AU760136B2 - Substituted benzo(DE)isoquinoline-1,3-diones - Google Patents

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

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AU760136B2
AU760136B2 AU26603/00A AU2660300A AU760136B2 AU 760136 B2 AU760136 B2 AU 760136B2 AU 26603/00 A AU26603/00 A AU 26603/00A AU 2660300 A AU2660300 A AU 2660300A AU 760136 B2 AU760136 B2 AU 760136B2
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conh
phenyl
benzo
pct
formula
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AU2660300A (en
Inventor
Gerhard Barnickel
Sabine Bernotat-Danielowski
Ralf Devant
Daljit Dhanoa
Todd Graybill
Werner Mederski
Guido Melzer
Peter Raddatz
James Rinker
Richard Soll
Zhengdong Wu
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Merck Patent GmbH
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Description

1- Substituted benzo [del isoquinoline-1, 3-diones The invention relates to substituted benzo[de]isoquinoline-1,3--diones of the formula I R R1 0 N 0~ in which R is H or NO 2 R is -Ret, -Het-S0 2 -Ar, -Het-R 5 -Het- (CH 2 -Ar, N0 2 -N=CH-Ar, NHAlk, NAAlk, NRA', NA' 2 -N N
NH
II
-y C2)-(H 4)-R 5 (CR 2 0
-OH]
3
-Y-.CR
2 )m-NA 2
(CR
2 -NHA',
(CR
2 0 -OR,
(CR
2 k-R, -Y C2
(CR
2 ,-Het, (CR 2 n-Ar, -Y (CR 2 a-Ar'- (CR 2 i-R 6, (CH 2
(CH
2 i-R
(CR
2 a-Het- (CR 2 -R 6 _Y (CR2) nNA- (CR2) iR 6
(CR
2 NH- (CR 2 j-R (CR 2 n-D- (CR 2 j-R,
(CR
2
(CR
2 j-R I (CR 2 n-NH- (CR 2 i-R, **8 :y (CH 2 nNA-(CH 2 iRI t- [X 1 I-O] U-x 2
_-R
6 or [X-NH] u-X 1
-OR,
R 2 is -Ar, -Ret 1, 1 -Ar' -Ret 1 -Ar' -(CR 2 n-R 3 Ar'-Y-(CH 2 )n-R f -Ar'-Y-C(A) 2 Het-R 3 -Ar' -Ret'-R 3 1 -Ar' -(CH 2 6 -Ar' -S0 2 -Het, -Ar' -NH-S0 2 -Het, Ar' -S0 2 -Ar' (CR 2 (CO-NH) WO 00/32577 PCT/EP99/08561
(OH
2 -Ar' (CH 2 n- (CO-NH) (CH 2 1 -Ar'
(CH
2 ),-CO-Het, -Ar' -(CH 2 (CO-NH) -(CH 2 j-D-H, -Ar'-
(CH
2 n- (CO-NH) (CR 2 -Ar'I (CH 2 (CO-NH)
(OH
2 j-Het 1 -Ar'I (CH 2 (CH (OH 2 i-Ar, -Ar' (OH 2 n- (00-NH) (OH 2 1 -CH (Ar 1 -Ar 2 -Ar' -S-
(CH
2 n- (00-NH) (CH 2 i-Ar, -Ar' (OH 2 (CO-NH)
(OH
2 j-R"1, -Ar' (OH 2 n- (CO-NH) (OH 2 i-Het', -Ar' (OH 2 (00-NH) (OH 2 ±-OH -Ar 2 or -Ar' -S-
(OH
2 (CO-NH) (OH 2 1
-D-H,
R 3 is O(O)A, OONH 2 CONHA, OONA 2 COON or COQA, R4 is Ph or OH, R 5 is OH 3
OH
2 Cl, CF 3 or Ph, R6 is NH 2 NRA, NA 2 NH(D-H) or NH-O(O)A, R 7 is NA(D-H), NRA, NH(D-H) or NA 2 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) -NRA or -NA- (C=NH) -NA 2 R 1is -CH(A)-Ph, Ar' is phenylene, biphenylene, naphthylene or pyrazol- 4-yl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, 00F 3 Hal, ON, NH 2 NHA, NA 2
NO
2
OF
3
SO
2
NH
2
SO
2 Ph, SO 2 NAH, SO 2
NA
2 Ar, Ar' and Ar 2 are each independently phenyl, biphenyl, stilbyl, pyridyl, pyrimidyl, quinolyl, 1-imidazolyl, pyrazolyl, indanyl, benzo[1,3]dioxol-5-yl, dibenzofuranyl, 9-H-fluorenyl, 9-H-carbazolyl, [1,11,41,1'1] terphenyl, anthracenyl, naphthalen-1yl, naphthalen-2-yl or fluoren-9-on-2-yl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, 00F 3 0-Ph, 0-Ph-OH 3 0H 2 -Ph, O-0H 2 -Ph, Hal, ON, NH 2 NRA, NA 2
NO
2
OF
3
SO
2
NH
2
SO
2 Ph,
SO
2 NAH, SO 2
NA
2 orR8 Ret is a saturated, partially or completely unsaturated mono-, bi- or tricyclic heterocyclic radical having 5 to 13 ring members, where 1 or 2 N and/or 1 or 2 S or 0 atoms can be present and the heterocyclic radical can be mono- or disubstituted by ON, Hal, OH, OA, OF 3 A, NO 2 oxo or R 5 1 where pyrazole is not bonded via N, 3 Het 1 is an unsaturated mono-, bi- or tricyclic heterocyclic radical having 5 to 13 ring members, where 1 or 2 N and/or 1 or 2 S or 0 atoms can be present and/or can be mono- or disubstituted by Hal, A, OH, OA, oxo or CF 3 or piperidine, morpholine, pyrrolidine or pyrrollidin-2-one, A is unbranched or branched alkyl having 1-8 C atoms, A' is unbranched or branched alkyl having 2-6 C atoms, Alk is unbranched alkyl having 4-8 C atoms, D is cycloalkylene having 4-7 C atoms or cyclohexen-1-yl, Hal is F, Cl, Br or I,
X,
X ,X 2 in each case independently of one another are alkylene having 1 to 12 C atoms, Y is O, S, NH or NA, i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, k is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, m is 0, 1 or 2, n is 0, 1, 2, 3 or 4, o is 1, 2, 3, 4, 5, 6, 7, 8, 9 or t is 0, 1 or 2, 25 u is 1 or 2, Wwhere if R 2 is 4-chlorophenyl, R 1 is not -NH-CH2-CH2-OH, and their pharmaceutically tolerable salts and solvates wherein
R
2 is not 2-benzimidazol-2-yl, and N-(4-ethoxyphenyl)-5-nitronaphthalimide is excluded.
Similar compounds having a benzo[de]isoquinoline-l,3-dione parent structure are disclosed as dyes in US 4,200,752, FR 2 272 215, FR 2 271 216 A, Chemical Abstracts, Vol. 73, No. 2, 13 July 1970, Chemical Abstracts, Vol. 57, No. 13, 24 December 1962 and Chemical Abstracts, Vol. 111, No. 13 November 1989.
The invention is based on the object of finding _\n.ovel compounds having valuable properties, in partii' u, 3acular those which can be used f or the production of medicaments.
WO 00/32577 PCT/EP99/08561 4 It has been found that the compounds of the formula I and their salts or solvates have very valuable pharmacological properties together with good tolerability. They act especially as GPIbIX inhibitors, in particular inhibiting the interaction of this receptor with the ligand von Willebrand factor (vWF).
This action can be demonstrated, for example, by a method which is described by S. Meyer et al. in J. Biol. Chem. 1993, 268, 20555-20562. Furthermore, the GPIbIX receptor is able to bind alpha-thrombin (N.J.
Greco, Biochemistry 1996, 35, 915-921), it likewise being possible to block this interaction by means of the compounds according to the invention.
The significance of GPIbIX as an adhesion receptor on platelets, which mediates the primary interaction of platelets with an arteriosclerotically modified vascular wall via binding to the vWF expressed there, has been described by many authors Z.M. Ruggeri in Thromb. Hemost. 1997, 78, 611-616). The activation of another platelet adhesion receptor,. GPIIbIIIa, following the GPIbIX-vWF interaction, leads to platelet aggregation and thus to thrombotic vascular occlusion.
A GPIbIX antagonist can thus prevent the start of thrombus formation and thus also release of active substances from the platelets which, for example, promote thrombus growth and have an additional trophic action on the vascular wall. This has been shown with inhibitory peptides or antibodies in various experimental models H Yamamoto et al., Thromb. Hemost.
1998, 79, 202-210).
In the case of higher shear forces, the blocking action of GPIbIX inhibitors exerts its maximum effect, as described by J.J. Sixma et al. in Arteriosclerosis, Thrombosis, and Vascular Biology 1996, 16, 64-71. According to the flow chamber method used there, the compounds of the formula I can be characterized as GPIbIX inhibitors in whole blood.
The inhibition of thrombus formation of the GPIbIX inhibitors can be measured by a modified Born WO 00/32577 PCT/EP99/08561 5 method (Nature 1962, 4832, 927-929) using botrocetin or ristocetin as an aggregation stimulant.
The compounds of the formula I according to the invention can therefore be employed as pharmaceutical active compounds in human and veterinary medicine. They act as adhesion receptor antagonists, in particular as glycoprotein IbIX antagonists, and are suitable for the prophylaxis and/or therapy of thrombotic disorders and sequelae deriving therefrom. The preferentially best action is to be expected in the case of thrombotic disorders in the arterial vascular system, but GPIbIX inhibitors also have an effect in the case of thrombotic disorders in the venous vascular bed. The disorders are acute coronary syndromes, angina pectoris, myocardial infarct, peripheral circulatory disorders, stroke, transient ischaemic attacks, arteriosclerosis, reocclusion/restenosis after angioplasty/stent implantation. The compounds can furthermore be employed as anti-adhesive substances where the body comes into contact with foreign surfaces such as implants, catheters or cardiac pacemakers.
Comparison medications which may be mentioned are aspirin and GPIIbIIIa antagonists introduced onto the market, in particular ReoPro®.
The invention relates to the compounds of the formula I and their salts and solvates, and to a process for the preparation of these compounds and their salts or solvates, characterized in that a) a compound of the formula I is liberated from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent, or b) a compound of the formula II in R 9 in which WO 00/32577 PCT/EP99/0561 6-
R
9 is Cl, Br, NO 2 or R 1 and R has the meaning indicated in Claim 1 is reacted with a compound of the formula III
H
2
N--R
2
III
in which R 2 has the meaning indicated in Claim 1, and, if necessary, the radical R 9 is converted into a radical R 1 or a radical R and/or R 2 and/or R 9 is converted into another radical R and/or R 2 and/or R 9 by, for example converting an amino group into a guanidino group by reaction with an amidinating agent, reacting an aryl bromide or iodide to give the corresponding coupling products by means of a Suzuki coupling with boronic acids, reducing a nitro group, sulfonyl group or sulfoxyl group, etherifying an OH group or subjecting an OA group to ether cleavage, alkylating a primary or secondary amino group, partially or completely hydrolysing a CN group, cleaving an ester group or esterifying a carboxylic acid radical, or carrying out a nucleophilic or electrophilic substitution, and/or a base or acid of the formula I is converted into one of its salts or solvates.
The compounds of the formula I can have a chiral centre and therefore occur in a number of stereoisomeric forms. All these forms R and S forms) and their mixtures the RS forms) are included in the formula I.
The compounds according to the invention also include so-called prodrug derivatives, i.e. compounds of the formula I modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the body to give the active compounds according to the invention.
WO 00/32577 PCT/EP99/08561 7 Furthermore, the invention relates to compounds of the formula I in which free amino groups are provided with appropriate conventional "amino protective groups".
Solvates of the compounds of the formula I are understood as meaning adducts of inert solvent molecules to the compounds of the formula I which are formed on account of their mutual power of attraction.
Solvates are, for example, mono- or dihydrates or alcoholates.
The abbreviations used have the following meanings: BOC tert-butoxycarbonyl CBZ benzyloxycarbonyl DCC dicyclohexylcarbodiimide DMF dimethylformamide Et ethyl Fmoc fluorenylmethoxycarbonyl Me methyl Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl OBut tert-butyl ester OMe methoxy OEt ethoxy POA phenoxyacetyl Ph phenyl tert-bu tert-butyl TFA trifluoroacetic acid In the above formulae, A is alkyl and has 1 to 8, preferably 1, 2, 3, 4 or 5 C atoms. Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, additionally also pentyl, 2- or 3-methylbutyl, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 3- or 4-methylpentyl, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl- 1-methylpropyl, l-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, heptyl, 4-, 2,4or 3,3-dimethylpentyl, 4-ethylpentyl, WO 00/32577 PCT/EP99/08561 1,3,3-, 1,4,4- or 2,2,3-trimethylbutyl or octyl.
A' is alkyl arnd has 2 to 6 C atoms, preferably 2, 3 or 4 C atoms. A' is preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
Alk is uribranched alkyl having 4 to 8 carbon atoms, preferably n-butyl, ri-pentyl, n-hexyl, r-heptyl or n-octyl.
Ar is preferentially phenyl, preferably as indicated monosubstituted phenyl, specifically preferentially phenyl, m- or p-methylphenyl, mor p-ethylphenyl, m- or p-propylphenyl, m- or p-isopropylphenyl, m- or p-tert-butylphenyl, mor p-aminophenyl, m- or p- (N,N-dimethylamino)phenyl, m- or p-sulfonamoylphenyl, m- or p-nitrophenyl, m- or p-hydroxyphenyl, m- or p-methoxyphenyl, m- or p-ethoxyphenyl, m- or p-phenoxyphenyl, m- or p-(phenylmethox)yphenyl, m- or p (trifluoromethyl)phenyl, m- or p-(trifluaramethoxy)phenyl, m- or p-fluorophenyl, m- or p-chlorophenyl, m- or p-bromophenyl, a-, m- or p-iodophenyl, 4-benzenesulfonyl-phenyl, 4-(4chloro-phenoxy) -phenyl, furthermore preferentially 3,4- or 3,4- or 3,4- or 3,4- or 3,4- or 3,4- or 2-chloro-3-methyl-, 2-chloro-4-methyl-, methyl-, 2-chloro-6-methyl-, 3-chloro-2-methyl-, 4chloro-2-methyl-, 5-chloro-2-methyl-, 3-chloro-4methyl-, 3-chloro-5-methyl-, 4-chloro-3-methylphenyl, 2-bromo-3-methyl-, 2-bromo-4-methyl-, methyl-, 2-bromo-6-methyl-, 3-bromo-2-methyl-, 4-bromo- 2-methyl-, 5-bromo-2-methyl-, 3-bromo-4-methyl-, 4-bromo-3-methylphenyl, 2-iodo-3methyl-, 2-iodo-4-methyl-, 2-iodo-5-methyl-, 2-iodo-6- WO 00/32577 PCT/EP99/08561I -9methyl-, 3 -iodo-2-methyl-, 4 -iodo-2--methyl-, 2-methyl-, 3 -iodo-4-methyl-, 3 -iodo-5-methyl-, 4 -iodo- 3-methylphenyl, 2 -chloro-3-methoxy-, 2 -chloro-4methoxy-, 2 -chloro-5-methoxy-, 2 -chloro-6-methoxy-, 3chloro-2-methoxy-, 4 -chloro-2--methoxy-, chloro-2-methoxy-, 3 -chloro-4--methoxy-, methoxy-, 4 -chloro-3-methoxyphenyl, 2-chloro-3hydroxy-, 2-chloro-4 -hydroxy-, 2 2 -chloro-6-hydroxy-, 3 -chloro-2-hydroxy-, 4chloro-2-hydroxy-, 5-chloro-2-hydroxy-, 3-chloro-4hydroxy-, 3 -chloro-5-hydroxy-, 4 -chloro-3-hydroxyphenyl, 3 -fluoro-4-methoxy, 4 -fluoro-3-methoxyphenyl, 2 -chloro-3-fluoro-, 2 -chloro-4-fluoro-, fluoro-, 2 -chloro-6-fluoro-, 3 -chloro-2-fluoro-, 4chloro-2-fluoro-, 5-chloro-2-fluoro-, 3-chloro-4fluoro-, 3 -chloro-5-fluoro-, 4 -chloro-3-fluorophenyl, 2 -fluoro-3-inethyl-, 2 -fluoro-4-methyl-, methyl-, 2 -fluoro-6-methyl-, 3 -fluoro-2-methyl-, 4fluoro-2-methyl-, S-f luoro-2-methyl-, 3-fluoro-4methyl-, 3 -fluoro-5-methyl-, 4 -fluoro-3-methylphenyl, or 3 4 -dimethoxyphenyl, 2-cyano-4,5dimethoxyphenyl, 5-chloro-2, 4 -dimethoxy-phenyl, 2cyano-3, 4 -dimethoxyphenyl or 3,4, S-trimethoxy-phenyl.
Furthermore, however, also preferentially unsubstituted biphenyl as indicated or alternatively monosubstituted biphenyl,. specifically preferentially biphenyl-4-yl or biphenyl-3-yl, 2 '-methylbiphenyl-4-yl, 3' -methylbiphenyl-4-yl, 4' -methylbiphenyl-4-yl, 2' -methylbiphenyl-3-yl, 3' -methylbiphenyl-3-yl, 4' -methylbiphenyl-3-yl, 2 -methylbiphenyl-4..yl, 3 -methylbiphenyl-4 -yl, 2 -methylbiphenyl-3-yl, 4 -methylbiphenyl-3-yl, 2' -tert-butylbiphenyl4yl, 2 '-tert-butylbiphenyl-3...yl, 4'-tert-butylbiphenyl..3yl, 4'-tert-butylbiphenyl3.yl, 3-tert-butylbiphenyl-4...yl 3 -tert-butylbipheny>.4 -yl, 2 -tertbutylbiphenyl.3.yl 4 -tert-butylbiphenyl..3-.yl, 2' -isopropylbiphenyl-4..yl, 3' -isopropylbiphenyl-4-..yl, 4' -isopropylbiphenyl-4-yl, 2' -isopropylbiphenyl-3.yl, 3 '-isopropylbiphenyl-3.yl, WO 00/32577 PCT/EP99/08561 10 4 '-isopropylbipheiyl-3-yl, 2-isopropylbiphenyl-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-f luorobiphenyl-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-rnethoxybiphenyl-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-nitrobipheriyl-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-tnifluoromethylbiphenyl-4 -yl, 2-trifluoromethylbiphenyl-3yl, 4 -tnifluoromethylbiphenyl-3-yl, 2' -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 -trif luoromethoxybiphenyl-3-yl, 4 -trif luoromethoxybiphenyl-3-yl, furthermore preferentially disubstituted biphenyls, such as 2' -methyl-3 I-nitrobiphenyl-4-yl, 2 '-rnethyl-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' U hy-5-nitrobiphenyl-4-yl, 3'-methyl-6nitrobiphenyl-4-yl, 4' -methyl-2' -nitrobiphenyl-4-yl, WO 00/32577 PCT/EP99/08561 11 4' -methy1-3'-nitrobiphenyl-4-y1, 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' -rrethyl-2' -nitrobiphenyl-3-yl, 3' -methyl-4 '-nitrobiphenyl-3-yl, 3' -methyl-S t nitrobiphenyl-3-yl, 3'-rnethyl-6' -nitrobiphenyl-3-yl, 4' -methyl-2 '-nitrobiphenyl-3-yl, 4 '-methyl-3' nitrobiphenyl-3-yl, 2' -methoxy-2-Inethylbiphenyl--4-yl, 3' -methoxy-2-rnethylbiphenyl-4-yl, 4' -methoxy-2methylbiphenyl-4-yl, 4' -methoxy-3-nitrobiphenyl-4-yl, 2' -chloro-3 '-fluorobiphenyl-4-yl, 2' -chloro-4'fluorobiphenyl-4-yl, 2' -chloro-5' -fluorobiphenyl-4-yl, 2' -chloro-6' -fluorobiphenyl-4-yl, 3' -chloro-2'fluorobiphenyl-4-yl, 3' -chloro-4 '-fluorobiphenyl-4-yl, 31 -chloro-5'-fluorobiphenyl-4-yl, 3'-chloro-6'fluorobiphenyl-4-yl, 4' -chloro-2' -fluorobiphenyl-4-yl, 4' -chloro-3' -fluorobiphenyl-4-yl, 2' -chloro-3' fluorobiphenyl-3-yl, 2' -chloro-4 '-fluorobiphenyl-3-yl, 2' -chloro-5 '-fluorobiphenyl-3-yl, 2 '-chloro-6' fluorobiphenyl-3-yl, 3' -chjioro-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, 3' -dimethoxy)biphenyl-4-yl, 2' ,4'-dimethoxy)biphenyl-4-yl, ,5'-dimethoxy)biphenyl-4-yl, (2',6'-dimethoxy)biphenyl-4-yl, -dimethoxy)biphenyl-4-yl, ,5'-dimethoxy)biphenyl-4-yl, (2',3'-dimethoxy)biphenyl-3-yl, ,4 '-dimethoxy) biphenyl-3-yl, ,5'-dimethoxy)biphenyl-3-yl, ,6'-dimethoxy)biphenyl-3-yl, 4'-dimethoxy)biphenyl) -3-yl, -dimethoxy) biphenyl-3-yl, -di (trifluoromethyl) )biphenyl-4-yl, ,4 '-di (trifluoromethyl) )biphenyl-4-yl, 5'-di (trifluoromethyl) )biphenyl-4-yl, 6' -di (trifluoromethyl) )biphenyl-4-yl, 31 1 4 '-di(trifluoromethyl))bipheny..4yl, di (trifluoromethyl) )biphenyl-4-yl, -di (trifluoromethyl) )biphenyl-3-yl, WO 00/32577 PCT/EP99/08561 -12 (2 1,4'-di (trifluoromethyl) )biphenyl-3-yl, (2',51di (trifluoromethyl) )biphenyl-3-yl, 61 -di (trif luoromethyl) biphenyl-3-yl, 3 -di (trifluoromethyl))biphenyl-3-yl,(3,1 -dimethyl)biphenyl-4-yl, '3-dimethyl)biphenyl- L1-yl, -dimethyl) biphenyl-4-yl, 2' -dimethyl) biphenyl-3-yl, -dimethyl)biphenyl- 3-yl or (2,4 '-dimethyl)biphenyl-3-yl.
Furthermore, however, also preferentially benzo[1,3]- 9-H-carbazolyl, quinolyl, dibenzofuranyl, 9-H-fluorenyl, 7-bromo-9H-f luoren-2-yl, 9H-fluoren-9ol-1-yl, fluoren-9-on-2-yl, imidazolyl, indanyl, 1-imidazolyl, pyrazolyl, 9-H-carbazolyl, Iterphenyl, anthracenyl, naphthalen-l-yl, naphthalen-2-yl, 4 -bromo-naphthalen-1-yl, 4-cyanonaphthalen-1--yl, 4-chloro-naphthalen-1-yl, 4-nitronaphthalen-1-yl, 4 -methoxy-naphthalen-2 -yl, 6-hydroxynaphthalen-1-yl, 7 -hydroxy-naphthalen-1 -yl, 8-hydroxynapththalen-1-yl or stilbyl.
Furthermore, Ar is preferentially pyridyl-2-, pyridyl-3-, pyridyl-4-yl, pyrazol-3-yl, pyrazol-4-yl or pyrimidin-2-, pyrimidin-4-, which is unsubstituted or substituted by A or Hal particularly preferentially pyridyl-2-, pyridyl-3-yl, 4 -chloro-pyridyl-2-yl, 1-methylpyrazol- 4-yl or pyrimidin-2-yl.
Ar' is preferentially phenylene, biphenylene, l-naphthylene or pyrazol-4-yl, which is unsubstituted or monosubstituted by A, OH, OA, CF 3
OCF
3 or Hal.
Unsubstituted phenylene or l-naphthylene, 2 -nethoxyphenylene, 2 -methyiphenylene, 3 -biphenylene, 4-biphenylene or 1-methylpyrazol-4-yl is particularly preferred.
Ar' and Ar 2 are in each case independently of one another Ar having the preferred meanings indicated beforehand. Phenyl is particularly preferred for Arl and Ar 2 independently of one another.
WO 00/32577 PCT/EP99/08561 13 In Ar' is preferentially unsubstituted or substituted phenylene, D having one of the preferred or particularly preferred meanings mentioned below.
is particularly preferred for -Ar'-D-H.
In -Ar'-Het i Ar' is preferentially unsubstituted or substituted phenylene, Het' having one of the preferred or particularly preferred meanings mentioned below.
tertte /W s
\N
butyl rt-butyl :K3 -C C-
S
WO 00/32577 PCT/EP99/08561 14 0 0 0 0 o or o is particularly preferred for -Ar'-Het 1 In -Ar'-Y-C(A) 2
-R
3 Ar' is preferentially unsubstituted or substituted biphenylene, where R 3 is preferentially an alkyloxycarbonyl group and A has a preferred meaning as mentioned above.
CH
3 0C 2 H 'H OC
H,
33 is particularly preferred for -Ar'-Y-C(A) 2
-R
3 In -Ar'-(CH 2 )n-R 3 Ar' is preferentially unsubstituted or substituted phenylene, naphthylene, biphenylene or pyrazol-4-yl, where R 3 is preferentially an amido group, alkylamido group or dialkylamido group, carboxyl group, alkyloxycarbonyl group or an alkylcarbonyl group and n can be 0, 1, 2, 3 or 4.
0 0
(CH
2 2 CH2 NH2
NH,
NH
2 WO 00/32577 WO 0032577PCT/EP99/0856 I 15 N -C 3
H
7 -CH 3 0
(CH
2 2
CH
3 (CH22
CH
3 H
CH
3 0
(CH
2 2 d
N
I-C
3
H
7
H
3
CH
3 co--N
(CH
2 2 CH 3 H-
CH
3 -C -CH24NH 2 0
CH
3 0OCH 3 O COOH
K
-0 -0 1\CH 3
ONH
2
-N
0 N\OH3 0
OCH
3 WO 00/32577 PCT/EP99/08561 16
O
HC
S 0
CH
3 0
HC
O
0CH 3
-H
3 or is particularly preferred for Ar'-(CH 2 )n-R 3 In Ar'-Y- (CH 2
-R
3 Ar' is preferentially unsubstituted or substituted phenylene, where Y is preferentially S or O, R 3 is preferentially an amido group, alkylamido group or dialkylamido group, alkyloxycarbonyl or an alkylcarbonyl group and n can be 0, 1, 2, 3 or 4.
S-CH
2
-CONH--(CH
2 2
-C(CH
3 3 or
S-CNH
2 0
S-CH
2
NH
2 is particularly preferred for -Ar'-Y-(CH 2 )n-R 3 In -Ar' -Het -R 3 Ar' is preferentially unsubstituted or substituted phenylene, where Het 1 has one of the meanings preferentially indicated in the following and R 3 is preferentially alkylcarbonyl.
WO 00/32577 PCTIEP99/08561 17 0
S
I
sU 0
S
or is particularly preferred for -Ar'-Het 1
-R
3 In -Ar'-(CH 2 )n-R 6 Ar' is preferentially unsubstituted or substituted phenylene or biphenylene, where R 6 is preferentially an amino group, alkylamino group, dialkylamino group or alkyloxycarbonylamino group and n can be 0, 1, 2, 3 or 4.
NH
2 0 Z-N/ CH 3
NH
2
CH
3 N\ H
CH
3 or H
CH
3 is particularly preferred for -Ar'-(CH 2 )n-R 6 In -Ar'-S0 2 -Het, Ar' is preferentially unsubstituted or substituted naphthylene or phenylene, where Het has one of the meanings preferentially indicated in the following.
WO 00/32577 PCT/EP99/08561 18
S
2 or S0 2
N
0 SO2 O is particularly preferred for -Ar'-S0 2 -Het.
In -Ar'-NH-S0 2 -Het, Ar' is preferentially unsubstituted or substituted phenylene, where Het is particularly preferred 5-methoxy-pyrimidin-2-yl.
N-SO2 0 HN CH is particularly preferred for -Ar'-NH-SO2-Het.
In -Ar'-S0 2
-R
7 Ar' is preferentially unsubstituted or substituted naphthylene, where R 7 is preferentially an alkylamino group, dialkylamino group, cycloalkylamino group or an alkylcycloalkylamino group.
02 02 or 02 HsC2
H
3 C
C
4H9 H 3 C is particularly preferred for -Ar'-SO 2
-R
7 In -Ar'-(CH 2 )n-(CONH)-(CH 2 )i-R 6 Ar' is preferentially unsubstituted or substituted phenylene, where R 6 is preferentially an amino group, alkylamino group, dialkylamino group or a cycloalkylamino group and n can be 0, 1, 2, 3 or 4 and i can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
WO 00/32577 PCT/EP99/08561 19
(CH
2 2
-CONH-(CH
2 3
-N(CH
3 2
(CH
2 2
CONH-(CH
2 4
-NH
2
(CH
2 2
CONH-(CH
2 2
-NH
2 or is particularly preferred for -Ar'-(CH 2 (CONH)
(CH
2 In (CH 2 (CONH) -(CH 2 j-D-H, Ar' is preferentially unsubstituted or substituted phenylene, where D has one of the preferred meanings mentioned below and n can be 0, 1, 2, 3 or 4 and i can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
(CH
2 2 CONH CONH CONH
-(CH
2 2
(CH
2 2
CONH-CH
2
(CH
2 2
CONH-(CH
2 2 or -d WO 00/32577 PCT/EP99/08561 20 is particularly preferred for
(CH
2 )n-(CONH)
(CH
2 i-D-H.
In -Ar'-S-(CH 2 n-(CONH) (CH 2 Ar' is preferentially unsubstituted or substituted phenylene, where D has one of the preferred meanings mentioned below and n can be 0, 1, 2, 3 or 4 and i can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
2
-CONH
or
/-S-CH
2 CONH -(CH 2 2 -0 is particularly preferred for -Ar' (CH 2 n- (CONH)- (CH2) i-D-H.
In -Ar' -(CH 2 )n-(CONH) (CH 2 i-R 11 Ar' is preferentially unsubstituted or substituted phenylene, where R n is -CH(A)-Ph, wherein A has one of the preferred meanings mentioned beforehand, Ph is phenyl and n can be 0, 1, 2, 3 or 4 and i can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
(CH
2 2 CONH\
CH
3 or
(CH
2 2
CONH-CH
2 F
CH
3 is particularly preferred for -Ar'-(CH 2 )n-(CONH)-(CH 2 )i-
R
1 In -Ar'-S-(CH 2 (CONH)- (CH 2 i-R 11 Ar' is preferentially unsubstituted or substituted phenylene, where R" is -CH wherein A has one of the preferred meanings mentioned beforehand, Ph is phenyl WO 00/32577 PCT/EP99/08561 21 and n can be 0, 1, 2, 3 or 4 and i can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
S-CH
2
-CONH-CH
2
CH
3 is particularly preferred for -Ar' -S-(CH 2 n-(CONH)-
(CH
2 )i-R 11 In -Ar'-(CH 2 )n-(CO)-Het, Ar' is preferentially unsubstituted or substituted phenylene, where Het has one of the preferred meanings mentioned in the following and n can be 0, 1, 2, 3 or 4.
(CH
2 2
C
is particularly preferred for -Ar'-(CH 2 )n-(CO)-Het.
In -Ar' (CH 2 (CONH)- (CH 2 )i-Ar, Ar' is preferentially unsubstituted or substituted phenylene, where Ar has one of the preferred meanings mentioned beforehand and n can be 0, 1, 2, 3 or 4 and i can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
CONH-
(CH
2 2 -CONH 2Br
CONH-
CN
WO 00/32577 -2
(CH
2 2 -CONH
CN
(CH
2 2
-CONH-(CH
2 2
/NO
2
CONH-(CH
2 2
/NO
2
(CH
2 2
-CONH-CH
2
NO
2
ONH-CH
2
NO
2
CONH-(CH
2 2
-N
(CH
2 2
-CONH-CH
2 (CH)2 CON-(C2
N
(CH
2 2
-CONH-(CH
2
N
PCT/EP99/08561 WO 00/32577 -2
ONH-CH
2
(CH
2 2 -CONH
CAH
~CAH
CONH
CAH
(CH
2 2 -CONH N I-CH 3
(C
2 2
CONH-CH
2
CH
3
ONH-CH
2 N CH 3
(CH
2 2 -CONH
(CH
2 2
-CONH-(CH
2 2 S2- C2)-CONH-CH2 /C -SQ-NH 2 PCT/EP99/0856 I WO 00/32577 -2
CONH-CH
2 O S0 2
-NH
2
(CH
2 2 -CONW O -H 3 CONH--
OH
3
CH
3
(OH
2 2 CONH-0OH 3
OH
3
CH
3 CONH-0CH 3
OH
3 PCT/EP99/08561 WO 00/32577 -2
CONH-(CH
2 2
(CH
2 2
-CONH-(CH
2 2
CI
CI
(CH
2 2 -CONH b
(CH
2 2
-CONH-CH
2
CI
CONH-CH
2
CI
CONH-(CH
2 2
CI
PCT/EP99/08561 WOO00/32577 -2
(CH
2 2
-CONH-(CH
2 2 cl
(OH
2 2
-CONH-CH
2
/CI
(CH
2 2 -CONH l
CONH-(CH
2 2 cl CONH CI
(CH
2 2 CO
NH-(CH
2 2
CH
3
CONH-(CH
2 2 H3 CH)-CONH
OH
3 PCT/EP99/0856 I WO 00/32577 -2 CONH
-CH
3
(CH
2 2
-CONH-CH
2
CONH-CH
2
CH)KCN
(CH
2 2 -CONH-H7 CONH-0
/(CH
2 2 -CONH OCH 3 PCT/EP99/08561 WO 00/32577 28
CF
3
(CH
2 2 CONH
CF
3
CF
3
(CH
2 2 CONH-- /\CI ONH CI
CF
3
CI
(CH
2 2
-CONH-CH
2 cCI
//CONH-CH
2 \l PCT/EP99/0856 I WOO00/32577 29- CI CI
CONH-CH
2
CI
CONH-CH
2 l
CI
CONH-(CH
2 2 cl
(CH
2 2
-CONH-CH-
2
CONH-CH
2 'o
(CH
2 2 CONH
CI
CONH
PCT/EP99/0856 I WO 00/32577 -3
CH
2 2 -CONH-. l CONH- c
CONH-CH
2
CONH-(CH
2
(CH
2 2
-CONH-(CH
2 3 PCTIEP99/0856 I WO 00/32577-
(CH
2 2
-CONH-(CH
2 4
CONH-(CH
2 4 0
(CH
2 2
-CONH-(CH
2 2
OH
3
CONH-(CH
2
H
3
OH
3
(OH
2 2 CONH
CH
OH
3
CONH
OH
3 PCT/EP99/08561 WO 00/32577 WO 0032577PCT/EP99/08561 32 CO N H
F
CONH-CH
2 /q
CF
CONH Q-F WO 00/32577 -3
CONH-CH
2
/\F
CONH-Q F
(CH
2 2
CONH-CH
2 F
CONH-CH
2
/\F
(CH
2 2
CONH-(CH
2 2
OCH
3 PCT/EP99O8561
CONH
WO 00/32577- 2 2 Z H3 _dCONH-q
OH
(CH
2 2
-CONH-(CH
2 2 '0'OCH 3
ONH-CH
2 OCF 3
(CH
2 2
-CONH-CH
2 '3'OCF 3
(CH
2 2 -CONH O OCH 3 CONH
OCH
3
CONH-(CH
2 2 OCH 3
(CH
2 2
-CONH-(CH
2 2 'O F PCT/EP99/0856 I WO 00/32577-
CONH-(CH
2 2
F
(CH
2 2
-CONH-CH
2
F
CONH-CH
2 PCT/EP99/08561
CONH
F
WO 00/32577 -3 OPh
(OH
2 2 CONH O OPh CONH O OPh C ONH H 3
CH
2 2 -CONH 0 C H 3
OCH
2 Ph
(OH
2 2 CONH
CONH--
0
(CH
2 2
-CONH-CH
2 PCT/EP99/0856 I WO 00/32577 WO 0032577PCT/EP99/08561 -37
CONH
CF
3
OCH
3 irt-butyl WO 00/32577 PC-F/EP99/08561 38tert-butyl C O N H d,te rt-b u ty l
CH
3
CONH-(CH
2 2
OCH
3
OCH
3
CH
2 2 -CONH 0CH
OCH
3
ONH-<
OCH
3
OCH
3
CONH-(CH
2 2
OCH
3
CH
3
CH
2 2
CONH-(CH
2 2 /\or
OCH
3
OCH
3
(CH
2 2
CONH-(CH
2 2
OCH
3 is particularly preferred for (CH 2 (CONH)
(CH
2 1 -Ar.
WO 00/32577 PCT/EP99/08561 39 In -Ar' (CH 2 (CONH) -(CH 2 Ar' is preferentially unsubstituted or substituted phenylene, where Ar has one of the preferred meanings mentioned be forehand and n can be 0, 1, 2, 3 or 4 and i can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
S-CH
2 -CONH Br S-0H--
CONH\/
CN'
S-CHI-CONH-(CH 2 2
&/NO
2
\S-OH
2
CONH-CH
2
NO
2 a S-CH--CONH-(CH 2 2
I
-N
S-OH
2
-CONH-(CH
2 2 S-CH2 -CONH-CH 2 1 \/S-CH 2 -CONH N N 2-CAH
S-OH
2 COH H/N
"CH
3
S-CH
2
-CONH-CH
2
OH
3 WO 00/32577 PCT/EP99/08561 40
S-CH
2 CONH S- CH 2
CONH-(CH
2 2 S0 2
-NH
2
S-CH
2
CONH-CH
2 S0 2
-NH
2 S- CH 2 CONH
CH
3
S-CH
2 -CONH CH 3
CH
3
S-CH
2
-CONH-(CH
2 2
S-CH
2
-CONH-CH
2
CH
2
-CONH-(CH
2 2
CI
S-CH
2 -CONH
S-CH
2
CONH-CH
2
CI
S-CHI-CONH-(CH 2 2
CI
SCH
2
-CONH.CH
2
\/C
S-CH
2 -CONH '&cl WO 00/32577 41
S-CH
2
CONH-(CH
2 2
\CH
3
S-CH
2 -CONH
\CH
3 /S-CH 2 -CONH-CH 2 /S-CH 2
-CONHO:
CH
2 CONH /\OCH 3
CI
CF
3
S-CH
2 -CONH
CF
3
CF
3
S-CH
2 CONH~c /\Cl
CI
S-CH2 -CONH-CH 2
CI
CI
S- CH 2 -CON H-(CH 2 2
CI
CI CI S-CH 2 CONH-CH2
CI
/S-CH
2
CONH-CH
2
CI
PCT/EP99/0856 I WO 00/32577 PCT/EP99/08561 -42
S-CH
2
CONH-(CH
2 2 /\cl
S-CH
2
-CONH-CH
2 c
/S-CH
2 -CONH
I
S-CH
2 -CONH cl
S-CH
2
-CONH-CH
2
CH
2
-CONH-(CH
2 3
/S-CH
2 -CONHQ
S-CH
2
-CONH-(CH
2 4
Q
S-CHi-CONH-(CH 2 2
CH
3 -S-CH 2 7-CONH
CH
3
CH
3
/S-CH
2 -CONH
CH
3
S-CH
2 -CONH WOO00/32577 43-
C
2
H
-O S-CH 2
-CONH
SCH
2 CONH F3 S CH 2 CONH
CH
2 /l
CF
S-CH
2
-CNHC
2
F
S-CH2 -CONH
-F
CI
S-CH2 -CONH-CH 2
F
S-CH
2
-CONH-(CH
2 2
OCH
3
S-CH
2
-CONH-CH
2 H3
S-CH
2 -CONH- H3
OCH
3 S- CH 2
-CONH-CH
2
OCF
PCT/EP99/08561 WO 00/32577 PCT/EP99/08561 44 /0 s- CH 2 7-CONH/
OCH
3
CH
2
CONH-(CH
2 2
/\F
0 S- CH 2 -CONH-CH 2
F
/0 S- CHi-CONH
F
0 S- CHi-CONH-/
I
OPh 0 S- CHi--CONH--/ S- CH-- CONH "'Ofh
S-CH
2 -CONH -O/CH 3 \S-CHi-CONH 100 S- CH 2
-CONH-CH
2 WO 00/32577 PCT/EP99/08561
F
S- CH 2 7-CONH
OCH
3
F
S- CH 2 CONH
CH
3
CF
3
S-CH
2 CONH
OCH
3 tert-butyl C- S C H 7 C O N te rt-b u ty l
CH
3 S- CH 2 7-CONH-(CH2 2
OCH
3
OCH
3 S-
CH
2 -CONH
\CH
or
OCH
3 0 S- CH 2 -CON-(CH 2 2
OCH
3 In -Ar'I- (CH 2 (CONH) -(CH 2 i-Het 1 Ar' is preferentially unsubstituted or substituted phenylene, where Het' has one of the preferred meanings mentioned in the following and n can be 0, 1, 2, 3 or 4 and i can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
WO 00/32577 WO 0032577PCT/EP99/08561 46 ,(CH2)2-CONH-(C"2)f-No (C H 2 2
-CONH-(CH'
2 0 2 2
-CONH-(CH
2 2 -No3 __d(CH 2 2
-CONH-(CH
2 3
-N
WO 00/32577 PCTIEP99/08561 47
S
CONH-CH
2
S
CH
2 2
-CONH-CH
2 0
(CH
2 2
-CONH-CH
2
\I
0 CO NH-CH 2 \<0I or d is particularly preferred for -Ar'-(CH 2 )n-(CONH)-(CH 2 )i- Het'.
In (CH 2 (CONH) -(CH 2 i-Het 1 Ar' is preferentially unsubstituted or substituted phenylene, where Het' has one of the preferred meanings mentioned in the following and n can be 0, 1, 2, 3 or 4 and i can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
S-CH
2
-CNH-(CH
2 2 -N0j 0
S-H
2
CONH-(CH
2 3
-N
ON-CH)2N
S
S-CH
2
-CONH-CH
2
\I
WO 00/32577 PCT/EP99/08561.'- 48
/S-CH
2
-CONH-CH
2 \1 is particularly preferred for -Ar'-S -(CH 2 (CONH)
(CH
2 ±-Het.
In -Ar'-(CH 2 (CH (CN))-(CH 2 i-Ar, Ar' is preferentially unsubstituted or substituted phenylene, where Ar has one of the preferred meanings mentioned beforehand and n can be 0, 1, 2, 3 or 4 and i can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
HCH
N:CH
3 HC2
CH
3
N
or
~H
N
is particularly preferred for -Ar -(CH 2 (CH (CN))
(CH
2 i-Ar.
In -Ar' -(CH 2 (CONH) -(CH 2 ±-CH (Arl) -Ar 2 Ar' is preferentially unsubstituted. or substituted phenylene, where Ar 1 and Ar 2 each independently of one another has one of the preferred meanings mentioned beforehand and n can be 0, 1, 2, 3 or 4 and i can be 0, 1, 2, 3, 4, 6, 7, 8, 9, 10, 11 or 12.
CON-(HCr-C
CONH-(CH
2
)-CH
-r CNHH-H WO 00/32577 PCT/EP99/08561 49
(CH
2 2
CONH-(CH
2 2 -CH or
(CH
2 2
CONH-CH
2
-CH
is particularly preferred for -Ar' -(CH 2 (CONH)
(CH
2 i-CH -Ar.
In -Ar'I (CH 2 n- (CONH) (CH 2 i-CH -Ar, Ar' is preferentially unsubstituted or substituted phenylene, where Ar 1 and Ar 2 each independently of one another has one of the preferred meanings mentioned bef orehand and n can be 0, 1, 2, 3 or 4 and i can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
S-CH
2 -CON H-(CH 2 2
-CH
or
S-CH
2 -CONH-CH 2
-CH
is particularly preferred for -Ar'-S-(CH 2
(CH
2 i-CH (Ar 1 -Ar.
In the above f ormulae, D is cycloalkylene and has 4 to 7, preferably 5 or 6, C atoms. Cycloalkylene is preferably cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, particularly preferentially cyclopentyl or WO 00/32577 PCT/EP99/08561 50 cyclohexyl. Furthermore, D is preferentially cyclohexen-1-yl.
Hal is preferably F, Cl, Br or iodine.
Het' is preferentially substituted or unsubstiLtuted furan-2-yl or 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-on-4-yl, 1, 2-dihydropyrazol- 3-on-5-y1, benzothiophen-2-yl, benzothiophen-3-yl, 3Hbenzothiazol-2-yl, benzofuran-2-yl, benzofuran-3-yl, imidazol-l--yl or benzo[1,3)dioxol-5-yl or piperidine-1-yl, pyrrolidine-1-yl or pyrrolidine-2-on-lyl. Furthermore furan-2-yl, carbazol-9-yl, 3,6-di-tertbutyl-carbazol-9-yl, thiazol-2-yl, thiazol-3-yl, 41-thiadiazol-2-yl, 5-trifluoromethyl-[l,3 34)thiadiazol-2-yl, 1, 5-dimethyl-1, 2-dihydropyrazol- 3-on-4-yl, benzofuran-2-yl, 6-methyl-benzothiazol-2-yl, 2, 3-dihydro-1H-indol-6-yl, benzothiophen-2-yl, imidazol-1-yl or benzo or piperidine-1-yl, morpholin-4-yl, pyrrolidine-1-yl or pyrrolidine-2-on-1-yl is particularly preferred.
In -Het'-Ar, Het 1 and Ar have one of the preferred meanings indicated above, where Ar is preferably phenyl. 4-phenylthiazol-2-yl, -thiadiazol-2-yl or 1, 5-dimethyl-2-phenyl- 1.2-dihydropyrazol-3-on-4-yl is particularly preferred f or Het'Ar In -Het'-R 3 Het' is preferably 2,3-dihydro-lHindol-6-yl and R3 is preferably CO(A).
0 %X
N'H
3 is particularly preferred for H-et 1 -Ar.
Het is preferably substituted or unsubstituted 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 4- or 5-imidazolyl, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 4- or 5-isoxazolyl, 4- or 5-thiazolyl, 4- or 5-isothiazolyl, 3- or WO 00/32577 PCT/EP99/08561 51 4-pyridyl, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, or l,2,4-triazol-l-, or -5-yl, 1- or 1,2,3-oxadiazol-4- or -5-yl, l,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or 1,2,4-thiadiazol-3- or -5-yl, l,2,3-thiadiazol-4- or 5- or 6-2H-thiopyranyl, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 6- or 7-benzofuryl, 6- or 7-benzothienyl, 6- or 7-1H-indolyl, 4- or 5-benzimidazolyl, 6- or 7-benzopyrazolyl, 6- or 7-benzoxazolyl, 3-, 6- or 7-benzisoxazolyl, 6- or 7-benzothiazolyl, 6- or 7-benzisothiazolyl, 6- or 7-benz-2,1,3oxadiazolyl, 7- or 8-quinolinyl, 7- or 8-isoquinolinyl, 4- or 9-carbazolyl, 1-, 8- or 9-acridinyl, 7- or 8-cinnolinyl, 7- or 8-quinazolinyl. The heterocyclic radicals can also be partially or completely hydrogenated. Het can thus also be 2,3-dihydro-2-, or -5-furyl, dihydro-2-, or -5-furyl, tetrahydro-2- or 3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, or 2,5-dihydro-1-, or 2- or 3-pyrrolidinyl, tetrahydro-l-, or -3-pyrrolyl, tetrahydro-l-, or 4-imidazolyl, 2,3-dihydro-l-, -7-lH-indolyl, 2,3-dihydro-l-, or tetrahydro-l-, or -4-pyrazolyl, 1,4-dihydro-l-, or -4-pyridyl, 1,2,3,4-tetrahydro-1-, or -6-pyridyl, l,2,3,6-tetrahydro-l-, or -6-pyridyl, 3- or 4-piperidinyl, 3- or 4-azepanyl, 3- or 4-morpholinyl, tetrahydro-2-, or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, or -5-yl, hexahydroor 4-pyridazinyl, hexahydro-1-, or WO 00/32577 PCT/EP99/08561 -52 2- or 3 -piperazinyl, 1,2,3,4-tetrahydro-1-, or -8-quinolinyl, l,2,3,4-tetrahydro-l-, or -8-isoquinolinyl.
Tetrahydro-1-pyrrolyl, 2, 3-dihydro-1H-indol-1-yl, 1-piperidinyl, 2, 6 -tetramethylpiperidin-4-yl, 4-morpholinyl, 1-piperazinyl, 4 -methylpiperazin-l-yl, 4 -phenylpiperazin-1-yl, 1,2,3, 4-tetrahydroquinolin-1-yl or 1,2,3, 4-tetrahydroisoquinolin-l-yl is particularly preferred.
In -Het-S0 2 -Ar, Het and Ar have one of the preferred meanings indicated above, where Het is preferably piperazine-1, 4-diyl.
-N -SO 2 Br is particularly preferred for -Het-S0 2 -Ar.
In -Het-R 5 Het has one of the preferred meanings indicated beforehand, where Het is preferably piperazine-1,4-diyl and R 5 is preferentially phenyl, methyl, chloromethyl or trifluoromethyl.
-N is particularly preferred for -Het-R 5 In -Het-(CH 2 H-et and Ar have one of the preferred meanings indicated above, where Het is preferably piperazine-1,4-diyl and n can be 0, 1, 2, 3 or 4.
0 -N H 2 "2 0 -N
-H-O
WO 00/32577 PCT/EP99/08561 53
N
-N or -N
N
N
is particularly preferred for -Het-(CH 2 )n-Ar.
X and/or X 1 and/or X 2 is alkylene and is preferably methylene, ethylene, propylene, butylene, furthermore also pentylene or hexylene.
Y is preferably O, S, NH or NA.
In -Y-(CH 2 )n-Het, Y is preferably 0, S, NH or NA, where Het has one of the preferred meanings indicated above and n is preferably 0, 1, 2, 3 or 4.
-NH-(CH
2 2 -N O -NH-(CH 2 3 -N
N-CH
3 or .NH N is particularly preferred for -Y-(CH 2 )n-Het.
In -Y-Ar'-R 3 Y is preferably O, S, NH or NA, where Ar' has one of the preferred meanings indicated beforehand and R 3 is preferentially an alkylcarbonyl group.
.NH 0
CH
3 is particularly preferred for -Y-Ar'-R 3 In -Y-(CH 2 )n-Ar, Y is preferably O, S, NH or NA, where Ar has one of the preferred meanings indicated above and n is preferably 0, 1, 2, 3 or 4.
N
N
-NH-(CH
2 2 -NH-CH 2
-NH-(CH
2 2
-NH-(CH
2 3 -N-N -NH
NH-CH
2 0 2
-NH
2 WO 00/32577 PCT/EP99/08561 -54
-NH-(CH
2 2 OH,
-NH-CH
2
-NH-CH
2
QNH
2 -NH CH 3 NH F.
-NH-\H2/ or
OH
3
H
2 2
OH
is particularly preferred for -Y-(CH 2 )n-Ar.
In (CH 2
(CH
2 1 -R 6 Y is preferentially 0, S, NH or NA, where Ar' has a preferred meaning indicated beforehand, R 6 is preferably amino or alkylamino and 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
2
NH
2
NH-CH
2 /\or
NH-CH
2 CH 2
-NH
2 is very particularly preferred for -Y-(CH 2 2 )i-R.
In -Y-(CH 2 2 )i-R 6 Y is preferentially 0, S, NH or NA, where D has a preferred meaning indicated be forehand, R 6 is preferably amino or alkylamino and 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.
H
2
NH
2
NH-CH
2 or
NH-CH
2 -X
CH
2
-NH
2 is very particularly preferred for (CR 2 n-D- (CH 2 i-R 6 WO 00/32577 PCT/EP99/08561 55 In -Y-(CH 2 )n-Het-(CH 2 )i-R 6 Y is preferentially O, S, NH or NA, where Het has a preferred meaning indicated beforehand, R 6 is preferably amino or alkylamino and 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 N -(CH 2 3
-NH
2 is very particularly preferred for -Y-(CH 2 )n-Het-(CH 2 )i-R 6 In -Y-(CH 2 )n-NA-(CH 2 )i-R 6 Y is preferentially 0, S, NH or NA, where A has a preferred meaning indicated beforehand, R 6 is preferably amino or alkylamino and 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
2 is very particularly preferred for -Y-(CH 2 )n-NA-(CH 2 )i-R 6 In -Y-(CH 2 )n-D-(CH 2 )i-R 8 Y is preferentially O, S, NH or NA, where D has a preferred meaning indicated beforehand, R 8 is preferably guanidino or alkylguanidino and 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
CH
2 N NH 2
H
.NH-CH
2 or
N
-NH-CH
2 CH 2 N NH 2 2-
H
is very particularly preferred for -Y-(CH 2 )n-D-(CH 2 )i-R 8 In -Y-(CH 2 )n-Ar'-(CH 2 )i-R 8 Y is preferentially O, S, NH or NA, where Ar' has a preferred meaning indicated beforehand, R 8 is preferably guanidino or alkylguanidino and 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
CH
2 -N NH 2
H
.NH-CH
2 WO 00/32577 PCT/EP99/08561 56
N
NH-(H2) N INH 2 or
H
N
.NH-CH
2 CH 2 -Nk NH2 is very particularly pref erred f or (CH 2
(CH
2 i-R.
In -Y-(CH 2
),-NA-(CH
2 )i-R 8 Y is preferentially 0, S, NH or NA, where A has a preferred meaning indicated beforehand, R 8 is preferably guanidino or alkylguanidino and n is 0, 1, 2, 3 or 4 and i isO0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. -NH-(CH2)3-N(CH 3
)-(CH
2 3
-NH-C(=NH)-NH
2 is very particularly preferred for -Y-(CH 2 2 1
-R.
In 1 2 -R 6 Y is preferentially 0, S, NH or NA, where X, X 1 and X 2 have a preferred meaning indicated beforehand. Furthermore,
R
6 is preferably amino, alkylamino or dialkylamino, t is 0, 1 or 2 and u is 1 or 2. -NH-(CH 2 3 -0-(CH 2 4
-O-(CH
2 3
-NH
2 is particularly preferred for
"_X
2
-R
6 Furthermore, in 1 -OH, Y is preferentially 0, S, NH or NA, where X and X1 have a preferred meaning indicated beforehand and u can be 1 or 2. -NH- (CH 2 2 -NH- (CH 2 2 -OH is particularly preferred for R is preferably H or NO 2
R
1 is preferably -Het, -Het-S0 2 -Ar, -Het-R -Het-(CH 2
NO
2 -N=CH-Ar, NHAlk, NAAlk, NHA', NA' 2 -N N N H -Y-Ar' -R 3
(CH
2 0 -R 3
(CH
2 I- (CHR 4
-R
5 -YC (CH 2 o0H] 13, (CH 2 m-NA 2 -Y (CH 2 mNHA'
(CH
2 n-Ar, (CH 2 n-Ar' (CH 2 -R 6
(CH
2
(CH
2 i-R 6
(OH
2 n-Het- (CH2) 6
(CH
2 n-NA- (OH 2
±-R
6
(OH
2 n-NH- (CH 2 1 -R 6
(CH
2 n-D- (OH 2 j-R 8
(CH
2 n-Ar'I (OH 2 j-R 8 ,r (OH 2 n-NH- (OH 2 8
(CH
2 a-NA- (CH 2 -R 8 1 WO 00/32577 PCT/EP99/08561 57 R 6 -Y-(CH2)n-C
N
[X'-O]u-X 2
-R
6 or -Y-[X-NH]u-X 1 -OH, where -Het, -Het-SO2-Ar, -Het-R 5 -Het- (CH2) n-Ar, -Y-Ar' -R 3
(CH
2 n-Het,
(CH
2 n-Ar,
(CH
2 n-Ar' (CH 2 i-R 6
(CH
2
(CH
2 i-R 6 (CHZ) n-Het- (CH 2 i-R 6
(CH
2 n-NA- (CH 2 i-R 6
(CH
2 n-D- (CH 2 i-R 8
(CH
2 )n-Ar' (CH 2 )i-R 8
(CH
2 n-NA- (CH 2 i-R 8 t- [XI-Ou-X 2
-R
6 and [X-NH]u-X -OH in particular have the preferred or particularly preferred meanings indicated beforehand.
Furthermore, Ar in -N=CH-Ar is preferably 2-hydroxyphenyl.
In NHAlk, Alk has a preferred meaning indicated beforehand.
NH-(n-CsH 11 is particularly preferred for NHAlk.
In NAAlk, A and Alk have a preferred meaning indicated beforehand, where N (CH3) (n-C 4 H9) is particularly preferred for NAAlk.
In NHA', A' has a preferred meaning indicated beforehand. NH-(n-C3H 7 is particularly preferred for NHA'.
Furthermore, A' in NA' 2 has a preferred meaning indicated beforehand, where N(C 2 Hs) 2 is particularly preferred for NA' 2 In as a R 1 substituent, Y is preferentially 0, S, NH or NA, where D has a preferred meaning indicated beforehand.
-NH-C
6 Hn 1 or -NH-C 5
H
9 is particularly preferred for -Y-D-H.
In -Y-(CH 2 )o-R 3 Y is preferentially O, S, NH or NA, where R 3 is preferably alkyloxycarbonyl and o can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or
-NH-(CH
2 )2-COOMe is particularly preferred for -Y-(CH 2
-R
3 In -Y-(CH2)n-(CHR 4
)-R
5 Y is preferentially O, S, NH or NA, where R 4 is preferably phenyl or hydroxyl,
R
5 is preferentially methyl, chloromethyl or trifluoromethyl and n is 0, 1, 2, 3 or 4.
WO 00/32577 PCT/EP99/08561 -58 Y
OH
-NH- H or -NH-CH 2
H
CH
3
CH
2
CI
is particularly preferred for -Y-(CH 2
),-(CHR
4 In -Y-C[(CH 2 3 Y is preferentially 0, S, NH or NA, where o can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or -NH-C CH 2 -OH] 3 is particularly preferred for
(CH
2 0 -OH)1 3 In CH 2 )m-NA 2 Y is preferentially 0, S, NH or NA, where A has a preferred meaning indicated beforehand and m can be 0, 1.or 2.
-NH- (CH 2 2 -N (C 2
H
5 2 or -N (CH 3
(CH
2 2 -N (C 2
H
5 2 is particularly preferred for -Y-(CH 2 )m-NA 2 In -Y-(CH 2 )m-NHA', Y is preferentially 0, S, NH or NA, where A' has a preferred meaning indicated beforehand and m can be 0, 1 or 2. -NH- (CH 2 2 -NH- (C 3
H
7 is particularly preferred for -Y-(CH 2 In -Y-(CH 2 Y is preferably 0, S, NH or NA, where o is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. -NH- (CH 2 2 -OH or -NH- (CH 2 5 -OH is particularly preferred for
(CH
2 0
-OH.
In (CH2) k-R 6 Y is preferentially 0, S, NH or NA, where R 6is preferably amino, alkylamino, dialkylamino, or cycloalkylamino and k can be 3, 4, 5, 6, 7, 8, 9, 11 or 12. -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 -N (CH 3 2 -NH- (CH 2 3 -NH (CHA), -N (CH 3
(CH
2 3 -NH (CH 3 or
-NH--(CH
2 3 -N
H
is particularly preferred for (CH 2 k-R 6 In (CH 2 Y is preferentially 0, S, NH or NA, where R 8 is preferably .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 can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, -11 or 12. -NH- (CH2) 2 -NH-C -NH 2 WO 00/32577 WO 0032577PCTIEP99/0856 1 59 -NH- (CH 2 3 -NH-C -NH 2 -NH- (CH 2 5 -NH-C -NH 2 -NH- (OH 2 7 -NH-C -NH 2 or
NH
-N-(CH
2 N- N NH H CH 3 -NH- (CH 2 4 -NH-C -NH 2 -NH- (CH 2 6 -NH-C -NH 2 is particularly preferred for -Y-(CH 2 )i-R.
In -N R and -Y-(CH 2 N
R
NH NH Y is preferentially 0, S, NH or NA, where R" i s preferably amino, alkylamino or dialkylamino and n can be 0, 1, 2, 3 or 4.
,NH
2 _C
NH
2 -N N NH and -NH-CH 2 \N is particularly preferred for -N -"4lR and I r-\N NH 4n NH R 2 is preferably -Ar, -Het'.
-Het 1 -Ar, -Ar' -Het',I (CH 2
(CH
2 n-R 3 -Ar' -Y-C 2
-R
3 -Het 1
-R
3 -Ar' -Het'-R 3 -Ar I- (CH 2 Ar' -SO 2 -Het, -Ar' -NH-SO 2 -Het, Ar' -SO 2 -Ar'-(CH 2 )n-(CO- CO-Het, -Ar' -(CH 2 (CO-NH) -(CH 2 j-D-H, -Ar' (CH 2 n- (CO- NH) (CH 2 1 -Ar, -Ar' (CH 2 (CO-NH) (CH2) 1 -Het', -Ar'I (CH 2 n- (CH (CN) )-(CH 2 i-Ar, -Ar'I (CHl2) n- (CO-NH)
(CH
2 ±-CH (Ar 1 -Ar 2 -Ar' (CH 2 (CO-NH) -(OH 2 i-Ar, -Ar' S- (CH 2 n- (CO-NH) (CH 2 i-R 11 -Ar'I S- (CH 2 (CO -NH)
(CH
2 ±-Het -Ar' (CH2) n- (CO-NH) (OH 2 1 -CH -Ar 2or -Ar'-S-(CH 2 )n-(CO-NH)-(CH 2 Ar, Ar', Arl I Ar2 A, D, Het, Het', R 3
R
6 Y, n and i in particular have one of the preferred or particularly preferred meanings indicated beforehand.
R 3 is preferably C(O)A, CONH 2 CONHA, CONA 2 COOH or COQA, where A has one of the preferred meanings indicated beforehand.
R 4 is preferentially phenyl or hydroxyl.
WO 00/32577 PCT/EP99/08561 60
R
5 is preferably methyl, chloromethyl, trifluoromethyl or phenyl.
R
6 is preferentially NH 2 NHA, NA 2 NH(D-H) or NHC(O)A, where A and D have a preferred meaning indicated beforehand.
R
7 is preferably NA(D-H), NHA, NH(D-H) or NA 2 where A and D have a preferred meaning indicated beforehand.
R
8 is preferentially
-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 where A has a preferred meaning indicated beforehand.
R
1 is preferentially -CH(A)-Ph, where A has a preferred meaning indicated beforehand.
Some preferred groups of compounds can be expressed by the following subformulae Ia to Iz and Il to 15, which correspond to the formula I R z R1 RRI 0 N 0 R2 and in which the radicals not designated in greater detail have the meanings indicated in formula I, but in which: in Ia R is NO 2
R
1 is NO 2 and
R
2 is Ar; in Ib R is H,
R
2 is Ar and
R
i is -Het, -Het-S0 2 -Ar, -Het-R 5
NO
2 NHAlk, NAAlk, NHA', NA' 2 -Y-Ar'-R 3
(CH
2
-R
3
(CH
2
(CHR
4
-R
5
(CH
2 o-OH]3,
(CH
2 )m-NA 2
(CH
2 m-NHA', (CH 2 -OH, (CH 2 k-R 6 WO 00/32577 PCTIEP99/0856 I 61
(CH
2 -Aet, -Y
(CE
2
R
6
(CH
2 -Ar' (CH 2 1
-R
8 (Cl- 2 n-NA- (CH 2
±-R
6 or
(CH
2 n-NH- (CH 2 j-R 6 inlIc R R 2 inId R inlIe R is is H, is -Het' and is N0 2 is H, is -Het'-A and is N0 2
H
is -Ar' -(CH 2 -R 3 and is -Het, -Het-SO 2 -Ar, -Het-R 5 -Het- (CH 2 nAr, NO 2 NHAl k, NAAlk, NHA', N 2, -Y-Ar' -R I (CH 2 0
-R,
-Y-(CH
2 )m-NA 2 -Y (CH 2 )m-NHA', -Y-(CH 2 0 0H,
(CH
2 n-Ar' (CH 2 i-R, Y- (CH 2 n-D- (CH 2 1
-R,
(CH
2 n-HeA- (CH 2 -R 6 is (2 (CH 2 and is-Y- (CH 2 Y (E 2
(CH
2 j-R 6 o is H, is -Ar'-SO 2 -Het and is (CH 2 k-R 6 or (CH 2 n-Ar (CH 2 i-R 6 inlIf R inlIg R WO 00/32577 WO 0032577PCTIEP99/0856 I 62 inlIh R in I R inlIk R 0R2 in IJ R is H, is -Ar' -S0 2 -R 7 and is (CH 2 k-R 6or (CH 2
(CH
2 1
-R
6 is H, is -Ar' (CH 2 n- (CONH) (CH 2 i-R5 and is (CH 2 k-R 6or (CH 2 )n-Ar' -(CH 2 )i-R 6 is H, is -Ar' (CH 2 n- (CONH) (CH 2 1 -D-H and is (CH 2 k-R 6
(CH
2 n-Ar' (CH 2 1
-R
6
(CH
2 a-Ar' (CH 2 1 -R 8 or
(CH
2 n-NA- (CH 2 8 is H, is -Ar' -(CH 2 (CONH) -(CH 2 )i-Ar and is (CH 2 k-R 6, (CH 2 n-Ar' (CH 2 j-R 6
(CH
2 n-Ar, (CR 2 j-R 8
(CH
2 a-Ar- (CH 2 -R 8
(CH
2 -AI- (CH 2 1
-R
8 R6S is H, is -Ar' -(CH 2 (CONH) -(CR 2 i-Het 1 and is (CR 2 i-Re,
(CH
2 n-D- (CH 2 j-R 8 ,1
(CH
2 n-Ar' (CR 2 -Re or
(OH
2 n-NA- (CR 2 j-R 8 inlIm R WO 00/32577 in I R R 2 m Rl inlIp R PCT/EP99/08561 63 is H, is (CH 2 (CH (CN))-(CH 2 ±-Ar and is (CH 2 k-R 6
(CH
2 n-D- (CH 2 ±-R6 or -Y-
(CH
2 n-Ar' (CH 2 j-R 6 is H, is -Ar' (CH 2 n- (CO-NH) (CH 2 i-CH (Ar 1 -Ar 2 and is (CH 2
(CH
2 n-D- (CH 2 j-R 8
(CH
2
(CH
2 1
-R
8 or is H, is -Ar'-Het 1 and is (Cl- 2 k-R6, (CH 2 n-Ar' (CH- 2 j-R 6
(CH
2 n-Ar'- (CH 2
-R
8 or (H)n D- (CH 2 1 -R 6 is H, is -Ar'-Het-R 3 and is (CH 2 k-R 6 or -Y-C(CH 2 n-D- (CH 2 j-R 6 is H is (CH 2 n-R 6 and is (CH 2 k-R 6 or (CH 2 n-D- (CH 2 i-R 6 is H, is -Ar'I-Y-C 2 -R 3 and is (CH 2 k-R 6 inlIq R inlIr R inIs R R 2 inIt is H, is -Arl-NH-S0 2 -Het and is (CH 2 )k-R 6 inlIu R inlIv R R 2 is H, is -Het 1 -R 3 and is (CH 2 k-R 6 is H, is -Ar'-D-H and WO 00/32577 -6 Rlis (CH 2 k-R 6 PCT/EP99/08561 inlIw R inIx R R 2 in Iy R inhz R R 2
R
1 Ru 2 is H, is -Ar (CH 2 (CON-) (CH 2 j-R 1 1 and is (CH 2 -Ar'-(CH 2 1 -R 6 is H, is -Ar' -(CH 2 ,-CO--Het and is (CH 2
(CH
2 1
-R;
is H, is -Ar'I (CH 2 (CO-NH) -(CH 2 i-Ar and is (CH 2 a-Ar' (CH 2 1 -R 6 is H, is -Ar'I (CH 2 (CO-NH) -(CH 2 j-Het' and is (CH 2 n-Ar'- (CH 2 j-R 6
(CH
2 n-Ar' (CH 2 j-R 8 is H, is -Ar' (CH 2 (CO-NH) -(Gil 2 i-DH and is (CH 2 n-Ar' (CH 2 1 -R 6
(CH
2 n-Ar' (CH 2 j-R 8 is H, is -Ar' (CH 2 (CO-NH) (Gil 2 and is (CH 2 n-Ar' (CH 2 j-R 6
(CH
2 n-Ar I (CH 2
±-R
8 inI12 R inI13 R is H, is and -Ar'I (CH 2 (CO-Nil) (CH 2 i-CH (Arl) -Ar 2 Rl is (CH 2 6
-Y-(CH
2 nAr I CH 2 jR 8 inI14 R
R
2 is H, is -Ar, -Ar I-Het', (Gil 2 i-Ar and -Ar I (CH 2 (CO-Nil) WO 00/32577 PCT/EP99/08561 i1 65 R' is
(CH
2 CH 2 i-R 8
(CH
2 n-D- (CH 2 j-R 8
(CH
2 n-NA- (CH 2 i-R 8 or (CH 2 n-Ar (CH 2
±-R
8 R is H, R 2 is -Ar, -Ar'-(CHOn (CO -NH) -(CHO .Ar, (CO-NH) (CHO)j-Het', -Ar I S- (CHO)n- (CO-NH) (CHO He t 1 -Ar'I (CHO)n- (CO-NH) (CHO)j-D-H, Ar' (CHO) n- (CO -NH) (CHO D -H, -Ar' (CHO)n- (CO -NH) (CHO) i- CH (Ar 1 -Ar, -Ar' (CHO) n- (CO -NH) (CHO) i- CH (Ar 1 -Ar 2 -Ar'-(CHO)n- (CO-NH) -(CHO).-R 11 or -Ar'I-S-
(CH
2 (CO-NH) (CHO)i-R" and
R
1 is (CH 2 n-Ar (CH 2 j-R 6 or
(CH
2 n-Ar' (CH 2 Preferred compounds of the formula I are in the following: (4-Guanidinomethyl-benzylamino) 3-dioxo- 1H-, 3H-benzo [del isoquinolin-2-yl] -phenyl}-N- (4sul famoyl-phenyl) -ethyl] -propionamide; N- (4-Chloro-phenyl) -ethyl] 6- (4guanidinomethyl-benzylamino) 3-dioxo-lH, 3Hbenzo (de] isoquinolin-2-yl] -phenyl)l-propionamide; 6- (3-Amino-propylamino) 5-trimethoxy-phenyl) benzo (de] isoquinoline-1, 3-dione; 6- 3 -Amino-propylamino) (7-hydroxy-naphthalen-1-yl) benzo [de] isoquinoline-l, 3-dione; 6- (3 -Amino -propyl amino) 3-dioxo-1H, 3Hbenzo [del isoquinolin-2-yl] 6- 3 -Axnino-propyl amino) 3-dimethoxy-phenyl) benzo [de] isoquinoline-1, 3-dione; WO 00/32577 PCT/EP99/08561 66 N- (3-Chioro-phenyl) -ethyl] (4guanidinomethyl-cyclohexylmethyl-amino) 3-diaxoiN, 3H-benzo [de] isoquinolin-2-yl] -phenyl)}-propionamide; N-[2-(4-Chloro-phenyl)-ethyl]-3-{3-[6-(4guanidinomnethyl-cyclohexylmethyl-amino) 3-dioxo- 1H, 3H-benzo [del isoquinolin-2-yl] -phenyl }-propionamide; 6- (3-Amino-propylamino) (4 '-methoxy-biphenyl-4-yl) benzo [del isoquinoline-1, 3-diane; 6- (3-Amina-propylamino) (4-carbazol-9-yl-phenyl) benzo [del isaquinoline-1, 3-diane; 6- (3-Amino-propylamino) -hydroxy-2-methylbiphenyl-4-yl) -benzo(de] isoquinoline-1, 3-diane; N- [2-(4'Methoxy-biphenyl-4-yl)-1,3-dioxo-2,3dihydro-1H-benzo [del isoquinolin-6-ylamino) -methyl)}benzyl) -guariidine; 3- (2-Guanidino-ethylamino) 3-dioxo-1H, 3Hbenzo~de] isoquinalin-2-yl] -phenyl}-N- (4-phenyl-butyl) propionamide; N- (4-Chioro-phenyl) -ethyl] 3- (2-guanidinoethylamino) 3-dioxo-lH, 3H-benzo [del isoquinolin-2-yl] phenyllI-propionamide; N- (4-Chloro-phenyl) -ethyl] (3-guanidinopropylamino) 3-dioxo-lH, 3H-benzo [del isoquinolin-2yl] -phenyl)}-propionamide; N- (2-(4-Chloro-phenyl)-ethyl]-3-[3-(6-{3-[ (3-guanidinopropyl) -methyl-amino] -propylamino}-1, 3-dioxo-lH, 3Hbenzo [del isoquinolin-2-yl] -phenyl 1-propionamide; WO 00/32577 PCT/EP99/08561 67 N-(2-(3-Chloro-phenyl)-ethyl]-3-{3-[6-(3-guanidinopropylamino)-1,3-dioxo-1H,3H-benzo[de]isoquinolin-2yl]-phenyl}-propionamide; 6-(3-Amino-propylamino)-2-(4'-methoxy-biphenyl-4-yl)benzo[de]isoquinoline-1,3-dione; N-[3-({2-[4-(3,6-Di-tert-butyl-carbazol-9-yl)-phenyl]- 1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-6ylamino]-methyl)-benzyl]-guanidine and 6-(3-Amino-propylamino)-2-(4-carbazol-9-yl-phenyl)benzo[de]isoquinoline-1,3-dione.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), namely under reaction conditions which are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se, but not mentioned here in greater detail.
The starting substances, if desired, can also be formed in situ such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
The compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis or by hydrogenolysis.
Preferred starting substances for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxyl groups, in particular those which instead of an H-N- group carry an R'-Ngroup, in which R' is an amino protective group and/or WO 00/32577 PCT/EP99/08561 68 those which instead of the H atom of a hydroxyl group carry a hydroxyl protective group, e.g. those which correspond to the formula I, but instead of a group COOH carry a group -COOR", in which R" is a hydroxyl protective group.
A number of identical or different protected amino and/or hydroxyl groups can also be present in the molecule of the starting substance. If the protective groups present are different from one another, in many cases they can be removed selectively.
The expression "amino protective group" is generally known and relates to groups which are suitable for protecting (for blocking) an amino group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. Typical groups of this type are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size is otherwise not critical; however, those having 1-20, in particular 1-8, C atoms are preferred. The expression "acyl group" is to be interpreted in the widest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl groups, aryloxycarbonyl groups and especially aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,
BOC,
2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, Fmoc; arylsulfonyl such as Mtr. Preferred amino protective groups are BOC, furthermore CBZ, Fmoc, benzyl and acetyl.
WO 00/32577 PCTIEP99/08561 69 The expression "hydroxyl protective group" is also generally known and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. Typical groups of this type are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups. The nature and size of the hydroxyl protective groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; groups having 1-20, in particular 1-10 C atoms, are preferred. Examples of hydroxyl protective groups are, inter alia, benzyl, p-nitrobenzoyl, p-toluolsulfonyl, tert-butyl and acetyl, benzyl and tert-butyl being particularly preferred.
The liberation of the compounds of the formula I from their functional derivatives is carried out depending on the protective group used for example using strong acids, expediently using TFA or perchloric acid, but also using other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, furthermore also alcohols such as methanol, ethanol or isopropanol, and also water. Furthermore, mixtures of the abovementioned solvents are possible. TFA is preferably used in an excess without addition of a further solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures for the cleavage are expediently between approximately 0 and WO 00/32577 PCTIEP99/08561 70 approximately 50OC; the reaction is preferably carried out between 15 and 30 0 C (room temperature).
The groups BOC and Obutyl can preferably be removed, for example, using TFA in dichloromethane or using approximately 3 to 5N HC1 in dioxane at 15-30 0
C,
the Fmoc group using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 0
C.
Hydrogenolytically removable protective groups CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst of a noble metal catalyst such as palladium, expediently on a support such as carbon).. Suitable solvents in this case are those indicated above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. As a rule, the hydrogenolysis is carried out at temperatures between approximately 0 and 100 0 C and pressures between approximately 1 and 200 bar, preferentially at 20-30 0
C
and 1-10 bar. Hydrogenolysis of the CBZ group takes place readily, for example, on 5 to 10% Pd/C in methanol or ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30 0
C.
Compounds of the formula I can also preferably be obtained by reacting "compounds of the formula II with compounds of the formula III. As a rule, the starting compounds of the formulae II and III are known or commercially available. The unknown compounds, however, can be prepared by methods known per se. The compounds of the formula II are naphthalene- 1,8-dicarboxylic anhydride derivatives. They can be prepared in a conventional manner from appropriately substituted 1,8-naphthalenedicarboxylic acids or corresponding derivatives. It is furthermore possible to introduce appropriate substituents into the aromatic by conventional electrophilic or alternatively nucleophilic substitutions.
The compounds of the formula III are primary amines, which, as a rule, are also commercially WO 00/32577 PCT/EP99/08561 71 available. Furthermore, syntheses for the preparation of primary amines, such as, for example, the Gabriel synthesis, can be used.
As a rule, the reaction is carried out in an inert solvent. Depending on the conditions used, the reaction time is between a few minutes and a number of days, the reaction temperature between approximately 0° and 150 0 C, normally between 20" and 130 0 C. The reactions can be carried out in analogy to the methods indicated in Eur. J. Chem. Chim. Ther. 1981, 16, 207- 212 and in J. Med. Chem. 1982, 25, 714-719.
Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, N-methylpyrrolidone (NMP), dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or mixtures of the solvents mentioned.
Derivatives having a free primary or an additional secondary amino group are expediently employed in protected form. Possible protective groups are those mentioned beforehand.
For the preparation of compounds of the formula I in which R 1 and/or R 2 are H 2 an appropriate amino-substituted compound can be treated with an amidinating agent. The preferred amidinating agent is l-amidino-3,5-dimethylpyrazole (DPFN), which WO 00/32577 PCT/EP99/08561 72 is employed, in particular, in the form of its nitrate, or pyrazole-1-carboxamidine. The reaction is expediently carried out with addition of a base such as triethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, e.g. DMF at temperatures between 0° and 150"C, preferably between 600 and 120"C.
For the preparation of compounds of the formula I in which R 2 is unsubstituted or substituted biphenyl, -Ar'-Het 1 -Ar'-Het 1
-R
3 -Ar' -(CH 2 )n-R 3 and/or -Ar'-(CH 2 )n-R 6 an appropriate compound of the formula I in which R 2 is aryl bromide or aryl iodide can be reacted with the appropriate boronic acid derivatives in a Suzuki reaction. The Suzuki reaction is expediently carried out in palladium-mediated form, preferably by addition of Pd(PPh 3 4 in the presence of a base such as potassium carbonate in an inert solvent or solvent mixture, e.g. DMF at temperatures between 00 and 150°, preferably between 600 and 1200. Depending on the conditions used, the reaction time is between a few minutes and a number of days. The boronic acid derivatives can be prepared by conventional methods or are commercially available. The reactions can be carried out in analogy to the methods indicated in Suzuki et al., J. Am. Chem. Soc. 1989, 111, 314ff. and Suzuki et al., Chem. Rev. 1995, 95, 2457ff.
For the esterification, an acid of the formula I (R 1 COOH or -Y-(CH 2 )n-COOH and/or R 2
COOH)
can be treated with an excess of an alcohol, expediently in the presence of a strong acid such as hydrochloric acid or sulfuric acid at temperatures between 00 and 100*C, preferably between 200 and 50 0
C.
Conversely, an ester of the formula I (R 1 COOA or
-Y-(CH
2 )n-COOA and/or R 2 COOA) can be converted into the corresponding acid of the formula I, expediently by solvolysis according to one of the methods indicated above, e.g. using NaOH or KOH in water-dioxane at temperatures between 0" and 40 0 C, preferably between and 30 0
C.
WO 00/32577 PCT/EP99/08561 73 Furthermore, free amino groups can be acylated in a customary manner using an acid chloride or anhydride, expediently in an inert solvent such as dichloromethane or THF and/or in the presence of a base such as triethylamine or pyridine at temperatures between -60C and A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation. Acids which give physiologically acceptable salts are particularly suitable for this reaction. Thus inorganic acids can be used, e.g.
sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g.
formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and disulfonic acids or laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. picrates, can be used for the isolation and/or purification of the compounds of the formula I.
On the other hand, compounds of the formula I with bases (e.g sodium or potassium hydroxide or carbonate) can be converted into the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, or into the corresponding ammonium salts.
All synthesis methods indicated here and all other suitable processes for the preparation of compounds of the formula I can also be carried out by WO 00/32577 PCT/EP99/08561 74 means of the novel methods of combinatorial chemistry, i.e. by robot- and computer-assisted syntheses, and subjected to mass screening (for this see: US 5,463,564; M. A. Gallop et al., J. Med. Chem. 1994, 37, 1233-1251 and 1385-1401 and M.J. Sofia, Drugs Discovery Today 1996, i, 27-34).
The invention furthermore relates to pharmaceutical preparations comprising at least one compound of the formula I and/or one of its physiologically acceptable salts, which are prepared, in particular, in an non-chemical way. In this case, the compounds of the formula I can be brought into a suitable dose form together with at least one solid, liquid and/or semi-liquid excipient or auxiliary and, if appropriate, in combination with one or more other active compounds.
These preparations can be used as medicaments in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral oral) or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceryl triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly. Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used, in particular, for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, are used for parenteral administration, and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. The preparations indicated can be sterilized and/or can contain auxiliaries such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts WO 00/32577 PCT/EP99/08561 75 for affecting the osmotic pressure, buffer substances, colourants, flavourings and/or one or more other active compounds, e.g. one or more vitamins.
The compounds of the formula I and their physiologically acceptable salts act as adhesion receptor antagonists, in particular glycoprotein IbIX antagonists, and can be employed for the prophylaxis and/or therapy of thrombotic disorders and sequelae deriving therefrom. The disorders are acute coronary syndromes, angina pectoris, myocardial infarct, peripheral circulatory disorders, stroke, transient ischaemic attacks, arteriosclerosis and reocclusion/restenosis after angioplasty/stent implantation.
In this case, the substances according to the invention are as a rule administered in the dose of the glycoprotein IIblIIa antagonist ReoPro® of preferably between approximately 1 and 500 mg, in particular between 5 and 100 mg, per dose unit. The daily dose is preferably between approximately 0.02 and 10 mg/kg of body weight. The specific dose for each patient depends, however, on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health and sex, on the diet, on the time and route of administration, and on the excretion rate, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Oral administration is preferred.
Above and below, all temperatures are indicated in In the following examples, "customary workingup" means: if necessary, water is added, if necessary, depending on the constitution of the final product, the mixture is adjusted to pHs between 2 and 10 and extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallization.
Mass spectrometry (MS) apparatuses Kratos Maldi III and Finnigan LCQ. values are determined.
WO 00/32577 PCT/EP99/08561 76
EXAMPLES
Example 1: A suspension of 6.6 g of 6,7dinitrobenzo[de]isochromene-1,3-dione in 100 ml of toluene is treated with 3.3 g of 2-ylamine and the mixture is heated under reflux. After reaction is complete, the reaction mixture is allowed to cool and is worked up as is customary.
2-(5-Chloropyridin-2-yl)-6,7-dinitrobenzo[de]isoquinoline- 1,3-dione is obtained.
Example 2: A suspension of 4 g of 6-chlorobenzo[de]isochromene-l,3-dione in 100 ml of toluene is treated with 4.6 g of 2 ,5-dichlorophenylamine and heated under reflux. After reaction is complete, the reaction mixture is allowed to cool and is worked up as is customary. 6-Chloro- 2-(2,5-dichlorophenyl)benzo[de]isoquinoline-1,3-dione is obtained. This compound is then heated in morpholine until conversion is complete. After cooling the reaction mixture, it is worked up as is customary and 2-(2,5-dichlorophenyl)-6-morpholin-4-ylbenzo[de]isoquinoline-1,3-dione is obtained. MS: calculated: 426; found: 427.
Analogously, by reaction of 6-chloro- 2-(2,5-dichlorophenyl)benzo[de]isoquinoline-1,3-dione with R 1 the following compounds of the formula Iba are obtained: R1 Iba WO 00/32577 PCT/EP99/0856
I
77 WO 00/32577 PCT/EP99/08561 -78 R" in R--H and in Iba ms calculated found 424 425
II
H
\472 473
-N-
CH 2
-NH
2
-N-CH
2
C
H
-N-C H Q NH 2
H
N
-N -(CH 2
H
N
-N CH 2
H
1 H 2 2 0
H
-N j--(CH N-CH 3
H
-NH (C 5
H
1 1 426 427 -NH (C 3
H
7 398 399 -N (CH 3
-C
4
H
9 426 427 -N (C 2
H
5 2 412 413 WO 00/32577 PCT/EP99/08561 79 Example 3: Analogously to Example 2, 6-chiorobenzo~de~isochrornene-1,3-dione is reacted with 3-chlorophenylamine and then with R 1 The following compounds of the formula Ibb are obtained: Ibb 0 N 0
&CI
R* in R-H and inlIbb MS calculated found Ph H
CH
3 -NC] 376 377 -N N 467 468 -NH-C (CH 2 OH) 3 -NH- (CH 2 3 -N (CH 3 2 407 408 CH H0 412 413
H
(H426 427
H
WO 00/32577 WO 0032577PCT/EP99/08561 80 404 390 438 WO 00/32577 WO 0032577PCT/EP99/08561 81 Example 4: Analogously to Example 2, 6-chlorobenzo~de]isochromene-1,3-dione is reacted with phenylamine and then with R 1 The following compounds of the formula Ibc are obtained: WO 00/32577 PCT/EP99/08561 82- Ibc 0 N 0 R' in Ri-H and in Ibc MS calculated found Ph -N H 392 393 -N3I 342 343 -N 433 434 -NH- (CH 2 3 -N (CH 3 2 373 374
-N-CH
2 378 379
H
-N -(CH 392 393
H
-N CH 2 SO 2
NH
2
H
H 2 2
HO
WO 00/32577 PCT/EP99/0856 I WO 00/32577 PCT/EP99/08561 84 in Ri-H and in Ibc MS calculated found -N-C22N 0 401 402 H V
N-CH
3
H
-N -(CH 2 3 396 397
H
-NH- (CH 2 2
-COOCH
3 374 375 -NH (C 5
H
11 358 359 -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 -N=CH
HO
-NH- (CH 2 5 -OH 374 375 -N 0 358 359 Example Analogously to Example 2, 6-chlorobenzo- [delisochromene-l,3-dione is reacted with 3-nitrophenylamine and then with The f ollowing compounds of the formula Ibd are obtained: WO 00/32577 PCT/EP99/08561 85 Ibd O N 0
NO
2 R" in R'-H and in Ibd MS calculated found Ph H
CH
3 N -NH- (CH 2 3 -N (CH 3 2 418 419 -N ]387 388 -NH- (CH 2 5 -OH 476 477
H
437 438 H
H
WO 00/32577 PCTIEP99/08561 86 WO 00/32577 PCT/EP99/08561 87 R' in R'-H and in Ibd MS calculated found -N J-(CH 2 3 N N-CH 3
H
-N -(CH 2 3 -N -/kN 441 442
H
-NH- (CH 2 2
-COOCH
3 419 420 -NH (C 5
H
11 403 404 -NH (C 3
H
7 375 376 -N (CH 3
-C
4
H
9 403 404 -N (C 2
H
5 2 389 390 -N 0 403 404 Example 6: Analogously to Example 2, 6-chlorobenzo- [del isochromene-1,3-dione is reacted with 3-methoxyphenylamine and then with R 1 The following compounds of the formula Ibe are obtained: Tbe WO 00/32577 PCTAEP99/08561 -88 R' in R*-H and in Ibe MS calculated found Ph -N H 422 423 -o386 387 -N]372 373 -N N 463 464 -NH- (CH 2 3 -N (CH 3 2 403 404 -N-CH 408 409
H
/N 422 423
H
-N CH] D SO 2
NH
2
H
H3
OH
-N 2 2
OH
386 387 -N
IC
2
NH
2 -N C 2_ C2-N2437 438
H
WO 00/32577 PCT/EP99/08561 -89 R" in Ri-H and in Ibe MS calculated found /N C ONH 2 423 424
H
N
423 424
H
N
-N -C H 409 410
H
-NJ-(CH 0 431 432
H
1 2)3 3
H
-NH- (CH 2 2
-COOCH
3 404 405 -NH (C 3
H
7 360 361 -N (CH 3
-C
4
H
9 388 389 CH)2374 375 -NH- (CH 2 5 -OH 404 405 -N 0 388 389 WO 00/32577 PCT/EP99/08561 90 Example 7: Analogously to Example 2, 6-chlorobenzo- [de]isochromene-1,3-dione is reacted with 4-styryiphenylamine and then with R 1 The following compounds of the formula Ibf are obtained:
/R\
I bf R' in Ri-H and in Ibf MS calculated found -NH- (CH 2 3 -N (CHA) 2 475 476
CH
2
-NH
2 5051
CH
2
H
CH
2
ONH
2 495 496
H
N
-N 495 496
H
N
H
CH
2 481 482
H
WO 00/32577 WO 0032577PCTIEP99/0856
I
Example 8: Analogously to Example 2, 6-nitrobenzo- [de]isochromene-l,3-dione is reacted with H- 2 N-Ar and then (if necessary) with R 1 The following compounds of the formula Ibg are obtained: Ibg 0 N 0 WO 00/32577 WO 0032577PCT/EP99/08561 92 Example 9: Analogously to [del isochromene-l, 3-dione Example 2, is reacted 6-chlorobenzowith 3-chioro- WO 00/32577 PCT/EP99/08561 93 4-methyiphenylamine and then with R 1 The following compounds of the formula Ibh is obtained: Ibh R" in R 1 -H and in Ibh -NH- (CH 2 2 -N (C 2
H
5 2 -N 0 -N N-OH 3 Ph H
O<H
3 -NH- (CH 2 2
-OH
Example Analogously to Example 2, 6-chlorobenzo- [delisochromene-1,3-dione is reacted with H 2 N-Ar and then with R 1 The following compounds of the formula Ibi are obtained: WO 00/32577 WO 0032577PCT/EP99/08561 94 0 N 0 Ar Ar R' in R-H andlIbg MS caic. f nd.
0 -NH- (CH 2 3
-NH
2 435 436 -NH- (CH- 2 5
-NH
2 -NH- (CH 2 7
-NH
2 H2c H2 H497 498
H
-NH- (CH- 2 3
-NH
2 433 434
(CH
2 5
-NH
2 -NH- (CR 2 7
-NH
2
CH
2
NH
2 N -CH 2
H
0 -NH- (CH 2 3
-NH
2
-NH-.(CR
2 5
-NH
2
(CH
2 7
-NH
2 C~rK2$ NH 2
IH
C
2
H,
5 -NH- (CH 2 3
-NH
2 462 463 N/ -NH- (CH 2 5
-NH
2 490 491 -NH- (CR 2 7
-NH
2 I--H
-CH
2
NH
2 5254 1H WO 00/32577 PCTIEP99108561 95 Ar R' in R-H and Ibg MS caic. f nd.
-NH- (CH 2 3
-NH
2 395 396 -NH- (CH 2 5
-NH
2 423 424 N-NH- (CH 2 7
-NH
2 451 452 H7C CH 2 -NH 45 458
H
N-NH- (CH 2 3
-NH
2 395 396 N-NH- (CH 2 s-NH 2 423 424 -NH- (CH 2 7
-NH
2 451 452 -NC2-d CH 2 NH 45 458
H
-NH- (CH 2 3 -NH2 396 397 NZ-NH- (CH 2 5
-NH
2 424 425 N-NH- (CH 2 7
-NH
2 452 453 N CH 2
-NH
2
H
N-NH- (CH 2 3
-NH
2 396 397 N-NH- (CH 2 5
-NH
2 424 425 N-NH- (CH 2 7
-NH
2 452 453 C 2 NH 458 459
H
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-iodophenylamine and the mixture is heated under reflux. After reaction is complete, the reaction mixture is allowed to cool and is worked up as is customary. 6-Nitro-2- (4-iodophenyl) benzo (de] isoquinoline-1,3-dione is obtained. 1.2 Equivalents of
K
2 C0 3 1.2 equivalents of Ph-B-(OH) 2 and 10 mol% of Pd((PPh) 3 4 are added to a solution of this compound in ml of DMF and it is heated at 80 0 C until conversion is complete. After filtering off the catalyst and WO 00/32577 PCT/EP99/08561 96 customary working UP, 6-nitro-2-biphenyl- 4-ylbenzo [de] isoquinoline-l, 3-dione is heated with 1, 3-diaminopropane until conversion is complete. Af ter cooling the reaction mixture, it is worked up as is customary and 6- (3 -aminopropyl amino) -2-biphenyl- 4-ylbenzo (del isoquinoline-1, 3-dione is obtained.
Analogously, by reaction of 6-nitro-2-(4iodophenyl)benzo [del isoquinoline-1, 3-dione with Ph-B-
(OH)
2 and R 1 the following compounds of the formula Ibk are obtained: R1 Ibk R" in R'-H und in Ibk -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
Example 12: Analogously to Example ill 6-nitro- 2 4 -iodophenyl) benzo (de]lisoquinoline-1, 3-dione is reacted with R1 0 (OH) 2 and R 1 The following compounds of the formula Ibl are obtained: WO 00/32577 Rl WO 0032577PCT/EP99/08561 97 R±u R' in Ri-H and Ibi -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2
CF
3 -NH- (CH 2 7
-NH
2 -N
NH
2
H
-NH- (CH 2 3 -NH 2 0 CF 3 -NH- (CH 2 s-NH 2 -NH- (CH 2 7
-NH
2 -N NH 2
H
CF
3 -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2
CF
3 -N
NH
2
H
-NH- (CH 2 3 -NH 2 O OCF 3 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2 H "C WO 00/32577 PCT/EP99/08561 98 R U R' in Ri1-H and IbJ.
H3c -NH- (CH 2 3
-NH
2
(CH
2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N NH 2
H
-NH- (CH 2 3
-NH
2
CH
3 -NH- (CH 2 s-NH 2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
-NH- (CH 2 3 -NH 2 0 OCH 3 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N NH 2
H
OCH
3 -NH- (CH 2 3
-NH
2 -NH- (CH 2 s-NH 2 b OCH 3 -NH- (CH 2 7
-NH
2 -N
NH
2
H
NH- (CH 2 3
-NH
2 -NH- (CH 2
S-NH
2 -NH- (CH 2 7
-NH
2 -N NH 2
H
-NH- (CH 2 3
-NH
2 -NH- (CH 2 s-NH 2
(CH
2 7
-NH
2 -N NH 2
H
WO 00/32577 PCT/EP99/08561 99 Ru R" inR-H and Ibi -NH- (CH 2 3
-NH
2 -NH- (CH 2 s-NH 2 q NO 2 -NH- (CH 2 7
-NH
2 -N
NH
2
H-"O
-NH- (CH 2 3
-NH
2
OH
3 NH- (CH 2 5
-NH
2 NOH -NH-
(CH
2 7
-NH
2 -N
NH
2
H
-NH- (CH 2 3
-NH
2 F -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
-NH- (CH 2 3
-NH
2 F -NH- (CH 2 5
-NH
2 C1 -NH- (CH 2 7
-NH
2 -N
NH
2
H
Example 13: Analogously to Example 11, 6-nitro- 2 3 -iodophenyl) benzo de] soqunolne1, 3dione is reacted with R1 0 (OH) 2 and R 1 The following compounds of the formula Ibm are obtained: WO 00/32577 WO 0032577PCT/EP99/0856 1 100 ibm Rlu Rl in Ri-H and Ibm
(CH
2 3
-NH
2 -NH- (CH 2 5
-NH
2
CF
3 -NH- (CH 2 7
-NH
2 -N
NH
2
H
-NH- (CH 2 3 -NH 2
CF
3 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
CF
3 -NH- (CH 2 3
-NH
2
(CH
2 5
-NH
2 -NH- (CH 2 7
-NH
2
CF
3 -N
NH
2
H
-NH- (CH2 3 -NH 2
OCF
3 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
WO 00/32577 PCT/EP99/08561 101 R±u R" in FR--H and Ibm
H
3 0; -NH- (CH 2 3
-NH
2
(CH
2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N NH 2 -NH-
(CH
2 3
-NH
2
CH
3 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
-NH- (CH 2 3-NH2
OCH
3 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N NH 2 H2 \3 -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -b -OCH3 -NH- (CH 2 7
-NH
2 -N NH 2 H2 -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2
(CH
2
-H
-N NH 2
H
WO 00/32577 PCT/EP99/08561 RIU~~ R -102- R-Lu R Tn-R-H and Ibm
(CH
2 3
-NH
2 -NH- (CH 2 5
-NH
2
NO
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
-NH- (CH 2 3
-NH
2
C
3 -NH- (CH 2 5
-NH
2
NO
2 -C -NH- (CH 2 7
-NH
2 -N
NH
2 NH- (CH 2 3 -NH2 0 F -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
-NH- (CH 2 3
-NH
2 F-NH-
(CH
2 5
-NH
2 C1 -NH- (CH 2 7
-NH
2 -N
NH
2
.H
-NH- (CH 2 3-NH 2 -NH- (CH 2 7
-NH
2 -N
NH
2 Example 14: Analogously to Example 11, 6-nitro-2-(3-iodo- 4-methylphenyl)benzo [del isoquinoline-l, 3-dione is reacted with R 10 (OH) 2 and The following compounds of-the formula Ibn are obtained: WO 00/32577 PCT/EP99/08561 103 Ibn o N 0
R'
CH
3 RIu R" in R'-H und Ibn (CH 2 3 -NH 2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
-NH- (CH 2 3
-NH
2
~OCH
3 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
-NH- (CH 2 3
-NH
2
C
3 -NH- (CH 2 5
-NH
2 N CH -NH
(CH
2 7
-NH
2 -N
NH
2
(CH
2 3
-NH
2 -NH- (CH 2 s-NH 2
H
3 C -NH- (CH 2 7
-NH
2 -N
NH
2
H
WO 00/32577 PCT/EP99/08561 104- Example Analogously to Example 11, 6-nitro-2-(4-iodo- 3-methylphenyl)benzo [de] isoquinoline-1, 3-dione is reacted with R 1 0 (OH) 2 and The following compounds of the formula Ibo are obtained:
H
3
C
Rl R"i mR-H and Ibo (CH 2 3 -NH 2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
(CH 2 3 -NH 2
OCH
3 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
-NH- (CH 2 3
-NH
2
C
3 -NH- (CH 2 5
-NH
2 NOH -NH- (Cl 2 7
-NH
2 -N
NH
2 WO 00/32577 PCT/EP99/08561 105 R.U R' in RT-H and Ibo
(CH
2 3
-NH
2
(CH
2 5
-NH
2
H
3 C -NH- (CH 2 7
-NH
2 -N NH 2
H
Example 16: Analogously to Example 2, 6-nitrobenzo[de]isochromene-1,3-dione is reacted with H 2 N-Het The following compounds of the formula Ic are obtained:
IC
o N 0 IH etl Het- R1 inlIc NI,
-NO
2
/-NN
S4
CF
3 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 the formula Id are obtained: WO 00/32577 PCT/EP99/08561 106 0~ N0 Het 1 -Ar Het' R- inId N N -NO 2
S
NN0
S
0 -N 2 Example 18: Analogously to Example 2, 6-nitrobenzo[de]isochromene-1,3-dione is reacted with 2- (3-aminophenyl)acetamide and t hen with R 1 The following compounds of the formula lea are obtained: WO 00/32577 PCT/EP99/08561 107 R" in Ri-H and in lea
M
H
(CH -H 1NH(C 2
)N
2 45845 -N-(CH-H 472 473 -1(C 2 )3 44N4
HH
Example 19: Analogously to Example 2, 6-nitrobenzo~de~isochromene-1,3-dione is reacted with 2 -(4-aminophenyl)acetamide and then with R 1 The following compounds of the formula.Ieb are obtained: R1 leb WO 00/32577 PCT/EP99/08561 -108 R' in Ri-H and in Ieb MS calculated found Ph I HCH3 -o413 414 3399 400 -N N -NH- (CH 2 5
-OH
-NH- (CH 2 3 -N (CH 3 2 430 431
CH
2
H
(Cl- 2 /49 450
H
CH
2 O
SO
2
NH
2
H
OH 465 466
H
-N 0 -NH- (CH 2 2-COOCH 3 431 432 464 465
H
IN C /NH -N O 2
N
2
H
WO 00/32577 PCT/EP99/08561 -109 R' in R'-H and in Ieb MS calculated found
N
-N-(C
H
N
-N -C H
H
-N 450 451
H
-N-C N 0458 459
H
-N -(CHN-CH 3
H
-N -C 2 3 N 455 456
H
-NH (C 5
H
11 -NH (C 3
H
7 387 388 -NH- (CH 2 5
-NH
2 NH- (CH 2 7
-NH
2 458 459 Example Analogously to Example 2, 6-nitrobenzo[de]isochromene-1,3-dione is reacted with 3-aminobenzamide and then with R 1 The following compounds of the formula Iec are obtained: WO 00/32577 WO 0032577PCTJEP99/0856 I 110 lec R" in R 1 -H and in Iec MS calculated found Ph
-NO
CH3
H
N
CH
2 3-NONH2 1641
H
WO 00/32577 PCT/EP99/08561 i l l R" in Ri-H and in Iec MS calculated found /N -(CH OH 451 452
H
-N 0 -NH- (CH 2 2
-COOCH
3 417 418 CH N 2 450 451
-N-C-
2
H
-N -CH 2
-NH
2
H
N
N- (H 2 2 /\436 437
H
-N -CH
H
2 02'
H
N
H
-N -C N 444 445
H
-N -H 2 3 -N N-OH 3
H
-N N
H
-NH (C 5
H
11 WO 00/32577 PCT/EP99/08561 112- R1 in R-H and in Iec
MS
calculated found -NH (C 3
H
7 -NH- (CR 2 5
-NH
2 -NH- (CH 2 7
-NH
2 Example 21: Analogously to Example 2, G-nitrobenzo[dejjisochromene-l,3-dione is reacted with 4-(4-aminophenyl)butyramide and then with R 1 The following compounds of the formula led are obtained: led R1 in Ri-H and in led
MS
calculated found -NH- (CH 2 4
-NH
2 -N-(H)7N2486 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 -N -C
H
WO 00/32577 PCT/EP99/08561 113 R' in and in led MS calculated found N 478 479
H
-N -C H
H
Example 22: Analogously to Example 2, 6-nitrobenzo[de]isochromene-l,3-dione is reacted with 3-(3-aminophenyl)propionamide and then with R 1 The following compounds of the formula lee are obtained: 0 N"K~lee I
CONH-
2 R" in RL-H and in ms R" in R'-H and in lee ms ca~c.caic.
lee cai. fcd fnd.
-N 0 429 430 -NH-(CH- 2 3
-NH(CH
3 430 431 -o427 428 -N-(CH 2 2 444 H H 445 -NO] 413 414 -N N-CH 2 -0 504 505- N 518 519 WO 00/32577 PCT/EP99/08561 114 R' in -RiT-H and in ms R" in Ri-H and in lee ms Iecaic. fnd. caic.
f nd.
Ph
N
I <CH 3 -N N H3 -NH- (CH 2 2 -COOMe N
CH
2 -o 542 H .NH-(CH 2 3
,N-(CH
2 3
NH
2 543 -N-C22463 464 498 H NH-e N9 -N -C 2 -)-SONH, -NH- (CH 2 2 -NH- (CH 2 2 446 OH44
N-(CH
2 2 OH -NH- (CH 2 2 -NH (C 3
H
7
H
-NH- (CH 2 5
-OH
-NH- (CH 2 3
(CH
2 4
(CH
2 3- 546
NH
2 547 -N (CH 3
-(CH
2 3 444 445- -N (CH 3
-(CH
2 2 472 NH (CH 3 N (C 2
H
5 2 473 -NH- (CH 2 3 -N (CH 3 2 44 445 -NH(CH 2 498 H49 -N -CH 2 -O N2CH 2
NH
2 48
-NH-CH
2 485
CH
2 CH-H -NH- (CH 2 3 -N (CH 3
-(CH
2 3 48 7
HNH
2 488 WO 00/32577 PCT/EP99/08561 11/557 PC/P9/8 R" in R'-H and in ms R" in R -H and in lee ms Iee caic. fnd. ac
N
464 465 431
N
H 1 2)20
H
N
-N -CH 2 450 451 -N-(CH N-C- 3 9 H 500 1 469 470 H
(CH
2 5
-NH
2 -NH (C 5
H
11 -NH- (CH 2 7
-NH
2 472 473 -NH (C 3
H
7 CH 2 -0J-CH 2
NH
2
H
WO 00/32577 PCT/EP99/08561 116 Example 23: Analogously to Example 2, 6-nitrobenzo[de]isochromene-l,3-dione is reacted with 3-amino- 4-methoxybenzamide and then with R 1 The following compounds of the formula Ief are obtained: R1 lef
H
3 00
CONH
2 R" in R'-H and in Ief MS calculated found -NH- (CH 2 4
-NH
2 -NH- (CH 2 7
-NH
2 -NH- (CH 2 8-NH 2 488 489 -N -(CH 2 2 N~ Kl 460 461 H H -NH- (CH 2 3 -N (CH 3 2 -N (H3N N
H
N
H
OH
2
NH
2
-N-CI
2
H
Example 24: Analogously to Example 2, 6-nitrobenzo~de]isochromene-1,3-dione is reacted with H 2 N-Ar'-(CH 2 3 and WO 00/32577 PCT/EP99/0856 I 117 then (if necessary) with R 1 The following Compounds of the formula leg are obtained:
R'
leg Ar'-(CH 2 3 Ar'-(CH 2 R' in R--H and in leg MS caic. fnd.
-N
2
COOCH
3 N
-NO
2
CONH-
2 -NH- (CH 2 7
-NH
2 514 515 -(CH227-4 N, C3H7CH 2
-NH
2 H
JCH
2 520 521
H-
(H -NN 511 512 -N -C 2 3
"N
H
-NH- (CH 2 7
-NH
2 542 543 IC22%C
CH
2
-NH
2 H -N H2 5 4 8 5 4 9
H-
-N (C N 539 540
H
WO 00/32577 PCTIEP99/08561 118 Example Analogously to Example 11, 6-nitro-2- (3iodophenyl) benzo [del isoquinoline-1, 3-dione or 6-nitro- 2- (4-iodophenyl) benzo (del isoquinoline-1, 3-dione is reacted with R 3
(CH
2
(OH)
2 and The following compounds of the formula Ieh (Ph-Ph=Ar') are obtained: R1 Ieh o N 0 Ar'-(CH 2 3 -Ar CH2)-R-'R' in R 1 -H and Ieh NH- (CH 2 3
-NH
2
COOH
(CH
2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N NH 2
H
(CH
2 3
-NH
2 NH-( CH 2 -NH- (CH 2 7
-NH
2 -N
NH
2 (CH 2
H
OCH
3 -NH- (CH 2 5-NH 2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
WO 00/32577 PCT/EP99/08561 -119 -Ar CH2)-R-' R' in R'-H and Ieh NH- (CH 2 3
-NH
2 -0 OCH 3 -NH- (CH 2 5
-NH
2
(CH
2 7
-NH
2 -N
NH
2
H
U -NH- (CH 2 3
-NH
2
CH
3 -NH- (CR 2 5
-NH
2 _NH- (CH 2 7
-NH
2 -N NH 2 0 C 2 C3-NH- (CH 2 5-NH 2 -NH- (CR 2 7
-NH
2 -N
NH
2
H
Example 26: Analogously to Example 2, 6-nitrobenzo~de]isochromene-l,3-dione is reacted with 2-(4-aminophenylsulfanyl)acetamide and then with The following compounds of the formula Ifa are obtained:
*N
Ifa WO 00/32577 PCT/EP99/08561 -120 R" in R-H and in Ifa MS calculated found -NH- (CH 2 4
-NH
2 448 449 -NH- (CH 2 7
-NH
2 490 491 -NH- (CR 2 8
-NH
2 -N -(CH 2 2 N 476 477 A
A
-NH- (CH 2 3 -N (CH 3 2 -N(C 2 3 NN 487 488
H
N
H
Example 27: Analogously to Example 2, 6-nitrobenzo~de]isochromene-l,3-dione is reacted with 2-(4-aminophenoxy)acetaamide and then with R3'-H. The following compounds of the formula Ifb are obtained: Ifb o N 0 0- CH 2
-CONH
2 WO 00/32577 PCT/EP99/08561 -121- R' in R'-H and in Ifb MS calculated found -NH- (CH 2 4
-NH
2 -NH- (CH 2 7
-NH
2 474 475 -NH- (CH 2 8
-NH
2 488 489 -C2f-N460 461 H
H
-NH- (CH 2 3 -N (CH 3 2 446 447 -N -(CH 2 3 -N N 471 472
H
N
H
CH
2
-NH
2 4841 -N CH 2
H
Example 28: Analogously to Example 2, 6-nitrobenzo~de]isochromene-1,3-dione is reacted with l--sulfonyl)naphthalen-1-ylamine and then with R 1 The following compounds of the formula Ig are obtained: WO 00/32577 WO 0032577PCT/EP99/08561 122 Ig R" in Ri-H and in Ig MS calculated found -NH- (CH 2 3
-NH
2 542 543 -NH- (CH 2 5
-NH
2 570 571 -NH- (CH 2 7
-NH
2
CH
2
NH
2 -N-C H
H
Example 29: Analogously to Example 2, 6-nitrobenzo[de]isochromene-l,3-dione is reacted with H 2 N-Ar'-S0 2 -R 7 and then with The following compounds of the formula Ih are obtained: o N 0 Ar'-S0 2
-R
7 WO 00/32577 PCT/EP99/08561 123 Ar'-S0 2 R" in R"-H and in Ih MS caic. f nd.
-NH- (CH 2 3N2584 585 -NH- (CH 2 5
-NH
2 612 613 ZN -NH- (CH 2 7
-NH
2 69
~CH
2
NH
2 64 67 0O2 -N -CH 2 4 2-NH-
(CH
2 3
-NH
2 544 545 N-NH- (CH 2 5
-NH
2 572 573 N-NH- (CH 2 7
-NH
2 600 601 69
~CH
2
NH
2 60 67 02 -N-C 6020 2 I-C- 2
H
3 C H4H _NH- (CH 2 3
-NH
2 516 517 N-NH- (CH 2 5
-NH
2 544 545 N -NH- (CH 2 7
-NH
2
CH
2 NH 2 5759 02-N- /H 2
H
3 C H Example Analogously to Example 2, 6-nitrobenzofde]isochromene-1, 3-dione is reacted with H 2
N-C
6
H
4
(CH
2 2
-CONH-
(CH
2 )i-NH 2 and then with R 1 The following compounds of the formula Ii are obtained: WO 00/32577 PCTIEP99/08561 -124 0 N 0
&~(CH
2 2
-CONH-(CH
2 )i-NH 2 i" Rin R-Hand inIi MS caic. f nd.
4 -NH- (CH 2 7
-NH
2 543 544
OH
2
NH
2 -N -H 2
H
2 -NH- (CH 2 7-NH 2 515 516
OH
2
NH
2
H
Example 31: Analogously to Example 2, 6-ni trobenzo[de]isochromene-1,3-dione is reacted with H 2 N-0 6
H
4
-(CH
2 2
-CONH-
0H 2 -0 6
H
1 1 and then with R 1 The following compounds of the formula Ika are obtained: WO 00/32577 PCT/EP99108561 125 R' in R'-H and in Ika MS calculated found -NH- (CH 2 7
-NH
2 568 564
CH
2
NH
2 I V 574 575
-N-CH
2
H
Example 32: Analogously to Example 2, 6-nitrobenzo[de]isochromene-1, 3-dione is reacted with H 2
N-C
6
H
4
(CH
2 2
-CONH-
(CH
2 2
-C
6
H
9 and with H 2
N-(CH
2 5
-NH
2 One equivalent of tert-butyl (tert-butoxycarbonyliminopyrazol-l-ylmethyl)carbamate is then added to a solution of 3- (5-aminopentylamino) 3-dioxo-1H, 3Hbenzo [del isoquinolin-2-yllphenyl)-N- (2-cyclohex- 1-enylethyl)propionamide in 60 ml of DMF and, after reaction is complete, the BOC protective groups are removed by addition of TFA in 1,2-dichloroethane.
N- (2 -Cyclohex- 1-enyl ethyl) 6- amino) 3-dioxo-lH, 3H-benzo (de] isoquinolin-2-yl] phenyllpropionamide is obtained.
The following compounds of the formula 1kb are obtained analogously by reacting H 2
N-C
6
H
4
(CH
2 2
-CONH-
(CH
2 2
-C
6
H
9 with the appropriate diamine in each case and tert-butyl (tert-butoxycarbonyliminopyrazol-l-ylmethyl)carbamate and removing the protective groups: WO 00/32577 PCT/EP99/08561 126in I1kb -NH- (CH 2 5 -NH-C -NH 2 -NH- (CH 2 2 -NH-C -NH 2 NH- (CH 2 7 -NH-C -NH 2
NH
CH
2 -N 'NH 2
H
-N-C H
H
HN
CH -4 ANH 2 H H -NH- (CH 2 3 -NH-C -NH 2 -NH-(H)3(H (CH 2 3-NH-C -NH- (CH 2 6-NH-C -NH 2 Example 33: Analogously to Example 2, 6-nitrobenzo (del isochromene-1, 3-dione is reacted with H 2
N-C
6
H
4
(CH
2 2
-CONH-
(CH
2 )i-Ar and then with R 1 The following compounds of the formula Ila are obtained: Ila o N 0
&(CH
2 2
-CONH-(CH
2 )i-Ar WO 00/32577 PCT/EP99/08561 127
-C
6
H
4
(CH
2 2 -CONH- R' in Ri-H and in Ila MS
(CH
2 i-Ar caic. fnd.
~N -NH- (CH 2 7
-NH
2
(CH
2 2 -CONH-CHi-
\/CH
2
NH
2
-N-CH
2 56 570
H
560 561
H
(CH
2 ).CONKD>NCH3 -NH- (CH 2 7
-NH
2 591 592 N-CH 2_
CH
2 -NH 2 597 598
H
(CH
2 2 -CONH-~~J -NH- (CH 2 7
-NH
2 624 625 NCH2C
CH
2 NH 2 630 631
H
621 622 -N -C23N-
H
-NH- (CH 2 7
-NH
2 596 597 (C22CONHCH 2 c-CI -N C
CH
2
NH
2
H
Example 34: Analogously to Example 32, 6-nitrobenzo[de]isochromene-1,3-dione is reacted with H 2
N-C
6
H
4
(CH
2 2
-CONH-(CH
2 3
-C
6
H
5 the appropriate diamine in each case and (if necessary) with tert-butyl (tertbutoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ilb are obtained: WO 00/32577 WO 0032577PCTIEP99/0856 I -128 1ib
(CH
2 2
-CONH-(CH
2 3 O in Ilb
MS
calculated found -NH- (CH 2 7
-NH
2 -NC2d
CH
2 N2 596 597 -NH- (CH 2 5 -NH-C -NH 2 604,8 605,3 -NH- (CH 2 2 -NH-C -NH 2 562,7 563,6 -NH- (CH 2 7 -NH-C -NH 2 632,8 633,4
CH
2 -N NH 2 644,8 645,5
H
HN
-N-CH
2 O 'CH 2
NH
2 638,8 639,5 H H -NH- (CH 2 3 -NH-C -NH 2 576,7 577,5 -NH- (CH 2 3 -N (CHO) (CH 2 3 -NH- 647,8 648,4 C -NH 2
NH
-N C20 CH 2 -N 1 NH2 644,8 645,7 1 H H -NH- (CH 2 6 -NH-C -NH 2 -NH- (CH 2 4 -NH-C -NH 2 590,7 591,7 WO 00/32577 PCT/EP99/08561 129 Example Analogously to Example 32, 6-nitrobenzo [de] isochroinene-l, 3-dione is reacted with H 2
N-C
6
H
4
(CH
2 2 -CONH- (CH 2 2
-C
6
H
4 -S0 2
-NH
2 the appropriate diamine in each case and tert-butyl (tert-butoxycarbonyliminopyrazol-l-ylmethyl)carbamate. After removal of the protective groups, the following compounds of the formula Ilc are obtained: 0 N 0
(CH
2 2 -CONH-(0H 2 2 8 2
-NH
2 R' in Ilc MS calculated found -NH- (CH 2 ).s-NH-C -NH 2 669,8 670,5 -NH- (CH 2 2 -NH-C -NH 2 627,7 628,4 -NH- (CH 2 7 -NH-C -NH 2 697,9 698,5
NH
CH
2 4(NNH 2
H
HN
CH
HZ
-N CH 2 -IC2- A NH 2 H H -NH- (CH 2 3 -NH-C -NH 2 641,8 642,3 -NH- (cH 2 3 -N (cH 3 (cH 2 3
-NH-
c -NH 2 -NJ- CH 2
CH
2 -N 'k NH 2 H H WO 00/32577 PCT/EP99/08561 130 R' in Ilc MS calculated found -NH- (CH 2 6 -NH-C -NH 2 683,8 684,4 -NH- (CH 2 4 -NH-C -NH 2 655,8 656,4
NH
-N-(CH
2 k NH 2 655,8 656,4 H CH 3
NH
(HN IkNH 2 703,8 704,0 H H NH 2 -N N4653,8 654,5
NH
-NJ-CH
2 681,8 682,5 H N Example 36: Analogously to Example 32, 6-nitrobenzo~de]isochromene-1,3-dione is reacted with H 2
N'-C
6
H
4
(CH
2 2
-CONH-C
6
H
5 the appropriate diamine in each case and tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl)carbamate. After' removal of the protective groups, the following compounds of the formula Ild are obtained: WO 00/32577 PCT/EP99/08561 131 R" in Ild MS calculated found -NH- (CH 2 5 -NI--C -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 2 590,7 591,4
NH
HH N) H 602,7 603,4
-N-CH
2 )-HC=H-H 3, 3, C -NH
CH
2 -Nj NH 2 573 H H -NH- (CH 2 3-NH-C -NH 2 5746 57,3 -NH- (CH 2 -NH3)- C=H) -NH- 65,6 549,3
C-(NH-H
2 NH546595
NH
-N-(2D-C H N NH 20, 0, H H
NHH
-N-C N N 546,6 54,5 \J NNH N H577
HN
Example 37: Analogously to Example 32, 6-nitrobenzo[de]isochromene-l,3-dione is reacted with WO 00/32577 PCT/EP99/08561 132-
CH
2 2
-CONH-(CH
2 )i
H
2 N d the appropriate diamine and tert-butyl. (tert-butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formulae Ilea-Ilef are obtained: 01 Ilea R' in Ilea MS calculated found -NH- (CH 2 5 -NH-C -NH 2 625,2 625,3 -NH- (CH 2 2 -NH-C -NH 2 583,1 583,2 -NH- (CH 2 7 -NH-C -NH 2 653,2 653,3
H
-N-CN H 2 5266,
HH
-N -CH 2 H-6 H H H -NH- (CH 2 3 -NH-C -NH 2 597,1 597,3 -NH- (cH 2 3 -N (CH 3
(CH
2 3 -NH- 668,2 668,3 C -NH 2 WO 00/32577 PCT/EP99/08561 -133 R' in Ilea
MS
calculated found
NH
-N -H 2
CH
2 -N f" NH 2 665,2 665,4 H H -NH- (CH 2 i-NH-C -NH 2 639,2 639,4 -NH- (CH 2 4 -NH-C
-NH
2 611,1 611,3
NH
-N-(CH 2N)N 611,1 611,6 H
CH
3
NH
-N -2C N 659,2 659,0 H H
NH
2 -N N4 2{ 609,1 609,6
NH
-N-CH -C NH2 637,2 637,6 H
N
Ileb o N 0
(CH
2 2
-CONH-(CH
2 2
CI
R' in Ileb ms calculated found -NH- (CH 2 s-NH-C
-NH
2 625,2 625,3 -NH- (CH 2 2 -NH-C
-NH
2 583,1 583,3 -NH- (OH 2 7 -NH-C -NH 2 653,2 653,4 WO 00/32577 PCTIEP99/08561 R" in Ileb
MS
calculated found
NH
CH
2 -N
NH
2 %665,2 665,4
H
-N-C
H
2
H
NH
-N-OH
2
O'CH
2 -N A, NH 2 659, 2 659,3 H H -NH- (CH 2 3 -NH-C -NH 2 597,1 597,3 -NH- (CH 2 3 -N (CH 3
(CH
2 3 -NH- 668,2 668,3 C -NH 2
NH
-N-OH
2 0 CH 2 -N ANH 2 665,2 665,3 H H -NH- (CH 2 6 -NH-C -NH 2 639,2 639,4 -NH- (CH 2 4 -NH-C -NH 2 611,1 611,3
NH
2N(H N N 611,1 611,6 H OH 3
NH
~N'kN 659,2 659,2 H H NH 2 -N N4{ 609,1 609,6
NH
-N-H
2 NH 2 637,2 637,6 H NH WO 00/32577 135 I leo 0 0C PCT/EP99/08561 R' in Ilec MS calculated found -NH- (CH 2 s-NH-C -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 2 653,2 653,5
NH
CH
2 -N A NH 2 665,2 665,4
H
-N JCH 2
H
NH
-N CH 2 H2N A NH 2 659,2 659,4 H
H
(CH
2 3 -NH-C -NH 2 597,1 597,3 -NH- (CH 2 3 -N (CH 3
(CH
2 3 -NH- 668,2 668,4 C
-NH
2
N
-N-OH
2 0 CH 2 -N A NH 2 652665,4 H
H
-NH- (CH 2 6 -NH-C -NH 2 639,2 639,5 -NH- (CH 2 4 -NH-C -NH 2 611,1 611,4
-N-(CH
2 N- N 1 &NH 611,1 612,4 H CH 3 WO 00/32577 WO 0032577PCT/EP99/08561 136 lied 0 N 0 Ci
(CH
2 2 -CONH /'6 R' in Iled
MS
calculated found -NH- (CH 2 5-NH-C
-NH
2 -NH- (CH 2 2 -NH-C
-NH
2 55,554 C 2 -H C(N 2 2
NH
/\CH
2 -I
NH
2 631,1 631,3 H H -N (CH 2 CN)-H56,593 C -NH WO 00/32577 PCT/EP99/08561 137 R" in led MS calculated found
NH
-N J-CH 2 :>CH-N fk NH 2 637,2 637,3 H H -NH- (CH 2 6 -NH-C -NH 2 611,1 611,3
-NH-(CH
2 4 -NH-C -NH 2 583,1 583,3
N&NH
2 583,1 583,4 H
CH
3
NH
-N-(H
2 2 N 'NH2 631,1 631,2 H H
NH
2 -N N4581,1 581,3
NH
-N-H N H2 609,1 609,3 H
NH
WO 00/32577 WO 0032577PCT/EP99/08561 138 I lee R" in Ilee MS calculated found -NH- (CH 2 5 -NH-C -NH 2 611,1 611,4 -NH- (CH 2 2 -NH-C -NH 2 569,1 569,4 -NH- (CH 2 7 -NH-C -NH 2 639,2 639,3 CH -N flNH 2 651,2 651,5
H
-N-CH
2
H
NH
CH
2
CH
2 -Ifl NH 2 645,2 645,4 H H -NH- (CH 2 3 -NH-C -NH 2 583,1 583,5 -NH- (CH 2 3 -N (CH 3
(CH
2 3 -NH- 654,2 654,2 C -NH 2 -N C N' NH 2 61, 651,6 H H -NH- (CH 2 6 -NH-C -NH 2 625,2 625,3 -NH- (CH2) 4 -NH-C (=NH1) -NH 2 597,1 597,4
NH
N kH H
CH
3 WO 00/32577 WO 0032577PCT/EP99/08561 139 R" in Ilef MS calculated found -NH- (CH 2 5 -NH-C -N1 2 597,1 597,2 -NH- (CH 2 2 -NH-C -NH 2 555,0 555,3 -NH- (CH 2 7 -NH-C -NH 2 625,2 625,3
NH
%H4 H 637,2 637,2
H
-N-C
H
2
H
NH
-OH 2 N 2 631,1 631,3 H H -NH- (CH 2 3 -NH-C -NH 2 569,1 569,3 -NH- (CH 2 3 -N (CH 3
(CH
2 3 -NH- 640,2 640,2 C -NH 2 WO 00/32577 PCT/EP99/08561 140 R' in Ilef
MS
calculated found
NH-
-N C20 CH 2 -N A, NH 2 637,2 637,5 H H -NH- (CH 2 6 -NH-C -NH 2 611,1 611,3 -NH- (CH 2 4 NH-C -NH 2 583,1 583,3 Example 38: Analogously to Example 32, 6-nitrobenzo [del isochromene-1, 3-dione is reacted with H 2
N-C
6
H
4 (CH-2) 2
-CONH-CH
2 -Ar, the corresponding diamine and tertbutyl (tert-butoxycarbonyliminopyrazol1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ilfa are obtained with H 2
N-C
6
H
4
(CH
2 2
CONH-CH
2
-C
1 0
H.
7 R-1 in Ilfa
MS
calculated found -NH- (CH 2 s-NH-C -NH 2 626,8 627,3 -NH- (CH 2 2 -NH-C -NH 2 584,7 585,3 -NH- (CH 2 7 -NH-C -NH 2 654,8 655,4 WO 00/32577 WO 0032577PCT/EP99/0856 I 141 After removal of the protective groups, the following compounds of the formula Ilfb are obtained with H 2
N-C
6
H
4
(CH
2 2
-CONH-CH
2
-C
9
H
9 WO 00/32577 WO 0032577PCT/EP99/0856 I 142 R' in Ilfb MS calculated found -NH- (CH 2 5 -NH-C -NH 2 602,7 603,3 -NH- (CH 2 2 -NH-C -NH 2 560,7 561,4 -NH- (CH 2 7 -NH-C -NH 2 630,8 631,3
H
HH
NH
=NJ-H CH-I NH 636 8 637,3 H H -NH- (CH 2 3 -NH-C -NH 2 574,7 575,6 -NH- (CH 2 3 -N (CH 3
(CH
2 3 -NH- 645,8 646,5 C -NH 2
NH
-N-CH2- N N 2, 643,5 H H -NH- (CH 2 6 -NH-C -NH 2 616,8 617,4 -NH- (CH 2 4 -NH-C -NH 2 588,7 589,4 WO 00/32577 PCT/EP99/08561 -143 in Ilfb
MS
calculated found
NH
1 2 612,7 613,6 H
CH-
3
NH
/N 'J ~NH 2 660,8 661,0 H H
NH
2 -N 610,7 611,6 __H2 638,8 639,6 H
NH
Example 39: Analogously to Example 32, 6-nitrobenzo[de]isochromene-l,3-dione is reacted with 3- (3-aminophenyl) 3 -chloro-4-methoxyphenyl) propionamide, the appropriate diamine and tert-butyl (tertbutoxycarbonyliminopyrazol-l-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ilg are obtained: hig
&(CH
2 2 -CONH Q
OCH
3 WO 00/32577 PCT/EP99/08561 144 R' in Ilg MS calculated found -NH- (CH 2 2 -NH-C -NH 2 585,1 585,2 -NH- (CH 2 7 -NH-C -NH 2 655,2 655,3
CH
2 A, NH 2 667,2 667,3
H
-N
CH
2 6
H
NH
CH-~N
2 661,2 661,2 H
H
-NH- (CH 2 3 -NH-C -NH 2 599,1 599,2 -NH- (CH 2 3 -N (CH 3
(CH
2 3 -NH- 670,2 670,3 C -NH 2
NH
-N -CH 2 0 CH 2 -Ifi NH 2 667,2 667,3 H
H
-NH- (CH 2 6 -NH-C -NH 2 641,2 641,3 -NH- (CH- 2 4 -NH-C -NH 2 613,1 613,3
NH
1 2613,1 613,5 *H
CH
3
NH
-N A, NH 661,2 661,2 H
H
,NH
2 611,1 611,4
-N-CH
2 N 639,2 639,4 H N WO 00/32577 PCT/EP99/0856
I
-145 Example Analogously to Example 32, 6-nitrobenzo~de]isochromene-1,3-dione is reacted with 3- (3-aminophenyl) (4-phenylbutyl) propionamide, the appropriate diamine and tert-butyl (tertbutoxycarbonyliminopyrazoll1ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ilh are obtained: R1 11h 0 N 0 &N
(CH
2 2
-CCNH-(CH
2 4 R' in Ilh
MS
calculated found -NH- (CH 2 5 -NH-C -NH 2 618,8 619,4 -NH- (CH 2 2 -NH-C -NH 2 576,7 577,3 -NH- (CH 2 v7-NH-C -NH 2 646,8 647,4
NH
CH
2 -N N H 658,8 659,4 -N -CH
H
/N C AlH 652,865, -N-C -O CH -Nj NH 2 H
H
-NH- (CH 2 3 -NH-C -NH 2 590,7 591,3 -NH- (CH- 2 3 -N (cH 3
(CH
2 3 -NH- 661,8 662,4 c
-NH
2 NH 658,8 659,5 -N -CH 2
CHNIR&NH
2 H
H
-NH- (CH 2 6 -NH-C
-NH
2 632,8 633,4 WO 00/32577 WO 0032577PCT/EP99/08561 146 Example 41: Analogously to Example 32, benzo [del isochromene-1, 3-dione is reacted with
CH
2 2
-CONH-(CH
2 )i
H
2 N 6-nitrothe appropriate diamine and tert-butyl (tertbutoxycarbonyliminopyrazol-1.ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formulae Ilia-Ilic are obtained: D 1 WO 00/32577 PCTIEP99/0856 I 147 WO 00/32577 PCT/EP99/08561 148- R1 I lib o N 0
&(CH
2 2 -CONH R' in Ilib ms calculated found -NH- (CH 2 5 -NH-C -NH 2 604,8 605,4 -NH- (OH 2 2 -NH-C -NH 2 562,7 563, 3 -NH- (CH 2 7 -NH-C -NH 2 632,8 633,4
NH
CH
2 -I NH 2 644,8 645,6
H
HN C H
HN
-rj-C 2
CH
2 638,8 639,5 H H -NH- (CH 2 3 -NH-C -NH 2 576,7 577,6 -NH- (CH 2 3 -N (CH 3 -(C1 2 3 -NH- 647,8 648,4 C -NH 2
NH
-N C2 CH 2 -N 4 H2 644,8 645,7 -NH- (CH 2 6 -NH-C -NH 2 618,8 619,4 -NH-(CH2) 4
-NH-C(=NH)-NH
2 590,7 591,4 N NH 2 590,7 591,8 23 1 H Cl] 3 2N-C llN 638, 8 639,3
H
2 2 -0 /2 N H H WO 00/32577 WO 0032577PCT/EP99/0856 I 149 R' in Ilib ms calculated found NH 2 -N N4 588,7 589,6
NH
H NH 616,861, R' in Ilic
MS
calculated found -NH- (CH 2 5 -NH-C -NH 2 590,7 591,3 -NH- (CH 2 2 -NH-C -NH 2 548,6 549,6 -NH- (CH 2 7 -NH-C -NH 2 618,8 619,4
NH
CH -N f' NH 2 630,8 631,7
H
H
NH
-N-CH
2 CH 2 -N A, NH 2 624, 7 625,4 H -H -NH- (CH2) 3 -NH-C -NH 2 562,7 563,5 -NH- (CH 2 3 -N (CH 3
(CH
2 -NH- 633,8 634,4 C -NH 2 WO 00/32577 PCT/EP99/08561 150 R' in Ilic
MS
calculated found
NP
-N--CH
2
CH
2 NH, 630,8 631,8 H H
-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-l,3-dione in 100 ml of glacial acetic acid is treated with 4.3 g of 3-(3aminophenyl)propionic acid and the mixture is heated under reflux. After reaction is complete, the reaction mixture is allowed to cool and is worked up as is customary. 3-[3-(6-Nitro-1,3-dioxo-2,3-dihydrolH-phenalen-2-yl)phenyl]propionic acid in 80 ml of THF is treated with 1.5 equivalents of oxalyl chloride, the mixture is stirred and 1.5 equivalents of 2 -p-tolylethylamine are added. After conversion is complete, the mixture is worked up as is customary. A solution of 3-[3-(6-nitro-1,3-dioxo-2,3-dihydro- 1H-phenalen-2-yl)phenyl]-N-( 2 -p-tolylethyl)propionamide in 80 ml of DMF is treated with one equivalent of propane-1,3-diamine and the mixture is heated under reflux. After customary working up, the amine obtained is heated with 1.5 equivalents of pyrazole-1carboxamidine and diisopropylethylamine in 80 ml of DMF. After reaction is complete and customary working up, 3-{3-[6-(3-guanidinopropylamino)-1,3-dioxo- 2, 3 -dihydro-1H-phenalen-2-yl]phenyl}-N-(2-p-tolylethyl)propionamide is obtained. MS: calculated: 576.7; found: 577.4.
Example 43: Analogously to Example 32, 6-nitrobenzo[de]isochromene-1,3-dione is reacted with WO 00/32577 PCT/EP99/08561 151
CH
2 2
-CONH-(CH
2 C'7
H
2 N d the appropriate diamine and tert-butyl (tertbutoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formulae Ilka-Ilke are obtained: I Ika 0 KI 0 R' in Ilka
MS
calculated found -NH- (CH 2 5 -NH-C -NH 2 645, 6 645,4 -NH- (CH 2 2 -NH-C -NH 2 603,5 603,3 -NH- (CH 2 7 -NH-C -NH 2 673, 6 673,4 %H~fLH 685,7 685,4
H
-N
-CH
2
H
NH
-Il-H N 2 679,6 679,3 H H -NH- (CH 2 3 -NH-C -NH 2 617,5 617,3
NH
-N-(CH
2
NH
2 631,6 631,4 1 23 H
OH
3 WO 00/32577 WO 0032577PCT/EP99/0856 I 152 in Ilkb MS calculated found -NH- (CH 2 5 -NH-C -NH 2 645, 6 645,3 -NH- (CH 2 2 -NH-C -NH 2 603, 5 603,3 -NH- (GEL 2 7 -NH-C -NH 2 673, 6 673,4
NH
%H-I N 2 685,7 685,5
H
-N JCH 2
H
NH
-N-CH
2 C CH -Ifl NH 2 679,6 679,3 H H -NH- (GEL 2 3 -NH-C -NH 2 617,5 617,5 WO 00/32577 PCT/EP99/08561 153 R' in 11kb MS calculated found -NH- (CH 2 3 -N (CH 3
(CH
2 3 -NH-C (=NHi) -NH 2 688, 7 688, 4
-N-CH
2 0 CH 2 -N '1 NH 2 657687,4 H H -NH- (CH 2 6 -NH-C -NH 2 659,6 659,4 -NH- (CH 2 4 -NH-C -NH 2 631, 6 633,3
NH
-N-(CH A, NH 2 631,6 632,4 H
CH
3
NH
-N 2 C N 679,6 679,1 H H S NH 2 NH 629,5 630,4 H NH 657,665, I Ikc o N 0
(CH
2 2
-CONH-CH
2 /1 3 CI in Ilkc MS calculated found -NH- (CH 2 5 -NH-C -NH 2 645, 6 645, 6 -NH- (CH 2 2 -NH-C -NH 2 603,5 604,6 -NH- (CH 2 7 -NH-C -NH 2 673, 6 673,4 WO 00/32577 PCTIEP99/08561 WO 00/32577 WO 0032577PCT/EP99/08561 155 I Ikd in Ilkd MS calculated found -NH- (CH 2 5 -NH-C -NH 2 645, 6 645,3 -NH- (CH 2 2 -NH-C -NH 2 603,5 603,3 -NH- (CH 2 7 -NH-C -NH 2 673,6 673,3
CH
2 -N )j NH 2 685,7 685,5
H
-N JCH 2
HN
2H 2 -I NH 2 679,6 679,3 H H -NH-(CH) 3 -NH-C -NH 2 617,5 617,4 -NH- (CH 2 3 -N (CH 3
(CH
2 3 -NH- 688,7 688,3 C -NH 2
NH
C2-: CH-'kNH 2 685,7 687,3 H H -NH- (CH 2 6 -NH-C -NH 2 659,6 659,4 -NH- (CH 2 4 -NH-C -NH 2 631, 6 631,4
NH
-N-(CH NH 2 631,6 631,4 H
CH
3 WO 00/32577 WO 0032577PCTIEP99/08561 156
-NH
-NJ-CH N NH 6579,6 658,4
HH
N H2N N N4695 2, o NH
(H
2 )C NH 5, 658,4
HN
0 NN0 -N "2)2CH 2 66, 665,1 -NH- (CH 2 5-NH-C -NH 2 63,5 631,2 -NH- (CH 2 -N H-(C)C -NH 2 674, 6 674, 2 WO 00/32577 PCTAEP99/08561 157 in Ilke MS calculated found -N C2JL- H2 671,6 671,2 H
H
-NH- (CH 2 6 -NH-C -NH 2 645,6 645,2 -NH- (CH 2 4 -NH-C -NH 2 617,5 619,2 Example 44: Analogously to Example 32, 6-nitrobenzo[de]isochromene-l,3-dione is reacted with 3-(3aminophenyl) (3-chloro-4-f luorobenzyl) propionamide, the appropriate diamine and tert-butyl (tertbutoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ilm are obtained: R' in urn MS calculated found -NH- (CH 2 5 -NH-C -NH 2 629,1 629,5 -NH- (CH 2 2 -NH-C -NH 2 587,1 587,5 -NH- (CH 2 7 -NH-C -NH 2 657,2 657,3 WO 00/32577 PCT/EP99/08561 158 H H
-NH-(C
2 3 -NHC(~H)-N 601, 601, tC 2 2-
O
3 672,2 672,3 O (NH-NH
HN
-N~-CH
2 -O CH 2 -N A NH 2 669,2 669,4 H H -NH- (CH 2 3-NH-C -NH 2 643,2 601,5 -NH- (CH 2 3-NH)- 3-NH- 615,21 615,5 61, 615,5-NH
NHH
H CH-0 CH2 ,N -N(C 2 663,2 663,7 H H
NH
2 -N-C NN-H 613,1 613,4
HN
WO 00/32577 PCT/EP99/08561 *-159 Example Analogously to Example 32, 6 -nitrobenzo [de] isochromene-1, 3-dione is reacted with
CH
2 2
-CONH-(CH
2 )i OCH 3
H
2 N d the appropriate diamine and tert -butyl (tertbut oxycarbonyl iminopyra.z ol 1 -ymethyl) carbamate. After removal of the protective groups, the following compounds of the formulae Ilna-Ilnc are obtained: R1 Ilna o N 0 &N
(CH
2 2
-CONH-CH
2
OC
3 R' in Ilna
MS
calculated found -NH- (CH 2 5 -NH-C -NH 2 606,7 607,4 -NH- (CH 2 2 -NH-C -NH 2 564,6 565,6 -NH- (CH 2 7 -NH-C -NH 2 634,8 635,3
NH
H N) H 646,8 647,6 -N -CH 2 3 -(N)-H57757,
-N-CH
2 -(H)-C1 2 -N A, 640,87 650,5 C -NH 2 WO 00/32577 WO 0032577PCT/EP99/08561 160 R' in Ilna MS calculated found 1H 2 I1f N 2 646,8 647,9 H H -NH- (CH 2 6 -NH-C -NH 2 620,8 621,3 -NH- (CH 2 4 -NH-C -NH 2 592,7 593,4
NH
1N(C 2 3 2 592,7 593,7 H
CH
3
NH
N (C N 2A'N 640,7 641,2 H H
NH
2 -N N- 590,7 591,6
NH
NHCH 618,7 619,6
H
0N 0 1m
(CH
2 2
-CONH-(CH
2 2 OCH 3 -NH- (CH 2 7 -NH-C -NH 2 648,8 649,5 WO 00/32577 PCT/EP99/08561 161 661, WO 00/32577 PCT/IEP99/08561 162 liInc
(CH
2 2 -CONH O
OCH
3 R" in Ilnc MS calculated found -NH- (CH 2 5 -NH-C -NH 2 592,7 593,3
-NH--(CH
2 2 -NH-C -NH 2 550,6 551,4 -NH- (CH2) 7 -NH-C -NH 2 620,8 621,3
NH
21 2632,8 633,4
H
-N-CH
1 H 2
H
-Ij-C 2
CH
2 1 2 626,7 627,3 H H -NH- (CH 2 3 -NH-C -NH 2 564,6 565,3 NH- (CH 2 3 -N (cH 3
(CH
2 3 -NH- 635,8 636,3 C -NH 2
_NH
-N-C H CH -N2kN 632,8 633,4 H H -NH- (CH 2 6 -NH-C -NH 2 606,7 607,3 -NH- (CH 2 4 -NH-C -NH 2 578,7 579,4 Example 46: Analogously to Example 32, benzo[de~isochromene-1,3-dione is reacted with 6-nitro- WO 00/32577 PCT/EP99/08561 163
F
CH
2 2
-CONH-(CH
2 )i
H
2 N the appropriate diamine and tert-butyl (tertbut oxycarbonyl iminopyra zo 1 -ylmethyl) carbamate. After removal of the protective groups,, the following compounds of the formulae Iloa-Iloc are obtained: o 0O R" in Iloa MS calculated found -NH- (CH 2 5 -NH-C -NH 2 608,7 609,4 -NH- (CH 2 2 -NH-C -NH 2 566,6 567,5 -NH- (CH 2 7 -NH-C -NH 2 636,8 637,3
NH
2 648,8 649,5
H
H
H H -NH- (CH 2 3 -NH-C -NH 2 580,7 581, 4 -NH- (cH 2 3 -N (cH 3
(CH
2 3 -NH- 651,8 652,4 C -NH 2
NH
-N-C H 2
CH
2 NH 648,8 649,6 H H -NH- (CH 2 6 -NH-C -NH 2 622,7 623,3 WO 00/32577 PCT/EP99/08561 164 R' in Iloa MS calculated found -NH- (CH 2 4 -NH-C -NH 2 594,7 595,5 R1 Ilob o N 0 &N
(CH
2 2
-CONH-CH
2 s
F
R' in Ilob MS calculated found -NH- (CH 2 5 -NH-C -NH 2 594,7 595,5 -NH- (CH 2 2 -NH-C -NH 2 552,6 553,4 -NH- (CH 2 7 -NH-C -NH 2 622,7 623,2
NH
CH
2 -4 N2 634,8 635,5
H
H
NH
H
2 '1 C 2 kN 2 628,7 629,4 H H -NH- (CE! 2 3 -NH-C -NH 2 566,6 567,5 -NH- (CH 2 3 -N (CH 3
(CH
2 3 -NH- 637,8 638, 3 C -NH 2
NH
1 ~-C 2
C
2 -Ifx NH 2 634,8 635,6 H H -NH- (CH 2 6 -NH-C -NH 2 608,7 609,3 -NH- (CH 2 4 -NH-C -NH 2 580,7 581,4 WO 00/32577 PCT/EP99/08561 165o N 0
F
(CH
2 2 -CON 6 R in hloc
MS
calculated found -NH- (CH 2 5-NH-C -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 2 608,7 609,3
NH
%H~fI~H 620,7 621,4
H
-N-CH
2 1H-
HN
1~-H H-l'N 2 614,7 615,2 H H
-NH-(CH
2 3 -NH-C -NH 2 552,6 553,4 Example 47: Analogously to Example 32, 6-nitrobenzo[de]isochromene-l,3-dione is reacted with 3- (3-aminophenyl) (3-phenoxyphenyl) propionamide, the appropriate diamine and tert-butyl (tertbutoxycarbonyliminopyrazol-l-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ilp are obtained: WO 00/32577 PCT/EP99/08561 166- R1
NUP
o N 0 OPh
(CH
2 2 -CONH
R
1 in Ilp
MS
calculated found -NH- (CH 2 5 -NH-C
-NH
2 -NH- (CH 2 7 -NH-C -NH 2 682,8 683,3
NH
CH
2 -N f" NH 2 694,8 695,4
H
-N-C H
H
-NH- (CH 2 2-NH-C -NH 2 62767, C -NH
-N~-CH
2 CH -N I#,NH 2 9, 9, H H -NH- (CH 2 3-NH-C -NH 2 6268,7 669,3
(CH-
2 -N H- C=H) 3-NH 640,7 641,5
NH
-N CH-N"'H2N H2 6940,7 641,5 H HH /N-(C2 6-H- (NH) NH 2 668,8 669,2 HN H WO 00/32577 PCT/EP99/08561 167 R' in Ilp MS calculated found
-NH
NH 638,7 639,5
NHH
-N-C H 667, H N NH 666,867, Example 48: Analogously to Example 32, -ito benzo[de]isochromene-1,3-dione is reacted with 3- (3-aminophenyl) (3-benzyloxyphenyl) propionamide, the appropriate diamine and tert-butyl (tertbutoxycarbonyliminopyrazol-l-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ilq are obtained: I Iq o. N 0 R" in Ilq MS calculated found -NH- (CH 2 5 -NH-C -NH 2 668, 8 669,3 -NH- (CH 2 2 -NH-C -NH 2 626,7 627,4 -NH- (CH 2 7 -NH-C -NH 2 696,8 697,3 WO 00/32577PCI9/05I PCT/EP99/08561 168 Example 49: Analogously to Example 32, 6-nitrobenzo [del isochromene-1, 3-dione is reacted with 3- (3-aminophenyl) -N-naphthalen-2-ylpropionamide, the appropriate diamine and tert-butyl (tertbutoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ilr are obtained: WO 00/32577 0 PCT/EP99/0856 I 169 li r
,(CH
2 2
-CONH-CH
2 WO 00/32577 PCT/EP99/08561 R' in
,NH
2 -N N4k
NHH
-N-CH 2 N4H H
NH
Example Analogously to Example 32, 6-nitrobenzo[de]isochromene-l,3-dione is reacted with 3- (3-aminophenyl) -N-benzylpropionamide, the appropriate diamine and tert-butyl (tert -butoxycarbonyliminopyrazol-l-ylmethyl)carbamate. After removal of the protective groups, the following compounds of the formula Is are obtained: o N 0 2 2 -CONH-CH 2 R' in Is MS calculated found -NH- (OH 2 5 -NH-C -NH 2 576,7 577,4 -NH- (OH 2 2 -NH-C -NH 2 534,6 535,5 -NH- (OH 2 7 -NH-C -NH 2 604,8 605,4
C
2 2 616,8 617,5
H
-N-C
1 H 2
H
-N-CH 0 CH- /H 610, 611,3 H H WO 00/32577 PCT/EP99/08561 171 R' in uls MS calculated found -NH- (CH 2 3 -NH-C(=NH) -NH 2 548,6 549,5 -NH- (Gil 2 3 -N (CH 3
(CH
2 3 -NH- 619,8 620,3 C -NH 2 -NH- (CH 2 6 -NH-C(=NH) -NH 2 590,7 591,3 -NH- (CH 2 4 -NH-C(=NH) -NH 2 562,7 563,5
NH
N NH 2 H CH3 _N ~H 616,8 617,6 -N-C H 2
CH
2 2 H
H
NH
N~ NflNH -N (C 2 2 2 H
H
,NH 2 -N-C N
N
1 2 NH
HH
Example 51: Analogously to Example 32, 6-nitrobenzo[de~isochromene-1,3-dione is reacted with 3- (3-aminophenyl) (3-f luoro-4-methoxyphenyl) propionamide, the appropriate diamine and tert-butyl (tertbutoxycarbonyliminopyrazol-l-ylmethyl) carbamate. After removal of the protective groups,, the following compounds of the formula Ilt are obtained: WO 00/32577 PCT/EP99/08561 172 lit o N 0
F
'N (CH 2 2 -CONH
OCH
3
R
1 in Ilt
MS
calculated found -NH- (CH 2 5 -NH-C
-NI-
2 -NH- (CH- 2 2 -NH-C -NH 2 568,6 569,3 -NH- (CH 2 7 -NH-C -NH 2 638,7 639,4
NH-
CH
2 -If' NH 2
H
H
-N C H- NH 644,7 645,3 -N-C2 2 H H -NH- (CH 2 3 -NH-C
-NH
2 -NH- (CH 2 3 -N (CH 3
(CH
2 3 -NH- 653,8 654,3 C
-NH
2
NH
-N-CH-i CH 2 -N f' NH 2 650,8 651,8 H
H
-NH- (CH 2 6 -NH-C -NH 2 624,7 625,3 -NH- (CH 2 4 -NH-C -NH 2 596,7 597,5
NH
-N-(CH
2 )3 N 596,7 597,7 H
CH
3 /N C Nlj NH 2 644,7 645,2 H
H
WO 00/32577 PCTIEP99/08561 -173 in Ilt MS calculated found
NH
2 -N454, 9,
NHH
-N-C H N-42, H NH 622,762, Example 52: Analogously to Example 32, 6-nitrobenzo~de]isochromene-1,3-dione is reacted with 3- (3-aminophenyl) (3-fluoro-4-methylphenyl) propionamide, the appropriate diamine and tert-butyl (tertbutoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ilu are obtained: Ilu 0 NI 0 R' inlIlu MS calculated found -NH- (CH 2 5 -NH-C -NH 2 594,7 595,3 -NH- (CH 2 2 -NH-C -NH 2 552,6 553,5 -NH- (CH 2 7 -NH-C -NH 2 622,7 623,4
NH
%H-f~H 634,8 635,5
H
-N-CH
2
H
WO 00/32577 PCT/EP99/08561 -174 R' in Ilu
MS
calculated found
-N-H
2 kH2 628,7 629,3 2 %H H H -NH- (CH 2 3 -NH-C -NH 2 566,6 567,5 -NH- (CH 2 3 -N (OH 3
(CH
2 -NH- 637,8 638,3 C -NH 2 2 N 634,8 635,6
H
2
H
2 H H -NH- (CH- 2 6 -NH-C -NH 2 608,7 609,3 -NH- (CH 2 4 -NH-C -NH 2 580,7 581,4 Example 53: Analogously to Example 32, benzo~de]isochromene-1,3-dione is reacted with
OCH
3
H
2 N d 6-nitrothe appropriate diamine and tert-butyl (tertbut oxycarbonyl.iminopyraz ol1- 1- ylmethyl) carbamate. After removal of the protective groups,, the following compounds of the formulae Ilva-Ilvb are obtained: I Iva WO 00/32577 PCT/EP99/08561 175 R' in Ilva
MS
calculated found -NH--(CH2) 5 -NH-C -NH 2 650,8 651,5 -NH- (CH 2 2 -NH-C -NH 2 608,7 609,5 -NH- (CH 2 7 -NH-C -NH 2 678,8 679,4
NH
%H-f"H 690,8 691,6
H
-N-CH)
3 NHCNH-H62763,
NH
-N-CH
2
-CH
2
NH
2 690,8 691,6 H H -NH- (CH 2 3-NH-C -NH 2 664,8 66354 -NH- (CH 2 )3-NH3)- C=H) -NH- 6936,7 637,5 C (NH)-NH
NN
HOCH
-NH- (CH 2 6-NH-C -NH 2 650,8 65,4 -NH- (CH 2 4-NH-C -NH 2 638,7 609,5 WO 00/32577 PTE9/86 PCT/EP99/08561 176 R' in Ilvb
MS
calculated found -NH- (CH 2 7 -NH-C -NH 2 678,8 679,4
NH
CH NA NH 2 9, 2 2 ~690,869, -N -CH 2
H
CH NH 68, H9 /H 6842 685,4 H H -NH- (CH 2 3 -NH-C -NH 2 622,7 623,4 -NH- (CH 2 3 -N (CHO) (CH 2 3 -NH- 693,8 694,4 C -NH 2 -N H20- C HN NjH 2 690,8 691,6 H H -NH- (CH 2 r-NH-C -NH~ 2 664,8 665,3 -NH- (CH 2 4 -NH-C -NH 2 636,7 637,4 Example 54: Analogously to Example 32, benzo~de]isochromene-l,3-dione is reacted with
CH
2 2
-CONH-CH
2 O
OCF
3
H
2 N- X 6-nitrothe appropriate diamine and tert-butyl (tertbutoxycarbonyliminopyrazol- 1 ylmethyl) carbamate. After removal of. the protective groups, the following compounds of the formulae 11w are obtained: WO 00/32577 WO 0032577PCT/EP99/08561 177 R' in 11w -NH- (CH 2 5 -NH-C -NH 2 -NH- (CH 2 2 -NH-C -NH 2 -NH- (CH 2 7 -NH-C -NH 2
NH
CH -N IN
H
-N -CH 2
H
NH
HN NH2CH H- C2- 2 H H -NH- (CH 2 3 -NH-C -NH 2 -NH- (CH 2 3 -N (CH 3
(CH
2 3
-NH-
C(=NH) -NH 2 -N-CH 0 21 2 H H -NH- (CH 2 6 -NH-C -NH 2 -NH- (CH 2 4 -NH-C -NH 2 Example Analogously to Example 32, benzo~delisochromene-1,3-dione is reacted with 0 H2N-d CH 2 2
-CONH-CH
2 \3I 6-nitro- WO 00/32577 PCT/EP99/08561 -178 the appropriate diamine and tert-buty. (tertbutoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formulae Im are obtained: E31
(CH
2 2 -CONH-CH 2 \0 R" in Im
MS
calculated found -NH- (CH 2 5 -NH-C
-NI-
2 -NH- (CH- 2 2 -NH-C -NH 2 524,6 525,3 -NH- (CH 2 7 -NH-C -NH 2 594,7 595,3
NH
H
2 I 1 ~N 2 606,7 607,3
H
-N -CH 2
H
I NH -N-C H 2
OH
2 2 600, 7 601,2 H H -NH- (CH 2 3 -NH-C -NH 2 538, 6 539,4 -NH- (cH 2 3 -N (cH 3 (cH 2 3 -NH- 609,7 610,3 C
-NH
2 -N-CH-O C2Nk H2 606,7 607,4 H H -NH-(CH)c 6
-NH-C(=NH)-NH
2 580,7 581,3 -NH- (CH 2 4 -NH-C
-NH
2 WO 00/32577 PCT/EP99/08561 179 Example 56: Analogously to Example 2, 6-nitrobenzo [del isochromene-1, 3-dione is reacted with 2- (4-aminophenyl) (4-dimethylaminophenyl) propionitrile and then with R 1 The following compounds of the formula In are obtained: R1 In 0 N 0
-CH
3 THCH2--\&/ NCH3 R'in Ri-H und in In MS calculated found -NH- (CH 2
NH
2 545 546 -NH- (CH 2 7
-NH
2 573 574
CH
2 NH 2 -N -CH 2
C
H
Example 57: 10 ml of TFA are added at room temperature to a solution of 2.4 g of tert-butyl 3 -(2-{4-[1-cyano- 2- 4 -dimethylaminophenyl) ethyl) phenyl}-l, 3-dioxo- 2, 3-dihydro-lH-benzo [de) isoquinolin-6-ylamino) propyl) carbamate in 40 ml of dichioromethane [obtainable by reaction of 6-nitrobenzo[de~isochromene-1,3-dione with 2- (4 -aminophenyl) 4 -dimethylaminophenyl) propionitrile and H2N- (CH 2 3 -NHBOC] and the reaction mixture is stirred until removal is complete. Af ter customary working upP (3-aminopropylamino) 3-dioxo- WO 00/32577 WO 0032577PCT/EP99/08561 180 1H, 3H-benzo [del isoquinolin-2-yl 1-3- (4-dimethylaminophenyl)propionitrile is obtained.
Example 58: Analogously to Example 32, benzo~de] isochromene-l, 3-dione is reacted with ,-,Ph
CH
2 2
-CONH-(CH
2 2
-CHP
H
2 N 6-nitrothe appropriate diamine and tert-butyl (tertbutoxycarbonyliminopyrazol-l-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ioa are obtained: loa 0 N 0
&~(CH
2 2
-CONH-(CH
2 2 -CH Rin boa MS calculated found -NH- (CH 2 S-NH-C -NH 2 680,8 681, 4 -NH- (CH2) 2 -NH-C -NH 2 638,8 639,6 -NH- (CH2) 7 -NH-C -NH 2 708,9 709,4
CH
2 -Ij1 NH 2 720,9 721,6
H
-N-CH
2
H
NH-
/N CH CH 2 -N 1" NH 2 714, 9 715,5 H H WO 00/32577 PCT/EP99/08561 -181 -NH- (CH 2 3-NH-C -NH 2 694,9 65,4 -NH- (CH 2 6-NH-C -NH 2 666,8 667,3 Example 59: Analogously to Example 32, 6-nitrobenzo- [deIisochromene-1,3-dione is reacted with
-C
CH
2 2
-CONH-CH
2 h~ H 2 N the appropriate diamine and tert-butyl (tertbutoxycarbonyliminopyrozol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula lob are obtained: D I lob WO 00/32577 PCT/EP99/08561 182 R' in lob
MS
calculated found -NH- (CH 2 2 -NH-C -NH 2 624,7 625,5 -NH- (CH 2 7 -NH-C -NH 2 694,9 695,4
NH
-iJ-H CH-fN 2 700,8 701,4 H H
NH
CH
2 -N fiL NH 2 706,9 707,6 -N -CH 2
H
-H-(CH
2 3 -NH-C -NH 2 638,8 639,6 Example Analogously to Example 11, 6-nitrobenzo[de]isochromene-l,3-dione is reacted with 4 -iodophenylamine or 3 -iodophenylamine I-Ar'-NH 2 Het 1
-B(OH)
2 and then with The following compounds of the formula Ip are obtained: 0N 0 Ar-Hetl -Ar'-H-et' R in R'-H and Ip (CH 2 3 -NH 2 \S I -NH- (CH2) 5
-NH
2 -NH- (CH 2 7
-NH
2
NH
2
H
WO 00/32577 PCTIEP99/08561 -183 -Ar'-Het-' R' in KR--H and Ip
(CH
2 3
-NH
2 I -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
0 -NH- (CH 2 3
-NH
2
-NH-(CH
2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
0 -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
S -NH- (CH 2 3
-NH
2 I -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2 S -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N NH 2
H
/s -NH- (CH 2 3
-NH
2 -NH- (CH 2 5 -NHi 2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
WO 00/32577 PCT/EP99/08561 184 -Ar' -Het" R" in R'-H and Ip /s -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 C (CH 2 7
-NH
2 -N
NH
2
H
0 (CH 2 3
NH
2 N -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
-NH- (CH 2 3
-NH
2 I -NH- (CH 2 5
-NH
2 -NH- (CH 2
,-NH
2 -N
NH
2
H
U) -NH- (CH 2 3
-NH
2 0 -NH- (CH 2 5
-NH
2 NH- (CH 2 7
-NH
2 -N
NH
2
H
U -NH- (CH 2 3
-NH
2 0 -NH- (CH 2 5-NH 2 -N
NH
2 Example 61: Analogously to Example 11, 6-nitrobenzo(de]isochromene-1,3-dione is reacted with 4-iodophenylamine or 3-iodophenylamine I-Ar' -NH 2
R
3 -Het 1
B(OH)
2 and then with The following compounds of the formula Iq are obtained: WO 00/32577 PCT/EP99/08561 -185 Iq 0 N 0 Ar'-Het 1
-R
3 -Ar -Het--R 4 R' in Ri-H and Iq U -NH- (CH 2 3
-NH
2 IS), CH 3 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2 0 -NH- (CH 2 3
-NH
2 s CH 3 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N NH 2
H
Example 62: Analogously to Example 11, 6-nitrobenzo~deisochromene-1,3-dione is reacted with 4-iodophenylamine or 3-iodophenylamine I-Ph-NH 2
R
6
(CH
2
(OH)
2 and then with R 1 -H (Ph-Ph The following compounds of the formula Ir are obtained: Ir o N 0 Ar-(CH 2 )r,-R 6 WO 00/32577 PCT/EP99/08561 186 -Ar' (CH 2 Rlin R"-H and Ir
(CH
2 3
-NH
2 -NH- (CH 2 5
-NH
2
NH
2 -NH- (CH 2 7
-NH
2 -N NH 2
H
-NH- (CH 2 3
-NH
2
(CH
2 5
-NH
2 NH- (CH 2 7
-NH
2 NH2-N NH 2
H
(CH
2 3
-NH
2 -O 0 -NH- (CH 2 5
-NH
2 CH3 -NH- (CH 2 7
-NH
2 -N
NH
2
H
-NH- (CH 2 3
-NH
2
(CH
2 5
-NH
2 -N0 -NH- (CH 2 7
-NH
2
H'CH
3 -N
NH
2
H
WO 00/32577 PCT/EP99/08561 187 Example 63: Analogously to Example 11, 6-nitro-2-(4iodophenyl)benzo- [de) isoquinoline-1, 3-dione is reacted with R 1 0 wherein R 10 is
O-C(CH
3 2 -CO-0C 2
H
and Propan-l, 3-diamine. (3-Amino-propylamino) 1, 3-dioxo-1H, 3H-benzo [del isoquinolin-2-yl] -biphenyl-4yloxyl-2-methyl-propionic acid ethyl ester is obtained.
Example 64: Analogously to Example 2, 6-chlorobenzo- [de]isochromene-l,3-dione is reacted with pyrimidine-2-sulfonic acid (4-amino-phenyl) -amide and Propan-1, 3-diamine. 5-Methoxy-pyrimidine-2-sulfonic acid (3-amino-propylamino) 3-dioxo-1H, 3Hbenzo [del isoquinolin-2-yl] -phenyl}-amide is obtained.
Example Analogously to Example 2, 6-chlorobenzo- [de]isochromene-l,3-dione is reacted with l-(6-amino- 2, 3-dihydro-indol-l-yl) -ethanone and propan-1, 3diamine. 2- (l-Acetyl-2, 3-dihydro-lH-indol-6-yl) (3amino-propyl amino) -benzo [del 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 propan-1, 3diamine. 6- (3 -Amino -propyl amino) 4- (pyrrolidine-1sulf onyl) -phenyll -benzo [del isoquinoline-l, 3-dione is obtained.
Example 67: Analogously to Example 2, 6-chlorobenzo- [del isochromene-1, 3-dione is reacted with 4-cyclohexylphenylamine and Propan-1,3-diamine. 6-(3-Amino- WO 00/32577 PCT/EP99/08561 188 propylamino) 4 -cyclohexyl-phenyl) benzo [del isoquinoline-1, 3-dione is obtained.
Example 68: Analogously to Example 2, 6 -chlorobenzo- [de]isochromene-1,3-dione is reacted with 3 -(3-aminophenyl) (2-phenyl-propyl) -propionamide and 3aminomethyl-benzylamine. 3- 6- (3-Aminomethylbenzylamino) 3-dioxo-1H, 3H-benzo [del isoquinolin-2yl] -phenyl}-N- (2-phenyl-propyl) -propionamide i s obtained.
Analogously, by reaction of 6-chlorobenzo- [de] isochromene-1, 3-dione with 3- (3-Amino-phenyl) (1phenyl-ethyl)-propionamide and 3-aminomethylbenzylamine, 3 3 6 3 -aminomethyl-benzylamino) -1,3dioxo-lH, 3H-benzo[de] isoquinolin-2-yl] -phenyl)-N- (1phenyl-ethyl) -propionamideis obtained.
Example 69: Analogously to Example 2, 6-chlorobenzo- [de]isochromene-1,3-dione is reacted with 3-(3-aminophenyl) 4-dihydro-2H-quinolin-1-yl) -propan-l-one and 3 -aminomethyl-cyclohexylamine. 6- [(3-Aninomethylcyclohexylmethyl) -amino] 3- 4-dihydro-2Hquinolin-l-yl) -3-oxo-propyl] -phenyl benzo [del isoquinoline-l, 3-dione is obtained.
Example Analogously to Example 2, 6-chlorobenzo- [de]isochromene-1,3-dione is reacted with H2N-Ar'-S-
(CH
2 ,-CONH- (CH 2 i-Ar and 3 -aminomethyl -ben zylamine. The following compounds of the formula Iya are obtained: WO 00/32577 PCTIEP99/08561I 189 WO 00/32577 -10 PCTIEP99/0856 I WO 00/32577 PCT/EP99/08561 191 r' (CH 2 11-CONH- (CH 2 i-Ar in I ya
CF
3
CF
3
\/S-CH
2 -CONH-/ cl
S-CH
2
-CONH-CH
2 o
-S-CH
2 -CONH-(CH 2
S-CH
2 -CONH-CH 2
CI
S-CH
2 -CONH-CH 2 cl
S-CH
2 -CONH-(CH 2 2 cl
CI
S-CH
2
-CONH-CH
2
CI
S-CH2 -CONH
CI
CI
~SCH2CONH cl SCH2 -CONHCH 2
S-CH
2 -CONH-(CH 2
S-CH
2 -CONHj S-CHi--CONH-(CH 2 4 WO 00/32577 -12-PCT/EP99/0856 1 Ar'I (CH 2 -CONH- (OH 2 i-Ar in I ya
S-CH
2
-CONH-(CH
2 2
H
S-CHi-CONH
CH
3
OH
3
S-H
2 -OONH
S-CH
2 -CONH SCH2
CONH-H
2 2H\ _C -S CH2 C NH -qCF 3
S-H
2
-ONH-CH
2 Q- F
S-CH
2 -CONH
-F
S-H
2
-CONH-H
2
F
0 -S -COH CONH-(0H 2 2 q
CH
0 -S C H -O O N H H 2 qC
H
S-CH
2 -CONH
OCH
O CH 2 7-ONH-(CH 2 2 0 CH -0 CH 2 7-CONH-CH 2 O CF WO 00/32577 PCT/EP99/08561 WO 00/32577 PCT/EP99/08561 Analogously to example 32, the compounds of the formula Iya as indicated above are reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-1-yl-methyl)carbamate.
After removing of the protection group, the following compounds of the formula lyb are obtained: WO 00/32577 WO 0032577PCT/EP99/08561 195 Ar' (CH 2 -CONH- (CH 2 1 -Ar in I yb
CONH.CH
2
NO
2 S CHI
-CONH-CH
2 'C 02
-D-S-CH-CONH-CH
2
SCH
2
CONH(CH
2 2 -o
SCH
2 CONHCH 2
KI\N
SCHI- CONH NGji-C- 2
H$
.CH3 -~-aS-CH 2 CONHH -G~N CH
-&S-CH-CONH
G -S-H 2 -CONH-CH 2
-O-H
,S-CH
2
-CONH------CH
3 OHH3
\/S-CH
2 -CONH-H 0H 2
-CONH-(CH
2 2
S-CH
2 -CONH WO 00/32577 PCTIEP99/0856 1 WO 00/32577 PCT/EP99/0856 I 197 WO 00/32577 PCT/EP99/08561 198- Ar (CH 2 -CONH- (CH 2 1 -Ar in I yb S- CH-CONH-CH 2 \CF S- CHi-CONH-CH 2
F
CI
S-CH2 -CONH
F
S- CH 2 CONH-CH 2
F
S-CH-CONH-(CH
2 2 \H
S-CH
2
-CONH-CH
2 /q
OC
S-CH--CONH
\CH
S- CHi--CONH-(CH 2 )2XO
OH
S- CHi--CONH-CH 2
O-OCF
3 S- CHf- CONH--j--OCH3 -Q 8- CH 2 -CONH-(CH 2 2
F
CHi-CONH-CH 2
F
CHi-CONH
F
S- CH 2 -CONH OPh 0 S- CHi--CONH WO 00/32577 PCT/EP99/0856 1 199 WO 00/32577 PCTIEP99/08561 200 Example 71: Analogously to Example 2, 6-chlorobenzo- [del isochromene-l, 3-dione is reacted with H 2 N-Ar'-S-
(CH
2 n-CONH- (CH 2 ±-Het' and 3-aminomethyl-benzylamine.
The following compounds of the formula Iza are obtained: Ar'-S-(CH 2 )n-CONH-(CH 2 )j-Het1 Ar (CH 2 ,-CONH- (CH 2 ±-Het 1 in Iza
S-CH
2 -CoNH(CH 2 )a-Nj~
S-CH
2 -CNH-(CH2) 2 -NcOj
S
\/S-CH
2 -CONH-CHr2 0
-S-CH
2
-CNH-CH
2 01 Analogously to example 32, the compounds of the formula Iza as indicated above are reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-l-yl-methyl) carbamate.- After removing of the protection group, the following compounds of the formula Izb are obtained: WO 00/32577 WO 0032577PCTIEP99/08561 201 Ar'-S-(CH 2
H-(CH
2 )j-Hetl Ar (CH 2 ,-CONH- (CH 2 j-Het 1 in I zb
S-CH
2 CONH(CH 2 2 NOj S-CH2CONH(CH 2 2 -N\2 7
S-CH
2 -CONH-CH 2 K~ l
S-CH
2 -CONH-CH 2 4~ Example 72: Analogously to Example 2, 6-chlorobenzo- [de]isochromene-1,3-dione is reacted with H 2 N-Ar'-S-
(CH
2 n-CONH- (CH 2 1 -D-H and 3-aminomethyl-benzylamine. The following compounds of the formula Ila are obtained: Ar'-S-(CH 2 )n-CON H-(CH 2 )j-D-H WO 00/32577 PCT/EP99/08561 202 Ar' (CH 2 ,-CONH- (CH 2 in Ila S-CHi--CONH S-CHi--CONH(CH2) 2 Analogously to example 32, the compounds of the formula Ila as indicated above are reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-l-yl-methyl) carbamate.
After removing of the protection group, the following compounds of the formula Ilb are obtained:
NH
Nj
NH
2 t1b 0 N 0 Ar-S-(CH 2 )n-CONH-(CH 2 )i-D-H
(CH
2 n-CONH- (CH 2 j-D-H in I lb S-CHi--CONH-(I
S-CH
2 CONH H 22 Example 73: Analogously to Example 2, 6-chlorobenzo- [delisochromene-l,3-dione is reacted with 2-(3-aminophenylsulfanyl) (2-phenyl-propyl) -acetamide and *3aminomethyl-benzylamine. 3- [6 (3-Aminomethylbenzylamino) 3-dioxo-lH, 3H-benzo [del isoquinolin-2yl] -phenylsulfanyl}-N- (2-phenyl-propyl) -acetamide is obtained.
WO 00/32577 PCT/EP99/08561I 203 Analogously to example 32, 2 3 [6-(3-Aminomethylbenzylamino) 3-dioxo-1H, 3H-benzo [de] isoquinolin-2yl] -phenylsulfanyl)-N- 2 -phenyl-propyl) -acetamide is reacted with tert-butyl (tertbutoxycarbonyliminopyrazol...yl.methyl) carbamate. After removing of the protection group (3guanidinomethyl-benzylamjno) 3-dioxo-1H, 3Hbenzo [del isoquinolin-2-yl] -phenylsulfanyl)-N- (2-phenylpropyl)-acetamide is obtained.
Example 74: Analogously to Example 2, [de] isochromene-l, 3-dione is reacted
(CH
2 -CONH- (CH 2 1 -CH- -Ar 2 and benzylamine. The following compounds of are obtained: 6-chlorobenzowith H 2 N-Ar'-S- 3-aminomethylthe formula 13a N' '%Q Ar-S-(CH 2 )n-CON H-(CH 2 )i-CH(Arl )-Ar 2 Ar' (CH 2 n-CONH- (CH 2 1 -CH (Ar 1 Ar 2in 13a
S-CH
2
-CONH-CH
2
-CH
I
Analogously to example 32, the compounds of the formula 13a as indicated above are reacted with tert-butyl (t ert -but oxycarbonyl iminopyzol..-.1yl methyl) carbamate.
WO 00/32577 PCT/EP99/08561 204 After removing of the protection group, the following compounds of the formula 13b are obtained: Ar'-S-(CH 2 )n-CONH-(CH 2 )i-CH(Ar')-Ar 2 Ar I (CH 2 -CONH- (CH 2 i-CH (Ar 1 Ar 2in in 13b
S-CH
2
-CONH-(CH
2 2
-CH
S-CH
2
-CONH-CH
2
-CH
Example Analogously to Example 2, 6-chlorobenzo- [del isochroinene-1, 3-dione is reacted with 2- (3-aminophenyl) (4-chloro-benzyl) -acetamide and 4aminomethyl-cyclohexylmethylamine. 2- 6- Aminomethyl-cyclohexylmethyl) -amino] 3-dioxo-lH, 3Hbenzo [de] isoquinolin-2-yl}-phenyl) (4-chloro-benzyl) acetamide is then, analogously to example 32, reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl)carbamate. After removing of the protection group N- (4-chloro-benzyl) 6-Il(4-guanidinomethylcyclohexylmethyl) -amino] 3-dioxo-lH, 3Hbenzo[de] isoquinolin-2-yl}-phenyl) -acetamide is obtained.
WO 00/32577 PCT/EP99/08561 205 Analogously is reacted 6-chlorobenzo [del isochromene- 1, 3-dione with 3- (3-amino-phenyl) -N-phenethylpropionamide and 4 -aminomethyl-cylohexylmethylamine and the following product 3 3 -{6-[(4-Arninomethylcyclohexylmethyl) -amino] 3-dioxo-1H, 3Hbenzo [de isoquinolin-2-yl I -phenyl) -N-phenethylpropionamide with tert-butyl (tertbut oxycarbonyl iminopyra zol- 1lyl-methyl) ca rbamate. After removing of the protection group 3- guanidinomethyl-cyclohexylmethyl) -amino] 3-dioxolH, 3H-benzo [de] isoquinolin-2-yl}I-phenyl) -N-phenethylpropionamide is obtained.
Example 76: Analogously to Example 2, 6-chlorobenzo- [dejisochromene-1,3-dione is reacted with H 2 N-Ar'-
(CH
2 n-CONH-- (CH 2 1 -Ar and 3 -aminomethyl -ben zylamine. The following compounds of the formula 16a are obtained: Ar CH2 ArON- (CH 2 i-CO nH-C 2
(CH
2 2 -CONH
/Q
Br WO 00/32577 PCTIEP99/08561I 206 WO 00/32577 WO 0032577PCT/EP99/0856
I
207 Ar I (CH 2 n-CONH- (CH 2 1 -Ar in I16a
ONH-CH
2
N
2 2
CAH
CONH N 2
(CH
2 2 -CONH-CH 2 N CH 3
ONH-CH
2
CH
3
(CH
2 2 CONH-(0H 2 2 2
-NH
2
(CH
2 2
CONH-CH
2 /0 \S0 2
-NH
2
CONH-CH
2 S0 2
-NH
2
(CH
2 2 -CON
CH
3 WO 00/32577 PCT/EP99/08561 WO 00/32577 PCT/EP99/08561 209 Ar' (CH 2 n-CONH- (CH 2 1 -Ar in 1 6a__ 4.
CONH-CH
2 cI
CONH-(CH
2 2
Q
CI
CONH--
CI
(CH
2 2
CONH-(CH
2 2 a c
CH
2 2 CONH \cl WO 00/32577 WO 0032577PCT/EP99/0856 1 210 Ar I (CH 2 -CONH- (CH 2 i-Ar in CONH(H) cl CONH /\CI
CH
2 2
CONH-(CH
2 2
/\CH
3
CH
2 2 CONH
CH
3 CONH
\CH
3
CONH-(CH
2 2 CH 3 CONH
\CH
3
(CH
2 2
CONH-CH
2 WO 00/32577 PCTIEP99/08561 WO 00/32577 PCT/EP99/08561 212- Ar' (CH 2 n-CONH- (CH 2 j-Ar in 1 6a
CF
3
(CH
2 2 CONH /\cl ONH-: CI
CF
3
CI
(CH
2 2
CONH-CH
2
CI
CONH-CH
2
(CH
22
-CONH-(CH
2 2
Z\
CI
(CH
2 2
CONH-CH
2
CONH-CH
2 WO 00/32577 PCT/EP99/08561 213- Ar' (CH 2 n-CONH- (CH 2 i-Ar in I16a
CONH-(CH
2 2 cl
(CH
2 2 CONH-CH 2 /C
CI
CONH-CH
2 \l
(CH
2 )r-CONH CONH c
CH
2 2 CONH cl
CI
CONH- CI WO 00/32577 PCT/EP99/08561 WO 00/32577 WO 0032577PCT/EP99/0856 I 215
(CH
2 2
CONH
CH
2 2 CONH WO 00/32577 PCT/EP99/08561 WO 00/32577 PCT/EP99/0856 I WO 00/32577 PCT/EP99/0856 I 218 WO 00/32577 PCT/EP99/08561 WO 00/32577 PCT/EP99/08561 WO 00/32577 PCTIEP99/0856 I WO 00/32577 PCT/EP99/0856 Analogously to example 32, the compounds of the formula I6a as indicated above are reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-l-yl-methyl)carbamate.
After removing of the protection group, the following compounds of the formula I6b are obtained: WO 00/32577 PCT/EP99/08561 -223 N NH 'N
NH
16b o N 0 Arx'-(CH 2 )n-CONH-(CH 2 )i-Ar Ar'-(CH 2
),-CONH-(CH
2 )i-Ar in 16b
CONH
Br
(CH
2 2 -CONH Br
CONH-<
CN
(CH
2 2 -CONH
CN
(CH
2 2
-CONH-(CH
2 2 -C
CONH-(CH
2 2 /NO 2
(CH
2 2
-CONH-CH
2 WO 00/32577 224 Ar'-(CH2),-CONH-(CH 2 )i-Ar in 16b
ONH-CH
2 -IQ NO 2
CONH-(CH
2 2 oN/
(CH
2 2
-CONH-CH
2
-N
(CH
2 2
-CONH-(CH
2 2
(CH
2 2
-CONH-CH
2 1
ONH-CH
2
~C
2
H
CONH N ~C 2
H
(CH
2 2
-CNH-CH
2
CH
3
(CH
22 -CO NH N( CH 3
CH
3 PCTIEP99/0856 I WO 00/32577 PCTIEP99/08561 WO 00/32577 PCT/EP99/0856 I 226 Ar'-(CH 2 ),-CONH- (CH 2 ±-Ar in 16b
CONH-CH
2
CONH-(CH
2 2
CONH--
CI
CONH-(CH
2 2 ci
CH
2 2
CONH-CH
2 cl CONH &c
CH
2 2 CONH
CH
3 CONH
CH
3 WO 00/32577 PCTIEP99/0856 I 227 Ar'-(CH 2 -CONH- (CH 2 i-Ar in 16b-
CONH-(CH
2 2 /\CH 3 -6 CONH
/\CH
3
CONH-CH
2
(CH
2 2
-CONH-(
CO NH-(
CH
2 2
-CONH-CH
2 CONH
OCH
3
CI
WO 00/32577 PCT/EP99/0856 I WO 00/32577 PCTIEP99/08561 229 Ar'-(CH 2
),,-CONH-(CH
2 )i-Ar in 16b
CI
(CH
2 2 CONH
C
CI
CONH c CONH- -CI
CONH-CH
2 CONH(CH)iJ
CONH--
CONH-(CH
2 4
CONH-(CH
2
)-&CH
3 WO 00/32577 PCT/EP99/0856 I WO 00/32577 PCT/EP99/08561 231 Ar'-(CH 2
),-CON--(CH
2 )i-Ar in 16b -1
(CH
2 2 CONH /Q F -6
CI
i I1
(CH
2 2
CONH-CH
2 p F
CONH-CH
2
F
(CH
2 2
CONH-(CH
2 2
H
(CH
2 2 CONH q 3
OCH
3 WO 00/32577 232 Ar'-(CH 2
)-CONH-(CH
2 )i--Ar in 16b CONH -qO
H
ONH-CH
2 OCF 3 CONW
OCH
3
CONH-(CH
2 2
OCH
3
(CH
2 2
CONH-(CH
2 2
F
CONH-(CH
2 2
F
PCT/EP99/08561 2- -4 -4- -i -f -f 4 4 i1 WO 00/32577 PCTIEP99/0856 I 233 WO 00/32577 PCTIEP99/08561 WO 00/32577 PCT/EP99/08561 235 Example 77: Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with H 2 N-Ar I-
(CH
2 ,-CONH- (CH 2 i-Ar and 3-aminomethyl-cyclohexylmethylamine. The following compounds of the formula 17a are obtained: N
NH
2 17a o N 0 Ar'-(CH 2
),,-CONH-(CH
2 )i-Ar Ar I (CH 2 -CONH- (CH 2 ±-Ar in 17a
(CH
2 2 -CONH<
(CH
2 2 -CONH /Pti i Example 78: Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with H 2 N-Ar'- (CH2) n-CONH- (CH 2 ±-Het 1 and 3-aminometl-yl-benzylamine.
The following compounds of the formula H8a are obtained: WO 00/32577 PCT/EP99/08561 236 Ar'-(CH 2
),,-CONH-(CH
2 )i-Hetl Ar- (CH 2 ,-CONH- (CH 2 j-Het' in1 WO 00/32577 WO 0032577PCT/EP99/0856
I
237
(CH
2 2 -CON H-(CH 2 3 -N ''N
(CH
2 2
-CONH-CH
2 '~0
S
CONH-CH
2 \<01
S
CH
2 2
-CONH-CH
2
\I
0
(CH
2 2 CON H-CH 2 I 0
CONH-CH
2
\I
Analogously to example 32, the compounds of the formula I~a as indicated above are reacted with tert-butyl (tert-butoxycarbonyliminopyrazol- 1.yl..methyl) carbamate.
After removing of the protection group, the following compounds of the formula 18b are obtained: WO 00/32577 PCT/EP99/0856 I 238 N Ar-(CH 2 )r-CON H-(CH 2 )i-Het'
A'-(CH
2 n-CONH- (CH 2 j-Het' I 8b WO 00/32577 WO 0032577PCT/EP99/08561 Example 79: Analogously to Example 2, 6-chlorobenzo- [dejisochromene-1,3-dione is reacted with H 2 N-Ar'-
(CH
2 ,-CONH- (CH 2 i-D-H- and 3-aminomethyl-benzylamine. The following compounds of the formula 19a are obtained: Ar'-(CH 2 )n-CONH-(CH 2
)-D-H
WOO00/32577 PCT/EP99/08561
CONH--
CONH
-(CH
2 2 0 Analogously to example 32, the compounds of the formula 19a as indicated above are reacted with tert-butyl (tert-butoxycarbonyliminopyrazol.1yl..methyl) carbamate.* After removing of the protection group, the following compounds of the formula 19b are obtained:
N
fjNH 2 19b 0 N 0 Ar (CH 2 n-CONH (CH 2 D-H in WO 00/32577 PCT/EP99/08561 241 Ar- (CH 2 -CONH- (CH 2 D-H in I19b -6CONH-- CONH
-(CH
2 2 -0 6C)- CN.H-
(H
2 2
CONH-(CH
2 II Example Analogously to Example 2, [de]isochromene-l,3-dione is reacted
(CH
2 -CONH- (CH2) 1 -CH (Ar 1 -Ar 2 and benzylamine. The following compounds Ii Qa are obtained: 6-chlorobenzowith H 2 N-Ar'I- 3 -aminomethylof the f ormula 110Ga WO 00/32577 242 Z Ar' (CH 2 CONH- (CH 2 ±-CH (Ar 1 Ar 2in PCT/EP99/08561 Analogously to example 32, the compounds of the formula as indicated above are reacted with tert-butyl (tert-butoxycarbonyliminopyrazo-1-yl.methyl) carbamate.
After removing of the protection group, the following compounds of the formula IlOb are obtained:
NH
NH
2 110Ob WO 00/32577 243 Ar' (CH 2 -CONH- (CH 2 i-CH (Ar 1 Ar 2 in Il0b
CONH-(CH
2 2
-CH-
PCT/EP99/0856
I
i sj (C22-CN-(H AGC 1
(CH
2 2
CONH-CH
2
-CH
Example 81: Analogously to Example 2, 6nitrobenzo[deisochromene.1,3-.dione is reacted with H 2
N-
C6H 4
-(CH
2 -R 3and then with Ri-H. The following compounds of the formula lla are obtained: l11a (C H 2
,-R
3 WO 00/32577 WO 0032577PCT/EP99/0856 I 244
-C
6
H
4
(CH
2 R 3
R
1 in R 1 -H and Illa 0 -H C2
-H
(OH
2 2 N2-NH-
(CH
2
-NH
2
NH
2 -NH- (CH 2 7-NH 2 -N
NH
2
H
N~
NH
2 H- C 2 -H 0 -NH-
(CH
2
-NH
2
(OH
2 2 -N -C 3
H
7 -N NH 2 5
-H
H -N
N
2
H
N~
NH
2 0-N NH2 -H3N
NH
2 -NH- (CH 2 3
-NH
2 0- N-C 3
H
7 -NH- (OH 2 5
-NH
2 -NH-
(CH
2 7 -NH 2 -N NH 2
H
N~
NH
2 -NH- (OH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 I--H -NH- (CH 2 7
-NH
2 H-N
NH
2
H
N INH 2 WO 00/32577 PCT[EP99/08561 -245-
-C
6
H
4
(CH
2 R 3
R
1 in R 1 -H and Illa -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 0
(CH
2 2 CH 3 -N NH 2 N (CH 2 2 CH~ I
CH
3
H
-N
NH
2 -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 CO-N- (CH2)2- CH -NN 2
HH
-N (CN)H2H 0 -NH- (CH 2 3-NH 2
OCH
3 -NH- (CH 2 5-NH 2 -N
NH
2 )7-H 0 2
H
CH 3 -N NH 2 -NH- (CH 2 3
-NH
2 HOO -N H- (CH 2 5
-NH
2 H 0 0 C
(CH
2 7
-NH
2 -N NH 2 H "O N
NH
2 Analogously to Example ii, 6-nitro-2- (3ioodophenyl) benzo [del isoquinoline-i, 3-diane or 6-nitro- 2- (4-iodophenyl) benzo [de) isoquinoline-i, 3-dione is reacted with H 2 N-Cl 2
H
8
(CH
2 -R 3 and then with Ri-H. The following compounds of the formula Ilib are obtained: WO 00/32577 WO 0032577PCT/EP99/08561 246 II lb -Cl 2
H
8
(CH
2 3
R
1 in R 1 -H and Ilib -NH- (CH 2 3
-NH
2 C3-NH-
(CH
2 5
-NH
2
CH
3 _NH- (CH 2 7
-NH
2
H
-NH- (CH' 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 H NH 2
H
-NH- (CH 2 3 -NH 2
CH
3 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H"O
-NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7-NH 2
NH
2
H
WO 00/32577 WO 0032577PCT/EP99/0856 I 247
-C
12
H
8
(CH
2
R
3 R1 in R'-H and Ilib -NH- (CH 2 3
-NH
2 -NH- (CH 2 5-NH 2 H 0 -N NH 2
H
Example 82: Analogously to Example 11, E-nitrobenzo- [de] isochromene-1, 3-diane is reacted with 4iodophenylamine or 3-iodophenylamine I-Ar'-NH 2 H-et 1
-B(OH)
2 and then with R 1 The following compounds of the formula Ip are obtained: RIp
I
-Ar -Heti -Ar' -Het 1
R
1 in R 1 -H and I-'
N
-NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
-N
NH
2
-N
HNH 2
NH
L'iH 2 WO 00/32577 PCT/EP99/08561 T 248 -Ar -Ret' R1 in R'-H and In
I
YIII'NC
S' C 3 -NH- (CR 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -N
NH
2
H
-N N NH 2 -t I tert-butyl -0-N tert-butyl -NR- (CR 2 3
-NR
2 -NH- (CR 2 5
-NR
2 -NH- (CR 2 7
-NR
2 -N NH 2
H
-N NH I I N 2
NH
-N H
NH
2 Example 83: Analogously to Example 2, 6-nitrobenzo- [del isochromene-l, 3-dione is reacted with R 6
(CH
2
NH
2 and then with The following compounds of the formula 112 are obtained: 112 N (CH 2 )rrRB WO 00/32577 PCT/EP99/08561 249
(CH
2
-R
6 R' in R 1 -H and 112 0 -NH-
(CH
2 3
-NH
2 N CH 3 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N NH 2
H
NCH 3 -NH- (CH 2 3
-NH
2 CH 3 -NH- (CH 2 5
-NH
2 -NH-
(CH
2 7 -NH 2 -N
NH
2
H
N 0 -NH- (CH 2 3
-NH
2 CH 3 -NH- (CH 2 5
-NH
2
(CH
2 7
-NH
2 -N NH 2 01
CH
3
H
Example 84: Analogously to Example 2, 6-nitrobenzo- [de~isochromene-1,3-dione is reacted with (4-aminophenyl) -phenyl-acetonitrile and then with R 1 The following compounds of the formula 113 are obtained: Ri 113
R
1 in R 1 -H and 113 -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 WO 00/32577 WO 0032577PCT/EP99/08561 250 R' in R'-H and 113 -N
NH
2
H
-N
NH
2
-N
H
NH
2 Example Analogously to Example 11, 6-nitro-2-(4-iodo- R -2phenyl) benzo- isoquinoline- 1, 3-diane is reacted with R 1 0
-B-(OH)
2 and with R 1 The following compounds of the formula 114 are obtained: 114 R12
RIO
RoR 1 inR 1 -H and 114 NH- (CH 2 3
-NH
2 -N
NH
2
-N
H
NH
2 WO 00/32577 PCT/EP99/08561 251 R___12 Rio R1 inR 1 and 114 /H CN -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N NH 2
H
3-CH 3 /\OH -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2 H /\NO 2 -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N NH 2 H
~~NH
-ae H
NHN
N0 2 /\OMe -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
Example 86: Analogously to Example 11, 6-nitro-2-(3-iodo- R 1 2 -phenyl) benzo- [del isoquinoline-1, 3-dione is reacted with R 1 0
-B-(OH)
2 and with R 1 The following compounds of the formula Ibm are obtained: WO 00/32577 WO 0032577PCTIEP99/0856 1 252 Ibm
R
1 in R 1 -H and Ibm -N
NH
2
-N
H "'ONH 2 Example 87: Analogously to Example 2, 6-nitrobenzo- [del isochromene-1, 3-dione is reacted with H 2 N-Ar and then with R 1 The following compounds of the formula Ibg are obtained: Ibg Ar
R
1 in R 1 -H and Ibg
C
2 -Ph NH- (CH 2 3
-NH
2 CH2-Ph -NH-
(CH
2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2 -N
NH
2 WO 00/32577 WO 0032577PCT/EP99/08561 253 Ar R" in R'-H and Ibg
NH
CH
2 -Ph H
NH
2 O-CH2-Ph -NH- (CH 2 3
-NH
2
O-H
2 -Ph -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
-N N
NH
2 -N H N 2 a Cl -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH1 2 7
-NH
2 -N
NH
2
H
-N N NH 2 1 2
H
NH
HH 2 -NH- (CH 2 5-NH 2
H
3 C-0 -NH- (CH 2 7
-NH
2 -N
NH
2
H
-N <N
NH
2
HN
K WO 00/32577 PCT/EP99/08561 254 Ar 3R' in R 1 -Hand Ibg
K
-NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N -NH 2
H
N
NH
2
HN
N N AH NH 2 4- -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N NH 2
H
-N
NH
NH
N H 2 4- -NH- (CR 2 3
-NH
2 -NH- (CH 2 5
-NH
2 -NH- (CR 2 7
-NH
2 -N
NH
2
H
-N N NH 2
HN
-N
H
"NH
2 -NH- (CR 2 3
-NH
2 Br -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -N
NH
2
H
WO 00/32577 PCT/EP99/08561 255 Ar
R
1 in R 1 -H and Ibg Br-N N, NH 2
NH
NH
2
OCH
3 -NH-
(CH
2 3
-NH
2
OCH
3 -NH- (CH 2 5
-NH
2 -NH- (CH1 2 7
-NH
2
OCH
3
OCH
3 -NH- (CH 2 3
-NH
2
(CH
2 5
-NH
2 -NH- (CH 2 7
-NH
2 -NH- (CH 2 3
-NH
2 S0 2 -NH- (CH 2 5
-NH
2
(CH
2 7
-NH
2
NH
N H H
NH
2
(CH
2 3
-NH
2 -NH- (CH 2 5
-NH
2
(CH
2 7
-NH
2 -NH- (CH 2 3
-NH
2
OCH
3 -NH-
(CH
2 5
-NH
2 NC OCH 3 -NH- (CH 2 7
-NH
2
OCH
3
(CH
2 3
-NH
2
OCH
3 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2
OCH
3
CF
3 -NH-
(CH
2 3
-NH
2 NH- (CH 2 s-NH 2 -NH- (CH 2 7
-NH
2 CF 3 -NH- (CH 2 3
-NH
2
CF
3 -NH- (CH 2 5
-NH
2
(CH
2 7
-NH
2 WO 00/32577 PCT/EP99/08561 256- Ar R 1 in R 1 -H and Ibg NC -NH- (CH 2 3
-NH
2
OCH
3 -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 OCH3 OCH 3 -H C 2 -H OCC 3 NH- (CH 2 -NH 2
OCH
3 -NH- (CH 2 7-NH 2 0 -NH- (CH 2 3-NH 2 0 -NH- (CH 2 5-NH 2 -NH- (CH 2 7-NH 2 F -NH- (CH 2 3-NH 2 F -NH- (CH 2 5-NH 2
(CH
2 7-NH 2 CH3 -NH- (CH 2 3-NH 2
OCH
3 -NH- (CH 2 5-NH 2
(CH
2 7-NH 2 -NH- (CH 2 3-NH 2
(CH
2 3
-NH
2 cl -NH- (CH 2 7-NH 2 CI -NH- (CH 2 3-NH 2
-N-CA
2
-H
CH-NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2
OCH
3 -NH- (CH 2 3
-NH
2 -NH- (CH 2 7-NH 2
OCH
3 -NH- (CH 2 3-NH 2 -NH- (CH 2 5-NH 2 -NH- (CH 2 7-NH 2
CN
WO 00/32577 PCT/EP99/08561 257 Ar R 1 in Rl-H and lb g -NH- (CH 2 3
-NH
2 N N-NH-
(CH
2 5
-NH
2 -NH- (CH 2 7
-NH
2 Br -NH- (CH 2 3
-NH
2 N N-NH-
(CH
2 5
-NH
2 -NH- (CH 2 7
-NH
2
NO
2 -NH- (CH 2 3
-NH
2 N N-NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2
OCH
3 OH -NH- (CH 2 3
-NH
2 -NH- (CH 2 5
-NH
2
(CH
2 7
-NH
2 -NH- (CH 2 3
-NH
2 N1z: N OH -NH- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -NH- (CH 2 3
-NH
2 N N CI -N4- (CH 2 5
-NH
2 -NH- (CH 2 7
-NH
2 -NH- (CH 2 3
-NH
2 N NNH-
(CH
2 5
-NH
2 -NH- (CH 2 7
-NH
2
CI
CH -NH- (CH 2 3
-NH
2
C
3 -NH- (CH 2 5
-NH
2 Br -NH- (CH 2 7-NH2 WO 00/32577 PCT/EP99/08561 258 Ar
R
1 in R 1 -H and Ibg_ -NH- (CH 2 5-NH 2
SO
2
NH
2 -NH- (CH 2 7-NH 2 -NH- (CH 2 3-NH 2 _OCH3-NH- (CH 2 5-NH 2
OCH
3 -NH- (CH 2 7-NH 2 N H (C H 2 3 N H 2 -NH- (CH 2 5-NH 2 OH -NH- (CH 2 7-NH 2 OH -NH- (CH 2 3-NH 2 IIZZII-NH- (CH 2 5-NH 2 N
(CH
2 7-NH 2
OH
-NH- (CH 2 3
-NH
2 -NH- (CH 2 ).7-NH 2 &OH -H C 2
-H
Example 88: The compound 3-1{4- (3-aminomethylbenzylamino) 3-dioxo-1H, 3H-benzo [de] isoquinolin-2yl I-phenyl 3-dimethyl-butyl) -propionamide according to example 81. is reacted with tert-butyl (tert-butoxycarbonylminopyrazol-1.l..ylmethyl) carbamate according to example 32. After removal of the protective group, N-(3,3-Dimethyl-butyl)-3-4[6(3.
guanidinomethyl-benzylamino) 3-dioxo-1H, 3Hbenzo [del isoquinolin-2-yl] -phenyl}-propionamide is obtained.
Example 89: Analogously to Example 2, 6-chlorobenzo- [de]isochromene-1,3-dione is reacted with 3-(4-aminophenyl) 3 -dimethylamino-propyl) -propionamide and C- 3 -aminomethyl-cyclohexyl) -methylamine. 3- 6- (3- Aminomethyl-cyclohexylmethyl) -amino] 3-dioxo-lH, 3H- WO 00/32577 PCT/EP99/08561 259 benzo [de I isoquinolin-2-yl}I-phenyl) (3 -dimethyl aminopropyl)-propionamide is obtained.
Example Analogously to Example 2, 6 -chlorobenzo- [de] isochromene-l, 3-dione is reacted with 2- (4-aminophenylsulfanyl) 3-dimethylbutyl) -acetamide and 3aminomethyl-benzylamine. (3-Aiinomethylbenzylamino) 3-dioxo-1H, 3H-benzo [de] isoquinolin-2yl] -phenylsulfanyl}-N- 3-dimethyl-butyl) -acetamide is obtained.
Example 91: Analogously to Example 2, 6chlorobenzo [de] isochromene-1, 3-dione is reacted with
H
2 N-Ar I (CH 2 n-R 3 and 3-aminomethyl-benzylamine. The following compounds of the formula 112 are obtained: I NH 2
HN"-
112 Ar'-Y-(CH 2 )n-R3 Ar (CH- 2 n-R 3 -a s-
CH
3 _N
CH
3 o CH 3 S
H
SN% I3 03 WO 00/32577 PCT/EP99/08561 260 Example 92: Analogously to Example 2, 6chlorobenzo~de]isochromene-1,3-dione is reacted with 4- (pyrrolidine-l-sulfonyl) -phenylamine and 3-aminomethylbenzylamine. 6- (3-Aminomethyl-benzylamino) [4- (pyrrolidine-l-sulfonyl) -phenyl] -benzo [de] isoquinoline- 1,3-dione is obtained.
Example 93: Equimolar amounts of (3-amino-propylamino) -1,3dioxo-1-, 3H-benzo [del isoquinolin-2-yl] benzonitrile (according to example 87, page 256, table line 1) and methanesulfonic acid are reacted according to known procedures to give the acid addition salt[6- (3 -amino-propyl amino) 3-dioxo-1H, 3Hbenzo [de] isoquinolin-2-yl methane sulfonate.
1 H-nmr (DMSO-d 6 8.80 (dd, J 1.0 and J =8.6 Hz, 1H), 8. 50 (dd, J 0. 8 and J 7. 4 Hz, 1H) 8. 34 J 8. 6 Hz, 1H) 7.94 t J =5.8 Hz, 1H), 7.76 (dd, J 7.4 and J 8.4 Hz, 1H), 7.71 (sbr, 2H (NH 2 7.55 1H), 7.30 1H), 6.90 J 8.8 Hz, 1H), 3.90 3H), 3.81 3H), 3.60-3.45 (in, 2H), 2.96 J 7.6 Hz, 2H), 2.31 3H), 2.08-1.94 (in, 2H).
Abbreviations of the nmr-signals (nmr =nuclear magnetic resonance): s singlet, d doublet, dd double doublet, t triplet, sbr broad singlet, m multiplet, q quadruplet, J coupling constant J in Hz WO 00/32577 PCT/EP99/08561 261 Analogously to Example 93 the following acid addtion salts are obtained: 3 3 6 2 -guanidino-ethylamino)1, 3dioxo-H, 3H benzo (del isoquinolin-2-yl-phenyl 1-N- (4 -phenyl-butyl) propionamide (example 40, p.145, table line 2) 3- 6- (2-guanidino-ethylamino) 3-dioxo-1H, 3Hbenzo [del isoquinolin-2-yl-phenyl 1-N- (4-phenyl-butyl) propionamide, methane sulfonate; 1 H-nmr (DMSO-d 6 8.73 (dd, J =1,0 and J 8.5 Hz, 1H) 8.46 (dd, J and J 7.3 Hz, 1H), 8.28 J 8.5 Hz, 1H), 7.88 J 5.6 Hz, 1H), 7.75 (dd, J 7.3 and J 8.4 Hz, 1H) 7.61 J 5.8 Hz, 1H) 7.40-7.36 (in, 1H), 7.28- 7.23 (mn, 3H), 7.16-7.10 (in, 4H), 6.89 J =8.7 Hz, 1H), 3.61-3.50 (in, 4H), 3.06 J 7.0 Hz, 2H), 2.89- 2.85 (mn, 2H), 2.53 J 7.6 Hz, 1H), 2.39 J 8.5 Hz, 2H), 2.36 3H), 1.56-1.49 (mn, 2H), 1.41-1.34 (mn, 2H).
N- (4-chloro-phenyl) -ethyl] {3-[l(3-guanidinopropyl) -methyl-amino) -propylamino}-l, 3-dioxo-1H, 3Hbenzo [de] isoquinolin-2-yl) -phenyl) -propionanide (example 37, p. 135, table line 7) N- (4-chloro-phenyl) -ethyl] (3.
guanidino-propyl) -methyl-amino] -propylainino}-1, 3-dioxo- 1H, 3H-benzo tde] isoquinolin-2-yl) -phenyl] -propionamide, methane sulfonate 'H-nmr (DMSO-d 6 10.49 (sbr, 1H), 8.85 J 8.5 Hz, 1H), 8.44 (dd, J 0.9 and J 7.3 Hz, 1H), 8.27 J 8.5 Hz, 1H), 8.01 (sbr, 1H(NH)), 7.94 J 5.6 Hz, 1H(NH)), 7.90 J 5.9 Hz, 1H(NH)), 7,73 (dd, J 7.4 and J 8.4 Hz, 1H) 7.42-7.38 (mn, 1H) 7.31 J =8.4 Hz, 2H) 7.26 J 7.7 Hz, 1H), 7.18 J =8.4 Hz, 2H), 7.14-7.11 (mn, 2H), 6.88 J 8.7 Hz, 1H), 3.65-3.45 WO 00/32577 PCTIEP99/08561 262 (mn, 3H), 3.31-3.15 (in, 6H), 3.11-3.04 (in, 18), 2.85 (t, J 7. 3 Hz, 2H) 2. 77 J 4. 9 Hz, 3H) 2. 67 J 7.3 Hz, 2.39 J 5.7 Hz, 1H), 2.35 3H), 2.21-2.14 (mn, 2H), 1.96-1.89 (mn, 2H).
N- (4-chioro-phenyl) -ethyl] (2-guanidinoethylanino) 3-dioxo-lH, 3H-benzo [de]I isoquinolin-2 -yl] phenyll-propionamide (example 37, p. 135, table line 2) N- (4-chloro-phenyl) -ethyl] -3-f 3- (2guanidino-ethyl amino) 3-dioxo-1H, 3Hbenzo [del isoquinolin-2-yl] -phenyl}I-propionanide, methane sulfonate; 1 H-ninr (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, 18) 8.27 J =8.5 Hz, 1H) 7. 94 J 5. 7 Hz, 1H 7. 80 J =5.2 Hz, 1H (NH)) 7. 76 J 5. 1 H z, 1H (NH) 7. 74 (dd, J 7. 3 and J 8. 5 Hz, 18) 7.40 J 7. 9 Hz, 18) 7.31 J 8. 4 Hz, 28) 7.26 J 7. 8 Hz, 18), 7. 18 J 8. 4 Hz, 28), 7. 14-7. 11 (mn, 28) 6.89 J 8. 7 Hz, 18) 3. 61- 3.56 (mn, 28), 3.55-3.50 (mn, 2H), 3.28-3.23 (mn, 28), 2.86 J =8.2 Hz, 28), 2.67 J 7.1 Hz, 28), 2. 40 J 3 hz, 28) 2. 35 38) N- (4-chioro-phenyl) -ethyl] (3-guanidinopropylamino) 3-dioxo-lH, 3H-benzo [de] isoquinolin-2yl]-phenyll-propionanide (example 37, p. 135, table line 6) N- (4-chloro-phenyl) -ethyl] -3-13- (3guanidino -propyl amino) 3-dioxo-1H, 38benzo (del isoquinolin-2-yl] -phenyl}I-propionainide, methane sulfonate; 1 8-nmr (DMSO-d 6 8.76 J 8.5 Hz, 18) 8.44 J =7.3 Hz, 1H) 8.27 J 8.5 Hz, 1H), 7.93 J 1H(NH)), 7.73 J 7.5 Hz, 18), 7.65 J =5.6 Hz, 1H), 7.40 J 8.0 Hz, 18), 7.31 J =8.4 Hz, 2H), WO 00/32577 PCT/EP99/0561 263 7.18 J 8.4 Hz, 2H), 71.4-7.11 2H), 6.84 Cd, J 8.7 Hz, 1H), 3.45 J 6.3 Hz, 2H), 3.31-3.22 (m, 4H), 2.86 J 8.0 Hz, 2H), 2.66 J 7.1 Hz, 2H), 2.41 J 8.2 Hz, 2H), 2.37 3H), 199-1.91 2H).
6-(3-aiino-propylaiino)-2-(2,3-dimethoxyphenyl)benzo[delisoquinoline-1,3-dione (example 87, P. 255, table line 3) 6-( 3 -amino-propylamino)-2-(2,3-dimethoxyphenyl)benzofde]isoquinoline-1,3-dione, methane sulfonate; 1 H-nmr (DMSO-d 6 8.75 (cd, J 0.9 and J 8.4 Hz, 1H), 8.46
J
0.8 and J 7.3 Hz, 1H), 8.30 J 8.5 Hz, 1H), 7.86 (sbr, 1H(NH)), 7.75 J 7.3 and J 8.4 Hz, 1H), 7.65 (sbr, 2H(NH)), 7.17-7.15 2H), 6.89-6.85 (m, 2H), 3.89 3H), 3.60 3H), 3.51 J 7.0 Hz, 2H), 2.97 Ct, J 7.8 Hz, 2H), 2.31 3H), 2.03-1.96 Cm, 2H).
6-( 3 -amino-propylamino)-2-(4'-iethoxy-biphenyl-4-yl)benzo[de)isoquinoline-1,3-dione (example 12, p. 98, table line 3) 6-( 3 -aiino-propylamino)-2-(4'-methoxy-biphenyl-4yl)-benzo[de]isoquinoline-1,3-dione, methane sulfonate; 1 H-nmr (DMSO-d 6 8.75 Cd, J 8.5 Hz, 1H), 8.48 Cd, J 6.6 Hz, 1H), 8.31 J 8.5 Hz, 1H), 7.84 (sbr, lH(NH)), 7.77-7.68 7H(2xNH)), 7.36 J 8.4 Hz, 2H), 7.07 J 8.8 Hz, 2H), 6.88 J 8.7 Hz, 1H), 3.83 Cs, 3H), 3.54-3.48 Cm, 2H), 2.98 Ct, J 7.8 Hz, 2H), 2.31 Cs, 3H), 2.04-1.96 2H).
6-C 3 -aiinopropylaino)-2-C4-carbazol-9-yl-phenyl)benzo[de]isoquinoline-1,3-dione (example 82, p. 247, table linel) WO 00/32577 PCT/EP99/08561 264 6- (3 -aminopropyl amino) (4-carbazol-9-yl-phenyl) benzo ide] isoquinoline-1, 3-diane, methane sulfonate; 1 H-nmr (DMSO-d 6 8.77 (dd, J 0.9 and J 8.6 Hz, 1Hi), 8.57 (dd, J= 0.8 and J 7.3 Hz, 1H), 8.36 J =8.5 Hz, 1H), 8.29 J 7.8 Hz, 2H), 7.87 J =5.7 Hz, 1H(NH)), 7.81-7.77 (in, 3H), 7.72 (sbr, 2H(NH)), 7.64 J 8.6 Hz, 2H), 7.53-7.47 (in, 4H), 7.36-7.32 (in, 2H), 6.91 (d, J 8.7 Hz, 1H), 3.57 J 5.9 Hz, 2H), 3.03-2.95 (mn, 2H), 2.31 3H), 2.05-1.98 (in, 2H).
N- (4 -methoxy-biphenyl-4-yl) 3-dioxo-2, 3dihydro-1H-benzo [de] isoquinolin-2-yl] -phenyll-N- (4phenyl-butyl) -propionamide (example 85, p. 251, table line 4) N- (4 1 -methoxy-biphenyl-4-yl) 3-dioxo-2, 3dihydro-1H-benzo [de] isoquinolin-2-yl] -phenyll (4phenyl-butyl) -propionamide, methane sulf onate; 1 H-nmr (DMSO-d 6 8.83 J =7.8 Hz, 1H), 8.56 J 6.5 Hz, 1H(NH)), 8.49 (dd, J =0.8 and J 7.3 Hz, 1H), 8.20 J Hz, 1H), 7.84 J 5.8 Hz, 1H(NH)), 7.78 (dd, J 7.4 and J 8. 4 Hz, 1H) 7".72 J 8. 5 Hz, 2H) 7. 68 J =8.8 Hz, 2H), 7.40-7.36 (mn, 4H), 7.34 J= Hz, 2H), 7.22-7.19 (mn, 1H), 7.07 J 8.8 Hz, 1H), 6.70 J =8.7 Hz, 1H) 4.70 J 5.9 Hz, 2H), 4.36 J =5.9 Hz, 2H), 3.82 3H), 2.30 (s, 3H).
6- 3 aiinopropyl amino) 7 -hydroxy-naphthalen-1-yl) benzo[de]isoquinoline-1,3-dione (example 87, p. 257, table line 6- (3-aminopropylamino) (7-hydroxy-naphthalen-1yl) -benzo [del isoquinoline-1, 3-dione, methane sulfonate; WO 00/32577 PCT/EP99/08561 265 1 H-nmr (DMSO-d 6 9.61 1H(OH)), 8.79 (dd, J 0.9 and J 8.6 Hz, 1H) 8.50 (dd, J 0. 8 and J 7. 3 Hz, 1H) 8. 33 J Hz, 1H), 7.93-7.87 (in, 2H), 7.79 (dd, J 7.4 and 8.4 Hz, 1H), 7.74 (sbr, 3H(NH)), 7.43-7.37 (in, 2H), 7. 10 (dd, J 2.4 and J 8. 9 Hz, 1H) 6. 91 J 8.7 Hz, 1H), 6.75 J 2.4 Hz, 1H), 3.53 J 6.3 Hz, 2H), 3.02-2.95 (mn, 2H), 2.31 3H), 2.05-1.98 (mn, 2H).
N- (4-chioro-phenyl) -ethyl] (4guanidinomethyl-benzylamino) 3-dioxo-1H, 3Hbenzo [del isoquinolin-2-yl] -phenyl I-propionamide (example 37, p. 135, table line N-[2-(4-chloro-pheny)-ethyl-3-3[6(4guanidinomethyl-benzylanino) 3-dioxo-1H, 3Hbenzo [del isoquinolin-2-y1] -phenyl }-propionamide, methane sulfonate; 'H-nznr (DMSO-d 6 8.82 (dd, J 0.8 and J 8.5 Hz, 1H), 8.55 (sbr, lH(NH)), 8.45 (dd, J =0.8 and J 7.3 Hz, 1H), 8.15 J 8.5 Hz, 1H) 7. 91 J 5.7 Hz, 1H (NH) 7.85 J =6.1 Hz, 1H(NH)), 7.76 (dd, J =7.4 and J 8.4 Hz, 1H), 7.44 J 8.2 Hz, 2H), 7.39 J 8.1 Hz, 1H), 7.32-7.23 (mn, 5H), 7.17 J 8.4 Hz, 2H), 7.12- 7.09. (mn, 2H), 6.58 J 8.7 Hz, 1H), 4.69 J= 4. 6 Hz, 2H) 4.33 J 6.2. Hz, 2H) 3.24 J 7.4 Hz, 2H), 2.84 J 8.3 Hz, 2H), 2.66 J 7.1 Hz, 2H), 2.39 J 8.0 Hz, 2H), 2.34 3H).
N- (3-chioro-phenyl) -ethyl] (3-16- guanidinoinethyl-cyclohexylnethyl) -amino] 3-dioxo- 1H, 3H-benzo [del isoquinolin-2-yl }-phenyl) -propionamide (example 37, p. 134, table line
N-[
2 3 -chloro-phe)...ethyl3(3.6.[ (4guanidinoinethyl-cyclohexylinethyl) -amino] 3-dioxo- 1H, 3H-benzo [de] isoquinolin-2-yl}-phenyl) -propionamide, methane sulfonate; WO 00/32577 PCT/EP99/08561 -266 'H-nmr (DMSO-d 6 8.79 J 8.5 Hz, 1H), 8.43 J 7.3 Hz, 1H), 8.24 (dd, J 3. 1 and J 8. 6 Hz, 1H) 7. 94 J 7 Hz, 1H(NH)), 7.84 (sbr, 1H(NH)), 7.78-7.69 (in, 1H), 7.40 J 8.0 Hz, 1H), 7.30-7.22 (in, 4H), 7.14-7.10 (in, 3H), 6.82 (dd, J 3.3 and J 8.8 Hz, 1H), 3.27 J 8 Hz, 2H) 3. 11 J 6.5 Hz, 2H) 2. 85 (t, J 7. 3 Hz, 2H) 2. 69 J 7. 3 Hz, 2H) 2. 39 J 7.4 Hz, 2H), 2.34 3H), 1.94-1.74 (in, 2H), 1.60-1.40 (mn, 4H), 1.05-0.90 (mn, 2H); (cis isomer:trans isomer= 2:1) N-112-(4-chloro-phenyl)-ethyl-( guanidinomethyl-cyclohexylnethyl) -amino) 3-dioxo- 1H, 3H-benzo [del isoquinolin-2-yl} -phenyl) -propionamide (example 37, p. 135, table line 8) N-[2-(4-chloro-phenyl)-ethyl...3...6.[ (4guanidinomethyl-cyclohexylmethyl) -amino] 3-dioxo- 1H, 3H-benzo [del isoquinolin-2-yl I-phenyl) -propionainide, methane sulfonate; 1H-ninr (DMSO-d 6 8.79 (dd, J 1.7 and J 7.8 Hz, 1H), 8.43 J 7.3 Hz, 1H), 8.24 (dd, J 3.2 and J 8.6 Hz, 1H), 7.92 J 5.7 Hz, 1H(NH)), 7.83 (sbr, 1H(NH)), 7.73-7.69 (in, 1H), 7.41-7.37 (in, 1H), 7.30 J =8.4 Hz, 2H), 7.25 J 7. 8 Hz, 1H) 7. 17 J B. 84 Hz, 2H) 7. 13-7. 10 (in, 2H), 6.81 (dd, J 2.9 and J 8.8 Hz, 1H) 3.25 J 7.3 hz, 2H), 3.11 J 6.4 Hz, 2H) 2. 85 J 8.2 Hz, 2H), 2.66 J 7.2 Hz, 2H), 2.39 J 7.4 Hz, 2H), 2.33 3H), 1.95-1.75 (mn, 2H), 1.6 0-1.40 (in, 4H), 1.05-0.90 (in, 2H), (cis isoiner:trans isomer 2:1).
4 -guanidinoinethyl-benzylamino) 3-dioxo- 1H, 3H-benzo (del isoquinolin-2-yl) -phenyl)} (4sulfainoyl-phenyl) -ethyl] -propionamide (example 35, p.
129, table line WO 00/32577 PCT/EP99/08561 267 (4-guanidinomethyl-benzylamino) 3-dioxo- 1H, 3H-benzo [ce] isoquinolin-2-yl] -phenyl 1-N- (4sulfamoyl-phenyl) -ethyl] -propionamide, methane sulfonate; 1 H-nmr (DMSO-d 6 8.88 J 8.5 Hz, 1H), 8.66 (sbr, 1H(NH)), 8.50 (dd, J 0.8 and J 7.3 Hz, 1H), 8.20 J 8.5 Hz, 1H), 7.93 1 6.0 Hz, 1H(NH)), 7.77 (di, J 8.3 Hz, 1H), 7.49 J =8.2 Hz, 2H), 7.40 J 8.4 Hz, 2H), 7.35-7.30 (in, 4H), 7.19-7.14 (mn, 3H), 6.73 (di, J 8.7 Hz, 1H), 4.71 J 6.1 Hz, 2H), 4.39 (di, J =6.1 Hz, 2H) 3.34 J 7.4 Hz, 2H), 2.90 J =8.6 Hz, 2H) 2.81 J 7.2 Hz, 2H), 2.45 J =8.3 Hz, 2H), 2.38 3H).
WO 00/32577 PCT/EP99/08561 268 The following examples relate to pharmaceutical preparations: Example A: Injection vials A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 1 of double-distilled water using 2N hydrochloric acid, sterile-filtered, dispensed into injection vials, lyophilized under sterile conditions and aseptically sealed. Each injection vial contains 5 mg of active compound.
Example B: Suppositories A mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 20 mg of active compound.
Example C: Solution A solution is prepared from 1 g of an active compound of the formula I, 9.38 g of NaH 2
PO
4 .2H 2 0, 28.48 g of Na 2
HPO
4 .12H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The mixture is adjusted to pH 6.8, made up to 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops.
Example D: Ointment 500 mg of an active compound of the formula I is mixed with 99.5 g of petroleum jelly under aseptic conditions.
Example E: Tablets A mixture of 1 kg of active compound of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 g of talc and 0.1 kg of magnesium stearate is compressed in a customary manner to give tablets such that each tablet contains 10 mg of active compound.
WO 00/32577 PCT/EP99/08561 269 Example F: Coated tablets Analogously to Example E, tablets are pressed which are then coated with a coating of sucrose, potato starch, talc, tragacanth and colourant in a customary manner.
Example G: Capsules 2 kg of active compound of the formula I are dispensed into hard gelatin capsules in a customary manner such that each capsule contains 20 mg of the active compound.
Example H: Ampoules A solution of 1 kg of active compound of the formula I in 60 ml of double-distilled water is sterile-filtered, dispensed into ampoules, lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 10 mg of active compound.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
269a Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that the prior art forms part of the common general knowledge in Australia.
:oo• cooF ooo• oo<s "0 o
H•
e

Claims (4)

1. Compounds of the formula I R R1 in which R is Hor N 2 Ri is -Het, -Het-S0 2 -Ar, -Het-R 5 -Het- (CH 2 N0 2 -N=CH-Ar, NHAlk, NAAlk, NRA', A2' -N NI -Y-Ar' -R 3 (CH 2 0 -R 3 -Y-(CR 2 ,i (CHR 4 -YC [(CR 2 0 -OH] 3 -Y-(CH 2 )m-NA 2 -Y-(CH 2 )m-NHA', -Y-(CR 2 0 -OH, -Y-(CH 2 k-R, -Y-(CR 2 )ijR', (CH 2 a-Ret, (CH 2 a-Ar, (CH 2 n-Ar' (CH 2 1 -R 6 (CH 2 D- (CH 2 1 -R 6 (CR 2 n-Het- (CH 2 j-R (CH 2 n-NA- (CR 2 ±-R 6 (CH 2 a-NH- (CH 2 i-R -Y-(CR 2 (CH 2 i-R 8 (CR 2 a-Ar' -(CR 2 (CR 2 a-NH- (CR 2 j-R', (CR 2 n-NA- (CR 2 i-R 8 ,I [X-OJ t- [X 1 U-X 2 _R 6 or (X-NR] R2 is -Ar, -Ret 1 -Ret 1 -Ar, -Ar' -Ret 1 (CR 2 -Ar' (CR 2 n-R -Ar' -Y-C 2 Ret'-R 3 -Ar' -Ret 1 -R 3 -Ar' (CR 2 6 -Ar' -S0 2 -Het, -Ar' -NR-S0 2 -Ret, Ar' -S0 2 -R 7 -Ar' (CR 2 n- (CO-NH) (CR 2 1 -R 6 -Ar'I (CR 2 (CO-NR) (CR 2 1 -R 1, -Ar' (CR 2 ),a-CO-Ret, -Ar' (CR 2 n- (CO-NR) (CR 2 j-D-H, -Ar' (CR 2 n- (CO-NH) (CH 2 -Ar'I (CR 2 (CO-NH) -Ar'I- (CR 2 n- (CO-NH) (CR 2 i-CH (Ar 1 -Ar 2 -Ar' -S- (CR 2 n- (CO-NH) (CR 2 -Ar' (CR 2 n- (CO-NH) WO 00/32577 PCT/EP99/08561 271 (CH 2 -Ar S- (CH 2 (CO-NH) (CH 2 i-Het', -A S C2 A' A or -Ar' -S- (CH 2 n- (CO-NH) (CH 2 R3 is C CONH 2 CONHA, CONA 2 COOH or COQA, R' is Ph orOH, is CH 3 CH 2 Cl, CF 3 or Ph, R6 is NH 2 NHA, NA 2 NH(D-H) or NH-C(O)A, R7 is NA(D-H), NHA, NH(D-H) or NA 2 R8 is -NH- (C=NH) -NH 2 -NH- (C=NH) -NHA, -NH- (C=NH) -NA 2 -NA- (C=NH) -NH 2 -NA- (C=NH) -NHA or -NA- (C=NH) -NA 2 R1is -CH(A)-Ph, Arl is phenylene, biphenylene, naphthylene or pyrazol-
4-yl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, OCF 3 Hal, CN, NH 2 NRA, NA 2 NO 2 CF 3 SO 2 NH 2 SO 2 Ph, SO 2 NAH, SO 2 NA 2 Ar, Ar' and Ar 2 are each independently phenyl, biphenyl, stilbyl, pyridyl, pyrimidyl, quinolyl, 1-imidazolyl, pyrazolyl, indanyl, benzo dibenzofuranyl,
9-H-fluorenyl, 9-H-carbazolyl, [11' 1''terphenyl, anthracenyl, naphthalen-1- yl, naphthalen-2-yl or fluoren-9-on-2-yl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, OCF 3 0-Ph, O-Ph-CH 3 CH 2 -Ph, 0-CH 2 -Ph, Hal, CN, NH 2 NHA, NA 2 N0 2 CF 3 SO 2 NH 2 SO 2 Ph, SO 2 NAH, S0 2 NA 2 or R 8 Het. is a saturated, partially or completely unsatura- ted mono-, bi- or tricyclic heterocyclic radical having 5 to 13 ring members, where 1 or 2 N and/or 1 or 2 S or 0 atoms can be present and the heterocyclic radical can be mono- or disubstituted by CN, -Hal, OH, OA, CF 3 A, NO 2 oxo or R 5 where pyrazole is not bonded via N, Het' is an unsaturated mono-, bi- or tricyclic heterocyclic radical having 5 to 13 ring members, where 1 or 2 N and/or 1 or 2 S or 0 atoms can be present and/or can be mono- or disubstituted by Hal, A, OH, OA, oxo or CF 3 or piperidine, morpholine, pyrrolidine or pyrrolidin-2-one, 272 A is unbranched or branched alkyl having 1-8 c atoms, A' is unbranched or branched alkyl having 2-6 C atoms, Alk is unbranched alkyl having 4-8 C atoms, D is cycloalkylene having 4-7 C atoms or cyclo- hexen-l-yl, Hal is F, Cl, Br or I, 1 2 X ,X in each case independently of one another are alkylene having 1 to 12 C atoms, Y is 0, S, NH or NA, i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, k is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, m is 0, 1 or 2, n is 0, 1, 2, 3 or 4, o is 1 2, 3, 4, 5, 6, 7, 8, 9 or t is 0, 1 or 2, :u is 1 or 2, where if R 2 is 4-chiorophenyl, R 1 is not -NH-CH 2 -CH 2 -OH, and their pharmaceutically tolerable salts and solvates wherein R 2is not 2-benzimidazol-2-yl, and N- (4-ethoxyphenyl) -5-nitronaphthalimide is excluded. 25 2. Compounds of the formula I according to Claim 1 6-benzylamino-2- 5-dichiorophenyl) -3a, 9b- dihydro-lH, 3 H-benzoldelisoquinoline-1,3-dione; b) 3-{3-116-(2-guanidinopropylamino) 3-dioxo- 3a, 9b-dihydro-1H, 3H-benzolde] isoquinolin-2-yl] phenyl}-N- 2 -p-tolylethyl)propionamide; c) 3-{3-[6-(2-guanidinomethylcyclohexyl- methyl) amino) 3-dioxo-3a, 9b-dihydro-1H, 3H- benzofde] isoquinolin-2-yllphenyl}- N- (2-p-tolylethyl)propionamide; d) 3-{3-16-(4-Guanidinomethyl-benzylamino)-1,3- dioxo-lH, 3H-boenzo [de] isoquinolin-2-yl] -phenyl N-[2-(4-sulfamoyl-phenyl)-ethyl]-propionamide; N-f2-(4-Chloro-phenyl)-ethyl]-3-{3-[6-(4- guanidinomethyl-benzylamino) 3-dioxo-1H, 3H- 272a benzo [de] isoquinolin-2-yl] -phenyl}- propionamide; a a j\U WO 00/32577 PCT/EP99/08561 273 f) 6- 3 -Amino -propyl amino) 4, phenyl) -benzo [del isoquinoline-1, 3-dione; g) 6- (3-Amino-propylamino) (7-hydroxy- naplithalen-1-yi) -benzo [de] isoquinoline-1, 3- dione; h) 6- (3 -Amino -p ropyl amino) 3-dioxo-1H, 3H- benzo[de] isoquinolin-2-yl] benzonitrile; i) 6- (3-Amino-propylamino) 3-diinethoxy- phenyl) -benzo [del isoquinoline-1, 3-dione; guani dinome thyl-cycohexymethy.-amino) 3- dioxo-1H, 3H-benzo [del isoquinolin-2-yl] -phenyl}- propionamide; k) N- (4-Chloro-phenyl -thyl] -3 (6(4 guanidinomethyl-cyclohexylmethyl aino) 3- dioxo-1H, 3H-benzo (del isoquinolin-2-ylJ -phenyl I prop ionamide; 1) 6- 3 -Amino -propyl amino) (4 -methoxy-biphenyl- 4-yl) -benzo [del isoquinoline-1, 3-dione; mn) 6- (3 -Amino-propyl amino) (4-carbazol-9-yl- phenyl) -benzo [del isoquinoline-l, 3-dione; n) 6- (3 -Amino -propyl amino) (4 -hydroxy-2-methyl- biphenyl-4-yl) -benzo [del isoquinoline-1, 3-dione; o) N- 2 (4'Methoxy-bipheny-4 3dioxo-. 2, 3-dihydro-lH--benzo [del isoquinolin-6-ylamino] methyl)I-benzyl) -guanidine; p) 3- f 3- (2-Guanidino-ethylamino) 3-dioxo- lH, 3H-benzo [del isoquinolin-2-yll -phenyl I (4- phenyl-butyl) -propionamide; guanidino-ethylamino) 3-dioxo-lH, 3H- benzo [del isoquinolin-2-yl] -phenyl) propionamide; guani dino -propyl amino) 3-dioxo-1H,
311- benzo [del isoquinolin-2-yl] -phenyl prop ionamide; WO 00/32577 PCT/EP99/08561 274 s) N-(2-(4-Chloro-phenyl)-ethyl]-3-[3-(6-{3-[(3- guanidino-propyl)-methyl-amino]-propylamino}- 1,3-dioxo-lH,3H-benzo[de]isoquinolin-2-yl]- phenyl)-propionamide; t) N-(2-(3-Chloro-phenyl)-ethyl]-3-{3-[6-(3- guanidino-propylamino)-1,3-dioxo-lH,3H- benzo[de]isoquinolin-2-yl]-phenyl}- propionamide; u) 6-(3-Amino-propylamino)-2-(4'-methoxy-biphenyl- 4-yl)-benzo[de]isoquinoline-l,3-dione; v) N-[3-({2-[4-(3,6-Di-tert-butyl-carbazol-9-yl)- phenyl]-1,3-dioxo-2,3-dihydro-1H- benzo[de]isoquinolin-6-ylamino]-methyl)- benzyl]-guanidine; w) 6-( 3 -Amino-propylamino)-2-(4-carbazol-9-yl- phenyl)-benzo[de]isoquinoline-l,3-dione. and their physiologically acceptable salts or solvates. 3. Process for the preparation of the compounds of the formula I according to Claim 1 and their salts or solvates, characterized in that a) a compound of the formula I is liberated from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent, or b) a compound of the formula II R R 9 in which R 9 is Cl, Br, NO 2 or R 1 where R has the meaning indicated in Claim 1 is reacted with a compound of the formula III H2N--R 2 III in which R 2 has the meaning indicated in Claim 1, and, if necessary, the radical R 9 is converted into a radical R 1 or WO 00/32577 PCT/EP99/08561 275 a radical R and/or R 2 and/or R 9 is converted into another radical R and/or R 2 and/or R 9 by, for example converting an amino group into a guanidino group by reaction with an amidinating agent, reacting an aryl bromide or iodide to give the corresponding coupling products by means of a Suzuki coupling with boronic acids, reducing a nitro group, sulfonyl group or sulfoxyl group, etherifying an OH group or subjecting an OA group to ether cleavage, alkylating a primary or secondary amino group, partially or completely hydrolysing a CN group, cleaving an ester group or esterifying a carboxylic acid radical, or carrying out a nucleophilic or electrophilic substitution, and/or a base or acid of the formula I is converted into one of its salts or solvates. 4. A pharmaceutical composition comprising an effective amount of a compound of formula I of claim 1 or a physiologically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. A pharmaceutical composition of claim 4 which is effective as a glycoprotein IbIX antagonist. 6. A pharmaceutical composition of claim 5, wherein said glycoprotein IbIX antagonist is effective for the control of thrombotic disorders and sequelae deriving therefrom. 7. A compound of formula I of claim 1, or a physiologically acceptable salt or solvate thereof as a medicament. 8. A compound of formula I of claim 1, or a physiologically acceptable salt or solvate thereof as a glycoprotein IbIX antagonist. 9. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts 276 or solvates for the production of a medicament for the control of thrombotic disorders and sequelae deriving therefrom or for use as anti-adhesive substances. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts or solvates in the treatment of illnesses, such as for the prophylaxis and/or therapy of thrombotic disorders, as well as sequelae such as, for example, myocardial infarct, arteriosclerosis, angina pectoris, acute coronary syndromes, peripheral circulatory disorders, stroke, transient ischaemic attacks, reocclusion/restenosis after angioplasty/stent implantations or as anti-adhesive substances for implants, catheters or heart pacemakers. 11. Compounds according to formula I, uses thereof and processes for the preparation of same as hereinbefore described with reference to the examples. DATED THIS 30th day of January, 2003. MERCK PATENT GMBH By Its Patent Attorneys DAVIES COLLISON CAVE e4- *ei e*~ ooo
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6429212B1 (en) * 1996-08-16 2002-08-06 Ishihara Sangyo Kaisha Ltd. Medicinal composition
EP1088821A1 (en) * 1999-09-28 2001-04-04 Applied Research Systems ARS Holding N.V. Pharmaceutically active sulfonamide derivatives
JP4448902B2 (en) * 2001-06-08 2010-04-14 株式会社医薬分子設計研究所 Sulfonamide derivatives
US6693198B2 (en) * 2002-04-22 2004-02-17 Xanthus Life Sciences, Inc. Amonafide salts
US8097725B2 (en) 2004-12-03 2012-01-17 Roche Diagnostics Operations, Inc. Luminescent indicator dye and optical sensor
FR2915685A1 (en) * 2007-05-02 2008-11-07 Thales Sa New fluorescent compounds of solid state in water, with naphthalimide base, useful for allowing the grafting on transducer, which is a biological substance, in biosensor and security or explosive detectors, and as markers
EP2970227B1 (en) 2013-03-15 2018-01-10 Alumend, LLC Compositions and methods of using the compositions for plaque softening
CN107417616A (en) 2013-05-01 2017-12-01 中央研究院 Treat the method and composition of beta Thalassemia and drepanocytosis
CN103450176B (en) * 2013-08-15 2016-07-06 大连理工大学 One class is containing 2-(4-aminophenyl) benzothiazole naphthalimide compound and application thereof
WO2016041511A1 (en) 2014-09-19 2016-03-24 Yen-Ta Lu Benzo-heterocyclic compounds and their applications
CN106905237B (en) * 2017-02-08 2019-05-14 上海师范大学 A kind of pH and weary oxygen double-bang firecracker answer the naphthalimide ratio fluorescent probe and its synthetic method of positioning tumor cell
CN110272388B (en) * 2019-07-08 2022-06-17 桂林医学院 4-dithioformic acid piperazine-3-nitro-1, 8-naphthalimide derivative and synthesis method and application thereof
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017278A1 (en) * 1996-10-21 1998-04-30 Allelix Biopharmaceuticals Inc. Neurotrophin antagonist compositions

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2423546C2 (en) * 1974-05-15 1983-01-27 Hoechst Ag, 6000 Frankfurt Process for the preparation of 4-amino-1,8-naphthalic acid-N-arylimide compounds
ES459497A1 (en) * 1977-06-04 1978-04-16 Made Labor Sa N(Aminoalkyl)-naphthalimides and their derivatives
DE3635711A1 (en) * 1986-10-21 1988-04-28 Knoll Ag 5-NITROBENZO (DE) ISOCHINOLIN-1,3-DIONE, THEIR PRODUCTION AND USE
AU4946697A (en) * 1996-10-28 1998-05-22 Merck Patent Gmbh Dihydrobenzoanthracenone, -pyrimidinone or dihydronaphtoquinolinone

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017278A1 (en) * 1996-10-21 1998-04-30 Allelix Biopharmaceuticals Inc. Neurotrophin antagonist compositions

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