprotection, the following compounds of formulas (IIia) to (IIic) are obtained:

f v

;>

• '• A'

'.λ ·: ·. · w'

7th

··, ··

- ”148-

R ¹ V · Ilia HS -NH- (CH ₂ ) ₅ -NH-C (= NH) -NH ₂ 604.8 605.4 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 562.7 563.4 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 632.8 633.4 NH _{2 from} CH ₂ -Nnh ₂ / - (H 644.8. 645.5 -N-CH ₂ - H NH - N - CH ₂ ——CH ₂ - 2η ₂ HH 638.8 639.4 -NH- (CH ₂ ) 3 -N (CH ₃ ) - (CH 3) 3 -NHC (= NH) -NH ₂ 647.8 648.4 Of NH \ Y N - CH ₂ - \ / N-CH ₂ NH ₂ HH 644.8 645.5 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 618.8 619.5 -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ 590.7 591.4

590.7

638.8

591, 6

639.3

-N —In NH, __ / NH 588.7 589.8 -N- -CHn— (N- NFL 4 616.8 617,7 1 H \ __ / NH

.4 *. ·· «·. ·; ·>,, ·: · .. · .. .. ··. · · · ·. > · »*.? '.'. ··. ··. ··· · • Λ-.ΛίΛ:; ····. · <· '. . ·.

• · ♦ «·· ·

R ¹ Vyllib MS -ΝΗ- (CH ₂ ) 5 -NH-C (= ΝΗ) -ΝΗ ₂ 604.8 605.4 -NH- (CH ₂ ) 2 -NH-C (= ΝΗ) -ΝΗ ₂ 562.7 563.3 -NH- (CH ₂ ) 7 -NH-C (= ΝΗ) -ΝΗ ₂ 632.8 633.4 ΝΗ J / ζΟΗ ₂ - Ν νη ₂ / - \ Η 644.8 645.6 N CH ₂ - / ~) Η ΝΗ —Ν - CH ₂ - / - CH ₂ —Ν ΝΗ ₂ Η ^ = ⁷ Η 638.8 639.5 -ΝΗ- (CH ₂ ) 3 -NH-C (= ΝΗ) -ΝΗ ₂ 576.7 577.6 -ΝΗ- _(CH2) 3-N _(CH3) - _(CH2) 3-ΝΗC (= ΝΗ) -ΝΗ ₂ 647.8 648.4 : ΝΗ -Ν - 0Η ₂ --CH ₂ -Ν ΝΗ ₂ Η '-' Η 644.8 645.7 -ΝΗ- (CH ₂ ) 6 -NH-C (= ΝΗ) -ΝΗ ₂ 618.8 619.4 -ΝΗ- (CH ₂ ) n -ΝΗ-C (= ΝΗ) -ΝΗ ₂ 590.7 • 591.4 ΝΗ A '-N- (CH ₂ ) ₃ —ΝΝΝ ΝΗ ₂ Η CH ₃ 590.7 591.8 ^: ΝΗ II N - _{(CH2) 2-N} ΝΗ -CY ₂ Η Η 638.8 639.3

".. · ..’. · ··. .

, · - ·. «·. · · · ·

·..·,.· · · · "·**'·"*.· - ·'"'- ·' ··' ' · in,

- 15Ž7 -.

R ^x . .7 Ilib Kindergarten ./¾ —N N — Z 588.7 589.6 \ - / NH A ~ \ / ¾ H + - NH 616.8 617.8

R ¹ : y Ilic MS -NH- (CH ₂ ) s -NH-C (= NH) -NH ₂ 590.7 591.3 -NH- (CH ₂ ) ₂ -NH-C (= NH) -NH ₂ 548.6 549.6 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 618.8 619.4 Jl / CH ₂ -ννη ₂ 630.8 631.7 Γ \ ^H N-CH ₂ -X) H NH / \ "A ..,. · N - CH, ^- \ / N-CH ₂ NH ₂ 624.7 625.4 H ^{7 = 7} H -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 562.7 563.5 -NH- (CH ₂ ) 3 -N (CH 2) - (CH ₂ ) 3 -NH- 633.8 634.4 C (= NH) -NH ₂

- 15 ^ -

R ¹ v. Ilic TIS NH N CH ₂ -S-CH ₂ - H '- H 630.8 631.8 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 604.8 605.2 -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ 576.7 577.5

Example 42

A suspension of 4.1 g of 6-nitrobenzo [de] isochromene-1,3-dione in

100 ml of glacial acetic acid are treated with 4.3 g of 3- (3-aminophenyl) propionic acid and the mixture is heated to reflux. Once the reaction is complete, allow the reaction mixture to cool and work up in the usual manner. 3- [3- (6-Nitro-1,3-dioxo-2,3-dihydro-1H-phenalen-2-yl) -phenyl] -propionic acid in 80 mL of THF is treated with 1.5 equivalents of oxalyl chloride, the reaction mixture is stirred and 1.5 equivalents of 2-p-tolylethylamine are added. Once the conversion is complete, the mixture is processed as usual. A solution of 3- [3- (6-nitro-1,3-dioxo-2,3-dihydro-1H-phenalen-2-yl) phenyl] -N- (2-p-tolylethylpropionamide) in 80 mL DMF was treated with 1 equivalent The amine obtained by conventional work-up is heated with 1.5 equivalents of pyrazole-1-carboxamidine and diisopropylethylamine in 80 ml of dimethylformamide. to give 3- {3- [6- (3-guanidinopropylamino) -1,3-dioxo-2,3-dihydro-1H-phenalen-2-yl] phenyl} -N- (2-p-tolylethyl) propionamide.

MS: Calcd .: 576.7, Found: 577.4.

Example 43

Analogously to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with a compound of formula

• ·

diamine and with tert-butyl (tert-butoxycarbonylamino-pyrazol-1-ylmethyl) carbamate. Removal of the protecting groups yields the following compounds of formulas (Ika) to (Ike):

R ¹

Cl

R ¹ V Ilka MS -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 645.6 645.4 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 603.5 603.3 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 673.6 673.4 - RH A / CH _{2 -} NH ₂ / - (H 685.7 685.4 -N - ^CH 2 - (2 / NH N - _CH2 ^CH2 -dd- ^{- NH2} HH 679.6 679.3 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 617.5 617.3 ------------------- NIT X N (CH _{2) 3} - N _NH2 H. CH ₃ 631.6 631.4

t. -153-. ✓ R ¹ vilka MS - NH -N- (CH ₂ ) ₂ - ^679.6 H ^{X = /} H 681.2 / - \ nh ₂ —N nA \ - / NH 629.5 630.5 / - \ ^NH 2 —N — CHo \ N — 4. ² V / NH

R ¹

R ¹ ?. ťllkb MS -NH- (CH ₂ ) s -NH-C (= NH) -NH ₂ 645.6 645.3 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 603.5 603.3 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 673.6 673.4 J --- NH / / N CH ₂ NH ₂ R \ ^H 685.7 685.5 —N — ch ₂ - <> 1 \ _____ f H : nh -N-CH 2 -H 4 = ⁷ H 679, 6 679.3 -NH- (CH ₂ ) s -NH-C (= NH) -NH ₂ 617.5 · 617.5

··. ', · ··. ·.

• 5 ·· ·

R ¹ · Vkllkb

-NH- _(CH2) 3-N _(CH3) - (CH2) ₃ -NH-C ( »NH) -NH ₂ 688.7

688.4-N-CH

I H

NH -------- CH ₂ —N 4 NH ₂ 685.7

H

687.4

-NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂

-NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂

659.6

631.6

659, 4

633.3 “NH

Λ

631.6

632.4

-N- (CH ₂ ) ₃ -N

679.6

679.1

N-CH

I ² H

(CH ₂ ) ₂ -CONH-CH ₂ 11c

R ¹ MS -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 645.6 645.6 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 603.5 604, 6 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 673.6 673.4

·:

Ϋ ··:

ttt »

A

.'ΛΑ: · γ ·· ”: ¾ · '/><; -. <·? ·> / Α: _; / ^: · ·· - ··' -Ϋ- <Υ ·.? ' ΥλΑ Y? γ - Υ // \ • ί *?; / / / / / / / <<< ··. ····· ·, 9 ··· y - <·; ·; '·· *>' · /. <· - * - Ί55 -. • · · · · R ¹ .v -vilke MS f ΝΗ J1 / CH ₂ ~ ip νη ₂ / - \ Η 685.7 686, 6 -Ν -CH ₂ - ΤΙΗ -Ν _CH2-CH2 -Y y N _NH2 H ^ H = ⁷ 679, 6. 681.3 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 617.5 618.6 ' -NH- (CH ₂ ) j-Ν (CH ₃ ) - (CH ₂ ) 3 -NHC (= NH) -NH ₂ 688.7 688.5 N - _CH2 - / \ N-CH ₂ NH ₂ H + - ⁷ H 685.7 686.5 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 659.6 659.4 -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ 631, 6 633.3 NH? -N- (CH ₂ ) ₃ —N? NH ₂ H CH ₃ 631.6 632.5 NR = N - (CH ₂ ) _{2 -} NH ₂ H ^{7 = 7} H 679, 6 679.1 7 ^ 2 —N N- < NH 629.5 630.4 ^NH 2 —N — CHn— (N-Jjj ² VY NH 657.6 658.6

* • · ··.

• ·

-156 -

Cl

R ¹ v- »vllkd MS -NH- (CH ₂ ) s -NH-C (= NH) -NH ₂ 645.6 645.3 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 603.5 603.3 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 673.6 673.3 : nh 11 _Ζ ΟΗ ₂ - N nh ₂ i - \ H 685.7 685.5 N -CH ₂ -QH '-' NH r_x Λ N - _CH2 - \ _{7-CH2-N NH2} HH 679.6 679.3 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 617.5 617.4 -NH- (CH ₂ ) 3 -N (CH ₃ ) - (CH ₂ ) ₃ -NH- C (= NH) -NH ₂ 688.7 688.3 NH N - CH ₂ - (\ N-CH ₂ NH ₂ · HH 685.7 687.3 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 659.6 659.4 -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ 631.6 631.4 ^NH 0 N _{(CH2) 3} - N ^ _NH2 631, 6 631.4 H. CH ₃

* ·. '·· ··>. ·. ·.

y. * · '.', .. 9, 9, 9;

• · · · · · · · · · · · -.

i;. · · · ·

- 157 - / R V.vllkd MS NR ^: N _{(CH2) 2} - <V H ^and NH ^{₂₆₇₉ "6} HH 679.1 / - \ N _NH2 N ^ \ - / NH 629.5 629.4 M _a h ^{657 '6} 658.4

R ¹

R ¹ In the villa MS -NH- (CH ₂ ) ₅ -NH-C (= = NH) -NH ₂ 631.6 631.2 -NH- (CH ₂ ) ₂ -NH-C (= = NH) -NH ₂ 589.5 589.1 -NH- (CH ₂ ) ₇ -NH-C (= = NH) -NH ₂ 659.6 659.2 _X NH 11 ^ch ₂ -N NH ₂ H 671.6 671.2 -N-CH ₂ - () H ^{λ /} NH 0 -CH ₂ —N NH ₂ H —N — CH ₂ - 665.6 665.1 -NH- (CH ₂ ) ₃ -NH-C (= = NH) -NH ₂ 603.5 603.2 -NH- _(CH2) jN (CH) - (CH ₂₎ 3-NH-C (= nhj-nh ₂₎ 674,6- 674.2

• ·· · · ·

-158 -

R ¹ : y Ilke ^: MS '...' .rl NH - N - CH ₂ - (CH ₂ -N 4 NH ₂ H '- ^/ H 671.6 671.2 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 645.6 645.2 -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ 617.5 619.2

Example 44

Analogously to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 3- (3-aminophenyl) -N- (3-chloro-

4-fluorobenzyl) propionamide, with a suitable diamine and with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. The following compounds of formula IIIm are obtained after deprotection:

R ¹

Cl

R ^and V Ilm MS -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 629.1 629.5 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 587.1 587.5 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 657.2 657.3

· ^; .. · .-. Μ5 · •• 4 '·. ···. · ... · ·· “. ··· .. · • · 9 · ··· 9 · · 9 9 • ' • · · · · • 9 9 999

- '•• 15? -

• · ·

Example 45

Analogously to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with a compound of formula

with a suitable diamine and with tert-butyl- (tert-butoxycarbonylimino-pyrazol-1-ylmethyl) carbamate. Removal of the protecting groups yields the following compounds of formulas (IIna) to (IIc):

R ¹ ý. ILNA ; MS * · «/ · · • t. -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 606.7 607.4 -NH- (CH ₂ ) ₂ -NH-C (= NH) -NH ₂ 564.6 565.6 -NH- (CH 3) 7 -NH-C (= NH) -NH ₂ 634.8 635.3 --ΝΉ A, ch ₂ —n nh ₂ 646.8 1 647.6 -N - CH ₂ - <> H NH-CH-N, -P-CH ₂ - ^NH ₂ H - H 640.7 641.5 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 578.7 579,6 -NH- _(CH) NOS (CH) - (CH ₂₎ J -NH- 649.8 650.5 C ( 'NH) _-NH2 -

τ i S4 -

R ¹

R ¹ Αν. iLNB MS | F. . | -NH- (CH ₂ ) s -NH-C (= NH) -NH ₂ 620.8 621.4 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 578.7 579.4 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 648.8 649.5

• · ·

• · ♦ · f ‘· '·. ···. ·· * ·. *. ·. · R,. ·., .. ·; ...

; <·. * · .- <- j .Λ · .. ·· /. · '· • ♦' · ♦. 4. .

• · · ···

-163 -

R ¹ V Ilnc MS -NH- (CH ₂ ) s -NH-C (= NH) -NH ₂ 592.7 593.3 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 550, 6 551.4 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 620.8 621,3 --- JJ DB / _CH2 ^- N _NH2 / - \ H 632.8 633.4 N CH _2-Y ') H 'Jl NH N - CH ₂ --CH ₂ N NH ₂ 626.7 627.3 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 564.6 565.3 -NH- (CH ₂ ) 3 -N (CH ₃ ) - (CH ₂ ) j -NHC (= NH) -NH ₂ 635.8 636.3 - ~ NR Λ —N CH ₂ - () - CH ₂ —N NH _Z HH 632.8 633.4 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 606.7 607.3 ' -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ 578.7 579.4

Example 46

Analogously to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with a compound of formula

// -

with a suitable diamine and tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. Removal of the protecting groups yields the following compounds of formulas Iloa to Iloc: R ¹

R ¹ V Iloa MS -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 608.7 609.4 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 566.6 567.5 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 636.8 637.3

NH

- II N - CH _{2 -ΛΑ-CH2-N} ^ _NH2 642.7 643.4 \ = / _H -NH- _(CH2) 3-NH-C (= NH) -NH ₂ 580.7 581.4 N (CH3) - (CH3) j -NH-651.8 652.4 C (-NH) -NH ₂ II N - CH ₂ -6-Λ-ΟΗ ₂ ^ -Ν ΗΗ ^{₂₆₄₈ '8} 649.6 \ —F H -NH- (GH ₂ ) ₆ -NH-C (= NH) -NH ₂ 622.7 623.3

- 16-5 -

R ^{@ 1} MS -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 594.7 595.5 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 552, 6 553,4 · -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 622.7 623.2 NH A yCH ₂ —N NH ₂ -N — CH ₂ - 634.8 635.5 NH —N — ch ₂ —Cy — ch ₂ —Ah ₂ HH 628.7 629 -4 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 566, 6 567.5 -NH- (CH ₂ ) 3 N (CH ₃ ) - (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 637.8 638.3 NR _CH2-N - / N-CH ₂ NH ₂ HH 634.8 635.6 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 608.7 .609,3 -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ 580.7 581.4

- 166 • ··. R ¹

R ¹ y. hoc MS -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 580.7 581.3 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 538.6 539.3. -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 608.7 609.3 NH J / from CH ₂ - n _NH2 620.7 621.4 -N-CH ₂ -θ H NH-N-CH ₂ --CH ₂ - Pas _2H ^ ⁷ = H, 614.7 615.2 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 552.6 553.4

Example 47

Analogously to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 3- (3-aminophenyl) -N- (3-phenoxyphenyl) propionamide, a suitable diamine and tert-butyl- (tert-butoxycarbonyliminopyrazole-). l-ylmethyl) carbamate. After deprotection, the following compounds of formula IIp are obtained:

x *

- 16¾ -

Example 48

In analogy to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 3- (3-aminophenyl) -N- (3-benzyloxyphenyl) propionamide, with a suitable diamine and tert-butyl (tert-butoxycarbonyliminopyrazole). -l-ylmethyl) carbamate. The following compounds of formula IIq are obtained after deprotection:

R ¹

R ¹ 'v11q MS -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 668.8 669.3 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 626.7 627.4 -NH- (CH ₂ ) t -NH-C (= NH) -NH ₂ 696.8 697.3

Example 49

Analogously to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 3- (3-aminophenyl) -N-naphthalen-2-ylpropionamide, with a suitable diamine and tert-butyl- (tert- butoxykarbonyliminopyrazol-l-ylmethyl) carbamate. After deprotection, the following compounds of formula IIr are obtained:

- ϊ-70-

Example 50

Analogously to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 3- (3-aminophenyl) -N-benzylpropionamide, a suitable diamine and tert-butyl- (tert-butoxycarbonyliminopyrazol-1-ylmethyl) ) carbamate. After deprotection, the following compounds of formula Ia are obtained:

R ¹ γ lis MS u 1 -NH- (CH _{2) 5} -NH-C = NH) -NH ₂ 576.7 577.4 -NH- (CH ₂ ) ₂ -NH-C [= NH) -NH ₂ 534.6 535.5 -NH- (CH ₂ ) ₇ -NH-C [= NH) -NH ₂ 604.8 605.4 NR J1. _{ζ οη} -ν ₂ NH ₂ 616.8 617.5 -N - CH ₂ - H --------- NR ₂ CH 2 - NH ₂ H 610.7 611.3

• · -

Example 51

Analogously to Example 32, 6-nitrobenzophde] isochromene-1,3-dione is reacted with 3- (3-aminophenyl) -N- (3-fluoro-4-methoxyphenyl) propionamide, with a suitable diamine and tert-butyl ( butoxykarbonyliminopyrazol tert-l-ylmethyl) carbamate.

The following compounds of formula IIt are obtained after deprotection:

• • • • • - -

R ¹ in Ilt MS -NH- (CH ₂ ) s -NH-C (= NH) -NH ₂ s -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 568.6 569.3 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 638.7 639.4

u ^ch ₂ —N NH ₂

H — N — CH ₉ i ^from H

ΝΠ644,7 N - CH ₂ CH ₂ NH ₂ N HH 645.3 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ -nh- (ch ₂ ) ₃ -n (ch ₃ ) - (ch ₂ ) ₃ -nh- 653.8 C (~ NH) -NH ₂ 654.3 NH N - CH, - / \ _CH2-N '''NH _J HH 650.8 651.8 -NH- _{(CH2) 6} -NH-C (= NH) -NH ₂ 624.7 625.3 -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ -596.7 .597,5

Λ

597.7

645.2 '····························· ·· ··· '17 ^ -

Example 52

Analogously to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 3- (3-aminophenyl) -N- (3-fluoro-4-methylphenyl) propionamide, with a suitable diamine and tert-butyl - (tert-l-butoxykarbony1iminopyrazol ylmety1) carbamate. After deprotection, the following compounds of formula (III) are obtained:

R ¹

R ¹ in clay MS -NH- (CH ₂ ) s -NH-C (= NH) -NH ₂ 594.7 595.3 -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 552.6 553.5 -NH- (CH ₂ ) ₇ -NH-C (= NH) -NH ₂ · 622.7 623.4

NR

- 175 -

R ¹ y. MS NH 2 —CH ₂ —N 4 NH 3 N - CH ₂ - H 628.7 629.3 -NH- _{(CH2) 3} -NH-C (= NH) -NH ₂ 566.6 567.5 -NH- (CH ₂ ) ₃ -NC (<= NH) -NH ₂ (CH ₃ ) - (CH ₂ ) ₃ -NH- 637.8 638.3 NH 2 Z-CH ₂ -N 4 NH ₂ ^X 'H - N - CH _2-H 634.8 635, 6 -NH- _{(CH2) 6} -NH-C (= NH) -NH ₂ 608.7 609.3 -NH- _(CH2) 4 -NH-C (= NH) -NH ₂ 580.7 581, 4

Example 53

Analogously to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with a compound of formula

and ₃ and ₃ with a suitable diamine and with tert-butyl (tert-butoxycarbonylimino pyrazol-1-ylmethyl) carbamate. After deprotection, the following compounds of formula IIva are obtained

176 -

R ¹ ν '. Ilva v. ys -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 650.8 651.5 -NH- (CH ₂ ) ₂ -NH-C (= NH) -NH ₂ 608.7 609.5 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 678.8 679.4 NR J 1 _z ch ₂ —n nh ₂ / - (H 690,8 691.6 N CH ₂ - H NH N - CH ₂ --CH ₂ -N ^ 'N H HH 684.8 685.5 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 622.7 623,5 -NH- (CH ₂ ) 3 -n (CH ₃ ) - (CH ₂ ) j -NHC (= NH) -NH ₂ 693.8 694.4 NH 1 --N - CH _{2 -} y - CH _{2 -} NH ₂ HH 690,8 691.6 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 664.8 665.4 ’ -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂ 636,7 637.5

R ¹ Ilvb MS r -NH- (CH ₂ ) s -NH-C (= NH) -NH ₂ 650.8 651.4 -NH- (CH ₂ ) ₂ -NH-C (= NH) -NH ₂ 608.7 609.5

- 17? -.

R ^{@ 1} - IIb MS -NH- _(CH2) 7-NH-C (= NH) -NH ₂ 678.8 679.4 11 __ / ^CH 2 ^NH _{2 690/8} 6 ₉₁ 8 N-CH 2 H H NR: - N - CH ₂ --CH ₂ - Ah, θθ ^, δ 685.4 Hm = ⁷ H -NH- (CH ₂ ) ₃ -NH-C (= NH) -NH ₂ 622.7 623.4 -nh- <CH ₂ ) ₃ -n (CH ₃ ) - (CH ₂ ) ₃ -nh- 693.8 694.4 C (= NH) -NH ₂ NH - N - CH ₂ - (CH ₂ -N 4 NH ₂ ⁶⁹⁰ < ^{8 69]} · / ⁶ HH -NH- (CH ₂ ) ₆ -NH-C (= NH) -NH ₂ 664.8 665.3 -NH- (CH ₂₎ 4 -NH-C (= NH) -NH ₂ 636.7 637.4

Example 54

In analogy to Example 32, 6-nitro-

with a suitable diamine and with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. The following compounds of formula IIw are obtained after deprotection:

d - 178 -

Example 55

In analogy to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with a compound of the formula

·. ·.

17? with a suitable diamine and with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After deprotection, the following compounds of formula (Im) are obtained:

R ¹ MS -NH- (CH ₂ ) s -NH-C (= NH) -NH ₂ -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 524.6 525.3 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂ 594.7 595.3 'NR J] / _CH2 ^- N _NH2 / - (H 606.7 607.3 N - CH ₂ -θ H ~ NR —N — ch ₂ —yy — ch ₂ —N NH ₂ H 4 = ⁷ H 600.7 601.2 -NH- (CH ₂ ) 3 -NH-C (= NH) -NH ₂ 538.6 539.4 -NH- (CH ₂ ) 3 N (CH ₃ ) - (CH ₂ ) 3 -NHC (= NH) -NH _: 609.7 610.3 NH N CH ₂ - (\ _CH2-N ^ H ^ _NH2 - ⁷ H 606.7 607.4 -NH- (CH ₂ ) 6 -NH-C (= NH) -NH ₂ 580.7 581.3 -NH- (CH ₂ ) 4 -NH-C (= NH) -NH ₂

· · · · · 4 '· · • * '4 ·· · • · • • • • • • • • 4 • 4 • · · · • · • • • · e · · · 4 * · · • • • 4 e ···

180 Example 56

Analogously to Example 2, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 2- (4-aminophenyl) -3- (4-dimethylaminophenyl) propionitrile followed by R 1 -H. The following compounds of formula (In) are obtained:

R ¹

N

R ¹ 'y. R ^x -H · in MS -NH- _{(CH2) p-NH2} 545 546 -NH- (CH _{2) 7} -NH ₂ 573 574 -N - CH ₂ - <5 H ^λ , ch ₂ —nh ₂

Example 57

At room temperature, 10 ml of TFA is added to a solution of 2.4 g of tert-butyl- [3- (2- {4- [1-cyano-2- (4-dimethylaminophenyl) ethyl] phenyl} -1,3-dioxo- 2,3-dihydro-1H-benzo [de] isoquinolin-6-ylamino) propylcarbamate in 40 ml of dichloromethane [obtainable by reaction of 6-nitrobenzo [de] isochromene-1,3-dione with 2- (4-aminophenyl) - 3- (4-dimethylaminophenyl) propionitrile and with the compound of formula H ₂ N- (CH ₂ ) g -NHBOC] and the reaction mixture is stirred until the reaction is complete. After usual work-up, 2- {4- [6- (3-aminopropylamino)] - 1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl} -3- (4-dimethylaminophenyl) propionitrile is obtained.

184 Example 58

In analogy to Example 32, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with a compound of formula

CH ₂ ) ₂ -CONH- (CH ₂ ) ₂ -CH

I with a suitable diamine and with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. The following compounds of formula Ioa are obtained after deprotection:

R ¹ Ioa MS -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 680.8 681.4 -NH- (CH ₂ ) ₂ -NH-C (= NH) -NH ₂ 638.8 639.6 -NH- (CH ₂ ) 7 -NH-C (= NH) -NH ₂  708.9 709,4

721.6

CH _{2 -} NH _{2 720} g H - N - CH ₂

H

—N - CH ₉ and ² H

NH

1 /

CH ₂ —N NH _{2,714 /} 9

H

715.5

v ₄ 181 - F R ¹ / Ioa MS - * 1 -NH- _{(CH2) 3} -NH-C (= NH) -NH ₂ 652.8 653, 6 -NH- (CH ₂ ) ₃ -N (CH ₃ ) - (CH ₂ ) ₃ -NH- 723.9 724.4 C (n = NH) -NH ₂ NH r- \ Á 720.9 721.6 —N - CH ₂ ' \) CH ₂ N NH ₂ H '-' H -NH- _{(CH2) 6} -NH-C (= NH) -NH ₂ 694.9 695.4 -NH- (CH ₂ ). -NH-C (= NH) -NH ₂ 666.8 667.3

Example 59

Analogously to Example 32, 6-nitro benzo [de] isochromene-1,3-dione is reacted with a compound of formula

ch ₂ ) ₂ -con-ch ₂ -ch *

with a suitable diamine and with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. The following compounds of formula Iob are obtained after deprotection:

R ¹ in ^Iob MS -NH- (CH ₂ ) 5 -NH-C (= NH) -NH ₂ 666 .8 667.3

“Ŕ ¹ in lob MS in. . . x -NH- (CH ₂ ) 2 -NH-C (= NH) -NH ₂ 624.7 625.5 -NH- (CH ₂ ) ₇ -NH-C (= NH) -NH ₂ 694.9 695.4 NH N - CH ₂ --CH ₂ - N ^ _NH2 HH 700.8 701.4

Example 60

Analogously to Example 11, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 4- (iodophenyl) amine or 3- (iodophenyl) amine (= J-Ar'-NH ₂ ), with Het ¹ -B- (OH) ₂ and then with R ¹ -H. The following compounds of formula Ip are obtained:

ip

-N'-Het ¹

R ^{1 in} R ^x -H a: Ip -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) s-NH ₂ -nh- (CH ₂ ) ₇ -nh ₂

-N'-Het ¹

R ^{@ 1} H @ R ^{@ 1} H @ @ @ @ @ @ @ @ -. Ip

-NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂

-NH- _(CH2) 3 'NH ₂

-NH- _{(CH2) p-NH2}

-nh- (ch ₂ ) ₇ -nh ₂

-NH- (CH ₂ ) ₃ -NH ₂

-NH- _{(CH2) p-NH2}

-NH- (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂

-NH- _{(CH2) p-NH2}

-NH- (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂

-NH- _{(CH2) p-NH2}

-NH- (CH _{2) 7} -NH ₂

-NH- (CH ₂ ) ₃ -NH ₂

-NH- (CH ₂ ) ₅ -NH ₂

-NH- (CH _{2) 7} -NH ₂

• r

Example 61

Analogously to Example 11, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 4- (iodophenyl) amine or 3- (iodophenyl) amine (= J-Ar 1 -NH ₂ ) with R ³ -Het ¹ -B (OH) ₂ and then with R ¹ - !!

The following compounds of formula Iq are obtained:

- 186 -

Example 62

Analogously to Example 11, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 4- (iodophenyl) amine or 3 (iodophenyl) amine (= J-Ph-NH ₂ ), with R ⁶ - ( CH ₂ ) _n -Ph-B- (OH) ₂ and then with R 1 -H (Ph-Ph = Ar '). The following compounds are generally obtained.

formula Ir: R ¹ A I ks l L ^{, r} ot | N'-fCHjln-R®

In analogy to Example 11, 6-nitro-2- (4-iodophenyl) benzo [de] isoquinoline-1,3-dione is reacted with a compound of formula R ¹⁰ -B- (OH) ₂ , where R ^{10 is a} group of formula

OC (CH ₃ ) ₂ -CO-OC ₂ H ₅ and with propane-1,3-diamine. There was thus obtained 2- {4 '- [6- (3-aminopropylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] biphenyl-4-yloxy} -2-methylpropionic acid ethyl ester.

- $ 18 Example 64

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with 5-methoxy-pyrimidine-2-sulfonic acid (4-aminophenyl) -amide and propane-1,3-diamine. There was thus obtained 5-methoxypyrimidine-2-sulfonic acid {4- [6- (3-aminopropylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} amide.

Example 65

Analogously to Example 2, 6-chlorobenzo [de] isochromen-1,3-dione is reacted with 1- (6-amino-2,3-dihydroindol-1-yl) ethanone and propane-1,3-diamine. 2- (1-Acetyl-2,3-dihydro-1H-indol-6-yl) -6- (3-aminopropylamino) benzo [de] isoquinoline-1,3-dione is obtained.

Example 66

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with 4- (pyrrolidine-1-sulfonyl) phenylamine and propane-1,3-diamine. 6- (3-Aminopropylamino) -2- [4- (pyrrolidine-1-sulfonyl) phenyl] benzo [de] isoquinoline-1,3-dione is obtained.

Example 67

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with 4-cyclohexylphenylamine and propane-1,3-diamine. 6- (3-Aminopropylamino) -2- (4-cyclohexylphenyl) benzo [de] isoquinoline-1,3-dione is obtained.

- 185 Example 68

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione was reacted with 3- (3-aminophenyl) -N- (2-phenylpropyl) propionamide and 3-aminomethylbenzylamine. There was thus obtained 3- {3- [6- (3-aminomethylbenzylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} -N- (2-phenylpropyl) propionamide.

Similar to the reaction of 6-chlorobenzo [de] isochromene-1,3-dione with 3- (3-aminophenyl) -N- (1-phenylethyl) propionamide and

3-Aminomethylbenzylamine gives 3- {3- [6- (3-aminomethylbenzylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} -N- (1-phenylethyl) propionamide .

Example 69

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with 3- (3-aminophenyl) -1- (3,4-dihydro-2H-quinolin-1-yl) propan-1 with 3-aminomethylcyclohexylamine. There was thus obtained 6 - [((3-aminomethylcyclohexylmethyl) amino] -2- (3- [3- (3,4-dihydro-2H-quinolin-1-yl) -3-oxopropyl) phenyl} benzo [de] isoquinoline- l, 3-dione.

Example 70

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with a compound of the formula

H ₂ N-Ar'-S- (CH ₂ ) _n -CONH- (CH ₂ ) -Ar and with 3-aminomethylbenzylamine. The following compounds of formula (Iya) are obtained.

r l · .-

• f ···· ·· ··

• 'Λ ·. · ,.

• <·

Ar'-S- (CH ₂ ) _n -CONH- (CH ₂ ) _r Ar

Ar 1 -S- (CH ₂ ) n -CONH- (CH ₂ ) 1 -Ar-Iya - ^with ~ CH ₂ CONH - Br -S-CH ₂ - CO-NH-CN ζΑ -OS-CH. CONH- (CHJ ₂ —NO, —Qs-ch ₂ -conh-ch ₂ -no ₂ - <^ s ~ _S-CH2 --CONH- (CH _{2) 2} - -Ζ ~ _S-CH2-CH --CONH - --CONH- _{-CH2 (CH2) 2} -Qj --ζ ~ ^> - _S-CH2-CH --CONH - -Q-s-ch-co ™ -θ-S-CH, -CONH CONH-CH —Θ-S-CH, —CONH -θ-Q - ^{S — CH} : - CONH (CH3), —δΟ, -ΝΗ, - ^{with -CH} 2 - CONH- ^CH 2 ^-CH 2 SO 2 NH 3 --S-CH - CON H J / ¹ '-CH

• ´ -. 'Jà * .. <·. ·. · < . ♦ · ·. / · - ·. · - .. .. - “<| · . -. _e · ... • • · - · · - < ·. · • · • • • · • • • · • · • · · · • · • • · · • • • • • • · · · · • · • · • · •

- • 19'1 -

Ar 1 -S- (CH ₂ ) n -CONH- (CH ₂ ) _X -Ar R 6 · Iya -θ-8-0Η ₃ —CONH-θ- ^ ™ ¹ --S-CH ₂ -CONH- (CH _{2) 2} - C —S — ch ₂ —conh-ch ₂ - Cl --S 'CH _{2 -} CONH- (CH ₂ ) ₂ - Cl - ^ ~ ^ -S-CH ₂ -CONH-C —S — ch ₂ —conh-ch ₂ Cl --S-CH ₂ -CONH- (CH ₂₎ j C --S-CH ₂ -CONH-CH ₂ - <^ ~ 7 ~ ^C _--S-CH2 CONH-Cl --S-CH - CONH (CH ₂₎ s - CH - ^ ~ ^ ~ ^S ~ ^CH from ^C0NH - ^CH ' -QS- CH - CONH-CH ₂ - CK-S ₂ - CONH - - ^ - ^ - ^s - ^ch ₂ - ^c ° ^nh —— ^och 'Cl

····

Ar 1 -S- (CH ₂ ) _n -CONH- (CH ₂ ) 1 - Ar in thi - - S - CH ₂ CONH - cf ₃ —S— ch _{2 —} CONH — f> ci - ^cl > - \ —s — ch ₂ —conh-ch ₂ - Cl - ^cl> - \ -QS- CH ₂ CONH (CH ₂₎ j N, Cl ClCl - s - CH ₂ CONH-CH ₂ - ^ 2 / - ^C> ~ \ --S-CH ₂ -CONH-CH ₂ Cl _--S-CH2 --CONH- (CH _{2) 2} - (> C -QS C-CH ₂ -CONH-CH ₂ - Cl _Cl-CH2 --S --CONH - C C-S-CH ₂ -CONH-yl ^ -CI _--S-CH2-CH2 --CONH - - ^S - CH _{2 -} CONH- (CH ₂ > 3- _--S-CH2 CONH -QS-CH ₂ -CONH-CH ₃ -

• · · · ·

Ar 1 -S- (CH ₂ ) n -CONH- (CH ₂ ) i -Ar in Iya --S — CH, - CONH- (CHJ, - - <Q> ~ _S-CH2 - CONH - ^ Q> _-CH3 - X ₁ --CH ₂ - CONH - <^ 2 / ^ ch ₃ -S-CH ₂ CONH - L AH _S —ζ ~ ^> - s — ch ₂ -CONH— s —Ζ ~~ ^ —s— ch ₂ - conh- ^ Λ \ f ₃ —Ζ ~~ ^ —s — ch ₂ —conh-ch ₂ - ^ cf ₃ —S — CH ₂ —CONH-CH ₂ ^F Cl --- S-CH ₂ -CONH-F Cl - ^ 2 ^) - p -CH ₂ - _CONH-CH2 -vJ / - ^f Cl -S-, CH-CONH- (CH _{2) 2} - OCH --S - CH _{2 -} CONH-CH ₂ - OCH, _--S-CH2 CONH- OCH - ^ 2y> ~ S _"CH2 --CONH-ICH), -OCH - ^ch '- ^conh ' ^{ch2 —C3-001 : 3}

Ar 1 -S- (CH ₂ ) n -CONH- (CH ₂ ) i -Ar -1-1-Iya --S — CH _Z CONH —— OCH ₃ --S - CH ₂ - CONH- (CH ₂ ) ₂ - ^ ~~ y ~ F —— ch ₂ —conh-ch ₂ - F -S- CH ₂ -CONH F --S— CH _{2 -} CONH— r '/ OPh -S — CH ₂ —CONH— ^ 2 / -S- _CH2 CONH-- ^0PH --S — CH, CONH — 0 CH, --CH ₂ --CONH- ^'0? —S— ch ₂ —conh-ch ₂ - --s — ch ₂ —conh-ch ₂ - F - ^ - y - S - CH ₂ CONH - OCH ₃ F - ^ ~ Y> -S- CH ₂ CONH - CH ₃ From ^CF 3 --S - CH _{2 -} CONH ₃ and ₃

. . · <♦ t t t t t · · · · · · · · t t t t t t t t t t t t t t t t t t ·

-: 5

Ar'-S- (CH ₂ ) _n -CONH- (CH ₂ ) i -Ar. Iya ✓tert-butyl - ^ ~~ y ~ S _CH2 - CONH - tert-butyl-1 ςρτζ —S — CH ₂ —CONH- (CH ₂ ) ₂ - 'OCH --S - CH _{2 -} CONH - och ₃ - / VS-CH-CONH _(CH2 ^ -V) -OCH

In analogy to Example 32, the compounds of formula (Iya) above are reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. The following compounds of formula Iyb are obtained after deprotection:

Ar'-Sr (CH ₂ ) _n -CONH- (CH ₂ ) _r Ar

Ar'-S- (CH ₂ ) _n -CONH- (CH ₂ ) i -Ar. .i Iyb CH ₂ —CONH— Br - ^^ - S-CH3 - CONH— . CN •

. ·; ··· '. · ·,; ·, · ·. <· -. · - · -1-; ·. · <. 7 · '·. . · * ·· · ·., .. ·· .. ·. · -. · '.-:. ··. ...... '. ... <Ο «.... ···. ·· .. - ·· .. · · χ · 44 · Λ; ν .χ. <· ;,. ·; · · · ···· · · · · · · · ·

-V19Ŕ -

Ar 1 -S- (CH ₂ ) _n -CONH- (CH ₂ ) i -Ar in Iyb -S-CH ₂ CONH (CHJ- ^ ~ ^ -N0 _{2 -S-CH2} --CONH-CHj-- no ₂ -Ηθ-s-CH-CONH- (CH ₂ ) ₂ - <θ> —Ζ ~~ ^ —s — ch ₂ —conh-ch ₂ - from = N-O-CH ₂ S --CONH- (CH _{2) 2} - --S-CH - CONH-CH ₂ - θ _{5 ΟΗ1} ΟΟΝΗ —Θ-S-CH-CONH -θ- <™ ₂ —Ζ ^ -S-CH— CONH-CH 3 - —Θ-S-CH, —CONH —θ “θ S-CH, - CONH (CH _{3) 3} -NH --SOj, -S-CH ₂ -CONH-CH ₂ -NH ₂ --sout £ ^ _{a C "2} - CONH - _CH ^^ x _Chi ^ £ _p -CONH-CH ^ _p Qh- -Ζθ-S-CH ₂ -CONH- (CH _{2) 2} - C —Θs — ch ₂ CONH-CH ₂ - Cl -Ζθ-p---CONH- _{CH2 (CH2) 2} - Cl --S-CH ₂ Cl --CONH--

^Ar, -S- _(CH2) n-CONH- (CH ₂₎ Ar-C. · IYB —S — ch ₂ —conh-ch ₂ - C ( - <~ ζ ^ -S-CH ₂ -CONH- (CH _{2) 2} - --With-CH ₂ -CONH-CH ₂ --Cl _--S-CH2-Cl --CONH _-S-CH2 --CONH- (CH _{2) 2} -Q-CH -S — CH ₂ -CONH-Q CH, - (C s - ch ₂ —con-ch ₂ - ZA _--S-CH2 CONH --ζ ~ _S-CH2 --CONH - OCH, Cl _{--S-CH2 CF3} --CONH- (CF ₃ —S — ^CH 2 CONH — ξ _)> - Cl -S- CH ₂ -CONH-CH ₂ - Cl _{--S-CH2-íCHJr} --CONH - ^^ C - ^ 00 ^ 3-0.-¾ ° Cl — s — ch ₂ - conh-ch ₂ —Y_y “ ^cl

^ .19 8 -

¹ 1 Ar -S- _(CH2) n-CONH- _(CH2) "Ar" IYB - ^C -> - ^S - CH _{2 -} CONH- (CH ₂ ) ₂ - ^Cl Cl — s — ch ₂ —conh-ch ₂ - Cl --S C-CH ₂ Cl --CONH-- _Cl-CH2 --S --CONH- £ ^ -CI —S — ch ₂ —conh-ch ₂ - -Ζ2 ^δ ^ ~ ^{CH2 -} C0NH- _(CH2) HQ> --- _S-CH2 --CONH- -Os -CH ₂ -CONH- (CH _{2) 4} - -S-CH ₂ -CONH- (CH _{2) 2} - ^^ - 01% - ^p -CH ₂ CONH - ^ yy ~ _CH3 CH ₃ —S — CH ₂ -CONH-CH ₃ - ^ ~ ^ -S-CH-CONH-θ- < - - ^ HT - / - Λ - S - CH - CONH - No - ^> - S - CH - CONH - ^{A A} CF _a

í ?? £ ·. , e · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-'ίΜ -

Ar ¹ S (CH ₂ ) n CONH- (CH ₂ ) 1 - Ar in Iyb _{-S-CH2 -CONH-CH2} - ^ _CF3 —S — ch ₂ —conh-ch ₂ - ^F Cl -S-CH ₂ -CONH-F-Cl —Qs-ch ₂ - conh-ch ₂ - \ _ y> “ ^F Cl ⁷ -QS- CH ₂ -CONH-CCHJ - ^ _OCH3 —S — ch ₂ —conh-ch ₂ - and ₃ -S- CH ₂ OCH --CONH- --S — CH3 - CONH- (CH3) ₂ ——OCH, -S- CH ₂ -CONH-CH ₃ --OCF -S-, CH ₂ -CONH-CH _{3 0} f —Qs-ch — conh- (ch ₂ ) ₂ - —S — ch ₂ —conh-ch ₂ - ^X F --S - CH _{2 -} CONH - F --S— CH _{2 -} CONH— , OPh —y ~ s— ch ₂ — CONH— •

-. '.' X'-i *

• · loo -

Ar 1 -S- (CH 2) n -CONH- (CH ₂ ) i -Ar 1b —S — CH, - CONH —— OPh --S - CH, - CONH - 0 - CH, —S — CH, CONH— ° -o - with - CH ₂ CONH-CH, - ABOUT --S — CH, —CONH-CH, - F —S — CH, —CONH —— OCH, F --S — CH, - CONH —— CH, / ^CF 3 - S - CH, - CONH - OCH, ytert-butyl --S— CH, - CONH— Tett-butyl - ^ ~~ y ~ S— CH, —CONH- (CH,), - 'Oh. / OCH, --— ^with - CH, - CONH- / och ₃ - OCH, --SCH, —CONH- (CH3) r-O-OCH,

Example 71

Ί.

2C4 -

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with a compound of formula

H ₂ N-Ar 1 -S- (CH ₂ ) _n -CONH- (CH ₂ ) and with 3-aminomethylbenzylamine. The following compounds are obtained

of the general formula Iza rv - \ N nh ₂ kJ. Iza ⁰ N ^ 0

Ar 1 -S- (CH ₂ ) _n -CONH- (CH ₂ ) _r Heti.

Ar 1 -S- (CH ₂ ) n -CONH- (CH ₂ ) 4 -Het ¹ in Iza - ^ ~ ^S “ ^CH2 - CONH-CCHJ— 0 - ^ ~ ^ “ ^s “ ^ch 2 — conh- (ch ₂ ) _3- - _{S ^ --CONH- _{-CH2 (CH2) 2} - —Q-s-ch, -conh-ch, - <0 —S — ch ₂ —conh-ch ₂ - <0]

In analogy to Example 32, the compounds of formula (Ia) above were reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. The following compounds of formula Izb are obtained after deprotection:

V, 202 -

Ar 1 -S- (CH ₂ ) _n -CONH- (CH ₂ ) _r Het ¹

Ar -S- (CH _{2) n} -CONH- _(CH2) ^ι-1 to Het. ~ Izb S — CH2 ₍ CONH-CCH3) - 0 -QS-CH _{2 -} CONH- (CH ₂ ) ₃ - --Y ^ _-S-CH2 --CONH- (CH _{2) 2} - z = \ —Z pcs-ch ₂ —conh-ch ₂ —Y - ^with ~ ^CH ₂ —conh-ch ₂ —γ]

Example 72

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with a compound of the formula

H ₂ N-Ar 1 -S- (CH ₂ ) _n -CONH- (CH ₂ ) 3 -DH and with 3-aminomethylbenzylamine. The following compounds of formula IIIa are obtained

Ar-S-ICH ^ -CONH-ÍCHjJrD-H

203 -

Ar ¹ -S- (CH ₂ ) _n -CONH- (CH ₂ ) 1 -DHVIIIa --S — CH ₂ -CONH - —Ζ ~~) —s — ch ₂ —conh ^ ^ ^ 2)

In analogy to Example 32, the compounds of formula (Ia) above were reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. The following compounds of formula IIb are obtained after deprotection:

N-S- (CH ₂ ) _n -CONH- (CH ₂ ) _r DH

Ar'-S- (CH ₂ ) _n -CONH- (CH ₂ ) iDH v. ILB --- S-CH ₂ -CONH) - (¢))) - S - CH ₂ - CONH - (CH ₃ -) -)

Example 73

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione was reacted with 2- (3-aminophenylsulfanyl) -N- (2-phenylpropyl) acetamide and 3-aminomethylbenzylamine. It will be obtained

2- {3- [6- (3-Aminomethyl-benzylamino) -1,3-dioxo-1H, 3H-benzo [d] isoquinolin-2-yl] -phenylsulfanyl} -N- (2-phenyl-propyl) -acetamide.

H Similar to Example 32, 2- {3- [6- (3-Aminoethylbenzylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenylsulfanyl} -N- (2- phenylpropyl) acetamide is reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. Removal of the protecting groups yields 2- {3- [6- (3-guanidinomethylbenzylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenylsulfanyl} -N- (2-phenylpropyl) acetamide.

Example 74

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with a compound of formula

H ₂ N-Ar'-S- (CH ₂ ) _n -CONH- (CH ₂ ) _± -O- (Ar ¹ ) -Ar ² and with 3-aminomethylbenzylamine. The following compounds of formula I3a are obtained

Ar 1 -S- (CH ₂ ) _n -CONH- (CH ₂ ) _r CH (Ari) -Ar 2

Ar 1 -S- (CH ₂ ) n -CONH- (CH ₂ ) i -CH (Ar ¹ ) Ar ² in I3a - - - - - - - CH _{2 -} CONH-CH ₃ -j ^w- --y n-S-CH, -CONH-CH ₂ CH

Analogously to Example 32, the compounds of formula (I3a) above are reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After

The following compounds are obtained by deprotection.

Ar'-S- (CH ₂ ) _n -CONH- (CH ₂ ) _i -CH (Ar ¹ ) -Ar ²

Ar 1 -S- (CH ₂ ) _n -CONH- (CH ₂ ) χ-CH (Ar ¹ ) Ar ² '- V. I3B —Ys — ch ₂ —conh- (cHj) ₂ -ch ^w X) N - (/ VS-CH ₂ -CONH-CH ₂ CH CXX Ό

Example 75

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione was reacted with 2- (3-aminophenyl) -N (4-chlorobenzyl) acetamide and 4-aminomethylcyclohexylmethylamine to afford 2- {3- [6- (4-Aminomethyl-cyclohexylmethyl) -amino] -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl} -phenyl) -N- (4-chloro-benzyl) -acetamide was reacted with tert-butyl- (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate After deprotection, N- (4-chlorobenzyl) -2- {3- [6- (4-guanidinomethylcyclohexylmethylamino) -1,3-dioxo-1H, 3H-benzo] is obtained. [de] isoquinolin-2-yl} phenyl) acetamide.

Similarly, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with

3- (3-aminophenyl) -N-phenethylpropionamide and with 4-aminomethylcyclohexylmethylamine and the obtained 3- (3- {6 - [(4-aminomethylcyclohexylmethyl) amino] -1,3-dioxo-1H, 3H-benzo [de] isoquinoline -2-yl} phenyl-N-phenethylpropionamide with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate After deprotection, 3- (3- (6 - ((4-guanidinomethylcyclohexylmethyl) amino) -1) is obtained. , 3-dioxo-ΙΗ, 3H-benzo [de] isoquinolin-2-yl} phenyl) -N-fenetylpropiónamid.

Example 76

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with a compound of formula

H ₂ N-Ar '- (CH ₂ ) _n -CONH- (CH ₂ ) —Ar and 3-aminomethylbenzylamine. The following compounds of formula I6a are obtained:

Ar 1 - (CH ₂ ) _n -CONH- (CH ₂ ) _i -Ar

Ar 1 - (CH ₂ ) _n -CONH- (CH ₂ ) i -Ar; . I6a CONH-hQ'O ^Xsr , (CH _{2) 2} -CONH-ol

- ‘•

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) 1 -Ar V: 16a • CON - ^> 'cn F ^ / _{(CH2) 2} -CONH- N - (CH ₂ ) ₂ -CONH- (CH ₂ ) - ΓΛ-ΓΛ ₂ -o _ '' ' -ABOUT / (CH ₂ ) ₂ -CONH-CH ₂ - Ao ₂ yCONH-CH ₂ —C- N = X ^ XONH- (CH ₂ ) ₂ - Aj z = N 4 / (CH ₂ ) ₂ -CONH- (CH ₂ ) ₂ 2J . (CH ₂ ) ₂ -CONH-CH ₂ - -Ό

. .; · ···, · ... · <*. ··· · · .. ·· «t *.:. · '··: ·.; ··»!

.9.-

H ·

Y. ·. /: / - · Λ

- 20 8 -

Ar - _{(CH2) n} -CONH- _(CH2) ι-v-Ar _'in I6a £ ONH-CH ₂ - Y / = \ ^ C ₂ h _with the (CH _{2) 2} -CONH-yJY ^N \ _c h ^ • H / = \ / CA _C0NH _ £ jH _N Y / = \ / ^ch 3, (CH ₂ ) ₂ -CONH-CH ₂ - conh.ch ₂ ^ Qn- ^ -n (CH ₂ ) ₂ - CONH - (CH ₂ ) j —so ₂ -nh ₂ -Q ". (CH _{2) 2} - -CH ₂ -CONH _2, -NH ₂ --Of O conh-ch ₂ ——so ₂ -nh ₂ (CH3), -ΟΟΝΗ-θ ^^ _ΟΗ3 -Ώ CONH <! \ - _R Y_ _i / · \ = / Y ^uh ₃

-20 <? -

Ar 1 - (CH ₂ ) n -CONH ₂ (CH ₂ ) i -Ar ^; I6a (CH _{2) 2} - CONH-d) -L-CH ₃ D _CON H Y 4 X _3% (CH ₂ ) ₂ - CONH- (CH ₂ ) ₂ "-G)" (CH ₂ ) ₂ -CONH-CH ₂ - / v -d CONH-CH ₂ ý y / ““ '“X x (CH _{2) 2} - CONH (CH _{2) 2} H

- '• ‘• 2 / -

Ar '- (CH ₂ ) n' CONH - (CH ₂ ) i -Ar 1 '; Cl _{(CH2) 2} - CONH- d. (CH ₂ ) ₂ - conh- ₂ - / Y conh-ch ₂ —d \ -o CONH- (CH ₂ ) ₂ - N -d CONH — dd ~ Q ^CI (CH 2 - CONH - (CH ₂ ) _{2 -} Cl - (CH _{2) 2} - CONH QC. -d

• · ·

- ^ν ·· 214 -

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) ₂ -Ar: I6a CONH _{(CH2) 2} Cl -fy -v /. CONH-V-Cl ₂ ) ₂ -conh- (ch2) ₂ —ch ₃ -d (CH ₂ ) ₂ - conh-f ₃ CONH — CH ₃ “O CONH _{(CH2) 2-f} ~ -C-CH ₃ CONH- X} (CH ₂ ) ₂ - CONH-CH _{2 - 2} o

- 215 -

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) χ-Ar v.46a (CH ₂ ) ₂ -CONH- (Vci X) CONH = Cl ^CF = ^C A (CH ₂ ) ₂ - con-ch ₂ -P y -Q CONH-CH ₂ -7 2 Their -CONmCH ^ ^ - ^^ ClCl (CH ₂ ) ₂ - conh-ch _{2 -} 7 \ Cl _x Cl CONH-CH ₂ - P 7 -o

· ’· · ·

- ”214-

Ar ¹ - (CH ₂ ) _n 'CONH- (CH ₂ ) 1 - Ar in I 6a CONH _{(CH2) 2} Cl -Ώ C (CH _{2) 2} - _CONH-CH2 --7 \ Cl _CONH-CH2 -7 yl-d (CHJ _r CONH - Cl CONH — y Cl. (CH ₂ ) ₂ - CONH - t -Cl Cl CONH-V-Cl-d

-215 f

Ar ¹ - (CH 2) n ^- CONH ^- (CH 2) i -Ar 1 '16a ., CONH-CH ₂ —ζ EJ ζΟΟΝΗ-ΙΟΗ, ν-ζ ^ / -tj (CH _{2) 2} - CONH (CH _{2) 3} - ^ 3 * d (CH ₂ ) ₂ - CONH - d ¹ CONH- TJ) _{(CH2) 2} - _CO-NH-CH2 - / -J (Cha- CONH (CH _{2) 4} -C CONH _{(CH2) 4-7} -

- 216 -.

F

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) i -Ar 1 -. I6a (CH _{2) 2} - CONH CCHj), - £-CH _{3-d /} CONH- (CH ₂ ) _r -Z ₃ -CH ₃ -o ch ₃ (CH ₂ ) ₂ -CONH-ΛΛ Aj ch ₃ CONH — dy JCHJ ₂ - CONH— <Jj CONH —— <j dD ( ^C 2 ^H 5 (CH ₂ ) ₂ -CONH-d 2 -d

- ^: 21? ~ ·

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) i -Ar. I6a £ ₂ H ₅ CONH— (CH ₂ ) ₂ -CONH- (f) -H (CHJj-C0NH-CH ₂ -C 2 conh-ch ₂ —f-d - CONH —'v -d ^cf - (CH _{2) 2} - CONH-CH ₂ - ^F (CH _{2) 2} - CONH-d CONH-CH ₂ -

—218 -.

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) 1 -Ar K-16a CONH - ^F ~ O ^Cl (CH ₂ ) ₂ - CONH-CH ₂ - / VF CONH-CHj · —C V-F k ”/ (CH _{2) 2} - CONH- _{(CH2) 2} - _OCH3 (CH ₂ ) ₂ -CONH- / OCH 8 (CH3); - CONH-CH; -ABOUT conh-ch ₂ —Λ \ / \ OCH, CONH _{(CH2) 2} - / o _ / ^z \ _OCH3 CONH — ξ /> / \ ^X and ₃

- 21 ¹ ) -

··. ·· ^ 210

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) 1 -Ar 1, 16a . Λ (CH ₂ ) ₂ - CONH-CH 2 - ([f) -d 1 -] conh-ch ₂ —C-d ^f CONH— / \ ABOUT F rcH ₂ ) ₂ - 'conh' ÍCH ₂ ) ₂ - conh - \ -d ^f _ CONH— / \ F - (CH ₂ ) ₂ -CONH-f! \ 5) "

- 224 -

Ar - _(CH2) n-CONH- _(CH2) ι-Ar re I6a Oph CONH — C ý A) ICH ₂ ) ₂ -CONH — OPh CONH - C - OPh - d CONH — O ^CH 3 O (CH ₂ ) ₂ -CONH ₂ -CH ₂ ^{CH 2} OCH Ph D CONH-'χ / ¹ E "/ ^{x ph} (CH ₂ ) ₂ - CONH-CH ₃ -

. ··· '······. ·.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· -; ; ·· '. ·;. · ´ · -c, "- Z ·. ·:

- 222'-.

Ar 1 - (CH ₂ ) _n -CONH- (CH ₂ ) χ-Ar v -. .. I6a F (CH;), - CONH - <- OCH, -about • F COHK ---- OCH. IN F (CH ₂ ) ₂ - CONH - CH ₃ V F CONH ——CH ₃ v cf ₃ (CH 2); ^CF 3 _ .CONH— —OCH, ✓tert-butyl (CH _{2) 2} -CONH-C 2 / \ tert-butyl

• · ·

• · · · · · · ·

In analogy to Example 32, the compounds of formula (Ia) above are reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After deprotection, the following compounds of Formula I6b are obtained:

♦ ,.

.. ---: -. -, α '

.. ···· »· ♦

λ. ·.

<··: ν

- 22 ý -

Ar 1 - (CH ₂ ) _n -CONH- (CH ₂ ) _r Ar

Ar - _{(CH2) n} -CONH- _(CH2) ι-Ar characterized. I6b .CONH-Q IN Z (CH ₂ ) ₂ -CONH -O CON-O -ABOUT / (CH ₂ ) ₂ -CONH - (} -θ Yn ^ / _{(CH2) 2} -CONH- _{(CH2) 2-d}} - ^{N °?} -about / CONH- _{(CH2) 2 2} x -XVno y (CH ₂ ) ₂ -CONH-CH ₂ -Q ₁₀

- 225 -.

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) χ-Ar V 16b yCONH-CH ₂ —Y -O Ao ₂ N = 1, CONH- (CH ₂ ) ₂ -? - d z = N / TCH ₂ ) ₂ -con- ₂ - / = N of (CH ₂ ) ₂ -CONH- (CH ₂ ) ₂ - -bJ , (CH _{2) 2} -CONH-CH ₂ - <^ ^N O conh-ch ₁ - f = \ ₍ C ₁ H ₃ ) ₍ CH ₂ ) ₂ -conh-4> -n _x "O r = \ / C ₂ H ₅ O / = \ / ^CH 3, (CH ₂ ) ₂ -CONH-CH ₂ - \ _ / - ⁿ x _C u -o (CH 2 -CONH -

- 226'-.

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) χ-Ar 16b (CH ₂ ) ₂ -CONH-CH ₂ —so ₂ -nh ₂ d conh-ch ₂ ——so ₂ -nh ₂ —Ό (ΟΗΛ-ΟΟΝΗ-θ-θ ^ χ ^ -about conh ^ Qa ^ _CH3 X / - (CH _{2) 2} CONH / ^CH 3 V4-d _C0NH ry4_ ^H c ³ H3 -Ό · conh-ch _{2 —} y y Xj conh- (ch ₂ ) ₂ —y

I

• · · · · · · · · · · ·

\ é · '> ·. '·. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · . · ·. - · · · · · · · · Ú ‘·’ '* · * <

..........., _λλ: ........ _in.

• X. · ·

- 222'- ·

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) 1 -Ar 16b conh- (ch ₂ ) ₂ —ΛΛ- ch ₃ CONH 2 -CH ₃ O conh-ch ₂ - \ - do (CH ₂ ) ₂ -conh -d _oo CONH- ~ d (CH ₂ ) ₂ -CONH-CH ₂ - d (CH ₂ ) ₂ -CONH --- -d CONH — OCH ₃ -O ~ ^a

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) 1 -Ar λ _V vlb Cl -, (CH _{2) 2} - CONH - d Cl CONH —¾ -d “ Cl CONH-C-CI-P , conh-ch ₂ -o , ΟΟΝΗ- (ΟΗ ₂ ) τ-ζ ^ CONH-yl -d conh- (ch ₂ ) ₄ —dd “Q _/ CONH- (CH ₂ ) _r -4 y-CH ₃ -d

- ^ν 23ή -.

Ar '- (CH 2) _n ' CONH- (CH ₂ ) _n -Ar 16b ^CH 3 (CH ₂ ) ₂ -CONH -? --O ch ₃ CONH-C 1 -d ^cHa 1 / CONH — ΛΛ — ý -d CONH - β-d (CH ₂ ) ₂ -CONH- ^dcFi (CH ₂ ) ₂ - CONH-CH ₂ - / 2 -d - conh-ch ₂ -'y -d CONH- \ \ F.

· · #

- ^ 232nd -

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) 1 -Ar 16b (CH 3) ₂ - CONH - ^F / O CONH-CH, - < V F W X CONH— (X F “O (CH ₂ ) ₂ - CONH-CH ₂ - / p-F -d ^Cl CONH-CH ₂ —C Vf (CH ₂ ) ₂ - CONH- (CH ₂ ) ₂ - and ₃ W • (CH ₂ ) ₂ -CONH -v and _3- V? conh-ch _{2 -} 4 y and ₃ CONH- (CHJ- /, OCH.

- 233 -

Ar 1 - (CH ₂ ) _n -CONH- (CH ₂ ) 1 -Ar 1: 16b CONH— / 7 -O ” ^0CH jCONH -CH ₂ O ₃ --ocf CONH —— OCH ₃ “W CONH- (CH _{2) 2} ^0CH 3-d ---- (CH ₂ ) ₂ - CONH - (CH ₂ ) ₂ -? , CONH (CH _{2) 2} --- F conh-ch ₂ —f ý ^F. • CONH — C \ ^F ÍCH ₂ ) ₂ - CONH — y / “O

- 23y - • ···

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) 1 -Ar 1b CONH-y-G> ° F / ^conh -0- ^o (CH ₂ ) ₂ -CONH - OPh - CONH - f ~ y> - OPh CONH - <5 ~ yl ~ --CH °. ~ O XCH ₂₎ j CON -dV ° ~ - TI CONH— “vJ ^{x Ph} F CONH —— OCH ₃ -

j:

-, 235 -.

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) i -Ar 1b F CONH-phenyl) -CH cf ₃ __ (CH ₂ ) ₂ - CONH - #C ° ^{C CH 3 CF} 3 CONH 3 -3 ° ^{C 3} and Tert-Butyl (CH ₂ ) ₂ -CONH- / 2 tert-butyl .tert-butyl .conh ^ Q tert-butyl - / ch ₂ ) ₂ -conh-hQJ -o - ~~ / och ₃ CONH - C y> X) ------------------- ^:: _{OCH3 /} CONH- _{(CH2) 2} - / _y-OCH3-d

- 23é -.

Example 77

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with a compound of formula

H ₂ N-Ar '- (CH ₂ ) _n -CONH- (CH ₂ ) _i Ar and with 3-aminomethylcyclohexylmethylamine. The following compounds of formula I7a are obtained:

Ar 1 - (CH ₂ ) _n -CONH- (CH ₂ ) _r Ar

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) i -Ar 1 - 17a z (CH ₂ ) ₂ -CONH - / (PS-PI-CONH 7 , (CH ₂ ) ₂ -CONH-A

Example 78

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with a compound of formula

H ₂ N-Ar '- (CH ₂ ) _n -CONH- (CH ₂ ) -Het ¹ with 3-aminomethylbenzylamine. The following compounds of formula I8a are obtained:

23? -

- 233 -

^Ar, - _(CH2) n-CONH- _(CH2) 0-Het ¹ I8a , (CH ₂ ) ₂ -CON H- (CH ₂ ) ₂ - "O _/ (CH ₂ ) ₂ -CONH- (CH ₂ ) ₃ - d (CH ₂ ) ₂ -CONH-CH ₂ . o -ti UQ , CONH-CH _{2 - [} X] (CH ₂ ) ₂ -CONH-CH ₂ —θΙ] -d (CH ₂ ) ₂ -CONH-CH ₂ -? -about 0-η .CONH -CH 2 θ]

In analogy to Example 32, the compounds of formula 18a above are reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After deprotection, the following compounds of formula I8b are obtained:

~ 2Η0 -

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) i -Het ¹ vo. _λ I8b (CH ₂ ) ₂ -CONH- (CH ₂ ) ₂ -O (CH ₂ ) ₂ -CONH- (CH ₂ ) ₃ - d (CH ₂ ) ₂ -CONH-CH ₂ X 4. o O , conh-ch ₁ - (CH ₂ ) ₂ -CONH-CH ₂ - d

Example 79

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with a compound of formula

H ₂ N-Ar '- (CH ₂ ) _n -CONH- (CH ₂ ) —DH and with 3-aminomethylbenzylamine. The following compounds of formula I9a are obtained:

Ar 1 - (CH ₂ ) _n -CONH- (CH ₂ ) i D H

- 24ή -

Ar'-CHCH-J-CONHHCH 3 -D-H Vv ' I9a (CH ₂ ) ₂ -CONH - ( CONH- / -d CONH _{(CH2) 2} H -ýd

In analogy to Example 32, the compounds of formula (I9a) above are reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbaraate. The following compounds of formula I9b are obtained after deprotection:

Ar 1 - (CH ₂ ) _n -CONH- (CH ₂ ) i D H

Ar ^, - (CH ₂ ) _n -CONH- (CH ₂ ) ₁ -DH 19b (CH ₂ ) ₂ -CONH -dd -d

* ······················································

- 242, -

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) iDH 19b CONH- CONH- (CH ₂ ) ₂ - (CH 2) - CONH-CH 2 - -ABOUT (CH3), - CONH- (CHJ, -d

Example 80

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with a compound of formula

H ₂ N-Ar 1 - (CH ₂ ) _n -CONH- (CH ₂ ) 3 -CH (Ar ¹ ) -Ar ² and with 3-aminomethylbenzylamine. The following compounds of formula I10a are obtained:

Ar 1 - (CH ₂ V CONH- (CH ₂ ) _r CH (Ari) -Ar 2

- 243 -.

Ar 1 - (CH ₂ ) n -CONH- (CH ₂ ) 1 -CH (Ar ¹ ) Ar ² y 110a Ό CONH- (CH ₂ ) ₂ -CH A) X), conh-ch ₂ -ch C. X. d 3 (CH ₂ ) ₂ - CONH - (CH ₂ ) ₂ --CH ₂ - ^; Ό _Z (CH ₂ ) ₂ - conh-ch ₂ -ch CX -d Ό

In analogy to Example 32, compounds of formula 110a above were reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. The following compounds of general formula 110b are obtained after deprotection:

Ar 1 - (CH ₂ ) _n -CONH- (CH ₂ ) _r CH (Ari) -Ar ² • s

Example 81

Analogously to Example 2, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with a compound of formula H ₂ N- ^c 6 ^H 4 - ( ^CH 2) n R ³ and then with R ¹ -, to give the following general compounds

(CH ₂ ) _n -R ₃

-. 245 -

-C6H4- _{(CH2) n} ^-R3 R ¹ y. R ^x -H ar Hla O / (CH ₂ ) ₂ -C (NH, -O -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -nh- (CH ₂ ) ₇ -nh ₂ / Ar ™ ² o / (CH ₂ ) ₂ -Y -d ^rH ' -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) 5 NH ₂ yA- ^{NH 2} o / (CH ₂ ) ₂ -AA ~ yyy ^nh2 iV ”· _the co-n-C ₇ H? ^R -NH- (CH ₂ ) 3 -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ · .co-N - CH ₃ Y ^A -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) s -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂

• · · ·

-.24 $ -

-C ₆ H ₄ - (CH ₂ ) _n -R ³ R ¹ in R ^x -H a. Hla 0 / (CH 2 -C CH, -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) _with -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ - H ch ₃ ✓ CO — N - (CH 3) ₂ <- _CH ^H CH, -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ ΊΧΤ ”· 0 0 _x ch ₃ -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ -NH- _{(CH2) 3-NH2,} -NH- (CH _{2) 5} -NH ₂ -NH- (CH ₂₎ 7 -NH ₂ ^{NH 2 _} SkQk

Analogously to Example 11, 6-nitro-2- (3-iodophenyl) benzo [de] isoquinoline-1,3-dione or 6-nitro-2- (4-iodophenyl) benzo [de] isoquinoline-1,3- the dione is reacted with H ₂ NC ₁₂ H ₈ - (CH ₂ ) _n - R and then with R 2 -H. The following compounds of formula IIIb are obtained:

(CH ₂ ) _n -R ₃

111b

- ^l : 24 7

-C ₁₂ H ₈ - (CH ₂ ) _n -R ³ R ¹ in R ¹ -H a. IIIb -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) s -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ H. C ^ -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) s -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ CHžXh. -NH- _{(CH2) 3 -NH2} -NH- _{(CH2) p-NH2,} -NH- _(CH2) 7-NH ₂ ^{NH 2} ^ ~ ííd2y P ~ Q ^ h ₃ c -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) 5 -NH ₂ -NH- (CH ₂ ) 7 -NH ₂

-C ₁₂ H ₈ - (CH ₂ ) _n -R ³ R ¹ v. R ^x -H and ... Illb h ₃ c -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ 'Γ'ΓΓ' ^ΝΗ2

Example 82

Analogously to Example 11, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with 4-iodophenylamine or 3-iodophenylamine (= J-Ar'-NH ₂ ), with Het ¹ -B (OH) ₂ and then with R 1 -H. The following compounds of formula Ip are obtained:

N'-Het ¹

-N'-Het ¹ R ¹ v. R ^x -H a. Ip -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ ITL .., -rcM

• · · ······ ·

- 245 -

-N'-Het ¹ R ¹ VR ^ H ai- Ip -NH- (CH ₂ ) ₃ -NH ₂ / ⁼⁼ \ // U -nh- (ch ₂ ) ₅ -nh ₂ VJZ \ 1 ' - ^ ch ₃ -NW ^x nh ₂ ^h M ^x nh ₂ H / Tert-butyl -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ “0 ~ ^N 0 -NH- (CH _{2) 7} -NH ₂ ^x nh ₂ —N γ Y - H U tert-butyl ^x nh ₂ H NH - < H U nh ₂

Example 83

Analogously to Example 2, 6-nitro benzo [de] isochromene-1,3-dione is reacted with a compound of the formula

R ⁶ - (CH ₂ ) _n -Ph-NH ₂ and then with R ¹ -H. The following compounds of general formula are obtained

(CH ₂ ) _n -R 6

112

• • - 250 - ···· · · · · • · · · · · · · · · · • · · · · · · · • ·· ·· ·· N '- _{(CH2) n} -R ^p R ¹ VR ^1- -H ô 112 -0-N \ h. -NH- (CH _{2) 3} -NH ₂ -NH- (CH _{2) 5} -NH ₂ -NH- (CH _{2) 7} -NH ₂ CH- z Nech ₃ -NH- (CH ₂ ) ₃ -NH ₂ . -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ N, - ( ^C H, CH ₃ -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ -ν · 0 ^ 0ήη ₂

Example 84

Analogously to Example 2, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with (4-aminophenyl) phenylacetonitrile and then with R 1 -H. The following compounds of formula (113) are obtained:

113

R ^x in R ^x -H a. . 113 -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) 5 -NH ₂ -NH- (CH _{2) 7} -NH ₂ -

• · · ·

- 254 -.

F

R ¹ R ^x -H a. 113 - Ν'θί ^ Ι ^ ΝΗ ²

Example 85

Analogously to Example 11, 6-nitro-2- (4-iodo-R ¹² -phenyl) benzo [de] isoquinoline-1,3-dione is reacted with R ¹⁰ -B- (OH) ₂ and then with R H. The following compounds of formula 114 are obtained:

R ¹² R ¹⁰ R ¹ a. . 114 H -ABOUT -NH- _{(CH2) 3-NH2} · Td

- 251 -

R ¹² R ¹⁰ R ¹ s, R ^x H, and 114 H --CN -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) _with -NH ₂ -nh- (CH ₂ ) ₇ -nh ₂ - N 3-CH ₃ --OH -NH- (CH ₂ ) 3 -NH ₂ -NH- (CH ₂ ) s -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ H -Q-NO ₂ -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) s -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ H -rcr < no ₂ -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂

Example 86

Analogously to Example 11, 6-nitro-2- (4-iodo-R ¹² -phenyl) benzo [de] isoquinoline-1,3-dione is reacted with R ¹⁰ -B- (OH) ₂ and then with R ¹ -H. The following compounds of formula Ibm are obtained:

Example 87

Analogously to Example 2, 6-nitrobenzo [de] isochromene-1,3-dione is reacted with H ₂ N-Ar and then with R 1 -H. The following compounds of formula Ibg are obtained:

R ¹

Ar

Ar R ^{@ 1} in R @ 4 H and Ibg --CH ₂ Ph -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) 7 -NH ₂ -Nyy 4 N ^H ₂

- 254 - ♦ · ·>> 254 254 254 254 254 254 254 254 254 254 254 254 254 254 254 254 254 254 254 254 254 254 254 254 254 ·· ··

Ar R ¹ . R @ 1 H and. .. IBG -CH ₂ -Ph ΊΧΟ .NH Λη. - O-CH ₂ -Ph -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ “ ₂ H U DXT ^x nh ₂ , NH A and U ^ň nh ₂ Ch ¹ -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ αΎΥ ^x nh ₂ H U -? ΎΥ ^x nh ₂ H naïve , NH A H U ” nh ₂ Ύ C> -ABOUT -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ h ₃ c-c 7 -NH- (CH _{2) 7} -NH ₂ ^ nh ₂ H U -Your ^ nh ₂ h. M NH - < H U nh ₂

• · · · · · · · · · · ·

- 255 -

Ar R ^1. ' C-H: Ibq dd about -NH- (CH ₂ ) ₃ -NH ₂ D -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) 7 -NH ₂ yyy ^ nh ₂ H U - <γγ Yh ₂ H M .NH A HU ^H nh ₂ ABOUT_ _o> Λ -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ N ^ YV ^x nh ₂ H U - ^ ΎΥ nh ₂ H M -ΎΥΊΐ Y ^h . HU ^H nh ₂ A -NH- (CH _{2) 3} -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ -fW ^x nh ₂ H U -ΓΎΥ ^x nh ₂ H M .NH - < H U ” nh ₂ A _r about Br -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH - (CH ₂ ) ₇ -NH ₂ -fr ^ nh ₂ H M

• · · ·

- 256 -

Ar R ¹ '; IBG - N '^ ^X || ^ | ^ ^Xnh ₂ och ₃ —OCH, -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ OCH ₃ .. OCH, 4i -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) s -NH ₂ -NH- (CH ₂ ) 7 -NH _{2 S} o ₂ - () -0 -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) 5 -NH ₂ -NH- (CH ₂ ) 7 -NH ₂ -0- ' -n -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ —OCH, nc ^^ och. -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ ./OCH3 —ZA — OCHa Ach ₃ -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) 7 -NH ₂ / - -0 -NH- (CH _{2) 3} -NH ₂ -NH- (CH _{2) 5} -NH ₂ -NH- (CH _{2) 7} -NH ₂ -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂

- 25? -

Ar R ^1. ' ν ^ -Η and- Ibg NC _ΛΑ — och ₃ ^ OCHj -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ ——Och ₃ Cl -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) s -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ ° d -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) s -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ OCH, d ocf ₃ -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) s -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ Cl -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) s -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ XW · -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ och ₃ -% - och ₃ -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) s -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ CN -NH- (CH ₂ ) ₃ -NH ₂ -ΝΗ- (ΟΗ ₂ ) ₅ -ΝΗ ₂ -NH- (CH ₂ ) ₇ -NH ₂

• · · ·

- 25Ž> -

Ar R ¹ '. yR ^x -H and:. IBG br -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ no ₂ -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ C with? 3 CF Ί3 -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ A N> ^ OH -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ ( x ^ -C -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ ¢ 0 Cl -NH- _{(CH2) 3 -NH2} -NH- _{(CH2) 5} -NH ₂ -NH- (CH _{2) 7} -NH ₂ ^ Q) - ^CH 3 Br -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂

- 259 a

Ar R ¹ VA. rM a. IBG _ ^^ - s ₂ ^nh ₂ -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) _with -NH ₂ -nh- (CH ₂ ) ₇ -nh ₂ —TT ^-ocH3 -nh- (CH ₂ ) ₃ -nh ₂ -NH- (CH ₂ ) _with -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ —Och ₃ OH -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂ ABOUT OH -NH- (CH _{2) 3} -NH _2, -NH - (CH _{2) 5} -NH ₂ -NH- (CH _{2) 7} -NH ₂ A ^ D ^ OH -NH- (CH ₂ ) ₃ -NH ₂ -NH- (CH ₂ ) ₅ -NH ₂ -NH- (CH ₂ ) ₇ -NH ₂

Example 88

3- {4- [6- (3-Aminomethylbenzylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} -N- (3,3-dimethylbutyl) propionamide according to Example 81 is reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate according to Example 32. Removal of the protecting group affords N- (3,3-dimethylbutyl-3- {4- [6- (3-guanidinomethylbenzylamino)]. (1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl) propionamide.

Example 89

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with 3- (4-aminophenyl) -N- (3,3-dimethylaminopropyl) propionamide and with C- (3-aminomethylcyclohexyl) methylamine. 3- {4- [6- (3-Aminomethyl-cyclohexylmethyl) -amino] -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] -phenyl} -N- (3,3-dimethylaminopropyl) is obtained. propionamide.

- 2Ϊ0 -

• ···· · · · ♦ · • • • · • • • · · • • · · • • ·· · ·· · ·

· · ·· · • • · ·· • • · · ··· · • · · • • · · · · ·· ···

Example 90

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione was reacted with 2- (4-aminophenylsulfanyl) -N- (3,3-dimethylbutyl) acetamide and 3-aminomethylbenzylamine. 2- {4- [6- (3-Aminomethylbenzylamino) -1,3-dioxo-1,3H-benzo [de] isoquinolin-2-yl] phenylsulfanyl} -N- (3,3-dimethylbutyl) acetamide is obtained.

Example 91

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione was reacted with H ₂ N-Ar'-Y- (CH ₂ ) _n -R ³ and 3-aminomethylbenzylamine. The following compounds of formula 112 are obtained:

Ar 1 -Y- (CH ₂ ) _n -R ³

Ar 1 -Y- (CH ₂ ) n -R ^{3 0} ch ₃ <F

- 264

Example 92

Analogously to Example 2, 6-chlorobenzo [de] isochromene-1,3-dione is reacted with 4- (pyrrolidine-1-sulfonyl) phenylamine and 3-aminomethylbenzylamine. 6- (3-Aminomethylbenzylamino) -2- [4- (pyrrolidine-1-sulfonyl) phenyl] benzo [de] isoquinoline-1,3-dione is obtained.

Example 93

An equimolar amount of [6- (3-aminopropylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] -4,5-dimethoxybenzonitrile according to Example 87 (page 256, table line 1), and methanesulfinic acid is reacted in a known manner to give [6- (3-aminopropylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] -4,5-dimethoxybenzonitrile methanesulfonate addition salt.

¹ H-nmr (DMSO-d ₆ ):

8.80 (dd, J = 1.0 and: J = 8.6 Hz, 1 H), 8.50 (dd, J = 0.8 a. J = 7, , 4 Hz, . 1H) 8.34 (d, J = _8,66 ) Hz, 1H) 7.94 (t ( N-H, J = 5.8 Hz, 1H), 7.76 (dd, J) = 7.4 a. J = 8.4 Hz, 1H) 7.71 (SBR 2H _(NH2)), 7.55 (s, 1 H), 7.30 (with, 1H), 6.90 (D, J = 8.8 Hz, 1H), 3.90 (s, 3H) 3.81 / (WITH, 3H), 3,60- -3.45 (M, 2H), 2.96 (t, J = = 7.6 Hz, 2H); 2.31 (s, 3H) 2,08- • 1, 94 (m, 2H).

Abbreviations related to nmr signals (nmr = nuclear magnetic resonance):

with s. D d. dd double doublet, T triplet, SBR wide singlet, m m,

262-q quadruplet,

J coupling constant J in Hz

In a similar manner to Example 93, the following acid addition salts were obtained:

3- {3- [6- (2-guanidinoethylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} -N- (4-phenylbutyl) propionamide (Example 40, p. 145, table row 2)

3- {3- [6- (2-guanidinoethylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} -N- (4-phenylbutyl) propionamide methanesulfonate. H-NMR _(DMSO-d6):

8.73 (dd, J = 1.0 and J = 8.5 Hz, 1H), 8.46 (dd, J = 8.5 Hz, 1H);

1.0 and 1 'J = 7.3 Hz, 1H), 8.28 (d, J = 8.5 Hz, 1H), 7.88 (t, J = 5.6 Hz, 1H), 7.75 (dd, J = 7.3 and J = 8.4 Hz, 1H), 7.61 (t, J = 5.8 Hz, 1H), 7.40-7.36 (m, 1H), 7.287 23 (m, 3H), 7.16-7.10 (m, 4H), 6.89 (d, J = 8.7 Hz,

1H), 3.61-3.50 (m, 4H), 3.06 (q, J = 7.0 Hz, 2H), 2.892.85 (m, 2H), 2.53 (d, J = 7.6 Hz, 1H), 2.39 (t, J =

8.5 Hz, 2H), 2.36 (s, 3H), 1.56-1.49 (m, 2H), 1.41-1.34 (m, 2H).

N- [2- (4-chlorophenyl) ethyl] -3- [3- (6- {3 - [(3-guanidinopropyl) methylamino) propyl} -1,3-dioxo-lH, 3H-benzo [de] isoquinolin -2-yl) phenyl] propionamide (Example 37, page 135, table line 7) N- [2- (4-chlorophenyl) ethyl] -3- [3- (6- {3 - [(3-guanidinopropyl) methylamino)] propylamino} -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl) phenyl] propionamide methanesulfonate.

¹ H-nmr (DMSO-d ₆ ):

10.49 (sbr, 1H); 8.85 (d, J = 8.5 Hz, 1H); 8.44 (dd, J)

= 0, 9 a: J = 7.3 Hz, 1H), 8.27 (d, J = 8.5) Hz, 1H), 8.01 (sbr, 1H, NH) 7.94 (t, J = 5.6 Hz, 1H (N H)), 7.90 (T, J 5.9 Hz, 1H (NH)), 7.73 (dd, J = 7.4 and · J = 8,4 / Hz, 1H), 7.42-7.38 (m, 1H) 7.31 (d, J = 8.4) Hz, 2H), 7 26 (d, J = 7.7) Hz, 1H), 7.18 (d, J = 8.4) Hz, 2H), 7, U -7.11 (m, 2H). 6.88 (d, J = 8.7 Hz, 1 H), 3, .65- -3.45

263 -

(m, 3H), 3.31-3.15 (m, 6H), 3.11-3.04 (m, 1H), 2.85 (t, J = 7.3 Hz, 2H), 2, 77 (d, J = 4.9 Hz, 3 H), 2.67 (t, J =

7.3 Hz, 2H), 2.39 (t, J = 5.7 Hz, 1H), 2.35 (s, 3H), 2.21-2.14 (m, 2H), 1 _of 96- 1 _of 89 (m, 2H).

N- [2- (4-chlorophenyl) ethyl] -3- {3- [6- (2-guanidinoethylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} propionamide (example 37, page 135, table row 2)

N- [2- (4-chlorophenyl) ethyl] -3- {3- [6- (2-guanidinoethylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl] propionamide methanesulfonate.

^x H-nmr (DMSO-d 6):

8.74 (dd, J = 1.0 and J = 8.6 Hz, 1H), 8.44 (dd, J = 1.0 and J = 7.3 Hz, 1H), 8.27 (d, J = 8.5Hz, 1H), 7.94 (t, J = 5.7Hz, 1H (NH)), 7.80 (t, J = 5.2Hz, 1H (NH)) 7.76 (t, J = 5.1 Hz, 1H (NH)), 7.74 (dd, J = 7.3 and J = J).

8.5 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 8.4 ')

Hz, 2H), 7.26 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 8.4 Hz,

2H), 7.14-7.11 (m, 2H), 6.89 (d, J = 8.7 Hz, 1H), 3,613.56 (m, 2H), 3.55-3.50 (m, 2H) 3.28-3.23 (m, 2H), 2.86 (t, J = 8.2Hz, 2H), 2.67 (t, J = 7.1Hz, 2H), 2.40 (t, J = 7.3 Hz, 2H), 2.35 (s, 3H).

N- [2- (4-chlorophenyl) ethyl] -3- {3- [6- (3-guanidinopropylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} propionamide (example 37, page 135, table row 6)

N- [2- (4-chlorophenyl) ethyl] -3- {3- [6- (3-guanidinopropylamino) -1,3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] phenyl} propiónamidmetánsulfonát .

¹ H-nmr (DMSO-d 6):

8.76

8.27

7.73

7.40

(D, J = 8 2 ⁵ Hz, 1H), 8.44 (D, J = 7.3 Hz, 1H) (D, J = 8 5 Hz, 1H), 7.93 (T, J = 5.6, 1H (NH)) (T, J = 7 ; 5 Hz, 1H), 7.65 (T, J = 5.6 Hz, 1H) (T, J = 8 .0 1 Hz, 1H), 7.31 (D, J = 8.4 Hz, 2H)

- 26 ^ -

7.18 (d, J = 8 _from 4 Hz, 2H), 71.4-7 11 (m, 2H); 6.84 (d, J) = ⁸ ; 7 Hz, 1H), 3.45 (t, J) = 6.3 Hz, 2H), 3.31-3.22 (m, 4H), 2.86 (T, J = 8.0Hz l , 2H), 2.66 (t, J = 7.1Hz, 2H), 2.41 . (D, J = 8.2 Hz, 2H); 2.37 (s, 3H), 1.99-1.91 (M, 2H).

6- (3-aminopropylamino) -2- (2,3-dimethoxyphenyl) benzo [de] isoquinoline-1,3-dione (Example 87, page 255, table line 3) 6- (3-aminopropylamino) -2- (2,3-dimethoxyphenyl) benzo [de] isoquinoline-1,3-dione methanesulphonate.

H-NMR (DMSO-d _s):

8 _; 75 (dd, J = 0.9,. J = 8.4 Hz, 1H), 8.46 (dd, _J, = 0.8, J = 7 _S 3 Hz, 1 H), 8.30 (d, J = 8.5 Hz, 1H), 7 _of 86 (sbr, 1H (NH)), 7.75 (dd, J = 7.3 and: J = 8.4 Hz, 1H), 7, 65 (bt, 2H (NH)), 7.17-7.15 (m, 2H), 6.89-6.85 (m,

2H), 3.89 (s, 3H), 3.60 (s, 3H), 3.51 (t, J = 7.0 Hz, 2H), 2.97 (t, J = 7.8 Hz, 2H), 2.31 (s, 3H), 2.03-1.96 (m, 2H).

6- (3-amino-propylamino) -2- (4 ¹ -methoxy-biphenyl-4-yl) -benzo [de] isoquinoline-1,3-dione (EXAMPLE 12, p. 98, line table 3)

6- (3-amino-propylamino) -2- (4'-methoxy-biphenyl-4-yl) -benzo [de] isoquinoline-1,3-dione methanesulphonate.

^* H-nmr _(DMSO-d6):

8.75 (d, J = 8.5 Hz, 1H), 8.48 (d, J = 6.6 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.84 (br, 1H (NH)), 7.77 to 7.68 (m, 7 H (2 * NH)), 7 _36} (d, J = 8.4 Hz., 2H), 7.07 (d, J =

8.8 Hz, 2H), 6.88 (d, J = 8.7 Hz, 1H), 3.83 (s, 3H), 3.54-3.48 (m, 2H), 2.98 ( t, J = 7.8 Hz, 2H), 2.31 (s, 3H), 2.04-1.96 (m, 2H).

6- (3-aminopropylamino) -2- (4-carbazol-9-ylphenyl) benzo [de] isoquinoline-1,3-dione (Example 82, page 247, table line 1) 6- (3-aminopropylamino) - 2- (4-carbazol-9-yl-phenyl) -benzo [de] isoquinoline-1,3-dione methanesulphonate.

¹ H-nmr (DMSO-d 6):

8.77 (dd, J = 0.9 and J = 8.6 Hz, 1H), 8.57 (dd, J = 0.8 and J = 7.3 Hz, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.29 (d, J = 7.8 Hz, 2H), 7.87 (t, J = 5 _of 7 Hz, 1H (NH)), 7.81-7 77 (m, 3H), _7,72 (sbr, 2H (NH)), 7.64 (d, J = 8.6)

Hz, 2H), 7.53-7.47 (m, 4H), 7.36-7.32 (m, 2H), 6.91 (d, J = 8.7 Hz, 1H), 3.57 (q, J = 5.9 Hz, 2H), 3.03-2.95 (m, 2H), 2.31 (s, 3H), 2.05-1.98 (m, 2H).

N- (3 - {[2- (4'-methoxy-biphenyl-4-yl) -1,3-dioxo-2,3-dihydro-benzo [de] isoquinolin-2-yl] phenyl} -N- ( 4-phenylbutyl) propionamide (Example 85, p. 251, Table 4)

N- (3 - {[2- (4'-methoxy-biphenyl-4-yl) -1,3-dioxo-2,3-dihydro-benzo [de] isoquinolin-2-yl] phenyl) -N- ( 4-phenyl-butyl) propiónamidmetánsulfonát.

¹ H-nmr (DMSO-d 6):

8.83 (d, J = 7.8 Hz, 1H) .delta 56 (t, J = 6.5Hz) 1 H (N H)), 8.49 (dd, J = 0.8 and J = 7 3 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.84 (t, J = 5.8) Hz, 1H (NH3), 7. 78 (Dd, J = M α: J = 8.4 Hz, 1H), 7, 72 (d, J = 8.5Hz, 2H) 7 '68 (D, J = 8.8 Hz, 2H), 7.40- -7.36 (m, 4H), 7.34 (D, J = 8.5 Hz, 2H), 7.22-7.19 (m, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.7Hz, 1H), 4.70 (d, J = ^5/9 Hz, 2H), 4.36 (d, J = 5.9 Hz, 2H), 3.82 (s, 3H), 2.30 (with,

.3H). .

6- (3-aminopropylamino) -2- (7-hydroxynaphthalen-1-yl) benzo [de] isoquinoline-1,3-dione (Example 87, p. 257, Table 5)

6- (3-amino-propylamino) -2- (7-hydroxy-naphthalen-l-yl) -benzo [de] isoquinoline-1,3-dione methanesulphonate.

- 266 -

¹ H-nmr (DMSO-d ₆ ):

9.61 (s, 1H (OH)) .delta _. 79 (dd, J = 0.9 and J = 8.6 Hz,

1H), 8.50 (dd, J = 0.8 and J = 7.3 Hz, 1H), 8.33 (d, J = 8 _f 5 Hz, 1H), 7.93-7.87 (m (2H), 7.79 (dd, J = 7.4 and 1H = 8.4 Hz, 1H), 7/74 (sbr, 3H (NH)), 7.43-7.37 (m, 2H) 7.10 (dd, J = 2.4 and J = 8.9 Hz, 1H), 6.81 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 2) 4 Hz, 1H), 3.53 (q, J = 6.3 Hz, 2H), 3.02-2.95 (m, 2H), 2.31 (s, 3H), 2.05-1 98 m

2H).

N- [2- (4-chlorophenyl) ethyl] -3- {3- [6- (4-guanidinomethylbenzylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} propionamide (example 37, page 135, table row 5)

N- [2- (4-chlorophenyl) ethyl] -3- {3- [6- (4-guanidinometylbenzylamino) -l, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] phenyl} propiónamidmetánsulfonát .

8.82 (dd, J = 0.8 and J = 8.5 Hz, 1H), 8.55 (sbr,

1H (NH)), 8.45 (dd, J = 0.8 and J = 7.3 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.91 ( t, J = 5.7 Hz, 1H (NH)), 7.85 (t, J = 6.1 Hz, 1H (NH)), 7.76 (dd, J = 7.4 and J = 8) 4 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.39 (t, J = 8.1 Hz,

1H), 7.32-7.23 (m, 5H), 7.17 (d, J = 8.4Hz, 2H), 7.127.09 (m, 2H), 6.58 (d, J = 8) 7 Hz, 1H), 4.69 (d, J =

4.6 Hz, 2H), 4.33 (d, J = 6.1 Hz, 2H), 3.24 (q, J = 7.4

Hz, 2H), 2.84 (t, J = 8.3 Hz, 2H), 2.66 (t, J = 7.1 Hz,

2H), 2.39 (t, J = 8.0 Hz, 2H), 2.34 (s, 3H).

N- [2- (3-chlorophenyl) ethyl] -3- <3- [6- (4-guanidinomethylcyclohexylmethyl) amino] -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl} phenyl ) propionamide (example 37, page 134, table row 5)

N- [2- (3-chlorophenyl) ethyl] -3- {3- [6- (4-guanidinometylcyklohexylmetyl) amino] 3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl} -phenyl ) propiónamidmetánsulfonát.

7 -

^* H-nmr _(DMSO-d6):

8.79 (d, J = 8.5 Hz, 1H), 8.43 (d, J = 7.3 Hz, 1H), 8.24 (dd, J = 3.1 and J = 8.6 Hz) 1 H, 7.94 (t, J = 5.7 Hz, 1 H (NH)), 7.84 (sbr, 1 H (NH)), 7.78-7.69 (m, 1 H), 7.40 ( t, J = 8.0 Hz, 1H), 70-7.22 (m, 4H), 7.14-7.10 (m, 3H), 6.82 (dd, J = 3.3 and J = 8.8 Hz, 1H), 3.27 (q, J = 6.8 Hz, 2H), 3.11 (t, J = 6.5 Hz, 2H), 2.85. (t, J = 7.3Hz, 2H), 2.69 (t, J = 7.3Hz, 2H), 2.39 (t, J =

7.4 Hz, 2H), 2.34 (s, 3H), 1.94-1.74 (m, 2H), 1.60-1.40 (m, 4H), 1.05-0, 90 (m , 2H); (cis isomer: trans isomer = 2: 1).

N- [2- (4-chlorophenyl) ethyl] -3- {3- [6- (4-guanidinomethylcyclohexylmethyl) amino] -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-4-yl] phenyl] propionamide ( Example 37, page 135, table line 8) N- [2- (4-chlorophenyl) ethyl] -3- {3- [6- (4-guanidinomethylcyclohexylmethyl) amino] -1,3-dioxo-1H, 3H- benzo [de] isoquinolin-2-yl} -phenyl) propiónamidmetánsulfonát.

¹ H-nmr (DMSO-d 6):

8.79 (Dd, J = 1.7 a; · J = ⁷ , 8 Hz, 1H), 8.43 (d J = ^7/3 Hz, 1H), 8.24 (dd, J = 3.2 and J = 8.6 Hz, 1H), 7.92 (T, J = 5 .7 Hz, 1H (NH)) ' ⁷ > 83 (bs, 1H (NH)), 7.73- 7.69 (M, 1H), 7.41-7,37 (M, 1H), 7.30 (d, J = 8.4) Hz, 2H); 7.25 (D, J = 7.8 Hz, 1  H), 7.17 (d, J = 8.4) Hz, 2H); 7.13 -7.10 (m, 2H) 6.81 (d , J = 2.9 and J = = 8.8 Hz, 1H), 3 .25 (q, J = ^7/3 hz, 2H), 3.11 (t, J = = 6.4 Hz, 2H); 2.85 (t, J = 8.2 Hz, ' 2H), 2.66 (t, J = ^{= 7} f2 Hz, 2H), 2.39 (t, J = 7.4 H l z, 2 H, 2.33 (s, 3H); 1,95- • 1.75 (M, 2H); 1.60-1.40 (M, 4H), 1.05-0.90 (m, 2H) ,); (cis

isomer: trans isomer = 2: 1).

3- {3- [6- (4-guanidinometylbenzylamino) -1,3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] phenyl} -N- [2- (4-sulfamoyl-phenyl) -ethyl] propionamide (example 35, page 129, table row 5)

3- {3- [6- (4-guanidometylbenzylamino) -1,3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] phenyl} -N- [2- (4-sulfamoyl-phenyl) -ethyl] propiónamidmetánsulfonát .

- 26 ž -

¹ H-nmr (DMSO-d 6):

8.88 (d, J = 8) 1.5 Hz, 1H), 8.66 (s br, 1 H (NH) )from 8.50 (Dd, J = 0.8 a / J = 7.3 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7 _; 93 (t, J = 6) 1.0 Hz, 1H (NH)), 7.7 7 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7 _χ 40 (d, J = 8.4 Hz, 2H); 7j 35 -7.30 (m, 4H), 7.19-7.14 (m, 3H), 6.73 (D, r J » 8.7 Hz, 1H), 4.71 (d, J = 6.1Hz, 2H) , 4.39 (d, . J = 6.1 Hz, 2H); 3.34 (q, J = 7.4Hz, 2H), 2.90 (t, J = = 8 _; 6 Hz, 2H); 2.81 (t, J = 7.2 Hz, 2H) 2.45 (t, J = = 8.3 Hz, 2H); 2.38 (s, 3H).

The following examples illustrate pharmaceutical compositions:

Example A. Injection ampoules

A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate in 3 l of double-distilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered and filled into vials, lyophilized under sterile conditions and vials sealed sterile. . Each vial contains 5 mg of active ingredient.

Example B. Suppositories

A mixture of 20 g of an active compound of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C. Solution

A solution of 1 g of an active compound of the formula I, 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of dihydrogen phosphate with 12 water molecules and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water is prepared. The pH of the solution is adjusted to 6.8, made up to 1 liter and sterilized by irradiation. This solution can be used as eye drops.

Example D. Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E. Tablets

Tablets are compressed in a conventional manner from a mixture of 1 kg of active compound of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate such that each tablet contains 10 mg of the active ingredient.

Example F. Coated tablets

Analogously to Example E, tablets are compressed and then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

EXAMPLE G. Capsules of kg of active ingredient of the formula I are filled into hard gelatin capsules in a known manner such that each capsule contains 20 mg of active ingredient.

Example H. Ampoules

A solution of 1 kg of active compound of the formula I in 60 l of double-distilled water is sterile filtered and filled into ampoules, lyophilized under sterile conditions and the ampoules sealed. Each ampoule contains 10 mg of active ingredient.

70

With equal success, the processes of the above examples can be repeated to replace the generally or specifically described reagents and / or preparation conditions of the above examples.

In view of the above, those skilled in the art will appreciate the features of the invention and that various modifications and modifications of the invention may be made within the scope of the invention according to different needs and conditions.

Industrial usability

The benzo [de] isoquinoline-1,3-dione derivative and pharmaceutically acceptable salts thereof are, as glycoprotein Ib1X antagonists, suitable for the manufacture of pharmaceutical compositions for the treatment of thrombotic disorders.

Claims (20)

wté py Compounds of formula I R ² R ¹ (I) wherein is R is hydrogen, NO ₂ , R ¹ Het, Het-SO 2 -Ar, Het-R ⁵ , -Het- (CH 2) _n -Ar, NO ₂ , -N = CH-Ar, -NHAlk, NAAlk, NHA ', NA' ₂ , a group -YDH, -Y-Ar'-R ³ , -Y- (CH 2) OR ³ , -Y- (CH 2) _R - (CHR ⁴ ) R ⁵ -, -YC - [(CH 2) 0-0H] 3, -Y- (CH 2) m -NA 2, -Y- (CH 2) m -NHA, -y- (ch 2) 0 -h, -y- (ch 2) r ⁶ , -y- (ch 2) ₁ -r ⁸ ₇ Y- _{(CH2) n} Het, -Y- (CH _{2) n} Ar, -Y- (CH ₂ ) _n -Ar '- (CH ₂ ) ₁ -R ⁶ , -Y- (CH ₂ ) _n -D- (CH ₂ ) 1 -R ⁶ , -Y- (CH ₂ ) _n -Het- (CH ₂ ) n -R ⁶ , -Y- (CH ₂ ) _n -NNA- (CH ₂ ) —R ⁶ , Y- _{(CH2) n} -NH- (CH ₂₎ -R ^6, Y- _{(CH2) n-D- (CH2)} ^t-R8, Y- _{(CH2) n-Ar} '- _(CH2) s-R ⁸ -Y- (CH _{2) n} -NH- (CH ₂₎ t -R ^8, -Y- (CH ₂ ) _n -N- (CH ₂ ) 1 ^- R ⁸ , a group of formula -7 / • · · · - 272 · -Y- [XO] _t - [X ¹ -OJu-X ² -R ⁶ or -Y- [X-NH] UX ¹ -OH, R ² -Ar, -Ar-DH, Het ^1, Het ¹ -N, -N'-Het ^1, N '(CH2) n R ^3, -Ar-Y- (CH 2) _n - R ³ , -Ar'-YC (A) 2 -R ³ , Het ¹ -R ³ , -Ar'-Het ¹ -R ³ , -Ar '- (CH 2) _n -R ⁶ , -Ar'-SO 2 - Het, -Ar'-NH-SO 2 -Het, -Ar'-SO 2 -R ⁷ , -Ar '- (CH 2) _n - (CO-NH) - (CH ₂ ) _i -R ⁶ , -Ar' - ( CH ₂ ) _n - (CO-NH) - (CH ₂ ) _i R ¹¹ , -Ar '- (CH 2) _n -CO-Het, -Ar' - (CH ₂ ) _n - (CO-NH) - (CH ₂ ) - DH, -Ar '- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) i -Ar, -Ar' - (CH ₂ ) _n - (CO-NH) - (CH ₂ ) _i -Het ¹ , -Ar '- (CH 2) n - (CH (CN)) - (CH 2) 1 -Ar, -Ar' - (CH 2) n - (CO-NH) - (CH 2) —CH- (Ar ¹ ) -Ar ² , -Ar 1 -S- (CH 2) _n - (CO-NH) - (CH ₂ ) 3 -Ar, -Ar 1 -S- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) -R ¹¹ , -Ar ¹ -S- (CH 2) _n - (CO-NH) - (CH ₂ ) —Het ¹ , -Ar 1 -S- (CH 2) _n - (CO-NH) - (CH ₂₎ i-CH (Ar ¹ ) Ar ² or -Ar 1 -S- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) 3 -DH, R ³ is C (O) A, CONH _2, CONHA, CONA _2, COOH or COOA, R ^{4 is} Ph or OH, r ^{5 is} CH ₃ , CH ₂ Cl, CF ₃ or Ph, R ^{6 is} NH ₂ , HNA, NA ₂ , NH (DH) or NH-C (O) A, R ^{7 is} NA (DH), NHA, NH (DH) or NA ₂ ; R ⁸ -NH- (C = NH) -NH ₂ , -NH- (C = NH) -NHA, -NH- (C = NH) NA ₂ , -NA- (C = NH) -NH ₂ , - NA- (C = NH) NHA or --NA-- (C = NH) NA _2, R ^{11 is} -CH (A) -Ph, - 273 " Ar 1 is a phenylene, biphenylene, naphthylene or pyrazol-4-yl group which is unsubstituted or has one, two or three substituents selected from the group consisting of A, OH, OA, OCF ₃ , Hal, CN, NH ₂ , NHA, NA ₂ , N0 _2, CF _3, SO ₂ NH _2, SO ₂ Ph, _SO2 preview, having _{from 2} to _2, Ar, Ar ¹ , Ar ² independently of one another are phenyl, biphenyl, stilbyl, pyridyl, pyrimidyl, quinolyl, 1-imidazolyl, pyrazolyl, indanyl, benzo [1,3] dioxol-5-yl or dibenzofuranyl, 9H-fluorenyl -carbazolyl, [1,1 ', 4', 1'''-Phenyl, anthracenyl, naphthalen-1-yl, naphthalen-2-yl or fluoren-9-one-2-yl, which is unsubstituted or has one, two or three substituents from the group consisting of A, OH, OA, OCF ₃ , O-Ph, O-Ph-CH ₃ , CH ₂ -Ph, OCH ₂ -Ph, Hal, cn, nh ₂ , nha, na ₂ , no ₂ , cf ₃ , ₂ nh ₂ , ₂ -ph, ₂ nah, SO ₂ NA ₂ and R ⁸ , A Het saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or tricyclic heterocyclic group having 5 to 13 ring members containing one or two nitrogen atoms and / or one or two sulfur or oxygen atoms in the heterocyclic moiety, the heterocyclic moiety being monosubstituted or disubstituted by CN, Hal, OH, OA, CF ₃ , A, NO ₂ , oxo and R ⁵ , wherein the pyrazole group is not bonded via a nitrogen atom, A Het ¹ saturated, monocyclic, bicyclic or tricyclic heterocyclic group of 5 to 13 ring members containing one or two nitrogen atoms and / or one or two sulfur or oxygen atoms in the heterocyclic moiety, wherein the heterocyclic moiety is monosubstituted or disubstituted by a group selected from the group including the group Hal, A, OH, OA, oxo and CF ₃ , or is - a piperidine, morpholine, pyrrolidine or pyrrolidin-2-one group, A branched or unbranched alkyl group having 1 to 8 carbon atoms, A 2 branched or unbranched alkyl group having 2 to 6 carbon atoms, Alk a straight-chain alkyl group having 4 to 8 carbon atoms, C 4 -C 7 cycloalkylene or cyclohexen-1-yl, Hal is fluorine, chlorine, bromine or iodine, X, X ¹ , X ² are independently C 1 -C 12 alkylene, Y is O or S or NH or NA, and 1, 2, 3 4 5 6 7, 8, 9, 10, 11 or 12 to 31 4 5 6 7, 8, 9 10, 11 or 12 m 0, 1 or 2 n 0, 1, 2, 3 or 4, about 1 2 3 4 5 6 7 8, 9, or 10 T 0, 1 or 2 at 1 or 2, • · • · - 2-5 ~ Where R ^{2 is} 4-chlorophenyl, R ^{1 is} not -NH-CH ₂ -CH ₂ -OH and their physiologically acceptable salts and solvates. 2. Compounds according to claim 1 of the formula I (f) 6- (3-aminopropylamino) -2- (3,4,5-trimethoxyphenyl) benzo [de] isoquinoline-1,3-dione; (g) 6- (3-aminopropylamino) -2- (7-hydroxynaphthalen-1-yl) benzo [de] isoquinoline-1,3-dione; (i) 6- (3-aminopropylamino) -2- (2,3-dimethoxyphenyl) benzo [de] isoquinoline-1,3-dione; (m) 6- (3-aminopropylamino) -2- (4-carbazol-9-ylphenyl) benzo [de] isoquinoline-1,3-dione; (n) 6- (3-aminopropylamino) -2- (4'-hydroxy-2-methylbiphenyl-4-yl) benzo [de] isoquinoline-1,3-dione; o) N- (3 - {[2- (4'-Methoxybiphenyl-4-yl) -1,3-dioxo-2,3-dihydro-4-benzo [de] isoquinolin-6-ylamino] methyl} benzyl) guanidine, v) N- [3 - ({2- [4- (3,6-di-tert-butylcarbazol-9-yl) phenyl] -1,3-dioxo-2,3-dihydro-1H-benzo [de] isoquinoline- 6-ylamino} methyl) benzyl] guanidine a w) 6- (3-aminopropylamino) -2- (4-carbazol-9-ylphenyl) benzo [de] isoquinoline-1,3-dione and their physiologically acceptable salts and solvates. 3. Compounds of formula I R. where means (I) ········· 27'6 R hydrogen, NO ₂ , R ¹ Het, Het-SO 2 -Ar, Het-R ⁵ , -Het- (CH 2) _n Ar, NO ₂ , -N = CH-Ar, -NHAlk, NAAlk, NHA ', NA' ₂ , a group of formula -YDH, -Y-Ar'-R ³ , -Y- (CH 2) OR ³ , -Y- (CH 2) _n - (CHR ⁴ ) R ⁵ -, -YC - [(CH 2) 0-0H] 3, -Y- (CH 2) m -NA 2, -Y- (CH 2) n -NHA ', -Y- (CH 2) q -OH, -Y- (CH 2) k R ⁶ , -Y- (CH 2) _i -R ⁸ - (CH _{2) n} Het, -Y- (CH _{2) n} -Ar-Y- _{(CH2) n-Ar} '- _(CH2) and ^6, Y- (CH _{2) n} -D- (CH ₂₎ ~ ^R6, -Y- (CH _{2) n} -Het- (CH ₂₎ ^- R ^6, Y- _{(CH2) n} -NA- _(CH2) and ^6, Y- (CH2) n "-NH- (CH 2) and ^6, Y- (CH2) _{m-D- (CH2)} ⁸ IR , -'i- (CH2) n-Ar '- (CH2) iR ⁸ -Y- (CH 2) _n -NH- (CH ₂₎ ⁸ iR, Y- _{(CH2) n} -NA- _(CH2 -R ⁸ , a group of formula -Y- [XO] _t - [X ¹ -O] uX ² -R ⁶ or -Y- [X-NH] UX ¹ -OH, R ² -Ar, Het ^1, Het ¹ -N, -N'-Het ^1, Ar '- _{(CH2) n} -R ^3, -Ar'-Y- (CH ₂ ) _n -R ³ , -Ar'-Het ¹ -R ³ , -Ar '- (CH ₂ ) _n -R ⁶ , -Ar'-SO ₂ -Het, -Ar'-SO ₂ -R ⁷ , -Ar '- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) i -R ⁶ , -Ar '- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) —DH, -Ar '- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) i -Ar, -Ar '- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) i -Het ¹ , -Ar '- (CH ₂ ) _n - (CH (CN)) - (CH ₂ ) i -Ar, -Ar '- (CH ₂ ) _n - (CO-NH) - (CH ₂ ) i -CH- (Ar ¹ ) -Ar ² , R ³ is C (O) A, CONH _2, CONHA, CONA _2, COOH or COOA, 27? • · · · · · R ^{4 is} Ph or OH, r ^{5 is} CHg, CH ₂ Cl, CF ₃ or Ph, R ^{6 is} NH ₂ , HNA, NA ₂ , NH (DH) or NH-C (O) A, R ^{7 is} NA (DH), NHA, NH (DH) or NA ₂ ; R ^{8 is} -NH- (C = NH) -NH ₂ , -NH- (C = NH) -NHA, -nh- (c = nh) to ₂ , -NA- (C = NH) -NH ₂ , - NA- (C = NH) NHA or --NA-- (C = NH) NA _2, Ar 1 is a phenylene, biphenylene, naphthylene or pyrazol-4-yl group which is unsubstituted or has one or two substituents from the group consisting of A, OH, OA, OCF ₃ , Hal, CN, NH ₂ , NHA, NA ₂ , NO ₂ , CF ₃ , SO ₂ NH ₂ , Sat ₂ nah, Sat ₂ to ₂ , Ar, Ar ¹ , Ar ² are, independently of each other, phenyl, biphenyl, stilbyl, pyridyl, pyrimidyl, quinolyl, 1-imidazolyl, pyrazolyl, indanyl, benzof1,3-dioxol-5-yl or dibenzofuranyl, 9H-fluorenes, 9H-fluorenes, 9H-fluorenes 1-yl, naphthalen-2-yl or fluoren-9-one-2-yl which is unsubstituted or has one, two or three substituents from the group A, OH, OA, OCF ₃ , O-Ph, OCH ₂ ~ Ph, Hal, CN, NH ₂ , NHA, NA ₂ , NO ₂ , CF ₃ , SO ₂ NH ₂ , SO ₂ NAH, SO ₂ NA ₂ and R ⁸ , Het a saturated, partially unsaturated or fully unsaturated monocyclic or bicyclic heterocyclic group of 5 to 10 ring members containing one or two nitrogen atoms and / or one or two sulfur or oxygen atoms in the heterocyclic moiety, the heterocyclic moiety being monosubstituted or disubstituted CN, Hal, OH, OA, CF ₃ , A, NO ₂ and R ⁵ , wherein the pyrazole group is not bonded via a nitrogen atom; - 27 ä ·· ···· A Het ¹ saturated, monocyclic or bicyclic heterocyclic group having 5 to 10 ring members containing one or two nitrogen atoms and / or one or two sulfur or oxygen atoms in the heterocyclic moiety, the heterocyclic moiety being monosubstituted or disubstituted by a group selected from the group consisting of Hal, a, OH, OA, and CF _3, A branched or unbranched alkyl group having 1 to 8 carbon atoms, A 'branched or unbranched alkyl group having 2 to 6 carbon atoms, Alk a straight-chain alkyl group having 4 to 8 carbon atoms, C 4 -C 7 cycloalkylene or cyclohexen-1-yl, Hal fluorine, chlorine, bromine or iodine, x, X ¹ , X is independently of one another an alkylene group having 1 to m carbon, Y O or S; NH or NA, and 0 out of 11 2 f 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 to 3 4 5 6 7 8 9 10, 11 or 12 m 0, 1, or 2 n 0, 1, 2, 3 or 4 about 1 2 3 4 5 6 7 8, 9, or 10 • · ♦ '· t, 1, or 2, with 1 or 2, wherein when R ² is 4-chlorophenyl, R ¹ is not -NH-CH ₂ CH ₂ OH, and physiologically acceptable salts and solvates thereof. 4. Compounds according to claim 1 of the formula I (a) 6-benzylamino-2- (2,5-dichlorophenyl) -3a, 9b-dihydro- -1H, 3H-benzo [de] isoquinoline-1,3-dione, b) 3- {3- [6- (2-guanidinopropylamino) -1,3-dioxo-3α, 9b-dihydro-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} -N- (2- p-tolyl-ethyl) -propionamide, c) 3- {3- [6- (2-guanidinomethyl-cyclohexylmethyl) -amino] -1,3-dioxo-3α, 9b-dihydro-1H, 3H-benzo [de] isoquinolin-2-yl] -phenyl} -N- ( 2 p -tolyl-ethyl) -propionamide, d) 3- {3- [6- (4-guanidinomethylbenzylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} -N- [2- (4-sulfamoylphenyl) ethyl] ] -propionamide, e) N- [2- (4-chlorophenyl) ethyl] -3- <3- [6- (4-guanidinomethylbenzylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl } -propionamide, j) N- [2- (3-chlorophenyl) ethyl] -3- {3- [6- (4-guanidinomethylcyclohexylmethylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl } -propionamide, k) N- [2- (4-chlorophenyl) ethyl] -3- {3- [6- (4-guanidinomethylcyclohexylmethylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} -propionamide, (l) 6- (3-aminopropylamino) -2- (4'-methoxybiphenyl-4-yl) benzo [de] isoquinoline-1,3-dione; p) 3- {3- [6- (2-guanidinoethylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl} -N- (4-phenylbutyl) propionamide, - 2 q) N- [2- (4-chlorophenyl) ethyl] -3- {3- [6- (2-guanidinoethylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl ] -phenyl} -propionamide, r) N- [2- (4-chlorophenyl) ethyl] -3- {3- [6- (3-guanidinopropylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl } -propionamide, s) N- [2- (4-chlorophenyl) ethyl] -3- [3- (6- {3 - [(3-guanidinopropyl) methylamino] propylamino} -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl) phenyl] propionamide, t) N- [2- (3-chlorophenyl) ethyl] -3- {3- [6- (3-guanidinopropylamino) -1,3-dioxo-1H, 3H-benzo [de] isoquinolin-2-yl] phenyl } -propionamide, u) 6- (3-aminopropylamino) -2- (4'-methoxybiphenyl-4-yl) benzo [de] isoquinoline-1,3-dione, and physiologically acceptable salts and solvates thereof. A process for the preparation of compounds of formula I according to claim 1, characterized in that (a) they are released from their functional derivatives by treatment with a solvolysis or hydrogenolysis agent; or b) a compound of formula II (II) wherein R ⁹ is chlorine, bromine, nitro or R ¹ and R ¹ is as defined above, reacts with a compound of formula III H ₂ N-R ² (III) Wherein R ² is as defined above and optionally R ⁹ is changed to R ¹ or n c) in a compound of formula I, the group R and / or R and / or R ⁹ is changed to another R and / or R ² and / or R ⁹ such that, for example, the amino group is converted to guanidino by reaction with an amidating agent; or aryl iodide to the corresponding coupling products by Suzuka coupling with boric acid, nitro, sulfonyl or sulfoxyl is reduced, the hydroxyl group is etherified or the OA group is ether-cleaved, the primary or secondary amino group is alkylated, the cyano group is partially or fully hydrolysed, an ester group or a carboxyl group is esterified, nucleophilic or electrophilic substitution is performed and / or d) the base or acid of formula I is converted into its salt or solvate. A pharmaceutical composition comprising an effective amount of a compound of formula I according to claims 1 and 2, or a physiologically acceptable salt thereof, and a physiologically acceptable excipient. 7. A pharmaceutical composition which is effective as a glycoprotein Ib1X antagonist. 8. A pharmaceutical composition which, as a glycoprotein Ib1X antagonist, is effective in the treatment of thrombotic disorders and the conditions derived therefrom. • ♦ · ľ ľ!!! · · ··· · · · ···. • · · · · · · · · · · · · · · A compound according to claims 1 and 2 or a physiologically acceptable salt or solvate thereof as a medicament. A compound according to claims 1 and 2, or a physiologically acceptable salt or solvate thereof, as a glycoprotein Ib1X antagonist. A compound according to claims 1 and 2, or a physiologically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of thrombotic disorders and disorders derived therefrom or for use as anti-sticking agents. Use of a compound according to claims 1 and 2 or a physiologically acceptable salt or solvate thereof for the treatment of diseases, for example for the prophylaxis and / or treatment of thrombotic diseases and their consequences, such as myocardial infarction, arteriosclerosis, angina pectoris, acute coronary syndromes, peripheral circulatory disorders, stroke, transient ischemic complaints, reocclusion / restenosis after stent implantation or as anti-adhesion agents for implants, catheters or cardiac stimulators. A process for the preparation of compounds of formula I according to claim 3 and 4, characterized in that: (a) released from their functional derivatives by treatment with a solvolysis or hydrogenolysis agent; or b) a compound of formula II ABOUT O (II) Where R ⁹ is a chlorine, bromine, nitro or R ¹ group and R ¹ is as defined above, reacts with a compound of formula III H ₂ N - R ² (III) wherein R ² is as defined above and optionally the group R ⁹ is changed to a group R ¹ , or n c) in the compound of formula I, the group R and / or R ⁶ and / or R ⁹ is changed to another R and / or R ² and / or R ⁹ by, for example, converting the amino group to a guanidino group by reaction with an amidating agent; arylbromide or aryl iodide to the corresponding coupling products by Suzuka coupling with boric acid, nitro, sulphonyl or sulphoxyl group is reduced, the hydroxyl group is etherified or the OA group undergoes ether cleavage, the primary or secondary amino group is alkylated, the cyano group is partially or completely hydrolysed, the ester group or the carboxyl group is esterified, the nucleophilic or electrophilic substitution is carried out and / or d) the base or acid of formula I is converted into its salt or solvate. A pharmaceutical composition comprising an effective amount of a compound of formula I according to claims 3 and 4, or a physiologically acceptable salt thereof, and a physiologically acceptable excipient. ···· ·· ···· - 28y - A pharmaceutical composition which is effective as a glycoprotein Ib1X antagonist according to claims 3 and 4. 16. A pharmaceutical composition according to claim 7, wherein the glycoprotein Ib1X antagonist is effective in the treatment of thrombotic disorders and the conditions derived therefrom. A compound according to claim 3 or 4 or a physiologically acceptable salt or solvate thereof as a medicament. A compound according to claims 3 and 4, or a physiologically acceptable salt or solvate thereof, as a glycoprotein Ib1X antagonist. A compound according to claims 3 and 4, or a physiologically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of thrombotic disorders and disorders derived therefrom or for use as an anti-sticking agent. Use of a compound according to claims 3 and 4 or a physiologically acceptable salt or solvate thereof for the treatment of diseases, for example for the prophylaxis and / or treatment of thrombotic diseases and their consequences, such as myocardial infarction, arteriosclerosis, angina pectoris, acute coronary syndromes, peripheral circulatory disorders, stroke, transient ischemic complaints, reocclusion / restenosis after stent implantation or as anti-adhesion agents for implants, catheters or cardiac stimulators.