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EP1144381A2 - Substituted benzo[de]isoquinoline-1,3-diones - Google Patents

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

Info

Publication number
EP1144381A2
EP1144381A2 EP99968783A EP99968783A EP1144381A2 EP 1144381 A2 EP1144381 A2 EP 1144381A2 EP 99968783 A EP99968783 A EP 99968783A EP 99968783 A EP99968783 A EP 99968783A EP 1144381 A2 EP1144381 A2 EP 1144381A2
Authority
EP
European Patent Office
Prior art keywords
phenyl
benzo
het
formula
dione
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99968783A
Other languages
German (de)
French (fr)
Inventor
Werner Mederski
Ralf Devant
Gerhard Barnickel
Sabine Bernotat-Danielowski
Guido Melzer
Peter Raddatz
Zhengdong Wu
Daljit Dhanoa
Richard Soll
James Rinker
Todd Graybill
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1144381A2 publication Critical patent/EP1144381A2/en
Withdrawn legal-status Critical Current

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Classifications

    • 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

Definitions

  • the invention relates to substituted benzo [de]- isoquinoline-1, 3-diones of the formula I
  • R is H or N0 2 ,
  • R 1 is -Het, -Het-S0 2 -Ar, -Het-R 5 , -Het- (CH 2 ) n -Ar, Alk, NAAlk, NHA' , NA' 2 ,
  • R" is -Ar, -Ar'-D-H, -Het 1 , -Het ⁇ Ar, -Ar'-Het 1 , -Ar'-(CH 2 ) n -R 3 , -Ar'-Y-(CH 2 ) n -R 3 , -Ar' -Y-C (A) 2 -R 3 , - Het x -R 3 , -Ar'-Het ⁇ R 3 , -Ar' - (CH 2 ) n -R 6 / -Ar' -S0 2 -Het, -Ar'-NH-S0 2 -Het, Ar'-S0 2 -R 7 , -Ar' - (CH 2 ) n - (CO-NH) - (CH 2 )i-R 6 , -Ar'-(CH 2 )n-(CO-NH)-(CH 2 )i-R 11
  • R 3 is C(0)A, CONH 2 , CONHA, CONA 2 , COOH or COOA
  • R 4 is Ph or OH
  • R 5 is CH 3 , CH 2 C1, CF 3 or Ph
  • R 6 is NH 2 , NHA, NA 2 , NH(D-H) or NH-C(0)A
  • R 7 is NA(D-H), NHA, NH(D-H) or NA 2
  • Ar' 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 , NHA, NA 2 , N0 2 , CF 3 , S0 2 NH 2 , S0 2 Ph, S0 2 NAH, S0 2 NA 2 , Ar, Ar 1 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,
  • 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
  • heterocyclic radical can be mono- or disubstituted by CN, Hal, OH, OA, CF 3 , A, N0 2 , oxo or R 5 , where pyrazole is not bonded via N, 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 cyclo- hexen-1-yl, Hal is F, Cl, Br or I, X,
  • X l , X 2 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 10, t is 0, 1 or 2, u is 1 or 2, where if R 2 is 4-chlorophenyl, R 1 is not -NH-CH 2 -CH 2 -OH, and their pharmaceutically tolerable salts and solvates.
  • the invention is based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments. It has been found that the compounds of the formula I and their salts or solvates have very valuable pharmacological properties together with good tolerability. They act especially as GPIblX inhibitors, in particular inhibiting the interaction of this receptor with the ligand von illebrand factor (v F) . 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 GPIblX receptor is able to bind alpha-thrombin (N.J.
  • GPIblX as an adhesion receptor on platelets, which mediates the primary interaction of platelets with an arteriosclerotically modified vascular wall via binding to the vWF expressed there, has been described by many authors (e.g. Z.M. Ruggeri in Thromb. Hemost . 1997, 78, 611-616).
  • GPIIbllla another platelet adhesion receptor, GPIIbllla, following the GPIblX-vWF interaction, leads to platelet aggregation and thus to thro botic vascular occlusion.
  • a GPIblX 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 (e.g. H Yamamoto et al., Thromb. Hemost. 1998, 79, 202-210) .
  • the blocking action of GPIblX inhibitors exerts its maximum effect, as described by J.J. Sixma et al. in Arteriosclerosis, Thrombosis, and Vascular Biology 1996, 16, 64-71.
  • the compounds of the formula I can be characterized as GPIblX inhibitors in whole blood.
  • the inhibition of thrombus formation of the GPIblX inhibitors can be measured by a modified Born 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 IblX antagonists, and are suitable for the prophylaxis and/or therapy of thrombotic disorders and sequelae deriving therefrom.
  • adhesion receptor antagonists in particular as glycoprotein IblX antagonists
  • glycoprotein IblX antagonists 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 GPIblX inhibitors also have an effect in the case of thrombotic disorders in the venous vascular bed.
  • the disorders are acute coronary syndromes, angina pectoris, myocardial infarct, peripheral circulatory disorders, stroke, transient ischaemic attacks, arteriosclerosis, reocclusion/restenosis after angio- plasty/stent implantation.
  • the compounds can 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 GPIIbllla 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
  • R 9 is Cl, Br, N0 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
  • the compounds of the formula I can have a chiral centre and therefore occur in a number of stereoisomeric forms. All these forms (e.g. R and S forms) and their mixtures (e.g. the RS forms) are included in the formula I.
  • the compounds according to the invention also include so-called prodrug derivatives, i.e. compounds of the formula I modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the body to give the active compounds according to the invention. Furthermore, 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 :
  • A is alkyl and has 1 to
  • Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, additionally also pentyl, 1-, 2- or 3-methylbutyl,
  • A' is alkyl and 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 unbranched alkyl having 4 to 8 carbon atoms, preferably n-butyl, n-pentyl, n-hexyl, n-heptyl or n-octyl.
  • Ar is preferentially phenyl, preferably - as indicated - monosubstituted phenyl, specifically preferentially phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-aminophenyl, o-, m- or p- (N,N-dimethylamino) phenyl, o-, m- or p-sulfonamoylphenyl, o-, m- or p-nitrophenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-
  • biphenyl - as indicated - or alternatively mono- substituted biphenyl, specifically preferentially biphenyl-4-yl or biphenyl-3-yl, 2 ' -methylbiphenyl-4-yl, 3 ' -methylbiphenyl-4-yl, 4 ' -methylbiphenyl-4-yl,
  • Ar is preferentially pyridyl-2-, pyridyl-3-, pyridyl-4-yl, pyrazol-3-yl, pyrazol-4-yl or pyrazol-5-yl, pyrimidin-2-, pyrimidin-4-, pyrimidin-5-yl, 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, 1-naphthylene or pyrazol-4-yl, which is unsubstituted or monosubstituted by A, OH, OA, CF 3 , OCF 3 or Hal. Unsubstituted phenylene or 1-naphthylene, 2-methoxyphenylene, 2-methylphenylene, 3-biphenylene, 4-biphenylene or l-methylpyrazol-4-yl is particularly preferred.
  • Ar 1 and Ar 2 are in each case independently of one another Ar having the preferred meanings indicated beforehand. Phenyl is particularly preferred for Ar 1 and Ar 2 independently of one another.
  • Ar' is preferentially unsubstituted or substituted phenylene, D having one of the preferred or particularly preferred meanings mentioned below.
  • Ar' is preferentially unsubstituted or substituted phenylene, Het 1 having one of the preferred or particularly preferred meanings mentioned below.
  • Ar' is preferentially unsubstituted or substituted biphenylene, where R 3 is preferentially an alkyloxycarbonyl group and A has a d above.
  • Ar' is preferentially unsubstituted or substituted phenylene, naphthylene, biphenylene or pyrazol-4-yl, where R 3 is preferentially an a ido group, alkylamido group or dialkylamido group, carboxyl group, alkyloxycarbonyl group or an alkylcarbonyl group and n can be 0, 1, 2, 3 or 4.
  • Ar' - (CH 2 ) n -R 3 is particularly preferred for Ar' - (CH 2 ) n -R 3 .
  • Ar' is preferentially unsubstituted or substituted phenylene, where Y is preferentially S or 0, 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.
  • 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. is particularly preferred for -Ar'-Het 1 -R 3
  • n -R e 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.
  • Ar' is preferentially unsubstituted or substituted naphthylene or phenylene, where Het has one of the meanings preferentially indicated in the following. is particularly preferred for -Ar' -S0 2 -Het .
  • Ar' is preferentially unsubstituted or substituted phenylene, where Het is particularly preferred 5-methoxy-pyrimidin-2-yl .
  • Ar' is preferentially unsubstituted or substituted naphthylene, where R 7 is preferentially an alkylamino group, dialkylamino group, cycloalkylamino group or an alkylcycloalkylamino group.
  • 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. CONH-(CH 2 ) 4 -NH 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.
  • 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.
  • Ar' is preferentially unsubstituted or substituted phenylene, where R 11 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.
  • Ar' is preferentially unsubstituted or substituted phenylene, where R 11 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.
  • 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.
  • 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.
  • 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,
  • Ar' is preferentially unsubstituted or substituted phenylene, where Het 1 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. is particularly preferred for -Ar' - (CH 2 ) n - (CONH) - (CH 2 ) -
  • Ar' is preferentially unsubstituted or substituted phenylene, where Het 1 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.
  • 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.
  • 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, 5, 6, 7, 8, 9, 10, 11 or 12.
  • 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, 5, 6, 7, 8, 9, 10, 11 or 12.
  • 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 cyclohexyl.
  • D is preferentially cyclo- hexen-1-yl.
  • Hal is preferably F, Cl, Br or iodine.
  • Het 1 is preferentially substituted or unsubsti- tuted 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, l,2-dihydropyrazol-3-on-4-yl, 1,2-dihydropyrazol- 3-on-5-yl, benzothiophen-2-yl, benzothiophen-3-yl, 3H- benzotriazol-5-yl, benzothiazol-2-yl, benzofuran-2-yl, benzofuran-3-yl, imidazol-1-yl or benzo [1, 3]dioxol-5-yl or piperidine-1-yl, pyrrolidine-1-yl or pyrrolidine-2-on-l- yl.
  • Het 1 and Ar have one of the preferred meanings indicated above, where Ar is preferably phenyl.
  • 4-phenylthiazol-2-yl, 5-phenyl- [1, 3, 4] -thiadiazol-2-yl or 1, 5-dimethyl-2-phenyl- 1, 2-dihydropyrazol-3-on-4-yl is particularly preferred for Het x -Ar.
  • Het 1 is preferably 2
  • 3-dihydro-lH- is preferably CO (A) .
  • Het 1 -Ar is particularly preferred for Het 1 -Ar.
  • Het is preferably substituted or unsubstituted 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1, 2, 3-triazol-l-, -4- or -5-yl, 1, 2, -triazol-l-, -4- or -5-yl, 1- or 5-tetrazolyl, 1, 2, 3-oxadiazol-4- or -5-yl, 1, 2, 4-oxadiazol-3- or -5-yl, 1, 3, 4-thiadiazol-2- or -5-yl, 1, 2, 4-thiadiazol-3- or -5-yl, 1, 2, 3-thiadiazol
  • heterocyclic radicals can also be partially or completely hydrogenated. Het can thus also be 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5- dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2, 3-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 2, 5-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -3-pyrrolyl, tetrahydro-1-, -2- or 4-imidazolyl, 2, 3-dihydro-l-, -2-, -3-, -4-, -5-,
  • Het and Ar have one of the preferred meanings indicated above, where Het is preferably piperazine-1, 4-diyl.
  • 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.
  • Het 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
  • 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 0, S, NH or NA.
  • 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.
  • Y is preferably O, S, NH or NA, where Ar' has one of the preferred meanings indicated beforehand and R is preferentially an alkylcarbonyl group.
  • Y is preferably 0, S, NH or NA, where Ar has one of the preferred meanings indicated
  • Y is preferentially
  • R 6 is preferably amino or alkylamino and n is 0, 1, 2, 3 or 4 and i is 0, 1, 2, or 12.
  • Y is preferentially 0, S, NH or NA, where D 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,
  • Y is very particularly preferred for -Y- (CH 2 ) n ⁇ D- (CH 2 ) i-R .
  • Y is preferentially
  • 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.
  • 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 .
  • Y is preferentially 0, 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,
  • 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.
  • 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 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • Y is preferentially 0, S, NH or NA, where X, X 1 and X 2 have a preferred meaning indicated beforehand.
  • 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 -0- (CH 2 ) 3 -NH 2 is particularly preferred for -Y- [X-O] t - [X 1 -0] u -X 2 -R 6 .
  • Y is preferentially 0, S, NH or NA, where X and X 1 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 -Y-[X-NH]u-X X -OH.
  • R is preferably H or N0 2 .
  • NHAlk Alk has a preferred meaning indicated beforehand.
  • NH-(n-C 5 Hu) is particularly preferred for NHAlk.
  • NAAlk A and Alk have a preferred meaning indicated beforehand, where N (CH 3 ) - (n-C 4 H 9 ) is particularly preferred for NAAlk.
  • NHA' A' has a preferred meaning indicated before- hand.
  • NH-(n-C 3 H ) is particularly preferred for NHA'.
  • A' in NA' 2 has a preferred meaning indicated beforehand, where N(C 2 H 5 ) 2 is particularly preferred for NA' 2 .
  • Y is preferentially 0, S, NH or NA, where D has a preferred meaning indicated beforehand.
  • -NH-C 6 Hn or -NH-C 5 H 9 is particularly preferred for -Y-D-H.
  • Y is preferentially 0, S, NH or NA, where R 3 is preferably alkyloxycarbonyl and o can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • -NH-(CH 2 ) 2 -COOMe is particularly preferred for -Y- (CH 2 ) 0 -R 3 .
  • Y is preferentially 0, 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. is particularly preferred for -Y- (CH 2 ) n - (CHR 4 ) -R 5
  • Y is preferentially 0, S, NH or NA, where o can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • Y is preferentially 0, S, NH or NA, where A has a preferred meaning indicated beforehand and m can be 0, 1 or 2.
  • Y is preferentially 0, S, NH or NA, where A' has a preferred meaning indicated beforehand and can be 0, 1 or 2.
  • A' has a preferred meaning indicated beforehand and can be 0, 1 or 2.
  • -NH- (CH 2 ) 2 -NH- (C 3 H ) is particularly preferred for -Y- (CH 2 ) ra -NHA' .
  • Y is preferably 0, S, NH or NA, where o is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • Y is preferentially 0, S, NH or NA, where R 6 is preferably amino, alkylamino, dialkylamino or cycloalkylamino and k can be 3, 4, 5, 6, 7, 8, 9,
  • Y is preferentially 0, S, NH or NA
  • Y is preferentially 0, S, NH or NA, where R 6 is preferably amino, alkylamino or dialkylamino and n can
  • R 2 is preferably -Ar, -Ar'-D-H, -Het 1 , -Het ⁇ Ar, -Ar'-Het 1 , -Ar' - (CH 2 ) n -R 3 , -Ar' -Y- (CH 2 ) n -R 3 , -Ar'-Y-C(A) 2 -R 3 , -Het ⁇ R 3 , -Ar' -Het x -R 3 , -Ar' - (CH 2 ) n -R 6 , - Ar'-S0 2 -Het, -Ar' -NH-S0 2 -Het, Ar' -S0 2 -R 7 , -Ar' - (CH 2 ) n - (CONH) - (CH 2 ) i-R 6 , -Ar' -(CH 2 ) n - (CO-NH) -(
  • R 3 is preferably C(0)A, CONH 2 , CONHA, CONA 2 , COOH or COOA, where A has one of the preferred meanings indicated beforehand.
  • R 4 is preferentially phenyl or hydroxyl.
  • R is preferably methyl, chloromethyl, trifluoromethyl or phenyl.
  • R 6 is preferentially NH 2 , NHA, NA 2 , NH(D-H) or NHC(0)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 11 is preferentially -CH(A)-Ph, where A has a preferred meaning indicated beforehand.
  • R 1 is N0 2 and R 2 is Ar;
  • R 2 is Ar and
  • R 1 is -Het, -Het-S0 2 -Ar, -Het-R 5 , N0 2 , NHAlk, NAAlk, NHA', NA' 2 , -Y-D-H, -Y-Ar'-R 3 , -Y- (CH 2 ) 0 -R 3 , -Y- (CH 2 ) n . (CHR 4 ) -R 5 ,
  • R is -Het 1 and r.1 is N0 2 ;
  • R 2 is -Het ⁇ Ar and R 1 is N0 2 ;
  • R 2 is -Ar'-(CH 2 ) n -R 3 and
  • R 1 is -Het, -Het-S0 2 -Ar, -Het-R 5 ,
  • R 2 is -Ar'-Y-(CH 2 ) n -R 3 and
  • R 1 is -Y-(CH 2 ) k -R 6 , -Y-(CH 2 ) n -Ar' -(CH 2 ) i-R 6 or -Y-(CH 2 ) n -Ar;
  • Ig R H
  • R R 22 i iss --AAr'-S0 2 -Het and R 1 is -Y-(CH 2 ) k -R D or -Y- (CH 2 ) n -Ar' - (CH 2 ) i-R°; in Ih R is H, R 2 is -Ar'-S0 2 -R 7 and
  • R 1 is -Y-(CH 2 ) k -R 6 or -Y- (CH 2 ) n -Ar'- (CH 2 ) i-R 6 ;
  • R 2 is -Ar' -(CH 2 ) n - (CONH) -(CH 2 ) i-R 6 and
  • R 1 is -Y-(CH 2 ) k -R 6 or -Y- (CH 2 ) n -Ar' - (CH 2 ) i-R 6 ;
  • R 2 is -Ar' -(CH 2 ) n - (CONH) -(CH 2 ) i-D-H and
  • R 1 is -Y-(CH 2 ) k -R 6 , -Y-(CH 2 ) n -Ar' -(CH 2 ) i-R 6 ,
  • R is H
  • R 2 is -Ar' -(CH 2 ) n - (CONH) -(CH 2 ) i-Ar and
  • R 1 is -Y-(CH 2 ) k -R 6 , -Y-(CH 2 ) n -Ar'-(CH 2 )i-R 6 (
  • R 2 is -Ar' -(CH 2 ) n - (CONH) -(CH 2 ) i-Het 1 and
  • R 1 is -Y-(CH 2 )i-R 8 , -Y-(CH 2 ) n -D-(CH 2 )i-R 8 ,
  • R 2 is -Ar'-(CH 2 ) n -(CH(CN) )-(CH 2 )i-Ar and
  • R 1 is -Y-(CH 2 ) k -R 6 ' -Y-(CH 2 ) n -D-(CH 2 )i-R 6 or -Y-
  • R 2 is -Ar' -(CH 2 ) n - (CO-NH) -(CH 2 ) i-CH (Ar ⁇ -Ar 2 and is -Y-(CH 2 )i-R B -Y-(CH 2 ) n -D-(CH 2 )i-R 8 ,
  • R 2 is -Ar'-Het 1
  • R 1 is -Y-(CH 2 ) k -R 6 , -Y-(CH 2 ) n -Ar' -(CH 2 ) i-R 6 ,
  • R is H, R R 22 iiss --AAr'-Het ⁇ R 3 and R 1 is -Y-(CH 2 ) k -R° or -Y- (CH 2 ) n -D- (CH 2 ) i-R°;
  • R 2 is -Ar'-(CH 2 ) n -R 6 and
  • R 1 is -Y-(CH 2 ) k -R 6 or -Y- (CH 2 ) n -D- (CH 2 ) i ⁇ R €
  • R 2 is -Ar'-Y-C(A) 2 -R 3 and
  • R 1 is -Y-(CH 2 ) k -R 6 ;
  • R 2 is -Ar'-NH-S0 2 -Het
  • R 1 is -Y- (CH 2 ) k -R 6 ;
  • R 1 is -Y-(CH 2 ) k -R 6 ;
  • R 2 is -Ar'-D-H and R 1 is -Y-(CH 2 ) k -R 6 ;
  • R" is -Y-(CH 2 ) n -Ar'-(CH 2 )i-R e
  • R 2 is -Ar'-(CH 2 ) n -CO-Het and R 1 is -Y-(CH 2 ) n -D-(CH 2 )i-R 6 ;
  • R is H
  • R 2 is -Ar' -S- (CH 2 ) n - (CO-NH) - (CH 2 ) i-Ar and
  • R 1 is -Y-(CH 2 ) n -Ar' -(CH 2 ) i-R 6 or
  • R 2 is -Ar' -S- (CH 2 ) n - (CO-NH) - (CH 2 ) i-Het 1 and
  • R 1 is -Y-(CH 2 ) n -Ar' -(CH 2 ) i-R 6 or
  • R 2 is -Ar' -S- (CH 2 ) n - (CO-NH) - (CH 2 )i-DH and R 1 is -Y-(CH 2 ) n -Ar' -(CH 2 ) i-R 6 or
  • R 2 is -Ar'-S- (CH 2 ) n - (CO-NH) -(CH 2 ) i-R 11 and R 1 is -Y-(CH 2 ) n -Ar' -(CH 2 ) i-R 6 or
  • R 2 is -Ar'-S- (CH 2 ) n - (CO-NH) - (CH 2 ) i-CH (Ar 1 ) -Ar 2 and R 1 is -Y-(CH 2 ) n -Ar' -(CH 2 ) i-R 6 or -Y- (CH 2 ) n -Ar'- (CH 2 ) i-R 8 ;
  • R 2 is -Ar, -Ar'-Het 1 , -Ar '- (CH 2 ) n - (CO-NH) -
  • R 1 is -Y-(CH 2 ) k -R 6 , -Y-(CH 2 )i-R 8 ;
  • R 2 is -Ar, -Ar'- (CH 2 ) n - (CO-NH) - (CH 2 ) i-Ar,
  • Preferred compounds of the formula I are in the following: 3- ⁇ 3- [6- (4-Guanidinomethyl-benzylamino) -1, 3-dioxo- 1H, 3H-benzo [de] isoquinolin-2-yl] -phenyl ⁇ -N- [2- (4- sulfamoyl-phenyl) -ethyl] -propionamide;
  • the compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben- eyl, Methoden der organischen Chemie [Methods of Organic Chemistry] , Georg-Thieme-Verlag, Stuttgart) , namely under reaction conditions which are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se, but not mentioned here in greater detail.
  • the starting substances if desired, can also be formed in situ such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
  • the compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis or by hydrogen- olysis.
  • Preferred starting substances for the solvolysis or hydrogenolysis 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' -N- group, in which R' is an amino protective group and/or those which instead of the H atom of a hydroxyl group carry a hydroxyl protective group, e.g. those which correspond to the formula I, but instead of a group - COOH carry a group -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.
  • 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.
  • acyl group is to be interpreted in the widest sense in connection with the present process.
  • 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.
  • 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.
  • alkanoyl such as acetyl, propionyl, butyryl
  • aralkanoyl such as phenylacetyl
  • aroyl such as benzoyl or toluyl
  • Preferred amino protective groups are BOC, furthermore CBZ, Fmoc, benzyl and acetyl.
  • 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.
  • hydroxyl protective groups are, inter alia, benzyl, p-nitrobenzoyl, p-toluolsulfonyl, tert-butyl and acetyl, benzyl and tert-butyl being particularly preferred.
  • the liberation of the compounds of the formula I from their functional derivatives is carried out - depending on the protective group used - for example using strong acids, expediently using TFA or perchloric acid, but also using other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene- or p-toluene- sulfonic acid.
  • strong acids expediently using TFA or perchloric acid
  • other strong inorganic acids such as hydrochloric acid or sulfuric acid
  • strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids
  • benzene- or p-toluene- sulfonic acid such as benzene- or p-toluene- sulfonic 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 approximately 50 °C; the reaction is preferably carried out between 15 and 30 °C (room temperature) .
  • the groups BOC and Obutyl can preferably be removed, for example, using TFA in dichloromethane or using approximately 3 to 5N HCl in dioxane at 15-30°C, the Fmoc group using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°C.
  • Hydrogenolytically removable protective groups can be removed, for example, by treating with hydrogen in the presence of a catalyst (e.g. of a noble metal catalyst such as palladium, expediently on a support such as carbon) .
  • a catalyst e.g. of a noble metal catalyst such as palladium, expediently on a support such as carbon
  • Suitable solvents in this case are those indicated above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF.
  • the hydrogenolysis is carried out at temperatures between approximately 0 and 100 °C and pressures between approximately 1 and 200 bar, preferentially at 20-30 °C and 1-10 bar.
  • Hydrogenolysis of the CBZ group takes place readily, for example, on 5 to 10% Pd/C in methanol or ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°C.
  • Compounds of the formula I can also preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
  • the starting compounds of the formulae II and III are known or commercially available.
  • the unknown compounds can be prepared by methods known per se.
  • the compounds of the formula II are naphthalene- 1, 8-dicarboxylic anhydride derivatives. They can be prepared in a conventional manner from appropriately substituted 1, 8-naphthalenedicarboxylic acids or corresponding derivatives. It is furthermore possible to introduce appropriate substituents into the aromatic by conventional electrophilic or alternatively nucleophilic substitutions.
  • the compounds of the formula III are primary amines, which, as a rule, are also commercially available. Furthermore, syntheses for the preparation of primary amines, such as, for example, the Gabriel synthesis, can be used.
  • the reaction is carried out in an inert solvent.
  • the reaction time is between a few minutes and a number of days, the reaction temperature between approximately 0° and 150°C, normally between 20° and 130°C.
  • the reactions can be carried out in analogy to the methods indicated in Eur. J. Chem. Chim. Ther. 1981, 16, 207- 212 and in J. Med. Chem. 1982, 25, 714-719.
  • Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol) , ethylene glycol dimethyl ether (diglyme) ; ketones such as acetone or butanone; amides such as acetamide, N-methylpyrrolidone (NMP
  • Derivatives having a free primary or an additional secondary amino group are expediently employed in protected form. Possible protective groups are those mentioned beforehand.
  • an appropriate amino-substituted compound can be treated with an amidinating agent.
  • the preferred amidinating agent is l-amidino-3, 5-dimethylpyrazole (DPFN) , which is employed, in particular, in the form of its nitrate, or pyrazole-1-carboxamidine.
  • reaction is expediently carried out with addition of a base such as triethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, e.g. DMF at temperatures between 0° and 150°C, preferably between 60° and 120°C.
  • a base such as triethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, e.g. DMF at temperatures between 0° and 150°C, preferably between 60° and 120°C.
  • the Suzuki reaction is expediently carried out in palladium-mediated form, preferably by addition of Pd(PPh 3 ) , in the presence of a base such as potassium carbonate in an inert solvent or solvent mixture, e.g. DMF at temperatures between 0° and 150°, preferably between 60° and 120°. Depending on the conditions used, the reaction time is between a few minutes and a number of days.
  • a base such as potassium carbonate
  • an inert solvent or solvent mixture e.g. DMF
  • 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.
  • a strong acid such as hydrochloric acid or sulfuric acid at temperatures between 0° and 100°C, preferably between 20° and 50°C.
  • free amino groups can be acylated in a customary manner using an acid chloride or anhydride, expediently in an inert solvent such as dichloromethane or THF and/or in the presence of a base such as triethylamine or pyridine at temperatures between -60°C and +30°C.
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation.
  • Acids which give physiologically acceptable salts are particularly suitable for this reaction.
  • 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.
  • compounds of the formula I with bases can be converted into the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, or into the corresponding ammonium salts.
  • 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.
  • 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.
  • preparations can be used as medicaments in human or veterinary medicine.
  • Possible excipients are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceryl triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly.
  • Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used, in particular, for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, are used for parenteral administration, and ointments, creams or powders are used for topical application.
  • the novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations.
  • the preparations indicated can be sterilized and/or can contain auxiliaries such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colourants, flavourings and/or one or more other active compounds, e.g. one or more vitamins.
  • auxiliaries such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colourants, flavourings and/or one or more other active compounds, e.g. one or more vitamins.
  • the compounds of the formula I and their physiologically acceptable salts act as adhesion receptor antagonists, in particular glycoprotein IblX 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.
  • the substances according to the invention are as a rule administered in the dose of the glycoprotein Ilbllla 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.
  • customary working- up means: if necessary, water is added, if necessary, depending on the constitution of the final product, the mixture is adjusted to pHs between 2 and 10 and extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallization. Mass spectrometry (MS) apparatuses Kratos Maldi III and Finnigan LCQ. (M+H) + values are determined.
  • MS Mass spectrometry
  • 6-nitro-2-biphenyl- 4-ylbenzo [de] isoquinoline-1, 3-dione is heated with 1, 3-diaminopropane until conversion is complete. After cooli the reaction mixture, it is worked up as is customary and 6- (3-aminopropylamino) -2-biphenyl- 4-ylbenzo [de] isoquinoline-1, 3-dione is obtained.
  • 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 dichloromethane [obtainable by reaction of 6-nitrobenzo [de] isochromene-1, 3-dione with 2- (4-aminophenyl) -3- (4-dimethylaminophenyl)propio- nitrile and H 2 N- (CH 2 ) 3 -NHBOC] and the reaction mixture is stirred until removal is complete.
  • Example 67 Analogously to Example 2, 6-chlorobenzo-
  • Example 68 Analogously to Example 2, 6-chlorobenzo-
  • 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with 3- (3-aminophenyl) -1- (3, 4-dihydro-2H-quinolin-l-yl) -propan-1-one and 3-aminomethyl-cyclohexylamine.
  • Example 70 Analogously to Example 2, 6-chlorobenzo-
  • Example 76 Analogously to Example 2, 6-chlorobenzo-
  • N- (3, 3-Dimethyl-butyl) -3- ⁇ 4- [6- (3- guanidinomethyl-benzylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] -phenyl ⁇ -propionamide is obtained.
  • 6- chlorobenzo [de] isochromene-1, 3-dione is reacted with 4- (pyrrolidine-1-sulfonyl) -phenylamine and 3-aminomethyl- benzylamine.
  • 6- (3-Aminomethyl-benzylamino) -2- [4- (pyrrolidine-1-sulfonyl) -phenyl] -benzo [de] isoquinoline- 1, 3-dione is obtained.
  • 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.
  • a mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and
  • Each suppository contains 20 mg of active compound.
  • a solution is prepared from 1 g of an active compound of the formula I, 9.38 g of NaH 2 P0 4 .2H 2 0, 28.48 g of Na 2 HP0 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.
  • Example F Coated tablets
  • Example E 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.
  • 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.

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Abstract

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

Description

Substituted benzo [de] isoquinoline-1 , 3-diones
This application is a continuation-in-part of Serial No. 09/199,413, the entirety of which is incorporated by reference herein.
The invention relates to substituted benzo [de]- isoquinoline-1, 3-diones of the formula I
R< in which
R is H or N02,
R1 is -Het, -Het-S02-Ar, -Het-R5, -Het- (CH2) n-Ar, Alk, NAAlk, NHA' , NA'2,
-Y-D-H, -Y-Ar'-R3, -Y-(CH2)o-R ,
-Y-(CH2)n-(CHR4)-R5 / -Y-C[(CH2)o-0H]3, -Y-(CH2)m-NA2,
-Y-(CH2)m-NHA', -Y-(CH2)o-0H, -Y-(CH2)k-Rb, -Y-(CH2)i-R8,
-Y-(CH2)n-Het, -Y-(CH2)n-Ar,
-Y- (CH2) n-Ar' - (CH2) i-R6, -Y- (CH2) n-D- (CH2) i-R6, -Y- (CH2) n-Het- (CH2) i-R6, -Y- (CH2) n-NA- (CH2) i-R6, -Y- (CH2) n-NH- (CH2) i-R6, -Y- (CH2) n-D- (CH2) i-R8, -Y- (CH2) n-Ar' - (CH2) i-R8, -Y- (CH2) n-NH- (CH2) i-R8,
-Y-(CH2)n-NA-(CH2)i-RB
-Y-fX-O t-C ^Olu-X^R6 or -Y-[X-NH]u-X1-OH,
R" is -Ar, -Ar'-D-H, -Het1, -Het^Ar, -Ar'-Het1, -Ar'-(CH2)n-R3, -Ar'-Y-(CH2)n-R3, -Ar' -Y-C (A) 2-R3, - Hetx-R3, -Ar'-Het^R3, -Ar' - (CH2)n-R6/ -Ar' -S02-Het, -Ar'-NH-S02-Het, Ar'-S02-R7, -Ar' - (CH2) n- (CO-NH) - (CH2)i-R6, -Ar'-(CH2)n-(CO-NH)-(CH2)i-R11, -Ar' - (CH2)n-CO-Het, -Ar'-(CH2)n-(CO-NH)-(CH2)i-D-H, -Ar'- (CH2) n- (CO-NH) - (CH2) i-Ar, -Ar' - (CH2) n- (CO-NH) - (CH2) i-Het1, -Ar' - (CH2) n- (CH (CN) ) - (CH2) i-Ar, -Ar'-(CH2)n- (CO-NH) -(CH2)i-CH(Ar1)-Ar2, -Ar'-S- (CH2) n- (CO-NH) - (CH2) i-Ar, -Ar' -S- (CH2) n- (CO-NH) - (CH2) i-R11, -Ar' -S- (CH2) n- (CO-NH) - (CH2) i-Het1,
-Ar'-S-(CH2)n- (CO-NH) - (CH2) i-CH (Ar1) -Ar2 or -Ar'-S- (CH2) n- (CO-NH) - (CH2) i-D-H, R3 is C(0)A, CONH2, CONHA, CONA2, COOH or COOA, R4 is Ph or OH, R5 is CH3, CH2C1, CF3 or Ph, R6 is NH2, NHA, NA2, NH(D-H) or NH-C(0)A, R7 is NA(D-H), NHA, NH(D-H) or NA2, R8 is -NH-(C=NH)-NH2, -NH- (C=NH) -NHA, -NH- (C=NH) -NA2, -NA-(C=NH)-NH2, -NA-(C=NH)-NHA or -NA- (C=NH) -NA2, R11 is -CH(A)-Ph,
Ar' is phenylene, biphenylene, naphthylene or pyrazol- 4-yl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, OCF3, Hal, CN, NH2, NHA, NA2, N02, CF3, S02NH2, S02Ph, S02NAH, S02NA2, Ar, Ar1 and Ar2 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, 1 ' , ' , 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, OCF3, O-Ph, 0-Ph-CH3, CH2-Ph, 0-CH2-Ph,
Hal, CN, NH2, NHA, NA2, N02, CF3, S02NH2, S02Ph,
S02NAH, S02NA2 or R8,
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 O atoms can be present and the heterocyclic radical can be mono- or disubstituted by CN, Hal, OH, OA, CF3, A, N02, oxo or R5, where pyrazole is not bonded via N, Het1 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 CF3 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 cyclo- hexen-1-yl, Hal is F, Cl, Br or I, X,
Xl, X2 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 10, t is 0, 1 or 2, u is 1 or 2, where if R2 is 4-chlorophenyl, R1 is not -NH-CH2-CH2-OH, and their pharmaceutically tolerable salts and solvates.
Similar compounds having a benzo [de] iso- quinoline-1, 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. Ill, No. 20, 13 November 1989.
The invention is based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments. It has been found that the compounds of the formula I and their salts or solvates have very valuable pharmacological properties together with good tolerability. They act especially as GPIblX inhibitors, in particular inhibiting the interaction of this receptor with the ligand von illebrand factor (v F) . 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 GPIblX 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 GPIblX as an adhesion receptor on platelets, which mediates the primary interaction of platelets with an arteriosclerotically modified vascular wall via binding to the vWF expressed there, has been described by many authors (e.g. Z.M. Ruggeri in Thromb. Hemost . 1997, 78, 611-616). The activation of another platelet adhesion receptor, GPIIbllla, following the GPIblX-vWF interaction, leads to platelet aggregation and thus to thro botic vascular occlusion.
A GPIblX 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 (e.g. H Yamamoto et al., Thromb. Hemost. 1998, 79, 202-210) .
In the case of higher shear forces, the blocking action of GPIblX 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 GPIblX inhibitors in whole blood.
The inhibition of thrombus formation of the GPIblX inhibitors can be measured by a modified Born 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 IblX 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 GPIblX inhibitors also have an effect in the case of thrombotic disorders in the venous vascular bed. The disorders are acute coronary syndromes, angina pectoris, myocardial infarct, peripheral circulatory disorders, stroke, transient ischaemic attacks, arteriosclerosis, reocclusion/restenosis after angio- plasty/stent implantation. The compounds can 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 GPIIbllla 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 which R9 is Cl, Br, N02 or R1, and R has the meaning indicated in Claim 1 is reacted with a compound of the formula III H2N—R2 III in which R2 has the meaning indicated in Claim 1, and, if necessary, the radical R9 is converted into a radical R1, or
(c) a radical R and/or R2 and/or R9 is converted into another radical R and/or R2 and/or R9 by, for example
- converting an amino group into a guanidino group by reaction with an amidinating agent,
- reacting an aryl bromide or iodide to give the corresponding coupling products by means of a Suzuki coupling with boronic acids,
- reducing a nitro group, sulfonyl group or sulfoxyl group,
- etherifying an OH group or subjecting an OA group to ether cleavage, - alkylating a primary or secondary amino group,
- partially or completely hydrolysing a CN group,
- cleaving an ester group or esterifying a carboxylic acid radical,
- or carrying out a nucleophilic or electrophilic substitution, and/or
(d) 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 (e.g. R and S forms) and their mixtures (e.g. the RS forms) are included in the formula I.
The compounds according to the invention also include so-called prodrug derivatives, i.e. compounds of the formula I modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the body to give the active compounds according to the invention. Furthermore, 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, 1-, 2- or 3-methylbutyl,
1,1-, 1,2- or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl,
1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-,
2,3- or 3, 3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl- 1-methylpropyl, l-ethyl-2-methylpropyl, 1,1,2- or
1, 2,2-trimethylpropyl, heptyl, 1-, 2-, 3-, 4-,
5-methylhexyl, 1,1-, 1,2-, 1,3-, 1,4-, 2,2-, 2,3-, 2,4- or 3, 3-dimethylpentyl, 1-, 2-, 3-, 4-ethylpentyl, 1,1,2-, 1,1,3-, 1,1,4-, 1,2,2-, 1,2,3-, 1,2,4-, 1,3,3-, 1,3,4-, 1,4,4- or 2, 2, 3-trimethylbutyl or octyl.
A' is alkyl and 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 unbranched alkyl having 4 to 8 carbon atoms, preferably n-butyl, n-pentyl, n-hexyl, n-heptyl or n-octyl.
Ar is preferentially phenyl, preferably - as indicated - monosubstituted phenyl, specifically preferentially phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-aminophenyl, o-, m- or p- (N,N-dimethylamino) phenyl, o-, m- or p-sulfonamoylphenyl, o-, m- or p-nitrophenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-phenoxyphenyl, o-, m- or p- (phenylmethox) yphenyl, o-, m- or p- (trifluoromethyl) phenyl, o-, m- or p- (trifluoromethoxy) phenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-iodophenyl, 4-benzenesulfonyl-phenyl, 4- (4- chloro-phenoxy) -phenyl, furthermore preferentially 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3, 5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3, 5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3, 5-dihydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3, 5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3, 5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3, 5-dibromophenyl, 2-chloro-3-methyl-, 2-chloro-4-methyl-, 2-chloro-5- methyl-, 2-chloro-6-methyl-, 3-chloro-2-methyl-, 4- chloro-2-methyl-, 5-chloro-2-methyl-, 3-chloro-4- methyl-, 3-chloro-5-methyl-, 4-chloro-3-methylphenyl, 2-bromo-3-methyl-, 2-bromo-4-methyl-, 2-bromo-5- methyl-, 2-bromo-6-methyl-, 3-bromo-2-methyl-, 4-bromo- 2-methyl-, 5-bromo-2-methyl-, 3-bromo-4-methyl-, 3-bromo-5-methyl-, 4-bromo-3-methylphenyl, 2-iodo-3- methyl-, 2-iodo-4-methyl-, 2-iodo-5-methyl-, 2-iodo-6- methyl-, 3-iodo-2-methyl-, 4-iodo-2-methyl-, 5-iodo- 2-methyl-, 3-iodo-4-methyl-, 3-iodo-5-methyl-, 4-iodo- 3-methylphenyl, 2-chloro-3-methoxy-, 2-chloro-4- methoxy-, 2-chloro-5-methoxy-, 2-chloro-6-methoxy-, 3- chloro-2-methoxy-, 4-chloro-2-methoxy-, 5- chloro-2-methoxy-, 3-chloro-4-methoxy-, 3-chloro-5- methoxy-, 4-chloro-3-methoxyphenyl, 2-chloro-3- hydroxy-, 2-chloro-4-hydroxy-, 2-chloro-5-hydroxy-, 2-chloro-6-hydroxy-, 3-chloro-2-hydroxy-, 4- chloro-2-hydroxy-, 5-chloro-2-hydroxy-, 3-chloro-4- hydroxy-, 3-chloro-5-hydroxy-, 4-chloro-3-hydroxy- phenyl, 3-fluoro-4-methoxy, 4-fluoro-3-methoxyphenyl, 2-chloro-3-fluoro-, 2-chloro-4-fluoro-, 2-chloro-5- fluoro-, 2-chloro-6-fluoro-, 3-chloro-2-fluoro-, 4- chloro-2-fluoro-, 5-chloro-2-fluoro-, 3-chloro-4- fluoro-, 3-chloro-5-fluoro-, 4-chloro-3-fluorophenyl, 2-fluoro-3-methyl-, 2-fluoro-4-methyl-, 2-fluoro-5- methyl-, 2-fluoro-6-methyl-, 3-fluoro-2-methyl-, 4- fluoro-2-methyl-, 5-fluoro-2-methyl-, 3-fluoro-4- methyl-, 3-fluoro-5-methyl-, 4-fluoro-3-methylphenyl, 2,5- or 3, 4-dimethoxyphenyl, 2-cyano-4,5- dimethoxyphenyl, 5-chloro-2, -dimethoxy-phenyl, 2- cyano-3, 4-dimethoxyphenyl or 3, 4, 5-trimethoxy-phenyl. Furthermore, however, also preferentially unsubstituted biphenyl - as indicated - or alternatively mono- substituted 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-methylbiρhenyl-3-yl,
4-methylbiphenyl-3-yl, 2 ' -tert-butylbiphenyl-4-yl, 3 ' -tert-butylbiphenyl-4-yl, 4 ' -tert-butylbiphenyl-4-yl, 2 ' -tert-butylbiphenyl-3-yl, 3 ' -tert-butylbiphenyl-3-yl, 4 ' -tert-butylbiphenyl-3-yl, 2-tert-butylbiphenyl-4-yl, 3-tert-butylbiphenyl-4-yl, 2-tertbutylbiphenyl-3-yl, 4-tert-butylbiphenyl-3-yl, 2 ' -isopropylbiρhenyl-4-yl, 3 ' -isopropylbiphenyl-4-yl, 4 ' -isopropylbiphenyl-4-yl, 2 ' -isopropylbiphenyl-3-yl, 3 ' -isopropylbiphenyl-3-yl, 4 ' -isopropylbiphenyl-3-yl, 2-isopropylbiphenyl-4-yl,
3-isopropylbiphenyl-4-yl, 2-isopropylbiphenyl-3-yl,
4-isopropylbiphenyl-3-yl, 2 ' -fluorobiphenyl-4-yl,
3 ' -fluorobiphenyl-4-yl, 4 ' -flυorobiphenyl-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-fluoro- biphenyl-3-yl, 2 ' -methoxybiphenyl-4-yl, 3'-methoxy- biphenyl-4-yl, 4 '-methoxybiphenyl-4-yl, 2 ' -methoxybiphenyl-3-yl, 3 ' -methoxybiphenyl-3-yl,
4 ' -methoxybiphenyl-3-yl, 2-methoxybiphenyl-4-yl, 3-methoxybiphenyl-4-yl, 2-methoxybiphenyl-3-yl, 4-methoxybiphenyl-3-yl, 2 ' -nitrobiphenyl-4-yl, 3 ' -nitrobiphenyl-4-yl, 4 ' -nitrobiphenyl-4-yl, 2'-nitro- biphenyl-3-yl, 3 ' -nitrobiphenyl-3-yl, ' -nitrobiphenyl- 3-yl, 2-nitrobiphenyl-4-yl, 3-nitrobiphenyl-4-yl, 2-nitrobiphenyl-3-yl, 4-nitrobiphenyl-3-yl,
2 ' -trifluoromethylbiphenyl-4-yl, 3 ' -trifluoromethylbiphenyl-4-yl, 4 ' -trifluoromethyl- biphenyl-4-yl, 2 ' -trifluoromethylbiphenyl-3-yl,
3 ' -trifluoromethylbiphenyl-3-yl, ' -trifluoromethyl- biphenyl-3-yl, 2-trifluoromethylbiphenyl-4-yl, 3-tri- fluoromethylbiphenyl-4-yl, 2-trifluoromethylbiphenyl-3- yl, 4-trifluoromethylbiphenyl-3-yl, 2 ' -trifluoromethoxybiphenyl-4-yl, 3 ' -trifluoromethoxy- biphenyl-4-yl, 4 ' -trifluoromethoxybiphenyl-4-yl, 2 ' -trifluoromethoxybiphenyl-3-yl,
3 ' -trifluoromethoxybiphenyl-3-yl, ' -tri- fluoromethoxybiphenyl-3-yl, 2-trifluoromethoxybiphenyl- 4-yl, 3-trifluoromethoxybiphenyl-4-yl,
2-trifluoromethoxybiphenyl-3-yl,
4-trifluoromethoxybiphenyl-3-yl, furthermore preferentially disubstituted biphenyls, such as 2 ' -methyl-3 ' -nitrobiphenyl-4-yl, 2 ' -methyl-4 ' -nitro- biphenyl-4-yl, 2 ' -methyl-5 ' -nitrobiphenyl-4-yl, 2'- methyl-6 ' -nitrobiphenyl-4-yl, 3 ' -methyl-2 ' - nitrobiphenyl-4-yl, 3 ' -methyl-4 ' -nitrobiphenyl-4-yl, 3 ' -methyl-5 ' -nitrobiphenyl-4-yl, 3 ' -methyl-6 ' - nitrobiphenyl-4-yl, 4 ' -methyl-2 ' -nitrobiphenyl-4-yl, 4 ' -methyl-3 ' -nitrobiphenyl-4-yl, 2 * -methyl-3 ' - nitrobiphenyl-3-yl, 2 ' -methyl-4 ' -nitrobiphenyl-3-yl, 2 ' -methyl-5 ' -nitrobiphenyl-3-yl, 2 ' -methyl-6 ' -nitro- biphenyl-3-yl, 3 ' -methyl-2 ' -nitrobiphenyl-3-yl, 3 ' -methyl-4 ' -nitrobiphenyl-3-yl, 3 ' -methyl-5 ' - nitrobiphenyl-3-yl, 3 ' -methyl-6 ' -nitrobiphenyl-3-yl, 4 ' -methyl-2 ' -nitrobiphenyl-3-yl, ' -methyl-3 ' - nitrobiphenyl-3-yl, 2 ' -methoxy-2-methylbiphenyl-4-yl, 3 ' -methoxy-2-methylbiphenyl-4-yl, 4 ' -methoxy-2- methylbiphenyl-4-yl, 4 ' -methoxy-3-nitrobiphenyl-4-yl, 2 ' -chloro-3 ' -fluorobiphenyl-4-yl, 2 ' -chloro-4 ' - fluorobiphenyl-4-yl, 2 ' -chloro-5 ' -fluorobiphenyl-4-yl, 2 ' -chloro-6 ' -fluorobiphenyl-4-yl, 3 ' -chloro-2 ' - fluorobiphenyl-4-yl, 3 ' -chloro-4 ' -fluorobiphenyl-4-yl, 3 ' -chloro-5 ' -fluorobiphenyl-4-yl, 3 ' -chloro-6 ' - fluorobiphenyl-4-yl, 4 ' -chloro-2 ' -fluorobiphenyl-4-yl, ' -chloro-3 ' -fluorobiphenyl-4-yl, 2 ' -chloro-3 ' - fluorobiphenyl-3-yl, 2 ' -chloro-4 ' -fluorobiphenyl-3-yl, 2 ' -chloro-5 ' -fluorobiphenyl-3-yl, 2 ' -chloro-6 ' - fluorobiphenyl-3-yl, 3 ' -chloro-2 ' -fluorobiphenyl-3-yl, 3 ' -chloro-4 ' -fluorobiphenyl-3-yl, 3 ' -chloro-5 ' - fluorobiphenyl-3-yl, 3 ' -chloro-6 ' -fluorobiphenyl-3-yl, 4 ' -chloro-2 ' -fluorobiphenyl-3-yl, 4 ' -chloro-3 ' - fluorobiphenyl-3-yl, (2 ' , 3 ' -dimethoxy) biphenyl-4-yl, 2 ' , 4 ' -dimethoxy) biphenyl-4-yl,
(2 ' , 5 ' -dimethoxy) iphenyl-4-yl, (2 ' , 6 ' -dimethoxy) - biphenyl-4-yl, (3 ' , 4 ' -dimethoxy) biphenyl-4-yl,
(3 ' , 5 ' -dimethoxy) biphenyl-4-yl, (2 ' , 3 '-dimethoxy) - biphenyl-3-yl, (2 ' , 4 ' -dimethoxy) biphenyl-3-yl, (2' ,5'-dimethoxy)biphenyl-3-yl, (2 ', 6' -dimethoxy) - biphenyl-3-yl, (3 ' , 4 ' -dimethoxy) biphenyl) -3-yl,
(3 ' , 5 ' -dimethoxy) biphenyl-3-yl, (2 ' , 3 ' -di (trifluoromethyl) ) biphenyl-4-yl, (2 ' , 4 ' -di (trifluoromethyl) ) biphenyl-4-yl, (2 ' , 5 ' -di (trifluoromethyl) ) biphenyl-4-yl, (2 ' , 6'-di (trifluoromethyl) ) biphenyl-4-yl, (3 ' , 4 ' -di (trifluoromethyl) ) biphenyl-4-yl, (3 ' , 5 » - di (trifluoromethyl) ) biphenyl-4-yl, (2 * , 3 ' -di (trifluoromethyl) ) biphenyl-3-yl, (2' , 4' -di (trifluoromethyl) ) biphenyl-3-yl, (2',5'- di (trifluoromethyl) ) biphenyl-3-yl, (2 ' , 6 ' -di (trifluoromethyl) ) biphenyl-3-yl, (3' , 4 '-di (trifluoromethyl) ) biphenyl-3-yl, (3' ,5'- di (trifluoromethyl) biphenyl-3-yl,
(2,2 '-dimethyl) biphenyl-4-yl, (2, ' 3-dimethyl)biphenyl- 4-yl, (2, 4 ' -dimethyl) biphenyl-4-yl,
(2,2' -dimethyl) biphenyl-3-yl, (2,3' -dimethyl) biphenyl- 3-yl or (2, ' -dimethyl) biphenyl-3-yl. Furthermore, however, also preferentially benzo [1,3]- dioxol-5-yl, 9-H-carbazolyl, quinolyl, dibenzofuranyl, 9-H-fluorenyl, 7-bromo-9H-fluoren-2-yl, 9H-fluoren-9- ol-l-yl, fluoren-9-on-2-yl, imidazolyl, indanyl, 1-imidazolyl, pyrazolyl, 9-H-carbazolyl, [1, 1 ' , 4 ' , 1 ' ' ] terphenyl, anthracenyl, naphthalen-1-yl, naphthalen-2-yl, 4-bromo-naphthalen-l-yl, 4-cyano- naphthalen-1-yl, 4-chloro-naphthalen-l-yl, 4-nitro- naphthalen-1-yl, 4-methoxy-naphthalen-2-yl, 6-hydroxy- naphthalen-1-yl, 7-hydroxy-naphthalen-l-yl, 8-hydroxy- napththalen-1-yl or stilbyl.
Furthermore, Ar is preferentially pyridyl-2-, pyridyl-3-, pyridyl-4-yl, pyrazol-3-yl, pyrazol-4-yl or pyrazol-5-yl, pyrimidin-2-, pyrimidin-4-, pyrimidin-5-yl, 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, 1-naphthylene or pyrazol-4-yl, which is unsubstituted or monosubstituted by A, OH, OA, CF3, OCF3 or Hal. Unsubstituted phenylene or 1-naphthylene, 2-methoxyphenylene, 2-methylphenylene, 3-biphenylene, 4-biphenylene or l-methylpyrazol-4-yl is particularly preferred. Ar1 and Ar2 are in each case independently of one another Ar having the preferred meanings indicated beforehand. Phenyl is particularly preferred for Ar1 and Ar2 independently of one another. In -Ar'-D-H, 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'-Het1, Ar' is preferentially unsubstituted or substituted phenylene, Het1 having one of the preferred or particularly preferred meanings mentioned below.
is particularly preferred for -Ar'-Het1.
In -Ar'-Y-C(A)2-R3, Ar' is preferentially unsubstituted or substituted biphenylene, where R3 is preferentially an alkyloxycarbonyl group and A has a d above.
is particularly preferred for -Ar ' -Y-C (A) 2-R3.
In -Ar'-(CH2)n-R3, Ar' is preferentially unsubstituted or substituted phenylene, naphthylene, biphenylene or pyrazol-4-yl, where R3 is preferentially an a ido group, alkylamido group or dialkylamido group, carboxyl group, alkyloxycarbonyl group or an alkylcarbonyl group and n can be 0, 1, 2, 3 or 4.
is particularly preferred for Ar' - (CH2)n-R3.
In Ar'-Y-(CH2)n-R3, Ar' is preferentially unsubstituted or substituted phenylene, where Y is preferentially S or 0, R3 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.
is particularly preferred for -Ar' -Y- (CH2)n-R3.
In -Ar' -Het1-R3, Ar' is preferentially unsubstituted or substituted phenylene, where Het1 has one of the meanings preferentially indicated in the following and R3 is preferentially alkylcarbonyl. is particularly preferred for -Ar'-Het1-R3
In -Ar'-(CH2)n-Re Ar' is preferentially unsubstituted or substituted phenylene or biphenylene, where R6 is preferentially an amino group, alkylamino group, dialkylamino group or alkyloxycarbonylamino group and n can be 0, 1, 2, 3 or 4.
is particularly preferred for -Ar' - (CH2) n-R6.
In -Ar' -S02-Het, Ar' is preferentially unsubstituted or substituted naphthylene or phenylene, where Het has one of the meanings preferentially indicated in the following. is particularly preferred for -Ar' -S02-Het .
In -Ar'-NH-S02-Het, Ar' is preferentially unsubstituted or substituted phenylene, where Het is particularly preferred 5-methoxy-pyrimidin-2-yl .
is particularly preferred for -Ar' -NH-S02-Het .
In -Ar'-S02-R7, Ar' is preferentially unsubstituted or substituted naphthylene, where R7 is preferentially an alkylamino group, dialkylamino group, cycloalkylamino group or an alkylcycloalkylamino group.
is particularly preferred for -Ar'-S02-R7.
In -Ar' -(CH2)n- (CONH) -(CH2) i-R6, Ar' is preferentially unsubstituted or substituted phenylene, where R6 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. CONH-(CH2)4-NH2
CONH-(CH2)2-NH2
is particularly preferred for -Ar' - (CH2) n- (CONH) - (CH2)i-R6.
In -Ar' -(CH2)n- (CONH) -(CH2) i-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.
is particularly preferred for -Ar' - (CH2)n- (CONH) - (CH2) i-D-H.
In -Ar'-S-(CH2)n- (CONH) -(CH2) i-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.
or
is particularly preferred for -Ar' -S- (CH2) n- (CONH) - (CH2) i-D-H.
In -Ar' -(CH2)n- (CONH) -(CH2) i-R11, Ar' is preferentially unsubstituted or substituted phenylene, where R11 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.
is particularly preferred for -Ar' - (CH2)n- (CONH) - (CH2) ±-
R11.
In -Ar' -S-(CH2)n- (CONH) -(CH2) i-R11, Ar' is preferentially unsubstituted or substituted phenylene, where R11 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.
is particularly preferred for -Ar' -S- (CH2) n- (CONH) - (CH2)i-Rn.
In -Ar'- (CH2)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.
is particularly preferred for -Ar' - (CH2)n- (CO) -Het .
In -Ar' -(CH2)n- (CONH) -(CH2) 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.
εON— V-?(zHθ)-HNOQ-z(zHθ)'
- zz - l9S80/66d3/-L3-I LLSZϋOO OΛV
CONH-(CH-)- ( CH,
s particularly preferred for -Ar' - (CH2) n- (CONH) (CH2)i-Ar. In -Ar' -S-(CH2)n- (CONH) -(CH2) 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-(CH2)2 — y — S02-NH2
C v-.OjiNπH--vC--.πH2,
fc >— S— CH2 CONH-(CH2)2 (
CH2 CONH-(CH2)2 ft — OCH3
ft _s— CH, CONH-CH, ft y — OCF,
In -Ar' -(CH2)n- (CONH) -(CH2) i-Het1, Ar' is preferentially unsubstituted or substituted phenylene, where Het1 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. is particularly preferred for -Ar' - (CH2) n- (CONH) - (CH2) -
HetJ
In -Ar' -S-(CH2)n- (CONH) - (CH2) i-Het1, Ar' is preferentially unsubstituted or substituted phenylene, where Het1 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.
or is particularly preferred for -Ar' -S- (CH2) n- (CONH)
In -Ar' - (CH2) n- (CH (CN) ) - (CH2) 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.
is particularly preferred for -Ar' - (CH2) n- (CH (CN) ) - (CH2)i-Ar.
In -Ar'-(CH2)n-(CONH)-(CH2)i-CH(Ar1)-Ar2, Ar' is preferentially unsubstituted or substituted phenylene, where Ar1 and Ar2 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, 5, 6, 7, 8, 9, 10, 11 or 12.
is particularly preferred for -Ar' - (CH2) n- (CONH) - (CH2 ) i-CH (Ar1 ) -Ar2.
In -Ar'-S-(CH2)n-(CONH)-(CH2)i-CH(Ar1)-Ar2, Ar' is preferentially unsubstituted or substituted phenylene, where Ar1 and Ar2 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, 5, 6, 7, 8, 9, 10, 11 or 12.
is particularly preferred for -Ar'-S-(CH2)n-(CONH) (CH2)i-CH(Ar1)-Ar2.
In the above formulae, 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 cyclohexyl. Furthermore, D is preferentially cyclo- hexen-1-yl.
Hal is preferably F, Cl, Br or iodine. Het1 is preferentially substituted or unsubsti- tuted 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, l,2-dihydropyrazol-3-on-4-yl, 1,2-dihydropyrazol- 3-on-5-yl, benzothiophen-2-yl, benzothiophen-3-yl, 3H- benzotriazol-5-yl, benzothiazol-2-yl, benzofuran-2-yl, benzofuran-3-yl, imidazol-1-yl or benzo [1, 3]dioxol-5-yl or piperidine-1-yl, pyrrolidine-1-yl or pyrrolidine-2-on-l- yl. Furthermore furan-2-yl, carbazol-9-yl, 3,6-di-tert- butyl-carbazol-9-yl, thiazol-2-yl, thiazol-3-yl, 5-methyl- [1, 3, 4] -thiadiazol-2-yl, 5-trifluoromethyl- [1, 3, 4] - thiadiazol-2-yl, 1, 5-dimethyl-l, 2-dihydropyrazol-
3-on-4-yl, benzofuran-2-yl, 6-methyl-benzothiazol-2-yl, 2, 3-dihydro-lH-indol-6-yl, 3H-benzotriazol-5-yl, benzothiophen-2-yl, imidazol-1-yl or benzo [1, 3]dioxol-5-yl or piperidine-1-yl, morpholin-4-yl, pyrrolidine-1-yl or pyrrolidine-2-on-l-yl is particularly preferred.
In -Het1-Ar, Het1 and Ar have one of the preferred meanings indicated above, where Ar is preferably phenyl. 4-phenylthiazol-2-yl, 5-phenyl- [1, 3, 4] -thiadiazol-2-yl or 1, 5-dimethyl-2-phenyl- 1, 2-dihydropyrazol-3-on-4-yl is particularly preferred for Hetx-Ar.
In -Het^R3, Het1 is preferably 2, 3-dihydro-lH- is preferably CO (A) .
is particularly preferred for Het1-Ar.
Het is preferably substituted or unsubstituted 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1, 2, 3-triazol-l-, -4- or -5-yl, 1, 2, -triazol-l-, -4- or -5-yl, 1- or 5-tetrazolyl, 1, 2, 3-oxadiazol-4- or -5-yl, 1, 2, 4-oxadiazol-3- or -5-yl, 1, 3, 4-thiadiazol-2- or -5-yl, 1, 2, 4-thiadiazol-3- or -5-yl, 1, 2, 3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-lH-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2, 1, 3- oxadiazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl. The heterocyclic radicals can also be partially or completely hydrogenated. Het can thus also be 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5- dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2, 3-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 2, 5-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -3-pyrrolyl, tetrahydro-1-, -2- or 4-imidazolyl, 2, 3-dihydro-l-, -2-, -3-, -4-, -5-, -6-, -7-lH-indolyl, 2, 3-dihydro-l-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1, 4-dihydro-l-, -2-, -3- or -4-pyridyl, 1, 2, 3, 4-tetrahydro-l-, -2-, -3-, -4-, -5- or -6-pyridyl, 1, 2, 3, 6-tetrahydro-l-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 1-, 2-, 3- or 4-azepanyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1, -dioxanyl, 1, 3-dioxan-2-, -4- or -5-yl, hexahydro- 1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-l-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolinyl, 1,2,3,4-tetrahydro-l-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolinyl. Tetrahydro-1-pyrrolyl, 2, 3-dihydro-lH-indol-l-yl, 1-piperidinyl, 2, 6-tetramethylpiperidin-4-yl,
4-morpholinyl, 1-piperazinyl, 4-methylpiperazin-l-yl, 4-phenylpiperazin-l-yl, 1,2,3, -tetrahydroquinolin-l-yl or 1,2, 3, 4-tetrahydroisoquinolin-l-yl is particularly preferred.
In -Het-S02-Ar, Het and Ar have one of the preferred meanings indicated above, where Het is preferably piperazine-1, 4-diyl.
is particularly preferred for -Het-S02-Ar.
In -Het-R5, Het has one of the preferred meanings indicated beforehand, where Het is preferably piperazine-1, 4-diyl and R5 is preferentially phenyl, methyl, chloromethyl or trifluoromethyl.
is particularly preferred for -Het-R5.
In -Het- (CH2)n-Ar, Het 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
-N M. // \\
>-CH2-C is particularly preferred for -Het- (CH2)n-Ar.
X and/or X1 and/or X2 is alkylene and is preferably methylene, ethylene, propylene, butylene, furthermore also pentylene or hexylene.
Y is preferably 0, S, NH or NA.
In -Y- (CH2)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-(CH2)2—N O NH-(CH2)3—N N—CH3
is particularly preferred for -Y- (CH2) n-Het .
In -Y-Ar'-R3, Y is preferably O, S, NH or NA, where Ar' has one of the preferred meanings indicated beforehand and R is preferentially an alkylcarbonyl group.
is particularly preferred for -Y-Ar'-R3.
In -Y-(CH2)n-Ar, Y is preferably 0, S, NH or NA, where Ar has one of the preferred meanings indicated
NH-(CH2)2 fc /)—OH • -NH-CH2 fc )
is particularly preferred for -Y- (CH2) n-Ar .
In -Y-(CH2) n-Ar' -(CH2) i-R6, Y is preferentially
0, S, NH or NA, where Ar' has a preferred meaning indicated beforehand, R6 is preferably amino or alkylamino and n is 0, 1, 2, 3 or 4 and i is 0, 1, 2, or 12.
is very particularly preferred for -Y- (CH2)n-Ar' - (CH2)i-R6.
In -Y-(CH2)n-D-(CH2)i-R6, Y is preferentially 0, S, NH or NA, where D has a preferred meaning indicated beforehand, R6 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,
is very particularly preferred for -Y- (CH2) n~D- (CH2) i-R . In -Y-(CH2)n-Het-(CH2)i-R6, Y is preferentially
0, S, NH or NA, where Het has a preferred meaning indicated beforehand, R6 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-(CH2)3 —N N—(CH2)3 NH2
is very particularly preferred for -Y- (CH2)n-Het- (CH2)i-R6.
In -Y-(CH2)n-NA-(CH2)i-R6, Y is preferentially 0, S, NH or NA, where A has a preferred meaning indicated beforehand, R6 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- (CH2) 3-N (CH3) - (CH2) 3-NH2 is very particularly preferred for -Y- (CH2)n-NA- (CH2) i-R6.
In -Y-(CH2)n-D-(CH2)i-R8, Y is preferentially 0, S, NH or NA, where D has a preferred meaning indicated beforehand, R8 is preferably guanidino or alkylguanidino and n is 0, 1, 2, 3 or 4 and i is 0, 1, 2, 3, 4, 5, 6,
is very particularly preferred for -Y- (CH2)n-D- (CH2) i-R8.
In -Y-(CH2) n-Ar' -(CH2) i-R8, Y is preferentially
0, S, NH or NA, where Ar' has a preferred meaning indicated beforehand, R8 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.
is very particularly preferred for -Y- (CH2)n-Ar' - (CH2)i-R8.
In -Y-(CH2)n-NA-(CH2)i-R8, Y is preferentially 0, S, NH or NA, where A has a preferred meaning indicated beforehand, R8 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. -NH- (CH2) 3-N (CH3) - (CH2) 3-NH-C (=NH) -NH2 is very particularly preferred for -Y- (CH2)n-Ar' - (CH2)i-R8.
In -Y-[X-0]t-[X1-0]u-X2-R6, Y is preferentially 0, S, NH or NA, where X, X1 and X2 have a preferred meaning indicated beforehand. Furthermore, R6 is preferably amino, alkylamino or dialkylamino, t is 0, 1 or 2 and u is 1 or 2. -NH- (CH2) 3-0- (CH2) 4-0- (CH2) 3-NH2 is particularly preferred for -Y- [X-O] t- [X1-0]u-X2-R6. Furthermore, in -Y- [X-NH.u-X^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-(CH2)2-NH-(CH2)2-OH is particularly preferred for -Y-[X-NH]u-XX-OH. R is preferably H or N02.
R1 is preferably -Het, -Het-S02-Ar, -Het-R5, , -N=CH-Ar, NHAlk, NAAlk, NHA', NA'2,
-Y-D-H, -Y-Ar'-RJ, -Y- (CH2) 0-R3, -Y- (CH2) n- (CHR4) -R5, -Y-C[(CH2)o-0H]3, -Y-(CH2)m-NA2, -Y- (CH2) m-NHA' , -Y-(CH2)o-0H, -Y-(CH2)k-R6, -Y-(CH2)i_R8, -Y- (CH2) n-Het, -Y-(CH2)n-Ar, -Y- (CH2) n-Ar' -(CH2) i-R6, -Y- (CH2)n-D- (CH2) i~R6,
-Y-(CH2) n-Het- (CH2) i-R6, -Y-(CH2)n-NA-(CH2)i-R6, -Y-(CH2)n-NH-(CH2)i-R6, -Y-(CH2)n-D-(CH2)i-R8, -Y-(CH2) n-Ar' -(CH2) i-R8, -Y-(CH2)n-NH-(CH2)i-R8, -Y-(CH2)n-NA-(CH2)i-R8, where -Het, -Het-S02-Ar, -Het-R5, -Het- (CH2) n-Ar, -Y-Ar'-R3, -Y-(CH2) n-Het, -Y-(CH2)n-Ar, -Y- (CH2)n~Ar' - (CH2) i-R6, -Y-(CH2)n-D-(CH2)i-R6, -Y- (CH2) n-Het-(CH2) i-R6,
-Y- (CH2) n-NA- (CH2) i-R6, -Y- (CH2) n-D- (CH2) i~R8,
-Y- (CH2) n-Ar' - (CH2) i-R8, -Y- (CH2) n-NA- (CH2) i-R8,
-Y- [X-0] t- [X1-0] u-^2-R' e and -Y- [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-hydroxy- phenyl .
In NHAlk, Alk has a preferred meaning indicated beforehand. NH-(n-C5Hu) is particularly preferred for NHAlk.
In NAAlk, A and Alk have a preferred meaning indicated beforehand, where N (CH3) - (n-C4H9) is particularly preferred for NAAlk. In NHA' , A' has a preferred meaning indicated before- hand. NH-(n-C3H ) is particularly preferred for NHA'.
Furthermore, A' in NA'2 has a preferred meaning indicated beforehand, where N(C2H5)2 is particularly preferred for NA'2. In -Y-D-H, as a R1 substituent, Y is preferentially 0, S, NH or NA, where D has a preferred meaning indicated beforehand. -NH-C6Hn or -NH-C5H9 is particularly preferred for -Y-D-H.
In -Y-(CH2)0-R3, Y is preferentially 0, S, NH or NA, where R3 is preferably alkyloxycarbonyl and o can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
-NH-(CH2)2-COOMe is particularly preferred for -Y- (CH2)0-R3. In -Y-(CH2)n-(CHR4)-R5, Y is preferentially 0, S, NH or NA, where R4 is preferably phenyl or hydroxyl, R5 is preferentially methyl, chloromethyl or trifluoromethyl and n is 0, 1, 2, 3 or 4. is particularly preferred for -Y- (CH2) n- (CHR4) -R5
In -Y-C[ (CH2)o-0H]3, Y is preferentially 0, S, NH or NA, where o can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
-NH-C [CH2-OH]3 is particularly preferred for
-Y-C[ (CH2)o-0H]3.
In -Y-(CH2)m-NA2, 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-(CH2)2-N(C2H5)2 or -N (CH3) - (CH2) 2-N (C2H5) 2 is particularly preferred for -Y- (CH2)m-NA2.
In -Y-(CH2)m-NHA' , Y is preferentially 0, S, NH or NA, where A' has a preferred meaning indicated beforehand and can be 0, 1 or 2. -NH- (CH2) 2-NH- (C3H ) is particularly preferred for -Y- (CH2)ra-NHA' .
In -Y- (CH2)o-0H, Y is preferably 0, S, NH or NA, where o is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. -NH- (CH2) 2-OH or
-NH- (CH2) 5-OH is particularly preferred for
-Y-(CH2)o-0H.
In -Y-(CH2)k-R6, Y is preferentially 0, S, NH or NA, where R6 is preferably amino, alkylamino, dialkylamino or cycloalkylamino and k can be 3, 4, 5, 6, 7, 8, 9,
10, 11 or 12. -NH-(CH2)3-NH2, -NH- (CH2) -NH2
-NH- ( CH2 ) 5-NH2 , -NH- ( CH2 ) 7-NH2 , -NH- ( CH2 ) 8~NH2 ,
-NH- (CH2) 3-N (CH3) 2 , -NH- (CH2) 3-NH (CH3) ,
-N ( CH3) - (CH2 ) 3-NH (CH3 )
is particularly preferred for -Y- (CH2) k-R6. In -Y-(CH2)i-R8, Y is preferentially 0, S, NH or NA, where R8 is preferably -NH- (C=NH) -NH2, -NH- (C=NH) -NHA, -NH-(C=NH)-NA2, -NA-(C=NH)-NH2, -NA- (C=NH) -NHA, -NA-(C=NH)-NA2 and i can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. -NH- (CH2) 2-NH-C (=NH) -NH2, -NH- (CH2) 3-NH-C (=NH) -NH2, -NH- ( CH2 ) 4-NH-C (=NH) -NH2 ,
-NH- ( CH2 ) 5-NH-C ( =NH ) -NH2 , -NH- ( CH2 ) 6-NH-C (=NH) -NH2 ,
is
In
Y is preferentially 0, S, NH or NA, where R6 is preferably amino, alkylamino or dialkylamino and n can
R2 is preferably -Ar, -Ar'-D-H, -Het1, -Het^Ar, -Ar'-Het1, -Ar' - (CH2)n-R3, -Ar' -Y- (CH2) n-R3, -Ar'-Y-C(A)2-R3, -Het^R3, -Ar' -Hetx-R3, -Ar' - (CH2)n-R6, - Ar'-S02-Het, -Ar' -NH-S02-Het, Ar' -S02-R7, -Ar' - (CH2) n- (CONH) - (CH2) i-R6, -Ar' -(CH2)n- (CO-NH) -(CH2) i-R11, -Ar'-(CH2)n- CO-Het, -Ar' -(CH2)n- (CO-NH) -(CH2) i-D-H, -Ar' - (CH2) n- (CONH) - (CH2) i-Ar, -Ar' - (CH2) „- (CO-NH) - (CH2) i-Het1, -Ar'-(CH2)n-(CH(CN) )-(CH2)i-Ar, -Ar' - (CH2) n- (CO-NH) - (CH2)i-CH(Ar1)-Ar2, -Ar' -S- (CH2) n- (CO-NH) - (CH2) i~Ar, -Ar' - S- (CH2) n- (CO-NH) - (CH2) i-R11, -Ar' -S- (CH2) n- (CO-NH) - (CH2) i-Het1, -Ar'-S-(CH2)n-(CO-NH) -(CH2)i-CH(Arx)-Ar2 or -Ar'-S-(CH2)n- (CO-NH) -(CH2) i-D-H, Ar, Ar', Ar1, Ar2, A, D, Het, Het1, R3, R6, R11, Y, n and i in particular have one of the preferred or particularly preferred meanings indicated beforehand.
R3 is preferably C(0)A, CONH2, CONHA, CONA2, COOH or COOA, where A has one of the preferred meanings indicated beforehand.
R4 is preferentially phenyl or hydroxyl. R is preferably methyl, chloromethyl, trifluoromethyl or phenyl.
R6 is preferentially NH2, NHA, NA2, NH(D-H) or NHC(0)A, where A and D have a preferred meaning indicated beforehand.
R7 is preferably NA(D-H), NHA, NH(D-H) or NA2, where A and D have a preferred meaning indicated beforehand.
R8 is preferentially -NH- (C=NH) -NH2, -NH-(C=NH)-NHA, -NH- (C=NH) -NA2, -NA- (C=NH) -NH2, -NA-(C=NH)-NHA, -NA- (C=NH) -NA2, where A has a preferred meaning indicated beforehand.
R11 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 la to Iz and II to 15, which correspond to the formula I
and in which the radicals not designated in greater detail have the meanings indicated in formula I, but in which:
in la R is N02,
R1 is N02 and R2 is Ar;
in lb R is H,
R2 is Ar and
R1 is -Het, -Het-S02-Ar, -Het-R5, N02, NHAlk, NAAlk, NHA', NA'2, -Y-D-H, -Y-Ar'-R3, -Y- (CH2) 0-R3, -Y- (CH2) n. (CHR4) -R5,
-Y-C[(CH2)0-OH]3, -Y-(CH2)m-NA2,
-Y-(CH2)m-NHA', -Y-(CH2)0-OH, -Y- (CH2) k-R6, -Y-(CH2) n-Het, -Y-(CH2)n-Ar,
-Y-(CH2) n-Ar' -(CH2) i-R6,
-Y-(CH2) n-Ar' -(CH2) i-R8,
-Y- (CH2) n-D- (CH2) i-R6, -Y- (CH2) n-Het- (CH2) i_R6,
-Y-(CH2) n-NA- (CH2) i-R6 or
-Y- (CH2) n-NH- (CH2) i-R6;
in Ic is H,
R is -Het1 and r.1 is N02;
in Id R is H,
R2 is -Het^Ar and R1 is N02;
in Ie R is H
R2 is -Ar'-(CH2)n-R3 and
R1 is -Het, -Het-S02-Ar, -Het-R5,
-Het- (CH2) n-Ar, N02, NHAlk, NAAlk, NHA', NA'2, -Y-D-H, -Y-Ar'-R3, -Y- (CH2) 0-R3,
-Y- (CH2) n- (CHR4) -R5, -Y-C [ (CH2) 0-OH] 3,
-Y-(CH2)m-NA2, -Y-(CH2)m-NHA', -Y- (CH2) o-0H, -Y-(CH2)k-R6, -Y-(CH2) n-Het, -Y- (CH2) n-Ar, -Y- (CH2) n-Ar' - (CH2) i-R6, Y- (CH2) n-D- (CH2) i-R6, -Y-(CH2) n-Het- (CH2) i-R6,
-Y-(CH2) n-NA- (CH2) i-R6, -Y-(CH2) n-NH- (CH2) i-R6,
in If R is H,
R2 is -Ar'-Y-(CH2)n-R3 and
R1 is -Y-(CH2)k-R6, -Y-(CH2) n-Ar' -(CH2) i-R6 or -Y-(CH2)n-Ar;
in Ig R is H, R R22 iiss --AAr'-S02-Het and R1 is -Y-(CH2)k-RD or -Y- (CH2) n-Ar' - (CH2) i-R°; in Ih R is H, R2 is -Ar'-S02-R7 and
R1 is -Y-(CH2)k-R6 or -Y- (CH2) n-Ar'- (CH2) i-R6;
in Ii R is H,
R2 is -Ar' -(CH2)n- (CONH) -(CH2) i-R6 and
R1 is -Y-(CH2)k-R6 or -Y- (CH2) n-Ar' - (CH2) i-R6;
in Ik R is H,
R2 is -Ar' -(CH2)n- (CONH) -(CH2) i-D-H and
R1 is -Y-(CH2)k-R6, -Y-(CH2) n-Ar' -(CH2) i-R6,
-Y-(CH2)i-R8, -Y-(CH2)„-D-(CH2)i-RB,
-Y-(CH2) n-Ar' -(CH2) i-R8 or
- Y-(CH2) n-NA- (CH2) i-R8 ;
in II R is H, R2 is -Ar' -(CH2)n- (CONH) -(CH2) i-Ar and
R1 is -Y-(CH2)k-R6, -Y-(CH2)n-Ar'-(CH2)i-R6 (
-Y-(CH2)n-Ar, -Y-(CH2)i-RH -Y-(CH2)n-D-(CH2)i-R8, -Y-(CH2) n-Ar' -(CH2) i-R8,
in Im R is H,
R2 is -Ar' -(CH2)n- (CONH) -(CH2) i-Het1 and
R1 is -Y-(CH2)i-R8, -Y-(CH2)n-D-(CH2)i-R8,
-Y-(CH2) n-Ar' -(CH2) i-R8 or - Y-(CH2) n-NA- (CH2) i-R8 ; in In R is H,
R2 is -Ar'-(CH2)n-(CH(CN) )-(CH2)i-Ar and
R1 is -Y-(CH2)k-R6' -Y-(CH2)n-D-(CH2)i-R6 or -Y-
(CH2) n-Ar'- (CH2) i-R6;
in Io R is H,
R2 is -Ar' -(CH2)n- (CO-NH) -(CH2) i-CH (Ar^-Ar2 and is -Y-(CH2)i-RB -Y-(CH2)n-D-(CH2)i-R8,
-Y-(CH2) n-Ar' -(CH2) i-R8 or -Y- (CH2) n-NA- (CH2) i-R8;
in Ip R is H,
R2 is -Ar'-Het1 and
R1 is -Y-(CH2)k-R6, -Y-(CH2) n-Ar' -(CH2) i-R6,
-Y-(CH2)n-Ar'-(CH2)i-Rε or -Y-(CH2)n-
D-(CH2)i-R6;
in Iq R is H, R R22 iiss --AAr'-Het^R3 and R1 is -Y-(CH2)k-R° or -Y- (CH2) n-D- (CH2) i-R°;
in Ir R is H
R2 is -Ar'-(CH2)n-R6 and
R1 is -Y-(CH2)k-R6 or -Y- (CH2) n-D- (CH2) i~R€
in Is R is H,
R2 is -Ar'-Y-C(A)2-R3 and
R1 is -Y-(CH2)k-R6;
in It R is H,
R2 is -Ar'-NH-S02-Het and
R1 is -Y- (CH2)k-R6;
in lu R is H, R2 is -Het^R3 and
R1 is -Y-(CH2)k-R6;
in Iv R is H,
R2 is -Ar'-D-H and R1 is -Y-(CH2)k-R6;
in Iw R is H,
R R^2 iiss --?A.r' -(CH2)n- (CONH) - (CH2) i-R11 and
R" is -Y-(CH2)n-Ar'-(CH2)i-Re
in lx R is H,
R2 is -Ar'-(CH2)n-CO-Het and R1 is -Y-(CH2)n-D-(CH2)i-R6;
in ly R is H,
R2 is -Ar' -S- (CH2)n- (CO-NH) - (CH2) i-Ar and
R1 is -Y-(CH2) n-Ar' -(CH2) i-R6 or
-Y- (CH2) n-Ar'- (CH2) i-R8;
in Iz R is H,
R2 is -Ar' -S- (CH2)n- (CO-NH) - (CH2) i-Het1 and
R1 is -Y-(CH2) n-Ar' -(CH2) i-R6 or
-Y- (CH2) n-Ar'- (CH2) i-R8;
in II R is H,
R2 is -Ar' -S- (CH2)n- (CO-NH) - (CH2)i-DH and R1 is -Y-(CH2) n-Ar' -(CH2) i-R6 or
-Y- (CH2) n-Ar'- (CH2) i-R8;
in 12 R is H,
R2 is -Ar'-S- (CH2)n- (CO-NH) -(CH2) i-R11 and R1 is -Y-(CH2) n-Ar' -(CH2) i-R6 or
-Y- (CH2) n-Ar'- (CH2) i-R8;
in 13 R is H,
R2 is -Ar'-S- (CH2)n- (CO-NH) - (CH2) i-CH (Ar1) -Ar2 and R1 is -Y-(CH2) n-Ar' -(CH2) i-R6 or -Y- (CH2) n-Ar'- (CH2) i-R8;
in 14 R is H,
R2 is -Ar, -Ar'-Het1, -Ar '- (CH2) n- (CO-NH) - R1 is -Y-(CH2)k-R6, -Y-(CH2)i-R8;
-Y- (CH2) n-D- (CH2) i-R8, -Y- (CH2) n-NA- (CH2) i-R8 or -Y- (CH2) n-Ar'- (CH2) i-R8;
in 15 R is H,
R2 is -Ar, -Ar'- (CH2)n- (CO-NH) - (CH2) i-Ar,
-Ar'-S- (CH2)n- (CO-NH) - (CH^-Ar, -Ar'- (CH2)n- (CO-NH) - (CH2) i-Het1, -Ar'-S- (CH2)n- (CO-NH) -
(CH2) i-Het1, -Ar'- (CH2)n- (CO-NH)- (CH2) i-D-H, -Ar'-S- (CH2)n- (CO-NH) - (CH2) i-D-H,
-Ar'- (CH2)n- (CO-NH) - (CH2) -CH (Ar1) -Ar2, -Ar" -S- (CH2)n- (CO-NH) - (CH2) -CH (Ar1) -Ar2, -Ar'- (CH2)n- (CO-NH) - (CH2) i-R11 or -Ar'-S-
(CH2)n- (CO-NH) - (CH2) i-R11 and R1 is -Y-(CH2) n-Ar' -(CH2) i-R6 or
-Y- (CH2) n-Ar' -(CH2) i-R8.
Preferred compounds of the formula I are in the following: 3-{ 3- [6- (4-Guanidinomethyl-benzylamino) -1, 3-dioxo- 1H, 3H-benzo [de] isoquinolin-2-yl] -phenyl}-N- [2- (4- sulfamoyl-phenyl) -ethyl] -propionamide;
N- [2- (4-Chloro-phenyl) -ethyl] -3-{3- [6- (4- guanidinomethyl-benzylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] -phenyl} -propionamide;
6- (3-Amino-propylamino) -2- (3, 4, 5-trimethoxy-phenyl) - benzo [de] isoquinoline-1, 3-dione;
6- (3-Amino-propylamino) -2- (7-hydroxy-naphthalen-l-yl) - benzo [de] isoquinoline-1, 3-dione;
6- [ (3-Amino-propylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] -4, 5-dimethoxy-benzonitrile;
6- (3-Amino-propylamino) -2- (2, 3-dimethoxy-phenyl) benzo [de] isoquinoline-1, 3-dione; N- [2- (3-Chloro-phenyl) -ethyl] -3-{3- [6- (4- guanidinomethyl-cyclohexylmethyl-amino) -1, 3-dioxo- 1H, 3H-benzo [de] isoquinolin-2-yl] -phenyl } -propionamide;
N- [2- (4-Chloro-phenyl) -ethyl] -3-{3- [6- (4- guanidinomethyl-cyclohexylmethyl-amino) -1, 3-dioxo- 1H, 3H-benzo [de] isoquinolin-2-yl] -phenyl} -propionamide;
6- (3-Amino-propylamino) -2- (4 ' -methoxy-biphenyl-4-yl) - benzo [de] isoquinoline-1, 3-dione;
6- (3-Amino-propylamino) -2- (4-carbazol-9-yl-phenyl) - benzo [de] isoquinoline-1, 3-dione;
6- (3-Amino-propylamino) -2- (4 ' -hydroxy-2-methyl- biphenyl-4-yl) -benzo [de] isoquinoline-1, 3-dione;
N- (3-{ [2- (4 'Methoxy-biphenyl-4-yl) -1, 3-dioxo-2, 3- dihydro-lH-benzo [de] isoquinolin-6-ylamino] -methyl }- benzyl) -guanidine;
3- {3- [6- (2-Guanidino-ethylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] -phenyl }-N- (4-phenyl-butyl) - propionamide;
N- (2- (4-Chloro-phenyl) -ethyl] -3-{ 3- [6- (2-guanidino- ethylamino) -1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] - phenyl} -propionamide;
N- (2- (4-Chloro-phenyl) -ethyl] -3-{ 3- [6- (3-guanidino- propylamino) -1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2- yl] -phenyl } -propionamide;
N- (2- (4-Chloro-phenyl) -ethyl] -3- [3- (6-{3- [ (3-guanidino- propyl) -methyl-amino] -propylamino}-l, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] -phenyl} -propionamide; N- (2- (3-Chloro-phenyl) -ethyl] -3-{3- [6- (3-guanidino- propylamino) -1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2- y1] -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-lH-benzo [de] isoquinolin-6- ylamino] -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 (e.g. in the standard works such as Houben- eyl, Methoden der organischen Chemie [Methods of Organic Chemistry] , Georg-Thieme-Verlag, Stuttgart) , namely under reaction conditions which are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se, but not mentioned here in greater detail. The starting substances, if desired, can also be formed in situ such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
The compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis or by hydrogen- olysis.
Preferred starting substances for the solvolysis or hydrogenolysis 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' -N- group, in which R' is an amino protective group and/or those which instead of the H atom of a hydroxyl group carry a hydroxyl protective group, e.g. those which correspond to the formula I, but instead of a group - COOH carry a group -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. The expression "hydroxyl protective group" is also generally known and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. Typical groups of this type are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups. The nature and size of the hydroxyl protective groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; groups having 1-20, in particular 1-10 C atoms, are preferred. Examples of hydroxyl protective groups are, inter alia, benzyl, p-nitrobenzoyl, p-toluolsulfonyl, tert-butyl and acetyl, benzyl and tert-butyl being particularly preferred.
The liberation of the compounds of the formula I from their functional derivatives is carried out - depending on the protective group used - for example using strong acids, expediently using TFA or perchloric acid, but also using other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene- or p-toluene- sulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents 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 approximately 50 °C; the reaction is preferably carried out between 15 and 30 °C (room temperature) .
The groups BOC and Obutyl can preferably be removed, for example, using TFA in dichloromethane or using approximately 3 to 5N HCl in dioxane at 15-30°C, the Fmoc group using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°C.
Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst (e.g. of a noble metal catalyst such as palladium, expediently on a support such as carbon) . Suitable solvents in this case are those indicated above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. As a rule, the hydrogenolysis is carried out at temperatures between approximately 0 and 100 °C and pressures between approximately 1 and 200 bar, preferentially at 20-30 °C and 1-10 bar. Hydrogenolysis of the CBZ group takes place readily, for example, on 5 to 10% Pd/C in methanol or ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°C.
Compounds of the formula I can also preferably be obtained by reacting compounds of the formula II with compounds of the formula III. As a rule, the starting compounds of the formulae II and III are known or commercially available. The unknown compounds, however, can be prepared by methods known per se. The compounds of the formula II are naphthalene- 1, 8-dicarboxylic anhydride derivatives. They can be prepared in a conventional manner from appropriately substituted 1, 8-naphthalenedicarboxylic acids or corresponding derivatives. It is furthermore possible to introduce appropriate substituents into the aromatic by conventional electrophilic or alternatively nucleophilic substitutions.
The compounds of the formula III are primary amines, which, as a rule, are also commercially available. Furthermore, syntheses for the preparation of primary amines, such as, for example, the Gabriel synthesis, can be used.
As a rule, the reaction is carried out in an inert solvent. Depending on the conditions used, the reaction time is between a few minutes and a number of days, the reaction temperature between approximately 0° and 150°C, normally between 20° and 130°C. The reactions can be carried out in analogy to the methods indicated in Eur. J. Chem. Chim. Ther. 1981, 16, 207- 212 and in J. Med. Chem. 1982, 25, 714-719.
Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol) , ethylene glycol dimethyl ether (diglyme) ; ketones such as acetone or butanone; amides such as acetamide, N-methylpyrrolidone (NMP) , dimethylacetamide or dimethylformamide (DMF) ; nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO) ; carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or mixtures of the solvents mentioned.
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 R1 and/or R2 are H2N-C (=NH) -NH-, an appropriate amino-substituted compound can be treated with an amidinating agent. The preferred amidinating agent is l-amidino-3, 5-dimethylpyrazole (DPFN) , which is employed, in particular, in the form of its nitrate, or pyrazole-1-carboxamidine. The reaction is expediently carried out with addition of a base such as triethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, e.g. DMF at temperatures between 0° and 150°C, preferably between 60° and 120°C.
For the preparation of compounds of the formula I in which R2 is unsubstituted or substituted biphenyl, -Ar'-Het1, -Ar' -Het^R3, -Ar' - (CH2) n-R3 and/or -Ar' - (CH2)n-R6, an appropriate compound of the formula I in which R2 is aryl bromide or aryl iodide can be reacted with the appropriate boronic acid derivatives in a Suzuki reaction. The Suzuki reaction is expediently carried out in palladium-mediated form, preferably by addition of Pd(PPh3) , in the presence of a base such as potassium carbonate in an inert solvent or solvent mixture, e.g. DMF at temperatures between 0° and 150°, preferably between 60° and 120°. Depending on the conditions used, the reaction time is between a few minutes and a number of days. The boronic acid derivatives can be prepared by conventional methods or are commercially available. The reactions can be carried out in analogy to the methods indicated in Suzuki et al . , J. Am. Chem. Soc. 1989, 111 , 314ff. and Suzuki et al., Chem. Rev. 1995, 95, 2457ff.
For the esterification, an acid of the formula I (R1 = COOH or -Y- (CH2)n-COOH and/or R2 = COOH) can be treated with an excess of an alcohol, expediently in the presence of a strong acid such as hydrochloric acid or sulfuric acid at temperatures between 0° and 100°C, preferably between 20° and 50°C. Conversely, an ester of the formula I (R1 = COOA or -Y- (CH2)n-COOA and/or R2 = 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°C, preferably between 10° and 30°C. Furthermore, free amino groups can be acylated in a customary manner using an acid chloride or anhydride, expediently in an inert solvent such as dichloromethane or THF and/or in the presence of a base such as triethylamine or pyridine at temperatures between -60°C and +30°C.
A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation. Acids which give 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 means of the novel methods of combinatorial chemistry, i.e. by robot- and computer-assisted syntheses, and subjected to mass screening (for this see: US 5,463,564; M. A. Gallop et al., J. Med. Chem. 1994, 37, 1233-1251 and 1385-1401 and M.J. Sofia, Drugs Discovery Today 1996, 1 , 27-34) .
The invention furthermore relates to pharmaceutical preparations comprising at least one compound of the formula I and/or one of its physiologically acceptable salts, which are prepared, in particular, in an non-chemical way. In this case, the compounds of the formula I can be brought into a suitable dose form together with at least one solid, liquid and/or semi-liquid excipient or auxiliary and, if appropriate, in combination with one or more other active compounds.
These preparations can be used as medicaments in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceryl triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly. Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used, in particular, for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, are used for parenteral administration, and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. The preparations indicated can be sterilized and/or can contain auxiliaries such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colourants, flavourings and/or one or more other active compounds, e.g. one or more vitamins.
The compounds of the formula I and their physiologically acceptable salts act as adhesion receptor antagonists, in particular glycoprotein IblX 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 Ilbllla antagonist ReoPro® of preferably between approximately 1 and 500 mg, in particular between 5 and 100 mg, per dose unit. The daily dose is preferably between approximately 0.02 and 10 mg/kg of body weight. The specific dose for each patient depends, however, on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health and sex, on the diet, on the time and route of administration, and on the excretion rate, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Oral administration is preferred.
Above and below, all temperatures are indicated in °C. In the following examples, "customary working- up" means: if necessary, water is added, if necessary, depending on the constitution of the final product, the mixture is adjusted to pHs between 2 and 10 and extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallization. Mass spectrometry (MS) apparatuses Kratos Maldi III and Finnigan LCQ. (M+H)+ values are determined. EXAMPLES
Example 1 :
A suspension of 6.6 g of 6,7- dinitrobenzo [de] isochromene-1, 3-dione in 100 ml of toluene is treated with 3.3 g of 5-chloropyridin- 2-ylamine and the 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-1, 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 R1-H, the following compounds of the formula Iba are obtained:
Example 3 :
Analogously to Example 2, 6-chloro- benzo [de] isochromene-1, 3-dione is reacted with 3-chlorophenylamine and then with R1-H. The following compounds of the formula Ibb are obtained:
Example 4 :
Analogously to Example 2, 6-chloro- benzo [de] isochromene-1, 3-dione is reacted with phenylamine and then with R1-H. The following compounds of the formula Ibc are obtained:
Example 5 :
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with 3-nitrophenylamine and then with R1-H. The following compounds of the formula Ibd are obtained:
Example 6:
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with 3-methoxyphenylamine and then with R1-H. The following compounds of the formula Ibe are obtained:
Example 7 :
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with 4-styrylphenylamine and then with R1-H. The following compounds of the formula Ibf are obtained:
Example 8 :
Analogously to Example 2, 6-nitrobenzo- [de] isochromene-1, 3-dione is reacted with H2N-Ar and then (if necessary) with R1-H. The following compounds of the formula Ibg are obtained:
Ar
Example 9 :
Analogously to Example 2 , 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with 3-chloro- 4-methylphenylamine and then with R1-H. The following compounds of the formula Ibh is obtained:
Example 10:
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with H2N-Ar and then with Rx-H. The following compounds of the formula Ibi are obtained:
Ar
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 K2C03, 1.2 equivalents of Ph-B-(OH)2 and 10 mol% of Pd((PPh)3)4 are added to a solution of this compound in 80 ml of DMF and it is heated at 80°C until conversion is complete. After filtering off the catalyst and customary working up, 6-nitro-2-biphenyl- 4-ylbenzo [de] isoquinoline-1, 3-dione is heated with 1, 3-diaminopropane until conversion is complete. After cooli the reaction mixture, it is worked up as is customary and 6- (3-aminopropylamino) -2-biphenyl- 4-ylbenzo [de] isoquinoline-1, 3-dione is obtained.
Analogously, by reaction of 6-nitro-2- (4- iodophenyl) benzo [de] isoquinoline-1, 3-dione with Ph-B- (OH)2 and R1-H, the following compounds of the formula Ibk are obtained:
Example 12:
Analogously to Example 11, 6-nitro- 2- (4-iodophenyl) benzo [de] isoquinoline-1, 3-dione is reacted with R10-B-(OH)2 and Rx-H. The following compounds of the formula Ibl are obtained:
Example 13 :
Analogously to Example 11, 6-nitro- 2- (3-iodophenyl) benzo [de] isoquinoline-1, 3-dione is reacted with R10-B-(OH)2 and R^H. The following compounds of the formula Ibm are obtained:
Example 14:
Analogously to Example 11, 6-nitro-2- (3-iodo- 4-methylphenyl) benzo [de] isoquinoline-1, 3-dione is reacted with R10-B-(OH)2 and Rx-H. The following compounds of the formula Ibn are obtained: Example 15 :
Analogously to Example 11, 6-nitro-2- (4-iodo-
3-methylphenyl) benzo [de] isoquinoline-1, 3-dione is reacted with R10-B-(OH)2 and R^H. The following la Ibo are obtained:
Example 16:
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with N-Het1. The following compounds of the formula Ic are obtained:
Example 17:
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with H2N-Het1-Ar. The following compounds of the formula Id are obtained:
Example 18:
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 2-(3-amino- phenyl) acetamide and then with Rx-H. The following compounds of the formula lea are obtained:
Example 19:
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 2-(4-amino- phenyl) acetamide and then with R1-H. The following compounds of the formula leb are obtained:
Example 20:
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 3-aminobenzamide and then with Rx-H. The following compounds of the formula Iec are obtained:
Example 21:
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 4-(4-amino- phenyl) butyramide and then with R1-H. The following compounds of the formula led are obtained:
Example 22:
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 3- (3-aminophenyl) - propionamide and then with R1-H. The following compounds of the formula lee are obtained:
Example 23 :
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 3-amino- 4-methoxybenzamide and then with R1-H. The following compounds of the formula Ief are obtained:
Example 24 :
Analogously to Example 2, 6-nitrobenzo [de] iso- chromene-1, 3-dione is reacted with H2N-Ar' - (CH2) n-R3 and then (if necessary) with R1-H. The following compounds of the formula leg are obtained:
Example 25 :
Analogously to Example 11, 6-nitro-2- (3- iodophenyl) benzo [de] isoquinoline-1, 3-dione or 6-nitro- 2- (4-iodophenyl) benzo [de] isoquinoline-1, 3-dione is reacted with R3- (CH2) n-Ph-B- (OH) 2 and Rx-H. The following compounds of the formula leh (Ph-Ph=Ar') are obtained:
Example 26:
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 2- ( 4-aminophenyl- sulfanyl) acetamide and then with R1-H. The following compounds of the formula Ifa are obtained:
Example 27 :
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 2-(4-amino- phenoxy) acetaamide and then with R1-H. The following compounds of the formula Ifb are obtained:
Example 28 :
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 5- (piperidine- 1-sulfonyl) naphthalen-1-ylamine and then with R1-H. The following compounds of the formula Ig are obtained:
Example 29 :
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with H2N-Ar' -S02-R7 and then with R1-H. The following compounds of the formula Ih are obtained:
Example 30:
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with H2N-C6H4- (CH2)2-CONH- (CH2)i-NH2 and then with Rx-H. The following compounds of the formula Ii are obtained:
Example 31:
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with H2N-CεH4- (CH2) 2-CONH- CH2-C6Hn and then with Rx-H. The following compounds of the formula Ika are obtained:
Example 32 :
Analogously to Example 2, 6-nitrobenzo [de] iso- chromene-1, 3-dione is reacted with H2N-C6H4- (CH2) 2-CONH-
(CH2)2-C6H9 and with H2N- (CH2) 5-NH2. One equivalent of tert-butyl (tert-butoxycarbonyliminopyrazol-1-yl- methyl) carbamate is then added to a solution of 3-
{3- [6- (5-aminopentylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] phenyl }-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-enylethyl) -3- {3- [6- (5-guanidinopentyl- amino) -1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] - phenyl}propionamide is obtained.
The following compounds of the formula Ikb are obtained analogously by reacting H2N-C6H4- (CH2) 2-CONH- (CH2)2-C6H9 with the appropriate diamine in each case and tert-butyl (tert-butoxycarbonyliminopyrazol-1-yl- methyl) carbamate and removing the protective groups:
R1
Example 33:
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with H2N-CδH4- (CH2) 2-CONH- (CH2)i-Ar and then with R1-H. The following compounds of the formula Ila are obtained:
Example 34 :
Analogously to Example 32, 6-nitro- benzo [de] isochromene-1, 3-dione is reacted with H2N-CεH4-
(CH2)2-CONH- (CH2) 3-C6H5, the appropriate diamine in each case and (if necessary) with tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula lib are obtained: Example 35 :
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with H2N-CδH4- (CH2)2-CONH-(CH2)2-C6H4-S02-NH2, the appropriate diamine in each case and tert-butyl (tert-butoxycarbonyl- iminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula lie are obtained:
Example 36:
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with H2N-CeH4- (CH2) 2-CONH-C6H5, the appropriate diamine in each case and tert-butyl (tert-butoxycarbonyliminopyrazol-1-yl- methyl) carbamate. After removal of the protective groups, the following compounds of the formula lid are obtained:
Example 37:
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with
the appropriate diamine and tert-butyl (tert-butoxy- carbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formulae Ilea-Ilef are obtained:
Example 38:
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with H2N-CeH4- (CH2) 2-CONH-CH2-Ar, the corresponding diamine and tert- butyl (tert-butoxycarbonyliminopyrazol-1-ylmethyl) - carbamate. After removal of the protective groups, the following compounds of the formula Ufa are obtained with H2N-C6H4- (CH2) 2-CONH-CH2-Ci0H7 : R1
After removal of the protective groups, the following compounds of the formula Ilfb are obtained with H2N-C6H4-(CH2)2-CONH-CH2-C9H9:
Example 39:
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 3- (3-aminophenyl) -N- (3-chloro-4-methoxyphenyl) propionamide, the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ilg are obtained:
Example 40:
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 3- (3-aminophenyl) -N- (4-phenylbutyl) propionamide, the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ilh are obtained:
Example 41:
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with
the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formulae Ilia-Ilic are obtained:
Example 42:
A suspension of 4.1 g of 6-nitrobenzo [de] isochromene-1, 3-dione in 100 ml of glacial acetic acid is treated with 4.3 g of 3- (3- aminophenyl) 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-l, 3-dioxo-2, 3-dihydro- lH-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-l, 3-dioxo-2, 3-dihydro- lH-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-1- carboxamidine 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-lH-phenalen-2-yl] phenyl }-N- (2-p-tolyl- ethyl) propionamide is obtained. MS: calculated: 576.7; found: 577.4.
Example 43:
Analogously to Example 32, 6-nitrobenzo [de] iso- chromene-1, 3-dione is reacted with the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following e are obtained:
Example 44:
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 3- (3- aminophenyl) -N- (3-chloro-4-fluorobenzyl) propionamide, the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ilm are obtained:
Example 45 :
Analogously to Example 32 , 6-nitro- benzo [de] isochromene-1 , 3-dione is reacted with
the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following e obtained:
Example 46:
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate, After removal of the protective groups, the following compounds of the formulae Iloa-Iloc are obtained:
Example 47 :
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 3- (3-aminophenyl) -N- (3-phenoxyphenyl) propionamide, the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate . After removal of the protective groups, the following compounds of the formula Up are obtained:
Example 48:
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 3- (3-aminophenyl) -N- (3-benzyloxyphenyl) propionamide, the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate . After removal of the protective groups, the following ned:
Example 49:
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 3- (3-aminophenyl) -N-naphthalen-2-ylpropionamide, the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ilr are obtained:
Example 50:
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 3- (3-aminophenyl) -N-benzylpropionamide, the appropriate diamine and tert-butyl (tert-butoxycarbonyl- iminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ils are obtained:
Example 51:
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 3- (3-aminophenyl) -N- (3-fluoro-4-methoxyphenyl) propionamide, the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula lit are obtained:
Example 52:
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 3- (3-aminophenyl) -N- (3-fluoro-4-methylphenyl) propionamide, the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formula Ilu are obtained:
Example 53:
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with
the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formulae Ilva-Ilvb are obtained:
Example 54 :
Analogously to Example 32 , 6-nitro- benzo [de ] isochromene-1 , 3-dione is reacted with
the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formulae Ilw are obtained:
Example 55 :
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with
the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate. After removal of the protective groups, the following compounds of the formulae Im are obtained:
Example 56:
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 2- (4-aminophenyl) -3- (4-dimethylaminophenyl) propio- nitrile and then with R1-H. The following compounds of the formula In are obtained:
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 dichloromethane [obtainable by reaction of 6-nitrobenzo [de] isochromene-1, 3-dione with 2- (4-aminophenyl) -3- (4-dimethylaminophenyl)propio- nitrile and H2N- (CH2) 3-NHBOC] and the reaction mixture is stirred until removal is complete. After customary working up, 2-{4- [6- (3-aminopropylamino) -1, 3-dioxo- IH, 3H-benzo [de] isoquinolin-2-yl}-3- (4-dimethylaminophenyl) propionitrile is obtained.
Example 58:
Analogously to Example 32, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with
the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrazol-1-ylmethyl) carbamate, After removal of the protective groups, the following compounds of the formula Ioa are obtained:
Example 59 :
Analogously to Example 32 , 6-nitrobenzo- [de ] isochromene-1 , 3-dione is reacted with
the appropriate diamine and tert-butyl (tert- butoxycarbonyliminopyrozol-1-ylmethyl) carbamate . After removal of the protective groups, the following compounds of the formula lob are obtained:
Example 60:
Analogously to Example 11, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 4-iodophenylamine or 3-iodophenylamine (= I-Ar'-NH2), Het1-B(OH)2 and then with R1-H. The following compounds of the formula Ip are obtained:
Example 61:
Analogously to Example 11, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 4-iodophenylamine or 3-iodophenylamine (= I-Ar'-NH2), R3-Hetx-B (OH) 2 and then with Rx-H. The following compounds of the formula Iq are obtained:
Example 62 :
Analogously to Example 11, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with 4-iodophenylamine or 3-iodophenylamine (= I-Ph-NH2) , R6- (CH2) n-Ph-B- (OH) 2 and then with R1-H (Ph-Ph = Ar' ) . The following compounds of the formula Ir are obtained:
Example 63 :
Analogously to Example 11, 6-nitro-2- (4- iodophenyl) benzo- [de] isoquinoline-1, 3-dione is reacted with R10-B-(OH)2, wherein R10 is
and Propan-1, 3-diamine. 2-{ 4 '- [6- (3-Amino-propylamino) - 1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] -biphenyl-4- yloxy}-2-methyl-propionic acid ethyl ester is obtained.
Example 64 :
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with 5-methoxy- pyrimidine-2-sulfonic acid (4-amino-phenyl) -amide and Propan-1, 3-diamine . 5-Methoxy-pyrimidine-2-sulfonic acid { 4- [6- (3-amino-propylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] -phenyl} -amide is obtained.
Example 65:
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with l-(6-amino-
2, 3-dihydro-indol-l-yl) -ethanone and propan-1, 3- diamine. 2- (l-Acetyl-2, 3-dihydro-lH-indol-6-yl) -6- (3- amino-propylamino) -benzo [de] isoquinoline-1, 3-dione is obtained.
Example 66:
Analogously to Example 2, 6-chlorobenzo-
[de] isochromene-1, 3-dione is reacted with 4-
(pyrrolidine-1-sulfonyl) -phenylamine and propan-1, 3- diamine. 6- (3-Amino-propylamino) -2- [4- (pyrrolidine-1- sulfonyl) -phenyl] -benzo [de] isoquinoline-1, 3-dione is obtained.
Example 67 : Analogously to Example 2, 6-chlorobenzo-
[de] isochromene-1, 3-dione is reacted with 4-cyclohexyl- phenylamine and Propan-1, 3-diamine. 6-(3-Amino- propylamino) -2- (4-cyclohexyl-phenyl) - benzo [de] 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) -N- (2-phenyl-propyl) -propionamide and 3- aminomethyl-benzylamine . 3- { 3- [6- (3-Aminomethyl- benzylamino) -1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2- yl] -phenyl }-N- (2-phenyl-propyl) -propionamide is obtained.
Analogously, by reaction of 6-chlorobenzo- [de] isochromene-1, 3-dione with 3- (3-Amino-phenyl) -N- (1- phenyl-ethyl) -propionamide and 3-aminomethyl- benzylamine, 3- {3- [6- (3-aminomethyl-benzylamino) -1,3- dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] -phenyl }-N- (1- phenyl-ethyl) -propionamideis obtained.
Example 69:
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with 3- (3-aminophenyl) -1- (3, 4-dihydro-2H-quinolin-l-yl) -propan-1-one and 3-aminomethyl-cyclohexylamine. 6- [ (3-Aminomethyl- cyclohexylmethyl) -amino] -2-{ 3- [3- (3, 4-dihydro-2H- quinolin-1-yl) -3-oxo-propyl] -phenyl }- benzo [de] isoquinoline-1, 3-dione is obtained.
Example 70: Analogously to Example 2, 6-chlorobenzo-
[de] isochromene-1, 3-dione is reacted with H2N-Ar'-S- (CH2)n-CONH- (CH2)i-Ar and 3-aminomethyl-benzylamine. The following compounds of the formula Iya are obtained:
Analogously to example 32, the compounds of the formula lya 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 Iyb are obtained:
Example 71 :
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with H2N-Ar'-S- (CH2)n-C0NH- (CH2) i-Het1 and 3-aminomethyl-benzylamine. The following compounds of the formula Iza are obtained:
ArJ-S-(CH2)n-CONH-(CH2)i-Het1
Analogously to example 32, the compounds of the formula Iza 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 Izb are obtained:
Example 72:
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with H2N-Ar'-S- (CH2) n-CONH- (CH2) i-D-H and 3-aminomethyl-benzylamine. The following compounds of the formula Ila are obtained:
Ar'-S-(CH2)n-CONH-(CH2)rD-H
Analogously to example 32, the compounds of the formula Ila 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 lib are obtained:
Ar'-S-(CH2)n-CONH-(CH2)rD-H
Example 73:
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with 2- (3-amino- phenylsulfanyl) -N- (2-phenyl-propyl) -acetamide and 3- aminomethyl-benzylamine . 2- { 3- [6- (3-Aminomethyl- benzylamino) -1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2- yl] -phenylsulfanyl}-N- (2-phenyl-propyl) -acetamide is obtained. Analogously to example 32, 2-{ 3- [6- (3-Aminomethyl- benzylamino) -1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2- yl] -phenylsulfanyl}-N- (2-phenyl-propyl) -acetamide is reacted with tert-butyl (tert- butoxycarbonyliminopyrazol-1-yl-methyl) carbamate. After removing of the protection group 2-{3-[6-(3- guanidinomethyl-benzylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] -phenylsulfanyl} -N- (2-phenyl- propyl) -acetamide is obtained.
Example 74:
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with H2N-Ar'-S-
(CH2) n-CONH- (CH2) i-CH (Ar1) -Ar2 and 3-aminomethyl- benzylamine. The following compounds of the formula I3a are obtained:
Analogously to example 32, the compounds of the formula I3a 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 I3b are obtained:
Ar'-S-(CH2)n-CONH-(CH2)rCH(Ari)-Ar2
Example 75:
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with 2- (3-aminophenyl) -N- (4-chloro-benzyl) -acetamide and 4- aminomethyl-cyclohexylmethylamine. 2— (3—{ 6— [ (4—
Aminomethyl-cyclohexylmethyl) -amino] -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl} -phenyl) -N- (4-chloro-benzyl) - acetamide is then, analogously to example 32, reacted with tert-butyl (tert-butoxycarbonyliminopyrazol-1-yl- methyl) carbamate. After removing of the protection group N- (4-chloro-benzyl) -2- (3-{ 6- [ (4-guanidinomethyl- cyclohexylmethyl) -amino] -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl}-phenyl) -acetamide is obtained. Analogously is reacted 6-chlorobenzo [de] isochromene- 1, 3-dione with 3- (3-amino-phenyl) -N-phenethyl- propionamide and 4-aminomethyl-cylohexylmethylamine and the following product 3- (3-{ 6- [ (4-Aminomethyl- cyclohexylmethyl) -amino] -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl } -phenyl) -N-phenethyl- propionamide with tert-butyl (tert- butoxycarbonyliminopyrazol-1-yl-methyl) carbamate. After removing of the protection group 3-(3-{6-[(4- guanidinomethyl-cyclohexylmethyl) -amino] -1, 3-dioxo- 1H, 3H-benzo [de] isoquinolin-2-yl} -phenyl) -N-phenethyl- propionamide is obtained.
Example 76: Analogously to Example 2, 6-chlorobenzo-
[de] isochromene-1, 3-dione is reacted with H2N-Ar'- (CH2) n-CONH- (CH2) i-Ar and 3-aminomethyl-benzylamine. The following compounds of the formula I6a are obtained:
Ar'-(CH2)n-CONH-(CH2)rAr
Ar '-(CH2) n-CONH- (CH2) i-Ar in
I6a
Ar' -(CH2) n-CONH- (CH2) i-Ar in
I6a
Analogously to example 32, the compounds of the formula 16a 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 I6b are obtained:
Ar '-(CH2) n-CONH- (CH2) i-Ar in 16b
Ar'-(CH2) n-CONH- (CH2) i-Ar in 16b
Example 77 :
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with H2N-Ar'- (CH2)n-C0NH- (CH2)i-Ar and 3-aminomethyl-cyclohexylmethyl- amine. The following compounds of the formula 17a are obtained:
Ar'-(CH2)n-CONH-(CH2)rAr
Example 78:
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with H2N-Ar'- (CH2)n-CONH- (CH2) i-Het1 and 3-aminomethyl-benzylamine. The following compounds of the formula I8a are obtained:
Ar'-(CH2)n-CONH-(CH2)rHet1
Analogously to example 32, the compounds of the formula I8a 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 I8b are obtained:
Example 79 :
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with H2N-Ar'- (CH2)n-CONH- (CH2) i-D-H and 3-aminomethyl-benzylamine. The following compounds of the formula I9a are obtained:
Ar'-(CH2)n-CONH-(CH2)rD-H
Analogously to example 32, the compounds of the formula I9a 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 I9b are obtained:
Example 80 :
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with H2N-Ar'-
(CH2) n-CONH- (CH2) i-CH (Ar1) -Ar2 and 3-aminomethyl- benzylamine. The following compounds of the formula
110a are obtained:
H(Ar1)-Ar2
Analogously to example 32, the compounds of the formula IlOa 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 110b are obtained:
Ar'-(CH2)n-CONH-(CH2)rCH(Ari)-Ar2
Example 81 :
Analogously to Example 2, 6- nitrobenzo [de] isochromene-1, 3-dione is reacted with H2N- C6H4- (CH2)n-R3 and then with Rl-H. The following compounds of the formula Ilia are obtained: R1
Analogously to Example 11, 6-nitro-2- (3- ioodophenyl) benzo [de] isoquinoline-1, 3-dione or 6-nitro- 2- (4-iodophenyl) benzo [de] isoquinoline-1, 3-dione is reacted with H2N-Cι2H8- (CH2)n-R3 and then with Rl-H. The following compounds of the formula Ilib are obtained:
Example 82:
Analogously to Example 11, 6-nitrobenzo-
[de] isochromene-1, 3-dione is reacted with 4- iodophenylamine or 3-iodophenylamine (= I-Ar'-NH2),
Het1-B(0H)2 and then with R1-H. The following compounds of the fo :
Ar'-Het1
Example 83 :
Analogously to Example 2, 6-nitrobenzo-
[de] isochromene-1, 3-dione is reacted with R6- (CH2) n~Ph-
NH2 and then with R1-H. The following compounds of the formula 112 are obtained:
Example 84:
Analogously to Example 2, 6-nitrobenzo- [de] isochromene-1, 3-dione is reacted with (4-aminophenyl) -phenyl-acetonitrile and then with R1-H. The following la 113 are obtained:
Example 85:
Analogously to Example 11, 6-nitro-2- (4-iodo-
R >12-phenyl) benzo- [de] isoquinoline-1, 3-dione is reacted with R10-B-(OH)2 and with R1-H. The following compounds of the formula 114 are obtained:
Example 86:
Analogously to Example 11, 6-nitro-2- (3-iodo- R12-phenyl) benzo- [de] isoquinoline-1, 3-dione is reacted with R10-B-(OH)2 and with Rx-H. The following compounds of the formula Ibm are obtained:
Example 87:
Analogously to Example 2, 6-nitrobenzo-
[de] isochromene-1, 3-dione is reacted with H2N-Ar and then with Rx-H. The following compounds of the formula
Ar
Example 88:
The compound 3-{ 4- [6- (3-aminomethyl- benzylamino) -1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2- yl] -phenyl } -N- (3, 3-dimethyl-butyl) -propionamide according to example 81 is reacted with tert-butyl (tert-butoxy-carbonyliminopyrazol-1-ylmethyl) carbamate according to example 32. After removal of the protective group, N- (3, 3-Dimethyl-butyl) -3-{4- [6- (3- guanidinomethyl-benzylamino) -1, 3-dioxo-lH, 3H- benzo [de] 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) -N- (3-dimethylamino-propyl) -propionamide and C- (3-aminomethyl-cyclohexyl) -methylamine. 3- (4-{ 6- [ (3- Aminomethyl-cyclohexylmethyl) -amino] -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl}-phenyl) -N- (3-dimethylamino- propyl) -propionamide is obtained.
Example 90:
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with 2-(4-amino- phenylsulfanyl) -N- (3, 3-dimethylbutyl) -acetamide and 3- aminomethyl-benzylamine. 2- {4- [6- (3-Aminomethyl- benzylamino) -1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2- yl] -phenylsulfanyl }-N- (3, 3-dimethyl-butyl) -acetamide is obtained.
Example 91:
Analogously to Example 2, 6- chlorobenzo [de] isochromene-1, 3-dione is reacted with H2N-Ar ' -Y- (CH2)n-R3 and 3-aminomethyl-benzylamine. The following compounds of the formula 112 are obtained:
Example 92 :
Analogously to Example 2, 6- chlorobenzo [de] isochromene-1, 3-dione is reacted with 4- (pyrrolidine-1-sulfonyl) -phenylamine and 3-aminomethyl- benzylamine. 6- (3-Aminomethyl-benzylamino) -2- [4- (pyrrolidine-1-sulfonyl) -phenyl] -benzo [de] isoquinoline- 1, 3-dione is obtained.
Example 93:
Equimolar amounts of [6- (3-amino-propylamino) -1, 3- dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] -4 , 5-dimethoxy- 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-propylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] - , 5-dimethoxy-benzonitrile, methane sulfonate.
xH-nmr (DMSO-d6) :
8.80 (dd, J = 1.0 and J = 8.6 Hz, IH) , 8.50 (dd, J = 0.8 and J = 7.4 Hz, IH) , 8.34 (d, J = 8.6 Hz, IH) , 7.94 (t (N-H), J = 5.8 Hz, IH) , 7.76 (dd, J = 7.4 and J = 8.4 Hz, IH) , 7.71 (sbr, 2H (NH2) ) , 7.55 (s, IH) , 7.30 (s, IH), 6.90 (d, J = 8.8 Hz, IH) , 3.90 (s, 3H) , 3.81 (s, 3H) , 3.60-3.45 (m, 2H) , 2.96 (t, J = 7.6 Hz, 2H) , 2.31 (s, 3H) , 2.08-1.94 (m, 2H) .
Abbreviations 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 Analogously to Example 93 the following acid addtion salts are obtained:
3-{3- [6- (2-guanidino-ethylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl-phenyl}-N- (4-phenyl-butyl) - propionamide (example 40, p.145, table line 2)
3- {3- [6- (2-guanidino-ethylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl-phenyl}-N- (4-phenyl-butyl) - propionamide, methane sulfonate;
^-nmr (DMSO-d6) :
8.73 (dd, J = 1,0 and J = 8.5 Hz, IH) , 8.46 (dd, J =
1.0 and J = 7.3 Hz, IH) , 8.28 (d, J = 8.5 Hz, IH) , 7.88 (t, J = 5.6 Hz, IH) , 7.75 (dd, J = 7.3 and J = 8.4 Hz, IH), 7.61 (t, J = 5.8 Hz, IH) , 7.40-7.36 (m, IH) , 7.28- 7.23 (m, 3H) , 7.16-7.10 (m, 4H) , 6.89 (d, J = 8.7 Hz, IH) , 3.61-3.50 (m, 4H) , 3.06 (q, J = 7.0 Hz, 2H) , 2.89- 2.85 (m, 2H) , 2.53 (d, J = 7.6 Hz, IH) , 2.39 (t, J = 8.5 Hz, 2H) , 2.36 (s, 3H) , 1.56-1.49 (m, 2H) , 1.41-1.34 (m, 2H) .
N-[2-(4-chloro-phenyl)-ethyl]-3-[3-(6-{3-[ (3-guanidino- propyl) -methyl-amino] -propylamino}-l, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl) -phenyl] -propionamide (example 37, p. 135, table line 7)
N- [2- (4-chloro-phenyl) -ethyl] -3- [3- (6-{ 3- [ (3- guanidino-propyl) -methyl-amino] -propylamino}-l, 3-dioxo- 1H, 3H-benzo [de] isoquinolin-2-yl) -phenyl] -propionamide, methane sulfonate
^-nmr (DMSO-d6) :
10.49 (sbr, IH) , 8.85 (d, J = 8.5 Hz, IH) , 8.44 (dd, J = 0.9 and J = 7.3 Hz, IH) , 8.27 (d, J = 8.5 Hz, IH) , 8.01 (sbr, 1H(NH)), 7.94 (t, J = 5.6 Hz, 1H(NH)), 7.90 (t, J 5.9 Hz, 1H(NH)), 7,73 (dd, J = 7.4 and J = 8.4 Hz, IH) , 7.42-7.38 (m, IH) , 7.31 (d, J = 8.4 Hz, 2H) , 7.26 (d, J = 7.7 Hz, IH) , 7.18 (d, J = 8.4 Hz, 2H) , 7.14-7.11 (m, 2H) , 6.88 (d, J = 8.7 Hz, IH) , 3.65-3.45 (m, 3H) , 3.31-3.15 (m, 6H) , 3.11-3.04 (m, IH) , 2.85 (t, J = 7.3 Hz, 2H), 2.77 (d, J = 4.9 Hz, 3H) , 2.67 (t, J = 7.3 Hz, 2H) , 2.39 (t, J = 5.7 Hz, IH) , 2.35 (s, 3H) , 2.21-2.14 (m, 2H) , 1.96-1.89 (m, 2H) .
N- [2- (4-chloro-phenyl) -ethyl] -3-{3- [6- (2-guanidino- ethylamino) -1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] - phenyl} -propionamide (example 37, p. 135, table line 2) N- [2- (4-chloro-phenyl) -ethyl] -3-{3- [6- (2- guanidino-ethylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] -phenyl} -propionamide, methane sulfonate;
1H-nmr (DMSO-d6) : 8.74 (dd, J = 1.0 and J = 8.6 Hz, IH) , 8.44 (dd, J = 1.0 and J = 7.3 Hz, IH) , 8.27 (d, J = 8.5 Hz, IH) , 7.94 (t, J = 5.7 Hz, 1H(NH)), 7.80 (t, J = 5.2 Hz, 1H(NH)), 7.76 (t, J = 5.1 Hz, 1H(NH)), 7.74 (dd, J = 7.3 and J = 8.5 Hz, IH) , 7.40 (t, J = 7.9 Hz, IH) , 7.31 (d, J = 8.4 Hz, 2H) , 7.26 (d, J = 7.8 Hz, IH) , 7.18 (d, J = 8.4 Hz, 2H) , 7.14-7.11 (m, 2H) , 6.89 (d, J = 8.7 Hz, IH) , 3.61- 3.56 (m, 2H) , 3.55-3.50 (m, 2H) , 3.28-3.23 (m, 2H) , 2.86 (t, J = 8.2 Hz, 2H) , 2.67 (t, J = 7.1 Hz, 2H) , 2.40 (t, J = 7.3 hz, 2H), 2.35 (s, 3H) .
N- [2- (4-chloro-phenyl) -ethyl] -3-{3- [6- (3-guanidino- propylamino) -1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2- yl] -phenyl} -propionamide (example 37, p. 135, table line 6) N- [2- (4-chloro-phenyl) -ethyl] -3-{3- [6- (3- guanidino-propylamino) -1, 3-dioxo-lH, 3H- benzo[de] isoquinolin-2-yl] -phenyl} -propionamide, methane sulfonate;
^-n r (DMSO-d6) :
8.76 (d, J = 8.5 Hz, IH) , 8.44 (d, J = 7.3 Hz, IH) ,
8.27 (d, J = 8.5 Hz, IH) , 7.93 (t, J = 5.6, 1H(NH)),
7.73 (t, J = 7.5 Hz, IH), 7.65 (t, J = 5.6 Hz, IH) ,
7.40 (t, J = 8.0 Hz, IH), 7.31 (d, J = 8.4 Hz, 2H) , 7.18 (d, J = 8.4 Hz, 2H) , 71.4-7.11 (m, 2H) , 6.84 (d, J
= 8.7 Hz, IH) , 3.45 (t, J = 6.3 Hz, 2H) , 3.31-3.22 (m,
4H) , 2.86 (t, J = 8.0 Hz, 2H) , 2.66 (t, J = 7.1 Hz,
2H), 2.41 (d, J = 8.2 Hz, 2H) , 2.37 (s, 3H) , 199-1.91 (m, 2H) .
6- (3-amino-propylamino) -2- (2, 3-dimethoxyphenyl) - benzo [de] isoquinoline-1, 3-dione (example 87, p. 255, table line 3) 6- (3-amino-propylamino) -2- (2, 3-dimethoxyphenyl) - benzo [de] isoquinoline-1, 3-dione, methane sulfonate;
^-nmr (DMSO-d6) :
8.75 (dd, J = 0.9 and J = 8.4 Hz, IH) , 8.46 (dd, J = 0.8 and J = 7.3 Hz, IH) , 8.30 (d, J = 8.5 Hz, IH) , 7.86 (sbr, 1H(NH)), 7.75 (dd, J = 7.3 and J = 8.4 Hz, IH) , 7.65 (sbr, 2H(NH)), 7.17-7.15 (m, 2H) , 6.89-6.85 (m, 2H) , 3.89 (s, 3H) , 3.60 (s, 3H) , 3.51 (t, J = 7.0 Hz, 2H), 2.97 (t, J = 7.8 Hz, 2H) , 2.31 (s, 3H) , 2.03-1.96 (m, 2H) .
6- (3-amino-propylamino) -2- (4 ' -methoxy-biphenyl-4-yl) - benzo [de] isoquinoline-1, 3-dione (example 12, p. 98, table line 3) 6- (3-amino-propylamino) -2- (4 ' -methoxy-biphenyl-4- yl) -benzo [de] isoquinoline-1, 3-dione, methane sulfonate;
xH-nmr (DMSO-d6) :
8.75 (d, J = 8.5 Hz, IH) , 8.48 (d, J = 6.6 Hz, IH) , 8.31 (d, J = 8.5 Hz, IH) , 7.84 (sbr, 1H(NH)), 7.77-7.68
(m, 7H(2xNH)), 7.36 (d, J = 8.4 Hz, 2H) , 7.07 (d, J = 8.8 Hz, 2H) , 6.88 (d, J = 8.7 Hz, IH) , 3.83 (s, 3H) ,
3.54-3.48 (m, 2H) , 2.98 (t, J = 7.8 Hz, 2H) , 2.31 (s, 3H), 2.04-1.96 (m, 2H) .
6- (3-aminopropylamino) -2- (4-carbazol-9-yl-phenyl) - benzo [de] isoquinoline-1, 3-dione (example 82, p. 247, table linel) 6- (3-aminopropylamino) -2- (4-carbazol-9-yl-phenyl) - benzo [de] isoquinoline-1, 3-dione, methane sulfonate;
xH-nmr (DMSO-d6) : 8.77 (dd, J = 0.9 and J = 8.6 Hz, IH) , 8.57 (dd, J = 0.8 and J = 7.3 Hz, IH) , 8.36 (d, J = 8.5 Hz, IH) , 8.29 (d, J = 7.8 Hz, 2H) , 7.87 (t, J = 5.7 Hz, 1H(NH)), 7.81-7.77 (m, 3H) , 7.72 (sbr, 2H(NH)), 7.64 (d, J = 8.6 Hz, 2H) , 7.53-7.47 (m, 4H) , 7.36-7.32 (m, 2H) , 6.91 (d, J = 8.7 Hz, IH), 3.57 (q, J = 5.9 Hz, 2H) , 3.03-2.95 (m, 2H) , 2.31 (s, 3H) , 2.05-1.98 (m, 2H) .
N- (3-{ [2- (4 '-methoxy-biphenyl-4-yl)-l,3-dioxo-2,3- dihydro-lH-benzo [de] isoquinolin-2-yl] -phenyl }-N- (4- phenyl-butyl) -propionamide (example 85, p. 251, table line 4)
N- (3-{ [2- (4 ' -methoxy-biphenyl-4-yl) -1, 3-dioxo-2, 3- dihydro-lH-benzo [de] isoquinolin-2-yl] -phenyl }-N- (4- phenyl-butyl) -propionamide, methane sulfonate;
1H-nmr (DMSO-d6) :
8.83 (d, J = 7.8 Hz, IH) , 8.56 (t, J = 6.5 Hz, 1H(NH)), 8.49 (dd, J = 0.8 and J = 7.3 Hz, IH) , 8.20 (d, J = 8.5 Hz, IH) , 7.84 (t, J = 5.8 Hz, 1H(NH)), 7.78 (dd, J = 7,4 and J = 8.4 Hz, IH) , 7.72 (d, J = 8.5 Hz, 2H) , 7.68 (d, J = 8.8 Hz, 2H), 7.40-7.36 (m, 4H) , 7.34 (d, J = 8.5 Hz, 2H) , 7.22-7.19 (m, IH) , 7.07 (d, J = 8.8 Hz, IH) , 6.70 (d, J = 8.7 Hz, IH) , 4.70 (d, J = 5.9 Hz, 2H) , 4.36 (d, J = 5.9 Hz, 2H) , 3.82 (s, 3H) , 2.30 (s, 3H) .
6- (3-aminopropylamino) -2- (7-hydroxy-naphthalen-l-yl) - benzo [de] isoquinoline-1, 3-dione (example 87, p. 257, table line 5) 6- (3-aminopropylamino) -2- (7-hydroxy-naphthalen-l- yl) -benzo [de] isoquinoline-1, 3-dione, methane sulfonate; ^-nmr (DMSO-d6) :
9.61 (s, IH(OH)), 8.79 (dd, J = 0.9 and J = 8.6 Hz, IH) , 8.50 (dd, J = 0.8 and J = 7.3 Hz, IH) , 8.33 (d, J = 8.5 Hz, IH), 7.93-7.87 (m, 2H) , 7.79 (dd, J = 7.4 and / = 8.4 Hz, IH) , 7.74 (sbr, 3H(NH)), 7.43-7.37 (m, 2H) , 7.10 (dd, J = 2.4 and J = 8.9 Hz, IH) , 6.91 (d, J = 8.7 Hz, IH) , 6.75 (d, J = 2.4 Hz, IH) , 3.53 (q, J = 6.3 Hz, 2H) , 3.02-2.95 (m, 2H) , 2.31 (s, 3H) , 2.05-1.98 (m, 2H) .
N- [2- (4-chloro-phenyl) -ethyl] -3-{3- [6- (4- guanidinomethyl-benzylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] -phenyl }-propionamide (example 37, p. 135, table line 5) N- [2- (4-chloro-phenyl) -ethyl] -3-{3- [6- (4- guanidinomethyl-benzylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] -phenyl} -propionamide, methane sulfonate;
xH-nmr (DMSO-d6) :
8.82 (dd, J = 0.8 and J = 8.5 Hz, IH) , 8.55 (sbr, 1H(NH)), 8.45 (dd, J = 0.8 and J = 7.3 Hz, IH) , 8.15 (d, J = 8.5 Hz, IH) , 7.91 (t, J = 5.7 Hz, 1H(NH)), 7.85 (t, J = 6.1 Hz, 1H(NH)), 7.76 (dd, J = 7.4 and J = 8.4 Hz, IH) , 7.44 (d, J = 8.2 Hz, 2H) , 7.39 (t, J = 8.1 Hz, IH), 7.32-7.23 (m, 5H) , 7.17 (d, J = 8.4 Hz, 2H) , 7.12- 7.09 (m, 2H) , 6.58 (d, J = 8.7 Hz, IH) , 4.69 (d, J = 4.6 Hz, 2H) , 4.33 (d, J = 6.1 Hz, 2H) , 3.24 (q, J = 7.4 Hz, 2H), 2.84 (t, J = 8.3 Hz, 2H) , 2.66 (t, J = 7.1 Hz, 2H) , 2.39 (t, J = 8.0 Hz, 2H) , 2.34 (s, 3H) .
N- [2- (3-chloro-phenyl) -ethyl] -3- (3-{ 6- [ (4- guanidinomethyl-cyclohexylmethyl) -amino] -1, 3-dioxo- 1H, 3H-benzo [de] isoquinolin-2-yl} -phenyl) -propionamide (example 37, p. 134, table line 5)
N- [2- (3-chloro-phenyl) -ethyl] -3- (3-{ 6- [ (4- guanidinomethyl-cyclohexylmethyl) -amino] -1, 3-dioxo- 1H, 3H-benzo[de] isoquinolin-2-yl} -phenyl) -propionamide, methane sulfonate; ^-nmr (DMSO-d6) :
8.79 (d, J = 8.5 Hz, IH), 8.43 (d, J = 7.3 Hz, IH),
8.24 (dd, J = 3.1 and J = 8.6 Hz, IH) , 7.94 (t, J = 5.7 Hz, 1H(NH)), 7.84 (sbr, 1H(NH)), 7 .78-7.69 ( , IH),
7.40 (t, J = 8.0 Hz, IH) , 7.30-7.22 (m, 4H) , 7.14-7.10 (m, 3H) , 6.82 (dd, J = 3.3 and J = 8.8 Hz, IH) , 3.27 (q, J = 6.8 Hz, 2H), 3.11 (t, J = 6.5 Hz, 2H) , 2.85 (t,
J = 7.3 Hz, 2H) , 2.69 (t, J = 7.3 Hz, 2H) , 2.39 (t, J = 7.4 Hz, 2H), 2.34 (s, 3H) , 1.94-1.74 (m, 2H) , 1.60-1.40
(m, 4H) , 1.05-0.90 (m, 2H) ; (cis isomer: trans isomer =
2:1) .
N- [2- (4-chloro-phenyl) -ethyl] -3- (3-{ 6- [ (4- guanidinomethyl-cyclohexylmethyl) -amino] -1, 3-dioxo-
1H, 3H-benzo [de] isoquinolin-2-yl }-phenyl) -propionamide
(example 37, p. 135, table line 8)
N- [2- (4-chloro-phenyl) -ethyl] -3- (3-{ 6- [ (4- guanidinomethyl-cyclohexylmethyl) -amino] -1, 3-dioxo- IH, 3H-benzo [de] isoquinolin-2-yl} -phenyl) -propionamide, methane sulfonate;
xH-nmr (DMSO-d6) :
8.79 (dd, J = 1.7 and J = 7.8 Hz, IH) , 8.43 (d, J = 7.3 Hz, IH) , 8.24 (dd, J = 3.2 and J = 8.6 Hz, IH) , 7.92
(t, J = 5.7 Hz, 1H(NH)), 7.83 (sbr, 1H(NH)), 7.73-7.69
(m, IH), 7.41-7.37 (m, IH) , 7.30 (d, J = 8.4 Hz, 2H) ,
7.25 (d, J = 7.8 Hz, IH) , 7.17 (d, J = 8.4 Hz, 2H) , 7.13-7.10 (m, 2H) , 6.81 (dd, J = 2.9 and J = 8.8 Hz, IH), 3.25 (q, J = 7.3 hz, 2H) , 3.11 (t, J = 6.4 Hz, 2H) , 2.85 (t, J = 8.2 Hz, 2H) , 2.66 (t, J = 7.2 Hz, 2H), 2.39 (t, J = 7.4 Hz, 2H) , 2.33 (s, 3H) , 1.95-1.75 (m, 2H), 1.60-1.40 (m, 4H) , 1.05-0.90 (m, 2H) , ); (cis isomer:trans isomer = 2:1).
3-{3- [6- (4-guanidinomethyl-benzylamino) -1, 3-dioxo- 1H, 3H-benzo [de] isoquinolin-2-yl] -phenyl}-N- [2- (4- sulfamoyl-phenyl) -ethyl] -propionamide (example 35, 129, table line 5) 3- { 3- [ 6- (4-guanidinomethyl-benzylamino) -1, 3-dioxo- 1H, 3H-benzo [de] isoquinolin-2-yl] -phenyl}-N- [2- (4- sulfamoyl-phenyl) -ethyl] -propionamide, methane sulfonate;
'H-nmr (DMSO-d6) :
8.88 (d, J = 8.5 Hz, IH) , 8.66 (sbr, 1H(NH)), 8.50 (dd, J = 0.8 and J = 7.3 Hz, IH) , 8.20 (d, J = 8.5 Hz, IH) , 7.93 (t, J = 6.0 Hz, 1H(NH)), 7.77 (d, J = 8.3 Hz, IH) , 7.49 (d, J = 8.2 Hz, 2H) , 7.40 (d, J = 8.4 Hz, 2H) , 7.35-7.30 (m, 4H) , 7.19-7.14 (m, 3H) , 6.73 (d, J = 8.7 Hz, IH) , 4.71 (d, J = 6.1 Hz, 2H) , 4.39 (d, J = 6.1 Hz, 2H) , 3.34 (q, J = 7.4 Hz, 2H) , 2.90 (t, J = 8.6 Hz, 2H) , 2.81 (t, J = 7.2 Hz, 2H) , 2.45 (t, J = 8.3 Hz, 2H) , 2.38 (s, 3H) .
The following examples 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 NaH2P04.2H20, 28.48 g of Na2HP04.12H20 and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The mixture is adjusted to pH 6.8, made up to 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops.
Example D: Ointment 500 mg of an active compound of the formula I is mixed with 99.5 g of petroleum jelly under aseptic conditions.
Example E: Tablets A mixture of 1 kg of active compound of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 g of talc and 0.1 kg of magnesium stearate is compressed in a customary manner to give tablets such that each tablet contains 10 mg of active compound. Example F: Coated tablets
Analogously to Example E, tablets are pressed which are then coated with a coating of sucrose, potato starch, talc, tragacanth and colourant in a customary manner.
Example G: Capsules
2 kg of active compound of the formula I are dispensed into hard gelatin capsules in a customary manner such that each capsule contains 20 mg of the active compound.
Example H : Ampoules
A solution of 1 kg of active compound of the formula I in 60 ml of double-distilled water is sterile-filtered, dispensed into ampoules, lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 10 mg of active compound.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims

What is claimed is :
Compounds of the formula I
in which
R is H or N02,
R1 iiss --HHeett,, --HHeet-S02-Ar, -Het-R5 -Het- (CH2) n-Ar, NAAlk, NHA' , NA' 2r
-Y-D-H, -Y-Ar'-R3, -Y- (CH2) 0-R3,
-Y- (CH2) n- (CHR4) -R5, -Y-C [ (CH2) o"OH] 3, -Y-(CH2)m-NA2,
-Y-(CH2)m-NHA', -Y-(CH2)o-0H, -Y- (CH2) k-R6, -Y- (CH2) i-R8, -Y-(CH2) n-Het, -Y-(CH2)n-Ar,
-Y- (CH2) n-Ar' - (CH2) i-R6, -Y- (CH2) n-D- (CH2) i-R6, -Y- (CH2) n-Het- (CH2) i-R6, -Y- (CH2) n-NA- (CH2) i-R6, -Y- (CH2) n-NH- (CH2) i-R6, -Y- (CH2) n-D- (CH2) i~R8, -Y- (CH2) n-Ar' - (CH2) i-R8, -Y- (CH2) n-NH- (CH2) i-R8,
-Y-[X-0]t-[X1-0]u-X2-R6 or -Y-CX-NHlu-X^OH,
R" is -Ar, -Ar'-D-H, -Het1, -Het1-Ar, -Ar'-Het1, -Ar'-(CH2)n-R3, -Ar'-Y-(CH2)n-R3, -Ar' -Y-C (A) 2-R3, - Het^R3, -Ar' -Het^R3, -Ar' - (CH2)n-R6, -Ar'-S02-Het, -Ar'-NH-S02-Het, Ar'-S02-R7, -Ar' - (CH2) n- (CO-NH) -
(CH2)i-R6, -Ar' - (CH2) n- (CO-NH) - (CH2) i-R 11 -Ar'-
(CH2)n-CO-Het, -Ar' -(CH2)n- (CO-NH) -(CH2) i-D-H, -Ar'- (CH2) n- (CO-NH) - (CH2) i-Ar, -Ar' - (CH2) n- (CO-NH) -
(CH2) i-Het1, -Ar' - (CH2) n- (CH (CN) ) - (CH2) i-Ar,
-Ar' - (CH2) n- (CO-NH) - (CH2) i-CH (Ar1) -Ar2, -Ar' -S-
(CH2) n- (CO-NH) - (CH2) i-Ar, -Ar' -S- (CH2) n- (CO-NH) - (CH2) i-R11, -Ar' -S- (CH2) n- (CO-NH) - (CH2) i-Het1,
-Ar'-S- (CH2)n- (CO-NH) - (CH2) -CH (Ar1) -Ar2 or -Ar' -S- (CH2) n- (CO-NH) - (CH2) i-D-H, R3 is C(0)A, CONH2, CONHA, CONA2, COOH or COOA, R4 is Ph or OH,
R5 is CH3, CH2C1, CF3 or Ph, R6 is NH2, NHA, NA2, NH(D-H) or NH-C(0)A, R7 is NA(D-H), NHA, NH(D-H) or NA2,
R8 is -NH-(C=NH)-NH2, -NH- (C=NH) -NHA, -NH- (C=NH) -NA2, -NA- ( C=NH ) -NH2 , -NA- ( C=NH ) -NHA or -NA- ( C=NH ) -NA2 ,
R11 is -CH(A)-Ph,
Ar' is phenylene, biphenylene, naphthylene or pyrazol- 4-yl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, OCF3, Hal, CN, NH2, NHA, NA2, N02, CF3, S02NH2, S02Ph, S02NAH, S02NA2, Ar, Ar1 and Ar2 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, 1 ' , 4 ' , 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, OCF3, O-Ph, 0-Ph-CH3, CH2-Ph, 0-CH2-Ph, Hal, CN, NH2, NHA, NA2, N02, CF3, S02NH2, S02Ph, S02NAH, S02NA2 or R8, 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, CF3, A, N02, oxo or R5, where pyrazole is not bonded via N, Het1 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 CF3 or piperidine, morpholine, pyrrolidine or pyrrolidin-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 cyclo- hexen-1-yl, Hal is F, Cl, Br or I, , X^X2 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 10, t is 0, 1 or 2, u is 1 or 2, where if R2 is 4-chlorophenyl, R1 is not -NH-CH2-CH2-OH, and their pharmaceutically tolerable salts and solvates .
2. Compounds of the formula I according to Claim 1 a) 6-benzylamino-2- (2, 5-dichlorophenyl) -3a, 9b- dihydro-lH, 3H-benzo [de] isoquinoline-1, 3-dione; b) 3- {3- [6- (2-guanidinopropylamino) -1, 3-dioxo-
3a, 9b-dihydro-lH, 3#-benzo [de] isoquinolin-2-yl] - phenyl }-N- (2-p-tolylethyl) propionamide; c) 3- {3- [6- (2-guanidinomethylcyclohexyl- methyl) amino] -1, 3-dioxo-3a, 9b-dihydro-li-', 3H- benzo [de] isoquinolin-2-yl] phenyl }- N- (2-p-tolylethyl) propionamide; d) 3-{ 3- [6- (4-Guanidinomethyl-benzylamino) -1, 3- dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] -phenyl }- N- [2- (4-sulfamoyl-phenyl) -ethyl] -propionamide; e) N- [2- (4-Chloro-phenyl) -ethyl] -3-{3- [6- (4- guanidinomethyl-benzylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] -phenyl}- propionamide; f) 6- (3-Amino-propylamino) -2- (3, 4, 5-trimethoxy- phenyl) -benzo [de] isoquinoline-1, 3-dione; g) 6- (3-Amino-propylamino) -2- (7-hydroxy- naphthalen-l-yl) -benzo [de] isoquinoline-1, 3- dione; h) 6- [ (3-Amino-propylamino) -1, 3-dioxo-lH, 3H- benzo[de] isoquinolin-2-yl] -4, 5-dimethoxy- benzonitrile; i) 6- (3-Amino-propylamino) -2- (2, 3-dimethoxy- phenyl) -benzo [de] isoquinoline-1, 3-dione; j ) N- [2- (3-Chloro-phenyl) -ethyl] -3-{3- [6- (4- guanidinomethyl-cyclohexylmethyl-amino) -1, 3- dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] -phenyl }- propionamide; k) N- [2- (4-Chloro-phenyl) -ethyl] -3-{3- [6- (4- guanidinomethyl-cyclohexylmethyl-amino) -1, 3- dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] -phenyl}- propionamide; 1) 6- (3-Amino-propylamino) -2- (4 ' -methoxy-biphenyl- 4-yl) -benzo [de] isoquinoline-1, 3-dione; m) 6- (3-Amino-propylamino) -2- (4-carbazol-9-yl- phenyl) -benzo [de] isoquinoline-1, 3-dione; n) 6- (3-Amino-propylamino) -2- (4 ' -hydroxy-2-methyl- biphenyl-4-yl) -benzo [de] isoquinoline-1, 3-dione; o) N-(3-{ [2-(4'Methoxy-biphenyl-4-yl)-l,3-dioxo-
2, 3-dihydro-lH-benzo [de] isoquinolin-6-ylamino] - methyl} -benzyl) -guanidine; p) 3-{ 3- [6- (2-Guanidino-ethylamino) -1, 3-dioxo- 1H, 3H-benzo [de] isoquinolin-2-yl] -phenyl }-N- (4- phenyl-butyl) -propionamide; q) N- (2- (4-Chloro-phenyl) -ethyl] -3-{3- [6- (2- guanidino-ethylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] -phenyl }- propionamide; r) N- (2- (4-Chloro-phenyl) -ethyl] -3-{3- [6- (3- guanidino-propylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] -phenyl }- propionamide; 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- ( ' -methoxy-biphenyl- 4-yl) -benzo [de] isoquinoline-1, 3-dione; v) N- [3- ( {2- [4- (3, 6-Di-tert-butyl-carbazol-9-yl) - phenyl] -1, 3-dioxo-2, 3-dihydro-lH- benzo [de] isoquinolin-6-ylamino] -methyl) - benzyl] -guanidine; w) 6- (3-Amino-propylamino) -2- (4-carbazol-9-yl- phenyl) -benzo [de] isoquinoline-1, 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
in which
R9 is Cl, Br, N02 or R1, where
R has the meaning indicated in Claim 1 is reacted with a compound of the formula III
H2N—R2 III in which R2 has the meaning indicated in Claim 1, and, if necessary, the radical R9 is converted into a radical R1, or (c) a radical R and/or R2 and/or R9 is converted into another radical R and/or R2 and/or R9 by, for example
- converting an amino group into a guanidino group by reaction with an amidinating agent,
- reacting an aryl bromide or iodide to give the corresponding coupling products by means of a Suzuki coupling with boronic acids,
- reducing a nitro group, sulfonyl group or sulfoxyl group,
- etherifying an OH group or subjecting an OA group to ether cleavage,
- alkylating a primary or secondary amino group,
- partially or completely hydrolysing a CN group, - cleaving an ester group or esterifying a carboxylic acid radical,
- or carrying out a nucleophilic or electrophilic substitution, and/or (d) a base or acid of the formula I is converted into one of its salts or solvates.
4. A pharmaceutical composition comprising an effective amount of a compound of formula I of claim 1 or a physiologically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
5. A pharmaceutical composition of claim 4 which is effective as a glycoprotein IblX antagonist.
6. A pharmaceutical composition of claim 5, wherein said glycoprotein IblX 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 IblX antagonist.
9. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts or solvates for the production of a medicament for the control of thrombotic disorders and sequelae deriving therefrom or for use as anti-adhesive substances.
10. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts or solvates in the treatment of illnesses, such as for the prophylaxis and/or therapy of thrombotic disorders, as well as sequelae such as, for example, myocardial infarct, arteriosclerosis, angina pectoris, acute coronary syndromes, peripheral circulatory disorders, stroke, transient ischaemic attacks, reocclusion/restenosis after angioplasty/stent implantations or as anti-adhesive substances for implants, catheters or heart pacemakers.
EP99968783A 1998-11-25 1999-11-09 Substituted benzo[de]isoquinoline-1,3-diones Withdrawn EP1144381A2 (en)

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US19941398A 1998-11-25 1998-11-25
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US39878399A 1999-09-20 1999-09-20
US398783 1999-09-20
PCT/EP1999/008561 WO2000032577A2 (en) 1998-11-25 1999-11-09 Substituted benzo[de]isoquinoline-1,3-diones

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SK7022001A3 (en) 2002-09-10
WO2000032577A3 (en) 2000-09-21
HUP0104520A2 (en) 2002-04-29
CN1330638A (en) 2002-01-09
NO20012544L (en) 2001-05-23
WO2000032577A2 (en) 2000-06-08
CZ20011782A3 (en) 2001-09-12
JP2002537225A (en) 2002-11-05
HUP0104520A3 (en) 2002-10-28
TW473474B (en) 2002-01-21
AU2660300A (en) 2000-06-19
ID28982A (en) 2001-07-19
CA2352045A1 (en) 2000-06-08
BR9915648A (en) 2001-08-14
KR20010080569A (en) 2001-08-22
NO20012544D0 (en) 2001-05-23
PL348204A1 (en) 2002-05-06
AU760136B2 (en) 2003-05-08

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