WO2000032577A2 - Benzo[de]isoquinoline-1,3-diones substituees - Google Patents

Benzo[de]isoquinoline-1,3-diones substituees Download PDF

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Publication number
WO2000032577A2
WO2000032577A2 PCT/EP1999/008561 EP9908561W WO0032577A2 WO 2000032577 A2 WO2000032577 A2 WO 2000032577A2 EP 9908561 W EP9908561 W EP 9908561W WO 0032577 A2 WO0032577 A2 WO 0032577A2
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Prior art keywords
phenyl
benzo
het
formula
dione
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PCT/EP1999/008561
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English (en)
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WO2000032577A3 (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
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Merck Patent Gmbh
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Priority to CA002352045A priority Critical patent/CA2352045A1/fr
Priority to JP2000585219A priority patent/JP2002537225A/ja
Priority to KR1020017006547A priority patent/KR20010080569A/ko
Priority to PL99348204A priority patent/PL348204A1/xx
Priority to BR9915648-2A priority patent/BR9915648A/pt
Priority to SK702-2001A priority patent/SK7022001A3/sk
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to HU0104520A priority patent/HUP0104520A3/hu
Priority to AU26603/00A priority patent/AU760136B2/en
Priority to EP99968783A priority patent/EP1144381A2/fr
Publication of WO2000032577A2 publication Critical patent/WO2000032577A2/fr
Publication of WO2000032577A3 publication Critical patent/WO2000032577A3/fr
Priority to NO20012544A priority patent/NO20012544L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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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  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés de formule (I) dans laquelle R, R1 et R2 ont les significations indiquées, ainsi que leurs sels ou solvates, utilisés comme antagonistes de glycoprotéine IbIX.
PCT/EP1999/008561 1998-11-25 1999-11-09 Benzo[de]isoquinoline-1,3-diones substituees WO2000032577A2 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
JP2000585219A JP2002537225A (ja) 1998-11-25 1999-11-09 置換ベンゾ［ｄｅ］イソキノリン−１，３−ジオン類
KR1020017006547A KR20010080569A (ko) 1998-11-25 1999-11-09 치환된 벤조[데]이소퀴놀린-1,3-디온
PL99348204A PL348204A1 (en) 1998-11-25 1999-11-09 Substituted benzo[de]isoquinoline-1,3-diones
BR9915648-2A BR9915648A (pt) 1998-11-25 1999-11-09 Benzo [de] isoquinolina-1,3-dionas substituìdas
SK702-2001A SK7022001A3 (en) 1998-11-25 1999-11-09 Derivative of benzo[de]isoquinoline-1,3-dione, process for the preparation thereof, use thereof and pharmaceutical composition comprising the same
CA002352045A CA2352045A1 (fr) 1998-11-25 1999-11-09 Benzo[de]isoquinoline-1,3-diones substituees
HU0104520A HUP0104520A3 (en) 1998-11-25 1999-11-09 Substituted benzo[de]isoquinoline-1,3-diones process for their preparation and pharmaceutical compositions containing them
AU26603/00A AU760136B2 (en) 1998-11-25 1999-11-09 Substituted benzo(DE)isoquinoline-1,3-diones
EP99968783A EP1144381A2 (fr) 1998-11-25 1999-11-09 Benzo[de]isoquinoline-1,3-diones substituees
NO20012544A NO20012544L (no) 1998-11-25 2001-05-23 Substituerte benzo[de]isokinolin-1,3-dioner

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US19941398A 1998-11-25 1998-11-25
US09/199,413 1998-11-25
US39878399A 1999-09-20 1999-09-20
US09/398,783 1999-09-20

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WO2000032577A2 true WO2000032577A2 (fr) 2000-06-08
WO2000032577A3 WO2000032577A3 (fr) 2000-09-21

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JP (1) JP2002537225A (fr)
KR (1) KR20010080569A (fr)
CN (1) CN1330638A (fr)
AU (1) AU760136B2 (fr)
BR (1) BR9915648A (fr)
CA (1) CA2352045A1 (fr)
CZ (1) CZ20011782A3 (fr)
HU (1) HUP0104520A3 (fr)
ID (1) ID28982A (fr)
NO (1) NO20012544L (fr)
PL (1) PL348204A1 (fr)
SK (1) SK7022001A3 (fr)
TW (1) TW473474B (fr)
WO (1) WO2000032577A2 (fr)

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WO2003007931A1 (fr) * 2001-06-08 2003-01-30 Institute Of Medicinal Molecular Design. Inc. Derives de sulfonamide
US6515129B1 (en) * 1996-08-16 2003-02-04 Ishihara Sangyo Kaisha Ltd. Pharmaceutical composition
WO2006058778A2 (fr) * 2004-12-03 2006-06-08 Roche Diagnostics Gmbh Colorant luminescent d'indication et capteur optique
FR2915685A1 (fr) * 2007-05-02 2008-11-07 Thales Sa Compose fluorescent a l'etat solide dans l'eau,procede de synthese et utilisation dans des capteurs
US8012995B1 (en) * 1999-09-28 2011-09-06 Merck Serono Sa Pharmaceutically active sulfonamide derivatives
WO2014149198A1 (fr) * 2013-03-15 2014-09-25 Alumend, Llc Compositions et procédés d'utilisation des compositions pour assouplissement de plaque
WO2016041511A1 (fr) 2014-09-19 2016-03-24 Yen-Ta Lu Composés benzo-hétérocycliques et leurs applications
CN110407865A (zh) * 2019-08-02 2019-11-05 山东师范大学 基于苯磺酰胺结构的式（i）化合物及其制备方法与应用
CN111518075A (zh) * 2020-04-17 2020-08-11 西南大学 萘酰亚胺哌嗪三唑类化合物及其制备方法和应用

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US6693198B2 (en) * 2002-04-22 2004-02-17 Xanthus Life Sciences, Inc. Amonafide salts
CN105492428A (zh) * 2013-05-01 2016-04-13 中央研究院 治疗β-地中海贫血和镰状细胞病的方法和组合物
CN103450176B (zh) * 2013-08-15 2016-07-06 大连理工大学 一类含2-（4-氨基苯基）苯并噻唑萘酰亚胺化合物及其应用
CN106905237B (zh) * 2017-02-08 2019-05-14 上海师范大学 一种pH和乏氧双响应定位肿瘤细胞的萘酰亚胺类比率荧光探针及其合成方法
CN110283123B (zh) * 2019-07-08 2022-06-17 桂林医学院 4-对甲苯磺酰基哌嗪-3-硝基-1,8-萘酰亚胺衍生物及其合成方法和应用
CN110272388B (zh) * 2019-07-08 2022-06-17 桂林医学院 4-二硫代甲酸哌嗪-3-硝基-1,8-萘酰亚胺衍生物及其合成方法和应用

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FR2271215A1 (fr) * 1974-05-15 1975-12-12 Hoechst Ag
FR2392978A2 (fr) * 1977-06-04 1978-12-29 Made Labor Sa Naphtalimides substitues utilisables comme medicaments
EP0268093A1 (fr) * 1986-10-21 1988-05-25 Knoll Ag 5-Nitrobenzo[de]isoquinoléine-1,3-diones, leur préparation et utilisation
WO1998017278A1 (fr) * 1996-10-21 1998-04-30 Allelix Biopharmaceuticals Inc. Compositions antagonistes de la neurotrophine
WO1998018764A1 (fr) * 1996-10-28 1998-05-07 Merck Patent Gmbh Dihydrobenzoanthracenone, -pyrimidinone ou dihydroanphtoquinolinone

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FR2271215A1 (fr) * 1974-05-15 1975-12-12 Hoechst Ag
FR2392978A2 (fr) * 1977-06-04 1978-12-29 Made Labor Sa Naphtalimides substitues utilisables comme medicaments
EP0268093A1 (fr) * 1986-10-21 1988-05-25 Knoll Ag 5-Nitrobenzo[de]isoquinoléine-1,3-diones, leur préparation et utilisation
WO1998017278A1 (fr) * 1996-10-21 1998-04-30 Allelix Biopharmaceuticals Inc. Compositions antagonistes de la neurotrophine
WO1998018764A1 (fr) * 1996-10-28 1998-05-07 Merck Patent Gmbh Dihydrobenzoanthracenone, -pyrimidinone ou dihydroanphtoquinolinone

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KEN-ICHI N ET AL: "N-Aryl-1,8-naphtalimides as highly sensitive fluorescent labeling reagents for canitine" DYES AND PIGMENTS., vol. 43, no. 3, 14 October 1999 (1999-10-14), pages 235-239, XP002138322 ELSEVIER APPLIED SCIENCE PUBLISHERS. BARKING., GB ISSN: 0143-7208 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6515129B1 (en) * 1996-08-16 2003-02-04 Ishihara Sangyo Kaisha Ltd. Pharmaceutical composition
US8012995B1 (en) * 1999-09-28 2011-09-06 Merck Serono Sa Pharmaceutically active sulfonamide derivatives
WO2003007931A1 (fr) * 2001-06-08 2003-01-30 Institute Of Medicinal Molecular Design. Inc. Derives de sulfonamide
US7547716B2 (en) 2001-06-08 2009-06-16 Institute Of Medicinal Molecular Design, Inc. Sulfonamide derivatives
WO2006058778A2 (fr) * 2004-12-03 2006-06-08 Roche Diagnostics Gmbh Colorant luminescent d'indication et capteur optique
WO2006058778A3 (fr) * 2004-12-03 2006-08-10 Roche Diagnostics Gmbh Colorant luminescent d'indication et capteur optique
US8097725B2 (en) 2004-12-03 2012-01-17 Roche Diagnostics Operations, Inc. Luminescent indicator dye and optical sensor
FR2915685A1 (fr) * 2007-05-02 2008-11-07 Thales Sa Compose fluorescent a l'etat solide dans l'eau,procede de synthese et utilisation dans des capteurs
WO2014149198A1 (fr) * 2013-03-15 2014-09-25 Alumend, Llc Compositions et procédés d'utilisation des compositions pour assouplissement de plaque
US10131635B2 (en) 2013-03-15 2018-11-20 Alumend, Llc Compositions and methods of using the compositions for plaque softening
WO2016041511A1 (fr) 2014-09-19 2016-03-24 Yen-Ta Lu Composés benzo-hétérocycliques et leurs applications
CN107087409A (zh) * 2014-09-19 2017-08-22 吕衍达 苯并杂环化合物及其应用
EP3194368A4 (fr) * 2014-09-19 2018-03-21 MacKay Medical Foundation the Presbyterian Church in Taiwan MacKay Memorial Hospital Composés benzo-hétérocycliques et leurs applications
CN107087409B (zh) * 2014-09-19 2020-07-31 吕衍达 苯并杂环化合物及其应用
CN110407865A (zh) * 2019-08-02 2019-11-05 山东师范大学 基于苯磺酰胺结构的式（i）化合物及其制备方法与应用
CN110407865B (zh) * 2019-08-02 2022-04-15 山东师范大学 基于苯磺酰胺结构的式（i）化合物及其制备方法与应用
CN111518075A (zh) * 2020-04-17 2020-08-11 西南大学 萘酰亚胺哌嗪三唑类化合物及其制备方法和应用
CN111518075B (zh) * 2020-04-17 2023-03-28 西南大学 萘酰亚胺哌嗪三唑类化合物及其制备方法和应用

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CN1330638A (zh) 2002-01-09
HUP0104520A3 (en) 2002-10-28
BR9915648A (pt) 2001-08-14
JP2002537225A (ja) 2002-11-05
TW473474B (en) 2002-01-21
CZ20011782A3 (cs) 2001-09-12
AU760136B2 (en) 2003-05-08
EP1144381A2 (fr) 2001-10-17
HUP0104520A2 (hu) 2002-04-29
CA2352045A1 (fr) 2000-06-08
AU2660300A (en) 2000-06-19
PL348204A1 (en) 2002-05-06
ID28982A (id) 2001-07-19
KR20010080569A (ko) 2001-08-22
NO20012544D0 (no) 2001-05-23
WO2000032577A3 (fr) 2000-09-21
NO20012544L (no) 2001-05-23
SK7022001A3 (en) 2002-09-10

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