WO2000031039A1 - Substituted benzo[de]isoquinoline-1,3-diones - Google Patents

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

Info

Publication number
WO2000031039A1
WO2000031039A1 PCT/EP1999/008560 EP9908560W WO0031039A1 WO 2000031039 A1 WO2000031039 A1 WO 2000031039A1 EP 9908560 W EP9908560 W EP 9908560W WO 0031039 A1 WO0031039 A1 WO 0031039A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
het
conh
group
compound
Prior art date
Application number
PCT/EP1999/008560
Other languages
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
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
Priority to MXPA01005228A priority Critical patent/MXPA01005228A/en
Priority to BR9915611-3A priority patent/BR9915611A/en
Priority to PL99347766A priority patent/PL347766A1/en
Priority to SK701-2001A priority patent/SK7012001A3/en
Priority to HU0104469A priority patent/HUP0104469A3/en
Priority to CA002351348A priority patent/CA2351348A1/en
Priority to AU15049/00A priority patent/AU1504900A/en
Priority to EP99957291A priority patent/EP1133475A1/en
Priority to JP2000583867A priority patent/JP2002530379A/en
Publication of WO2000031039A1 publication Critical patent/WO2000031039A1/en
Priority to NO20012543A priority patent/NO20012543L/en

Links

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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to substituted benzo [de]- isoquinoline-1, 3-diones of the formula I
  • R is H, A or CH 2 -Ph
  • R 1 is -Het, -N-[(CH 2 ) s -OH] 2 , -N- [ (CH 2 ) s -OA] 2 , -NA-(CH 2 ) S -Ar, -NA- (CH 2 ) m -R 5 , -Y- (CH 2 ) m -R 5 , -Y-(CH 2 ) 2 -NHA, -Y-(CH 2 ) 2 -NH-(CH 2 ) s -OH, -Y- (CH 2 ) 2 -NA 2 , -Y-(CH 2 ) m -OH, -Y-(CH 2 ) n -(CHR 4 ; -R 3 , -Y-(CH 2 ) n -R 4 R q
  • R J is CH 3 ,
  • R° is NH 2 , NHA, NA 2 , NHAr, -NH-(CH 2 ) n -OH or -NH-(CH 2 ) n -OA,
  • R D is H or R 5
  • R 7 is -Ar'-(CH 2 ) n -R b or -Ar' - (CH 2 ) n -R "
  • Ar' is phenylene, cycloalkylene or biphenylene, which is unsubstituted or mono- or disubstituted by A, OH, OA, Hal, CN, NH 2 , NHA, NA 2 , N0 2 , CF 3 , CO-A, S0 2 NH 2 , S0 2 NAH, S0 2 NA 2 ,
  • Ar is phenyl, cycloalkyl, naphthyl, cyclohex-1-enyl, biphenyl, bicyclohexyl, 4-cyclohexyl-phenyl, benzo [1, 3] dioxol-5-yl, or indanyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, O-Ph, 0-CH 2 -Ph, 0-Ph-CH 3 , 0 (cycloalkyl) , Hal, CN, NH 2 , NHA, NA 2 , NH-C(0)A, (CH 2 ) n -NH 2 , (CH 2 ) n - NHA, (CH 2 ) n -NA 2 , N0 2 , CF 3 , C(0)A, S0 2 -Ph, S0 2 NH 2 , S0NAH, S0 2 NA 2 or S0 2 NA-Ph,
  • Ar 1 and Ar 2 are each independently phenyl
  • Het is a saturated, partially or completely unsatura- ted mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by CN, Hal, OH, OA, CF 3 , A, N0 2 , CO, CO-A or R 5 ,
  • Het 1 is an unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or
  • 2 N and/or 1 or 2 S or 0 atoms can be present and/or can be mono- or disubstituted by Hal, OH,
  • A is unbranched or branched alkyl having 1-6 C atoms
  • Hal is F, Cl, Br or I, X,
  • X ⁇ X 2 in each case independently of one another are alkylene having 1 to 12 C atoms,
  • Y is 0, S or NH i is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, m is 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 or 12 , n,o in each case independently of one another are 0,
  • the invention is based on the object of finding novel compounds having valuable properties, in parti- cular those which can be used for the production of medicaments .
  • 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 Willebrand factor (vWF) . This action can be demonstrated, for example, by a method which is described by S. Meyer et al. in J. Bioi. Chem. 1993, 268, 20555-20562.
  • the GPIblX alpha-thrombin receptor (N.J. Greco, Biochemistry 1996, 35, 915-921) can also be blocked by the compounds mentioned.
  • 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 thrombotic 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.
  • 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.
  • the invention relates to the compounds of the formula I and their salts or solvates, and to a process for the preparation of these compounds and their salts or solvates, characterized in that a) a compound of the formula I is liberated from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent, or b) a compound of the formula II
  • R 9 is Cl, Br, N0 2 or R 1 , and
  • R 1 has the meaning indicated in Claim 1 is reacted with a compound of the formula III
  • R 9 is Cl, Br, N0 2 or R 1 , where R 1 has the meaning indicated in Claim 1 is reacted with a compound of the formula V L (CHRJi R 2 V in which L is Cl, Br, or I, OH or a reactive esterified
  • 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.
  • 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.
  • 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.
  • A is alkyl and has 1 to 6, preferably 1, 2, 3 or 4 C atoms.
  • Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, additionally also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1 2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl- 1-methylpropyl, l-ethyl-2-methylpropyl, 1,1,2- or 1, 2, 2-trimethylpropyl, .
  • Ar is preferentially phenyl, preferably
  • 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-ethoxypheny
  • Ar is also preferentially unsubstituted biphenyl - as indicated - or alternatively monosubstituted biphenyl, specifically preferentially biphenyl-4-yl or biphenyl-3-yl, 2 ' -methylbiphenyl-4-yl, 3 ' -methylbiphenyl-4-yl, 4 ' -methylbiphenyl-4-yl, 2 ' -methylbiphenyl-3-yl,
  • Ar is preferably cycloalkyl, particularly preferred cyclohexyl or cyclopentyl.
  • Ar 1 and Ar 2 are each independently phenyl.
  • Ar' preferentially is phenylene, cyclohexylene or biphenylene, which is unsubstituted or monosubstituted by Hal or CN.
  • Ar' is preferentially unsubstituted or substituted phenylene or cycloalkylene, where R 5 is preferentially an amino, alkylamino or dialkylamino group and where n can be 0,
  • Ar' is preferably unsubstituted or substituted phenylene or cycloalkylene, where R 8 is preferentially an amido, an alkylamido or dialkylamido group or -CONH- (CH 2 ) 0 -Ar,
  • CONHCCgHn is particularly preferred for -Ar' - (CH 2 ) n -R
  • Cycloalkyl having 3 to 8 carbon atoms is preferentially cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; particularly preferred cyclohexyl or cyclopentyl .
  • Cycloalkylene having 3 to 8 carbon atoms is preferentially cyclobutylene, cyclopentylene, cyclohexylene, or cycloheptylene; particularly preferred cyclohexylene.
  • cycloalkyl having 3 to 8 carbon atoms is preferentially cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy; particularly preferred cyclopentyloxy.
  • Hal is preferably F, Cl, Br or iodine.
  • Het 1 is preferentially substituted or unsubstituted 2-, 3-, or 4-pyridyl, 2- or 3-benzo[b] thiophenyl, lH-indol-2-yl, lH-indol-3-yl, 4-, 5-, 6-, 7-fluoro-lH-indol-2-yl, 4-, 5-, 6-, 7-fluoro- lH-indol-3-yl, 4-, 5-, 6-, 7-methyl-lH-indo-2-yl, 4-, 5-, 6-, 7-methyl-lH-indol-3-yl, 4-, 5-, 6-, methoxy-lH- indol-2-yl or 4-, 5-, 6-, 7-methoxy-lH-indol-3-yl, 4-Pyridyl, 3-benzo [b] thiophenyl, lH-indol-3
  • Het is preferably substituted or unsubstituted 2- or 3-furyl, 2- or 3-thienyl, 2-chloro-thienyl-5-yl, 2-acetyl-thienyl-5-yl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 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, 4-triazol-l-, -4- or -5-yl, 1- or 5-tetrazolyl, 1, 2, 3-oxadiazol-4- or -5-yl, 1, 2, -oxadiazol-3- or -5-yl, 1, 3, 4-thiadia
  • 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, pyrrolidine-2-on-l-yl, tetrahydro-1-, -2- or -3-pyrrolyl, tetrahydro-1-, -2- or 4-imidazolyl, 2, 3-dihydro-l-, -2-
  • 2-, 3- or 4-pyridyl 1-imidazolyl, 2-methyl-l-imidazolyl, 2-pyrimidinyl, 5-fluoro-lH- indol-2-yl, 2, 3-dihydro-l-, -2-, -3-, -4-, -5-, -6-, -7-lH-indolyl, 1-quinolinyl, 1-isoquinolinyl, 1, 2, 3, 4-tetrahydroisoquinoline-l-yl, tetrahydro- 1-pyrrolyl, 1-piperidinyl, 2, 6-tetramethyl- piperidine-4-yl, 1-azepanyl, 4-morpholinyl, 1- piperazinyl, 4-methyl-piperazin-l-yl, 4-phenyl- piperazin-1-yl or 4-phenylmethylpiperazin-l-yl is particularly preferred.
  • Het and Ar have one of the preferred meanings indicated above, where Het is preferably piperidine-1, 4-diyl or piperazine-1, 4-diyl and n can be 0, 1, 2, 3, or 4.
  • Het has one of the preferred meanings indicated above, where in -Het-Het the first heterocycle is preferably piperidine-1, 4-diyl or
  • Y is preferably 0, S or NH, where Het has one of the preferred meanings indicated above and R 6 is preferentially H, amino or alkylamino.
  • n and o independently of one another are preferably 0, 1, 2, 3 or 4.
  • NH-(CH 2 ) 3 —N N—(CH 2 ) 3 NH 2 are particularly preferred for -Y- (CH 2 ) n -Het (CH 2 ) 0 -R 6 .
  • Y is preferentially 0, S, or NH, where Ar' has a preferred meaning indicated beforehand and R 6 is preferably H, amino or alkylamino and n and o independently of one another are 0, 1, 2, 3 or 4.
  • Y is preferentially O, S, or NH, where Ar' has a preferred meaning indicated beforehand and R 11 is preferably -NH-
  • 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 preferentially 0, S or NH, where X, X 1 and X 2 have a preferred meaning indicated beforehand.
  • R 5 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 ) -0-(CH 2 ) 3 -NH 2 is particularly preferred for -Y- [X-O] t - [X 1 -0] U -X 2 -R 5 .
  • Y is preferentially 0, S or NH, particularly preferentially NH.
  • R is preferably H, A, or CH 2 -Ph, where A has a preferred meaning indicated above. H, sec-butyl or CH 2 -Ph is particularly preferred.
  • R 1 is preferably -Het, -N- [ (CH 2 ) s -OH] 2 . -N-[(CH 2 ) s -OA] 2 , -NA-(CH 2 ) S -Ar, -NA- (CH 2 ) m ⁇ R 5 , -Y-(CH 2 ) ra -R 5 , -Y-(CH 2 ) 2 -NHA, -Y- (CH 2 ) 2 -NA 2 ,
  • s in -N-[ (CH 2 ) s -OH] 2 and -N- [ (CH 2 ) ⁇ -OA] 2 is preferably 1, 2, 3 or 4 and A has the preferred meaning indicated beforehand.
  • -N- [ (CH 2 ) 2 -OH] 2 is particularly preferred for -N-[(CH 2 ) s -OH] 2 .
  • a and Ar have a preferred meaning indicated beforehand and s is preferably 1, 2,
  • a in -NA- (CH 2 ) S -R 5 as a substituent for R 1 has a preferred meaning indicated beforehand, where R 5 is preferably amino, alkylamino or dialkylamino and s is 1, 2, 3 or 4.
  • R 5 is preferably amino, alkylamino or dialkylamino and s is 1, 2, 3 or 4.
  • -N (CH 3 ) - (CH 2 ) 3 -NH (CH 3 ) and -N(CH 3 ) -(CH 2 ) 2 -N(C 2 H 5 ) 2 are particularly preferred for -NA-(CH 2 ) S -R 5 .
  • -Y-(CH 2 ) m -R 5 Y is preferentially 0, S or NH, where R 5 is preferably amino, alkylamino or dialkylamino and m is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • R 5 is preferably amino, alkylamino or dialkylamino and m is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • -NH- (CH 2 ) 3 -NH 2 -NH-(CH 2 ) 3 -NH(CH 3 ), -NH- (CH 2 ) 3 -N (CH 3 ) 2 ,
  • -NH- (CH 2 ) 4 -NH 2 , -NH-(CH 2 ) 5 -NH 2 , -NH- (CH 2 ) 7 -NH 2 and -NH- (CH 2 ) 8 -NH 2 are particularly preferred for -Y-(CH 2 ) m -R 5 .
  • Y is preferably 0, S or NH, where A has a preferred meaning indicated beforehand.
  • -NH- (CH 2 ) 2 -NH (C 2 H 5 ) , -NH- (CH 2 ) 2 -NH (C 3 H 7 ) and -NH- (CH 2 ) 2 -NH[CH(CH 3 ) 2 ] are particularly preferred for -Y-(CH 2 ) 2 -NHA.
  • Y is preferably 0, S or NH, where s is 1, 2, 3 or 4.
  • -NH- (CH 2 ) 2 -NH (CH 2 ) 2 -0H is particularly preferred for -Y- (CH 2 ) 2 -NH- (CH 2 ) S -0H.
  • Y is preferably 0, S or NH, where m is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • -NH- (CH 2 ) 5 ⁇ OH is particularly preferred for -Y- (CH 2 ) m -0H.
  • Y is preferably 0, S or NH, where R 3 is preferably methyl, R 4 is preferentially Ar and n is 0, 1, 2, 3 or 4.
  • -NH- (CHPh) -CH 3 is particularly preferred for -Y- (CH 2 ) n - (CHR 4 ) -R 3 .
  • Y is preferentially 0, S or NH, where in this formula R 4 is preferably COOH or COOA, A has a preferred meaning indicated beforehand and n is 0, 1, 2, 3 or 4.
  • -NH- (CH 2 ) 2 -COOMe is particularly preferred .
  • Y is preferentially 0, S, NH, where A has a preferred meaning indicated beforehand, R 5 is preferably amino, alkylamino or dialkylamino and n and o in each case independently of one another are 0, 1, 2, 3 or 4.
  • -NH-(CH 2 )3-N(CH 3 )-(CH 2 ) 3 -NH 2 is particularly preferred for -Y- (CH 2 ) n -NA- (CH 2 ) 0 -R 5 .
  • i is preferentially 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, particularly preferentially 1, 2, 3, 5, 7, 10 or 11.
  • R 2 is preferably H, OH, OA, COOH, COOA, Ar, CH(Ph)-Ph, Het 1 , R 5 , R 7 or R 8 , where A, Ar and Het 1 have a preferred meaning indicated beforehand.
  • R 3 is preferentially CH 3 . H
  • R 5 is preferentially amino, alkylamino, dialkylamino, NHAr, -NH- (CH 2 ) n ⁇ OH or -NH- (CH 2 ) n -OA, where A and Ar have a preferred meaning indicated beforehand and n is 0, 1, 2, 3, or 4. -NH- (CH 2 ) 2 -OH is particularly preferred for -NH- (CH 2 ) n -OH.
  • R 6 is H or R 5 , where R 5 has a preferred meaning indicated beforehand.
  • R 7 is preferentially -Ar' - (CH 2 ) n -R 8 or -Ar'-(CH 2 ) n -R 5 , where -Ar' - (CH 2 ) n -R 8 and -Ar' - (CH 2 ) n -R 5 have a preferred or particularly preferred meaning indicated beforehand.
  • R 8 is preferably CONH 2 , CONHA, CONA 2 ,
  • CONH- (CH 2 ) o -CH (Ar ⁇ -Ar 2 , and CONH- (CH 2 ) 0 -R 5 have a preferred or particularly preferred meaning indicated beforehand in -Ar ' - (CH 2 ) n -R 8 .
  • CH (CH 3 ) -CONH 2 is HA-CONH 2 .
  • R 11 . i is preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, particularly preferred 1, 2, 3, 4, 5 or 6.
  • m is preferably 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, particularly preffered 3, 4, 5, 6, 7 or 8.
  • n and o are in each case independently of one another preferably 0, 1, 2, 3 or 4.
  • s is preferably 1, 2, 3 or 4.
  • t is preferably 0, 1 or 2.
  • u is preferably 1 or 2.
  • R' is H
  • R 1 is -Het, -N-[ (CH 2 ) s -OH] 2 , -Y-(CH 2 ) n -R 4 or R 4 and is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • R is H, R 2 is OH R 1 is -Het or -Y- (CH 2 ) n - (CHR 4 ) -R 3 and i is 2;
  • R 1 is -Het, -Y-(CH 2 ) n -(CHR 4 )-R 3 ,
  • R is H
  • R 2 is Ar
  • R 1 is -Het, -NA-(CH 2 ) S -Ar, -Y- (CH 2 ) m -R 5 , -Y- (CH 2 ) m -OH, -Y- (CH 2 ) n - (CHR 4 ) -R 3 , -Y-(CH 2 ) n -R 4 , -Y-(CH 2 ) n -Het-(CH 2 ) 0 -R 6 ,
  • R 2 is Het 1 ,
  • R 1 is -Het, -NA-(CH 2 ) S -Ar, -Y- (CH 2 ) m -R 5 , -Y-(CH 2 ) m -OH, -Y-(CH 2 ) n -(CHR )-R 3 , -Y-(CH 2 ) n -Ar' (CH 2 ) 0 -R 6 or -Het- (CH 2 ) n -Ar and i is 1 or 2;
  • R ⁇ is R 3 .
  • R 1 is -Het, -Y-(CH 2 ) m -R 5 , -Y- (CH 2 ),_-OH,
  • R is H
  • R 2 is R 8
  • R 1 is -Het
  • -NA-(CH 2 ) m -R 5 -Y- (CH 2 ) m -R 5 ,
  • R is H
  • R 2 is R 7
  • R 1 is -Het
  • -NA- (CH 2 ) m -R 5 -Y- (CH 2 ) m -R 5 ,
  • R 1 is -Het, -Y-(CH 2 )m-R 5 , -Y- (CH 2 ) n ⁇ Het- (CH 2 ) 0 -R e oorr --YY-(CH 2 ) n-Ar' -(CH 2 ) o-R and is 1;
  • R 2 is CONH 2 ,
  • R 1 is -Het, -NA-(CH 2 ) m -R 5 , -Y- (CH 2 ) m -R 5 , -Y-(CH 2 ) 2 -NH-(CH 2 ) s -OH, -Y- (CH 2 ) m -OH,
  • R 2 is CONHA, R 1 is -Y-(CH 2 ) m -R 5 or -Y- (CH 2 ) n -Ar' - (CH 2 ) 0 ⁇ R 6 and i is 2;
  • R is H
  • R 2 is C0NH-(CH 2 ) o -Ar
  • R 1 is -Y-(CH 2 ) m -R 5 , -Y-(CH 2 ) n-Het- (CH 2 ) o- 6 or
  • R 2 is C0NH-(CH 2 ) o -Het
  • R 1 is -Y-(CH 2 ) m -R 5 , or -Y- (CH 2 ) n -Ar' - (CH 2 ) 0 -R 6 and i is 2;
  • R 2 is CONH- (CH 2 ) o -CH (Ar ⁇ -Ar 2 ,
  • R 1 is -Y-(CH 2 ) n-Ar' -(CH 2 ) o- 6 and i is 2; in Ir R is H,
  • R 2 is CONH-Ar ' -NH-CO-Ar
  • R 1 is -Y-(CH 2 ) n -Ar' -(CH 2 ) o -R 6 and i is 2;
  • R 2 is CONH-Ar '-Het
  • R 1 is -Y-(CH 2 ) n-Ar' -(CH 2 ) o-R 6 and i is 2;
  • R 2 is CH(Ph)-Ph
  • R 1 is -Y-(CH 2 ) m -R 5 , or -Y-(CH 2 ) n -J is 2;
  • R 2 is Ar'-(CH 2 ) n -R 8 ,
  • R 1 is -Y-(CH 2 )m-R 5 , -Y-(CH 2 ) n-Ar' -(CH 2 ) o-R 6 or
  • R 2 is Ar, R 8 or Ar ' - (CH 2 ) n -R 8 ,
  • R 1 is -Y-(CH 2 ) m -R 5 , or -Y- (CH 2 ) n -Ar' - (CH 2 ) 0 -R 6 and i is 1 or 2.
  • the starting substances 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.
  • 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 HC1 in dioxane at 15-30°C, the Fmoc group using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°C.
  • Hydrogenolytically removable protective groups 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
  • 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.
  • DPFN 5-dimethylpyrazole
  • 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.
  • an appropriate compound of the formula I in which R 2 is aryl bromide or aryl iodide can be reacted with the appropriate boronic acid derivatives in a Suzuki reaction.
  • the Suzuki reaction is expediently carried out in palladium-mediated form, preferably by addition of Pd(PPh 3 ) 4 , in the presence of a base such as potassium carbonate in an inert solvent or solvent mixture, e.g. DMF at temperatures between 0° and 150°, preferably between 60° and 120°.
  • the reaction time is between a few minutes and a number of days.
  • the boronic acid derivatives can be prepared by conventional methods or are commercially available. The reactions can be carried out in analogy to the methods indicated in Suzuki et al., J. Am. Chem. Soc. 1989, 111 , 314ff. and Suzuki et al., Chem. Rev. 1995, 95, 2457ff.
  • the compounds of the formula IV are derived from the anhydrides of the formula II and can be prepared from these by reaction with ammonia under conditions known per se. As a rule, the imides of the formula IV, however, are known and commercially available.
  • the substituent R 1 can preferably be introduced into the aromatic by substitution.
  • the alcohols, activated alcohols or halides of the formula V are known and their preparation is familiar to the person skilled in the art, so that a description of the syntheses is unnecessary here.
  • the reaction of the compounds of the formula IV with compounds of the formula V is preferably carried out in an inert solvent, with addition of a base and at temperatures and with reaction times as indicated beforehand.
  • Suitable acid-binding agents are preferably alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates or other salts of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium, calcium or caesium.
  • the addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the amine component of the formula IV may also be favourable.
  • Derivatives having a free primary or an additional secondary amino group are expediently employed in protected form.
  • Possible protective groups are those mentioned beforehand.
  • 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.
  • a suspension of 4 g of 6-chlorobenzo [de] iso- chromene-1, 3-dione in 100 ml of toluene is treated with 0.8 g of methylamine and heated under reflux. After reaction is complete, the reaction mixture is allowed to cool and is worked up as is customary. 6-Chloro- 2-methylbenzo [de] isoquinoline-1, 3-dione is obtained. This compound is then heated in morpholine until conversion is complete. After cooling the reaction mixture, it is worked up as is customary and 2-methyl- 6-morpholin-4-ylbenzo [de] isoquinoline-1, 3-dione is obtained.
  • Example 18 Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with 6-amino-hexanoamide and then with R 1 -H.
  • the following compounds of the formula Igd are obtained:
  • nnmmrr--_signals nmr nuclear magnetic resonance
  • Example 38 Analogously to Example 2, 6-nitrobenzo-
  • 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
  • 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.
  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Psychiatry (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

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

Description

Substituted benzo [de] isoquinoline-1 , 3-diones
This application is a continuation-in-part of Serial No. 09/199,409, the entirety of which is incorporated by reference herein.
The invention relates to substituted benzo [de]- isoquinoline-1, 3-diones of the formula I
Figure imgf000003_0001
in which
R is H, A or CH2-Ph,
R1 is -Het, -N-[(CH2)s-OH]2, -N- [ (CH2) s-OA] 2, -NA-(CH2)S-Ar, -NA- (CH2) m-R5, -Y- (CH2)m-R5, -Y-(CH2)2-NHA, -Y-(CH2)2-NH-(CH2)s-OH, -Y- (CH2) 2-NA2, -Y-(CH2)m-OH, -Y-(CH2)n-(CHR4; -R3, -Y-(CH2)n-R4 Rq
-Y-(CH2)n-Het-(CH2)0-Rfc -Y-(CH2)n-Ar'-(CH2)o-R0, -Het-(CH2)n-Ar, -Het-Het, -Y- (CH2) S-Ar' - (CH2) 0-Rn,
Figure imgf000003_0002
or -Y-(CH2)n-NA-(CH2)0-R5, R2 is H, OH, OA, COOH, COOA, CH(Ph)-Ph, Ar, Het1, R= R7 or R8
RJ is CH3,
R4 is -CH=CH2, -Ar, COOA, COOH
Figure imgf000003_0003
R° is NH2, NHA, NA2, NHAr, -NH-(CH2)n-OH or -NH-(CH2)n-OA,
RD is H or R5 R7 is -Ar'-(CH2)n-Rb or -Ar' - (CH2) n-R" R8 is C0NH2, CONHA, CONA2, CONH- (CH2) 0-Ar, CONH- (CH2)0-Het, CONH- (CH2) 0-R5, CONH- (CH2) 0-CH (Ar1) - Ar2, CONH-(CH2)0-CH(A)-Ph, CONH- (CH2) 0-Ar ' -NH-CO-Ar, CONH-Ar'-Het or CHA-CONH2, R11 is -NH-(C=NH)-NH2, -NH- (C=NH) -NHA, -NH- (C=NH) -NA2, -NA- (C=NH) -NH2, -NA- (C=NH) -NHA or -NA- (C=NH) -NA2,
Ar' is phenylene, cycloalkylene or biphenylene, which is unsubstituted or mono- or disubstituted by A, OH, OA, Hal, CN, NH2, NHA, NA2, N02, CF3, CO-A, S02NH2, S02NAH, S02NA2,
Ar is phenyl, cycloalkyl, naphthyl, cyclohex-1-enyl, biphenyl, bicyclohexyl, 4-cyclohexyl-phenyl, benzo [1, 3] dioxol-5-yl, or indanyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, O-Ph, 0-CH2-Ph, 0-Ph-CH3, 0 (cycloalkyl) , Hal, CN, NH2, NHA, NA2, NH-C(0)A, (CH2)n-NH2, (CH2)n- NHA, (CH2)n-NA2, N02, CF3, C(0)A, S02-Ph, S02NH2, S0NAH, S02NA2 or S02NA-Ph,
Ar1 and Ar2 are each independently phenyl,
Het is a saturated, partially or completely unsatura- ted mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by CN, Hal, OH, OA, CF3, A, N02, CO, CO-A or R5,
Het1 is an unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or
2 N and/or 1 or 2 S or 0 atoms can be present and/or can be mono- or disubstituted by Hal, OH,
OA,
A is unbranched or branched alkyl having 1-6 C atoms,
Hal is F, Cl, Br or I, X,
X^X2 in each case independently of one another are alkylene having 1 to 12 C atoms,
Y is 0, S or NH i is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, m is 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 or 12 , n,o in each case independently of one another are 0,
1, 2, 3 or 4, s is 1, 2, 3 or 4, t is 0, 1 or 2, u is 1 or 2, where if R2 is Ar or H, R1 is not
Figure imgf000005_0001
and their pharmaceutically tolerable salts and solvates.
Similar compounds having a benzo [de] iso- quinoline-1, 3-dione parent structure as dyes are disclosed in US 4,200,752, FR 2 271 216 A and Chemical Abstracts, Vol. Ill, No. 20, November 1989. US 3,821,383 describes benzo [de] isoquinoline- acetic acid derivatives as active compounds in a pharmaceutical preparation against diabetes mellitus. Similar benzo [de] isoquinolines are also disclosed in EP 0 243 841 A and DE 37 07 652 A, which carry alkylamino groups mainly in the 2-position. These derivatives are suitable for the treatment of solid tumours and certain forms of leukemia, as well as for the control of viral disorders. The benzo [de] iso- quinoline derivatives from US 5,235,045 are mainly present alkylated or alternatively fluoroalkylated in the 2-position and cause a chemical change to the lipid membrane of viruses or other target cells.
The invention is based on the object of finding novel compounds having valuable properties, in parti- cular those which can be used for the production of medicaments .
It has been found that the compounds of the formula I and their salts or solvates have very valuable pharmacological properties together with good tolerability. They act especially as GPIblX inhibitors, in particular inhibiting the interaction of this receptor with the ligand von Willebrand factor (vWF) . This action can be demonstrated, for example, by a method which is described by S. Meyer et al. in J. Bioi. Chem. 1993, 268, 20555-20562. The GPIblX alpha-thrombin receptor (N.J. Greco, Biochemistry 1996, 35, 915-921) can also be blocked by the compounds mentioned.
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 thrombotic 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 medication introduced onto the market which may be mentioned are aspirin and GPIIbllla antagonists .
The invention relates to the compounds of the formula I and their salts or solvates, and to a process for the preparation of these compounds and their salts or solvates, characterized in that a) a compound of the formula I is liberated from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent, or b) a compound of the formula II
Figure imgf000007_0001
in which
R9 is Cl, Br, N02 or R1, and
R1 has the meaning indicated in Claim 1 is reacted with a compound of the formula III
H2N—(CHR)i -R' III in which R, R2 and i have the meanings indicated in
Claim 1, and, if necessary, the radical R9 is converted into a radical R1, or
(c) a compound of the formula IV
Figure imgf000008_0001
in which
R9 is Cl, Br, N02 or R1, where R1 has the meaning indicated in Claim 1 is reacted with a compound of the formula V L (CHRJi R2 V in which L is Cl, Br, or I, OH or a reactive esterified
OH group and R, R2 and i have the meanings indicated in Claim 1 and, if appropriate, the radical R9 is converted into a radical R1, or
(d) a radical R and/or R2 and/or R9 is converted into another radical R and/or R2 and/or R9 by, for example
- converting an amino group into a guanidino group by reaction with an amidinating agent,
- reacting an aryl bromide or iodide to give the corresponding coupling products by means of a
Suzuki coupling with boronic acids,
- reducing a nitro group, sulfonyl group or sulfoxyl group,
- etherifying an OH group or subjecting an OA group to ether cleavage,
- alkylating a primary or secondary amino group,
- partially or completely hydrolysing a CN group,
- cleaving an ester group or esterifying a carboxylic acid radical, - or carrying out a nucleophilic or electrophilic substitution, and/or
(e) a base or acid of the formula I is converted into one of its salts or solvates.
The compounds of the formula I can have a chiral centre and therefore occur in a number of stereoisomeric forms. All these forms (e.g. R and S forms) and their mixtures (e.g. the RS forms) are included in the formula I.
The compounds according to the invention also include so-called prodrug derivatives, i.e. compounds of the formula I modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the body to give the active compounds according to the invention.
Furthermore, free amino groups as substituents of compounds of the formula I can be provided with appropriate conventional protective groups. Solvates of the compounds of the formula I are understood as meaning adducts of inert solvent molecules to the compounds of the formula I which are formed on account of their mutual power of attraction. Solvates are, for example, mono- or 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 methyl ester OEt ethyl ester POA phenoxyacetyl Ph phenyl
TFA trifluoroacetic acid
In the above formulae, A is alkyl and has 1 to 6, preferably 1, 2, 3 or 4 C atoms. Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, additionally also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1 2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl- 1-methylpropyl, l-ethyl-2-methylpropyl, 1,1,2- or 1, 2, 2-trimethylpropyl, .
Ar is preferentially phenyl, preferably
- as indicated - monosubstituted phenyl, specifically preferentially phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-aminophenyl, o-, m- or p- (N, N-dimethylamino) phenyl, o-, m- or p-sulfonamoylphenyl, o-, m- or p-nitrophenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o- , m- or p-phenoxyphenyl, o-, m- or p- (phenylmethox) yphenyl, o-, m- or p-
(trifluoromethyl) phenyl, o-, m- or p- (trifluoromethoxy) phenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-iodophenyl, 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 2,,33--,, 2 2,,44--,, 2 2,,55--,, 2 2,,66--,, 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, 3-diethylaminomethyl-4- hydroxy-phenyl, l-dimethylamino-2- (toluene-4-sulfonyl) - phenyl-4-yl, N-ethyl-2-methyl-N-phenyl-5-yl- benzenesulfonamoyl, 3-cyclopentyloxy-4-methoxy-phenyl, 3, 4-bis-benzyloxy-phenyl, 2-cyano-4, 5-dimethoxyphenyl, 5-chloro-2, 4-dimethoxy-phenyl, 2-cyano-3,4- dimethoxyphenyl or 3, 4, 5-trimethoxy-phenyl, furthermore, however, also preferentially unsubstituted naphthyl, cyclohex-1-enyl, benzo [1, 3] -dioxol-5-yl, 4- cyclohexyl-phenyl, bicyclohexyl or indanyl . Furthermore, however, Ar is also preferentially unsubstituted biphenyl - as indicated - or alternatively monosubstituted biphenyl, specifically preferentially biphenyl-4-yl or biphenyl-3-yl, 2 ' -methylbiphenyl-4-yl, 3 ' -methylbiphenyl-4-yl, 4 ' -methylbiphenyl-4-yl, 2 ' -methylbiphenyl-3-yl,
3 ' -methylbiphenyl-3-yl, 4 ' -methylbiphenyl-3-yl,
2-methylbiphenyl-4-yl, 3-methylbiphenyl-4-yl,
2-methylbiphenyl-3-yl, 4-methylbiphenyl-3-yl, 2 ' -tert- butylbiphenyl-4-yl, 3 ' -tert-butylbiphenyl-4-yl,
4 ' -tert-butylbiphenyl-4-yl, 2 ' -tert-butylbiphenyl-3-yl,
3 ' -tert-butylbiphenyl-3-yl, ' -tert-butylbiphenyl-3-yl,
2-tert-butylbiphenyl-4-yl, 3-tert-butylbiphenyl-4-yl,
2-tertbutylbiphenyl-3-yl, 4-tert-butylbiphenyl-3-yl,
2 ' -isopropylbiphenyl-4-yl, 3 ' -isopropylbiphenyl-4-yl,
4 ' -isopropylbiphenyl-4-yl, 2 ' -isopropylbiphenyl-3-yl,
3 ' -isopropylbiphenyl-3-yl, 4 ' -isopropylbiphenyl-3-yl,
2-isopropylbiphenyl-4-yl, 3-isopropylbiphenyl-4-yl,
2-isopropylbiphenyl) , 4-isopropylbiphenyl-3-yl,
2 ' -fluorobiphenyl-4-yl, 3 ' -fluorobiphenyl-4-yl,
4 ' -fluorobiphenyl-4-yl, 2 ' -fluorobiphenyl-3-yl,
3 ' -fluorobiphenyl-3-yl, 4 ' -fluorobiphenyl-3-yl,
2-fluorobiphenyl-4-yl, 3-fluorobiphenyl-4-yl,
2-fluorobiphenyl-3-yl, 4-fluorobiphenyl-3-yl,
2 ' -methoxybiphenyl-4-yl, 3 ' -methoxybiphenyl-4-yl,
4 ' -methoxybiphenyl-4-yl, 2 ' -methoxybiphenyl-3-yl,
3 ' -methoxybiphenyl-3-yl, < 4■ ' -methoxybiphenyl-3-yl, 2- methoxybiphenyl-4-yl, 3-methoxybiphenyl-4-yl,
2-methoxybiphenyl-3-yl, 4-methoxybiphenyl-3-yl,
2 ' -nitrobiphenyl-4-yl, 3 ' -nitrobiphenyl-4-yl, ' -nitrobiphenyl-4-yl, 2 ' -nitrobiphenyl-3-yl,
3 ' -nitrobiphenyl-3-yl, 4 ' -nitrobiphenyl-3-yl,
2-nitrobiphenyl-4-yl, 3-nitrobiphenyl-4-yl, 2-nitro- biphenyl-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, 4 ' -trifluoromethyl- biphenyl-3-yl, 2-trifluoromethylbiphenyl-4-yl, 3-tri- fluoromethylbiphenyl-4-yl, 2-trifluoromethylbipheny1-3- yl, 4-trifluoromethylbiphenyl-3-yl,
2 ' -trifluoromethoxybiphenyl-4-yl, 3 ' -trifluoromethoxy- biphenyl-4-yl, 4 ' -trifluoromethoxybiphenyl-4-yl,
2 ' -trifluoromethoxybiphenyl-3-yl, 3 ' -trifluoromethoxybiphenyl-3-yl, 4 ' -tri- fluoromethoxybiphenyl-3-yl, 2-trifluoromethoxybiphenyl- 4-yl, 3-trifluoromethoxybiphenyl-4-yl,
2-trifluoromethoxybiphenyl-3-yl, 4-trifluoromethoxybiphenyl-3-yl, furthermore preferentially disubstituted biphenyls, such as 2 ' -methyl-3 ' -nitrobiphenyl-4-yl, 2 ' -methyl-4 ' -nitro- biphenyl-4-yl, 2 ' -methyl-5 ' -nitrobiphenyl-4-yl, 2'- methyl-6 ' -nitrobiphenyl-4-yl, 3 ' -methyl-2 ' - nitrobiphenyl-4-yl, 3 ' -methyl-4 ' -nitrobiphenyl-4-yl, 3 ' -methyl-5 ' -nitrobiphenyl-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- ' -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 ' -nitrobiρhenyl-3-yl, 4 ' -methyl-3 ' - nitrobiphenyl-3-yl, 2 ' -methoxy-2-methylbiphenyl-4-yl, 3 ' -methoxy-2-methylbiphenyl-4-yl, 4 ' -methoxy-2- methylbiphenyl-4-yl, 4 ' -methoxy-3-nitrobiphenyl-4-yl, 2 ' -chloro-3 ' -fluorobiphenyl-4-yl, 2 ' -chloro-4 ' - fluorobiphenyl-4-yl, 2 ' -chloro-5 ' -fluorobiphenyl-4-yl, 2' -chloro-6 ' -fluorobiphenyl-4-yl, 3 ' -chloro-2 ' - fluorobiphenyl-4-yl, 3 ' -chloro- ' -fluorobiphenyl-4-yl, 3 ' -chloro-5 ' -fluorobiphenyl-4-yl, 3 ' -chloro-6 ' - fluorobiphenyl-4-yl, 4 ' -chloro-2 ' -fluorobiphenyl-4-yl, 4 ' -chloro-3 ' -fluorobiphenyl-4-yl, 2 ' -chloro-3 ' - fluorobiphenyl-3-yl, 2 ' -chloro- ' -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) biphenyl-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 ' , ' -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) iphenyl-4-yl, (2, ' 3-dimethyl) biphenyl-
4-yl, (2, ' -dimethyl) biphenyl-4-yl, (2, 2' -dimethyl) biphenyl-3-yl, (2, 3 ' -dimethyl) biphenyl-
3-yl or (2, 4 ' -dimethyl) biphenyl-3-yl .
Furthermore, Ar is preferably cycloalkyl, particularly preferred cyclohexyl or cyclopentyl. Ar1 and Ar2 are each independently phenyl. Ar' preferentially is phenylene, cyclohexylene or biphenylene, which is unsubstituted or monosubstituted by Hal or CN.
In -Ar' - (CH2)n_R5, Ar' is preferentially unsubstituted or substituted phenylene or cycloalkylene, where R5 is preferentially an amino, alkylamino or dialkylamino group and where n can be 0,
Figure imgf000014_0001
is particularly preferred for -Ar' - (CH2) n _R In -Ar'-(CH2)n-R8, Ar' is preferably unsubstituted or substituted phenylene or cycloalkylene, where R8 is preferentially an amido, an alkylamido or dialkylamido group or -CONH- (CH2) 0-Ar,
-C0NH-(CH2)o-Het, -CONH-(CH2)0-CH(Ar1)-Ar2, -CONH- (CH2) 0~
CH (A) -Ph or -CONH- (CH2 ) 0-R5 and where n is 0 , 1 , 2 , 3 or
4 .
Figure imgf000015_0001
/ % CONH(C3H7) , — ( ) — CONH(C3H7)
Figure imgf000015_0002
CONHCCsH^) or
CONHCCgHn)
Figure imgf000015_0003
is particularly preferred for -Ar' - (CH2) n-R
Figure imgf000015_0004
Figure imgf000016_0001
Figure imgf000016_0002
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
are furthermore particularly preferred for
-Ar'- (CH2)n-R8 where R8 is -CONH- (CH2) 0-Ar .
Figure imgf000023_0002
Figure imgf000024_0001
is particularly preferred for -Ar' - (CH2) n-R where R is -C0NH-(CH2)o-Het.
Figure imgf000024_0002
Figure imgf000025_0001
is particularly preferred for -Ar' - (CH2 ) n-R8 where R8 is
-CONH- ( CH2 ) o-CH (Ar1 ) -Ar2
Figure imgf000025_0002
is particularly preferred for -Ar' - (CH2) n-R where R is -CONH- (CH2) o-CH (A) -Ph. Furthermore,
Figure imgf000025_0003
is particularly preferred for -Ar' - (CH2) n-R where R is
-CONH-(CH2)o-R5-
Cycloalkyl having 3 to 8 carbon atoms is preferentially cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; particularly preferred cyclohexyl or cyclopentyl .
Cycloalkylene having 3 to 8 carbon atoms is preferentially cyclobutylene, cyclopentylene, cyclohexylene, or cycloheptylene; particularly preferred cyclohexylene.
0 (cycloalkyl) having 3 to 8 carbon atoms is preferentially cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy; particularly preferred cyclopentyloxy.
Hal is preferably F, Cl, Br or iodine. Het1 is preferentially substituted or unsubstituted 2-, 3-, or 4-pyridyl, 2- or 3-benzo[b] thiophenyl, lH-indol-2-yl, lH-indol-3-yl, 4-, 5-, 6-, 7-fluoro-lH-indol-2-yl, 4-, 5-, 6-, 7-fluoro- lH-indol-3-yl, 4-, 5-, 6-, 7-methyl-lH-indo-2-yl, 4-, 5-, 6-, 7-methyl-lH-indol-3-yl, 4-, 5-, 6-, methoxy-lH- indol-2-yl or 4-, 5-, 6-, 7-methoxy-lH-indol-3-yl, 4-Pyridyl, 3-benzo [b] thiophenyl, lH-indol-3-yl, 5- fluoro-lH-indol-3-yl, 5-methyl-lH-indol-3-yl, 5- or 6- methoxy-lH-indol-3-yl are furthermore particularly preferred.
Het is preferably substituted or unsubstituted 2- or 3-furyl, 2- or 3-thienyl, 2-chloro-thienyl-5-yl, 2-acetyl-thienyl-5-yl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 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, 4-triazol-l-, -4- or -5-yl, 1- or 5-tetrazolyl, 1, 2, 3-oxadiazol-4- or -5-yl, 1, 2, -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, 1, l-dioxo-lH-lλ6-benzo [b] thiophen-5-yl or 2, 2-dioxo-2, 3-dihydro-lH-2λ6-benzo [c] thiophen-5-yl . The heterocyclic radicals can also be partially or completely hydrogenated. Het can thus also be 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2, 5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2, 3-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 2, 5-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, pyrrolidine-2-on-l-yl, 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, -dihydro-l-, -2-, -3- or -4-pyridyl, 1, 2, 3, -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, 4-dioxanyl, 1, 3-dioxan-2-, -4- or -5-yl, hexahydro- 1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2, 3, -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.
2-, 3- or 4-pyridyl, 1-imidazolyl, 2-methyl-l-imidazolyl, 2-pyrimidinyl, 5-fluoro-lH- indol-2-yl, 2, 3-dihydro-l-, -2-, -3-, -4-, -5-, -6-, -7-lH-indolyl, 1-quinolinyl, 1-isoquinolinyl, 1, 2, 3, 4-tetrahydroisoquinoline-l-yl, tetrahydro- 1-pyrrolyl, 1-piperidinyl, 2, 6-tetramethyl- piperidine-4-yl, 1-azepanyl, 4-morpholinyl, 1- piperazinyl, 4-methyl-piperazin-l-yl, 4-phenyl- piperazin-1-yl or 4-phenylmethylpiperazin-l-yl is particularly preferred.
In -Het- (CH2)n-Ar, Het and Ar have one of the preferred meanings indicated above, where Het is preferably piperidine-1, 4-diyl or piperazine-1, 4-diyl and n can be 0, 1, 2, 3, or 4.
Figure imgf000028_0001
is particularly preferred for -Het- (CH2) n-Ar .
In -Het-Het, Het has one of the preferred meanings indicated above, where in -Het-Het the first heterocycle is preferably piperidine-1, 4-diyl or
Figure imgf000028_0002
is particularly preferred for -Het-Het. In -Y-(CH2)n-Het-(CH2)o-R6, Y is preferably 0, S or NH, where Het has one of the preferred meanings indicated above and R6 is preferentially H, amino or alkylamino. Furthermore, n and o independently of one another are preferably 0, 1, 2, 3 or 4.
Figure imgf000028_0003
/ \
NH-(CH2)3—N N—(CH2)3 NH2
Figure imgf000029_0001
are particularly preferred for -Y- (CH2)n-Het (CH2) 0-R6.
Furthermore, in -Y- (CH2) n-Ar' - (CH2) 0-R6, Y is preferentially 0, S, or NH, where Ar' has a preferred meaning indicated beforehand and R6 is preferably H, amino or alkylamino and n and o independently of one another are 0, 1, 2, 3 or 4.
Figure imgf000029_0002
is particularly preferred for -Y- (CH2) n-Ar' - (CH2) 0-R6.
Furthermore, in -Y- (CH2) S-Ar' - (CH2) 0-Ru, Y is preferentially O, S, or NH, where Ar' has a preferred meaning indicated beforehand and R11 is preferably -NH-
(C=NH)-NH2 and s and o independently of one another are
0, 1, 2, 3 or 4.
Figure imgf000030_0001
is particularly preferred for -Y- (CH2) S-Ar' - (CH2) G-Rn.
X and/or X1 and/or X2 is alkylene and is preferably methylene, ethylene, propylene, butylene, furthermore also pentylene or hexylene.
In -Y-[X-0]t-[X1-0]u-X2-R5, Y is preferentially 0, S or NH, where X, X1 and X2 have a preferred meaning indicated beforehand. Furthermore, R5 is preferably amino, alkylamino or dialkylamino, t is 0, 1 or 2 and u is 1 or 2. -NH-(CH2)3-0-(CH2) -0-(CH2)3-NH2 is particularly preferred for -Y- [X-O] t- [X1-0] U-X2-R5.
Y is preferentially 0, S or NH, particularly preferentially NH. R is preferably H, A, or CH2-Ph, where A has a preferred meaning indicated above. H, sec-butyl or CH2-Ph is particularly preferred.
R1 is preferably -Het, -N- [ (CH2) s-OH] 2. -N-[(CH2)s-OA]2, -NA-(CH2)S-Ar, -NA- (CH2) m~R5, -Y-(CH2)ra-R5, -Y-(CH2)2-NHA, -Y- (CH2) 2-NA2,
-Y-(CH2)2-NH-(CH2)s-OH, -Y- (CH2) m-0H, -Y- (CH2) „- (CHR4) -R3, -Y-(CH2)n-R4, R4, -Y-(CH2)n-Het-(CH2)o-R6,
-Y-(CH2)n-Ar'-(CH2)o-R6, -Het- (CH2) n-Ar, -Het-Het, -Y-[X-0]t-[XX-0]u-X2-R5 or -Y-(CH2)n-NA-(CH2)0-R5, where -Het, -Y-(CH2)n-Het-(CH2)o-R6, -Y- (CH2) n"Ar' - (CH2) 0-R6, -Y-(CH2)S-Ar'-(CH2)0-Rn, -Het- (CH2) n-Ar, -Het-Het and -Y- [X-0]t- [X1-0]u-X2-R5 in particular have the preferred meanings indicated beforehand. Furthermore, s in -N-[ (CH2)s-OH]2 and -N- [ (CH2) Ξ-OA] 2 is preferably 1, 2, 3 or 4 and A has the preferred meaning indicated beforehand. -N- [ (CH2) 2-OH] 2 is particularly preferred for -N-[(CH2)s-OH]2. In -NA- (CH2) S-Ar, A and Ar have a preferred meaning indicated beforehand and s is preferably 1, 2,
Figure imgf000031_0001
is particularly preferred for -NA- (CH2) S-Ar .
Furthermore, A in -NA- (CH2) S-R5 as a substituent for R1 has a preferred meaning indicated beforehand, where R5 is preferably amino, alkylamino or dialkylamino and s is 1, 2, 3 or 4. -N (CH3) - (CH2) 3-NH (CH3) and -N(CH3) -(CH2)2-N(C2H5)2 are particularly preferred for -NA-(CH2)S-R5.
In -Y-(CH2)m-R5 Y is preferentially 0, S or NH, where R5 is preferably amino, alkylamino or dialkylamino and m is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. -NH- (CH2) 3-NH2, -NH-(CH2)3-NH(CH3), -NH- (CH2) 3-N (CH3) 2,
-NH- (CH2) 3-NH [CH (CH3) 2] , -NH- (CH2) 3-NH (C6Hn) ,
-NH- (CH2)4-NH2, -NH-(CH2)5-NH2, -NH- (CH2) 7-NH2 and -NH- (CH2) 8-NH2 are particularly preferred for -Y-(CH2)m-R5. In -Y-(CH2)2-NHA and -Y- (CH2) 2-NA2, Y is preferably 0, S or NH, where A has a preferred meaning indicated beforehand. -NH- (CH2) 2-NH (C2H5) , -NH- (CH2) 2-NH (C3H7) and -NH- (CH2)2-NH[CH(CH3)2] are particularly preferred for -Y-(CH2)2-NHA. In -Y-(CH2)2-NH-(CH2)s-OH, Y is preferably 0, S or NH, where s is 1, 2, 3 or 4. -NH- (CH2) 2-NH (CH2) 2-0H is particularly preferred for -Y- (CH2) 2-NH- (CH2) S-0H. In -Y- (CH2)m-OH, Y is preferably 0, S or NH, where m is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. -NH- (CH2) 5~OH is particularly preferred for -Y- (CH2)m-0H.
In -Y-(CH2)n-(CHR4)-R3, Y is preferably 0, S or NH, where R3 is preferably methyl, R4 is preferentially Ar and n is 0, 1, 2, 3 or 4. -NH- (CHPh) -CH3 is particularly preferred for -Y- (CH2) n- (CHR4) -R3. In -Y- (CH2)n-R4, Y is preferentially 0, S or NH, where in this formula R4 is preferably COOH or COOA, A has a preferred meaning indicated beforehand and n is 0, 1, 2, 3 or 4. -NH- (CH2)2-COOMe is particularly preferred . In -Y-(CH2)n-NA-(CH2)o-R5, Y is preferentially 0, S, NH, where A has a preferred meaning indicated beforehand, R5 is preferably amino, alkylamino or dialkylamino and n and o in each case independently of one another are 0, 1, 2, 3 or 4. -NH-(CH2)3-N(CH3)-(CH2)3-NH2 is particularly preferred for -Y- (CH2) n-NA- (CH2) 0-R5. i is preferentially 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, particularly preferentially 1, 2, 3, 5, 7, 10 or 11.
R2 is preferably H, OH, OA, COOH, COOA, Ar, CH(Ph)-Ph, Het1, R5, R7 or R8, where A, Ar and Het1 have a preferred meaning indicated beforehand. R3 is preferentially CH3. H
Figure imgf000032_0001
where Ar and A have a preferred meaning indicated before :hand .
Figure imgf000032_0002
is particularly preferred for
Figure imgf000032_0003
R5 is preferentially amino, alkylamino, dialkylamino, NHAr, -NH- (CH2) n~OH or -NH- (CH2) n-OA, where A and Ar have a preferred meaning indicated beforehand and n is 0, 1, 2, 3, or 4. -NH- (CH2) 2-OH is particularly preferred for -NH- (CH2) n-OH.
R6 is H or R5, where R5 has a preferred meaning indicated beforehand.
R7 is preferentially -Ar' - (CH2) n-R8 or -Ar'-(CH2)n-R5, where -Ar' - (CH2) n-R8 and -Ar' - (CH2) n-R5 have a preferred or particularly preferred meaning indicated beforehand.
R8 is preferably CONH2, CONHA, CONA2,
CONH- (CH2) o-Ar, CONH- (CH2) 0-Het , CONH- (CH2) o~CH (Ar1) -Ar2,
CONH-Ar'-NH-CO-Ar, CONH-Ar ■ -Het , CONH- (CH2) 0-R5 or
CHA-CONH2, where A, CONH- (CH2) 0-Ar, CONH- (CH2) 0-Het,
CONH- (CH2) o-CH (Ar^-Ar2, and CONH- (CH2) 0-R5 have a preferred or particularly preferred meaning indicated beforehand in -Ar ' - (CH2) n-R8. CH (CH3) -CONH2 is HA-CONH2.
Figure imgf000033_0001
is particularly preferred for CONH-Ar ' -NH-CO-Ar .
Figure imgf000033_0002
Figure imgf000034_0001
is particularly preferred for CONH-Ar ' -Het .
R11 is -NH-(C=NH)-NH2, -NH- (C=NH) -NHA,
-NH-(C=NH)-NA2, -NA-(C=NH)-NH2, -NA- (C=NH) -NHA or
-NA- (C=NH) -NA2, where A has a meaning indicated beforehand. -NH- (C=NH) -NH2 is particularly preferred for
R11. i is preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, particularly preferred 1, 2, 3, 4, 5 or 6. m is preferably 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, particularly preffered 3, 4, 5, 6, 7 or 8. n and o are in each case independently of one another preferably 0, 1, 2, 3 or 4. s is preferably 1, 2, 3 or 4. t is preferably 0, 1 or 2. u is preferably 1 or 2.
Some preferred groups of compounds can be expressed by the following subformulae la to Iv, which correspond to the formula I
Figure imgf000035_0001
and in which the radicals not designated in greater detail have the meanings indicated in formula I, but in which:
in la R is H,
R' is H,
R1 is -Het, -N-[ (CH2)s-OH]2, -Y-(CH2)n-R4 or R4 and is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
in lb R is H, R2 is OH R1 is -Het or -Y- (CH2) n- (CHR4) -R3 and i is 2;
in Ic R is H, R2 is COOA,
R1 is -Het, -Y-(CH2)n-(CHR4)-R3,
-Y-(CH2)n-Ar'-(CH2)o-R6, -Het- (CH2) n-Ar or -NA-(CH2)S-Ar and i is 2;
in Id R is H, R2 is Ar,
R1 is -Het, -NA-(CH2)S-Ar, -Y- (CH2) m-R5, -Y- (CH2)m-OH, -Y- (CH2) n- (CHR4) -R3, -Y-(CH2)n-R4, -Y-(CH2)n-Het-(CH2)0-R6,
-Y-(CH2)n-Ar' (CH2)0-R6 or -Het- (CH2) n~Ar and i is 1 or 2; in Ie R is H,
R2 is Het1,
R1 is -Het, -NA-(CH2)S-Ar, -Y- (CH2)m-R5, -Y-(CH2)m-OH, -Y-(CH2)n-(CHR )-R3,
Figure imgf000036_0001
-Y-(CH2)n-Ar' (CH2)0-R6 or -Het- (CH2) n-Ar and i is 1 or 2;
in If R is H,
R^ is R3 ,
R1 is -Het, -Y-(CH2)m-R5, -Y- (CH2),_-OH,
-Y- (CH2) „- (CHR4) -R3, -Y- (CH2) n- ,
-Y-(CH2)n-Het-(CH2)0-R6,
-Y-(CH2)n-Ar'-(CH2)o-R6 or -Het- (CH2) n"Ar and is 3 or 5;
in Ig R is H, R2 is R8, R1 is -Het, -NA-(CH2)m-R5, -Y- (CH2) m-R5,
-Y- (CH2) 2-NH- (CH2) s-OH, -Y- (CH2)m-OH,
-Y- (CH2) n- (CHR4) -R3, -Y- (CH2) n-R4,
-Y- (CH2) n-Het- (CH2) o-R6,
-Y- (CH2) n-Ar' - (CH2) o-R6, -Het- (CH2) n-Ar,
-Het-Het, -Y- [X-O] t- [Xx-0] U-X2-R5 or
-Y-(CH2)n-NA-(CH2)0-R5 and is 1, 2, 7, 10 or 11;
in Ih R is H, R2 is R7, R1 is -Het, -NA- (CH2) m-R5, -Y- (CH2)m-R5,
-Y- (CH2) 2-NHA, -Y- (CH2) 2-NH- (CH2) s"OH, -Y- (CH2)m-OH, -Y- (CH2) n- (CHR4) -R3, -Y- (CH2) n-R4, -Y- (CH2) n-Het- (CH2) 0" 6, -Y-(CH2) n-Ar' -(CH2) o-R6, -Y-(CH2) s-Ar' -(CH2) o-R11, -Het- (CH2) „-Ar,
-Het-Het, -Y- [X-O] t- [Xx-0] U-X2-R5 or
- -YY--((CCHH22))„n--NNA-(CH2)0-R5 and is 1 or 2; in Ik R is A or CH -Ph, R2 is R8,
R1 is -Het, -Y-(CH2)m-R5, -Y- (CH2) n ~Het- (CH2) 0-Re oorr --YY-(CH2) n-Ar' -(CH2) o-R and is 1;
in Im R is H,
R2 is CONH2,
R1 is -Het, -NA-(CH2)m-R5, -Y- (CH2)m-R5, -Y-(CH2)2-NH-(CH2)s-OH, -Y- (CH2) m-OH,
-Y- (CH2) n- (CHR4) -R3, -Y- (CH2) n-R , -Y- (CH2) n-Het- (CH2) o-R6, -Y- (CH2) n-Ar' - (CH2) o-R6, -Het- (CH2) n-Ar ,
-Het-Het, -Y- [X-O] t- [Xx-0] U-X2-R5 or
- -YY--((CCHH22))nn--NNAA--((CCHH22))oo--RR5 and is 1, 2, 7, 10 or 11;
in In R is H,
R2 is CONHA, R1 is -Y-(CH2)m-R5 or -Y- (CH2) n-Ar' - (CH2) 0~R6 and i is 2;
in Io R is H, R2 is C0NH-(CH2)o-Ar,
R1 is -Y-(CH2)m-R5, -Y-(CH2) n-Het- (CH2) o- 6 or
-Y-(CH2) n-Ar' -(CH2) o-R6 and i is 1 or 2;
in Ip R is H,
R2 is C0NH-(CH2)o-Het,
R1 is -Y-(CH2)m-R5, or -Y- (CH2) n-Ar' - (CH2) 0-R6 and i is 2;
in Iq R is H,
R2 is CONH- (CH2) o-CH (Ar^-Ar2,
R1 is -Y-(CH2) n-Ar' -(CH2) o- 6 and i is 2; in Ir R is H,
R2 is CONH-Ar ' -NH-CO-Ar,
R1 is -Y-(CH2) n-Ar' -(CH2) o-R6 and i is 2;
in Is R is H,
R2 is CONH-Ar '-Het,
R1 is -Y-(CH2) n-Ar' -(CH2) o-R6 and i is 2;
in It R is H,
R2 is CH(Ph)-Ph,
R1 is -Y-(CH2)m-R5, or -Y-(CH2)n-J is 2;
in Iu R is H,
R2 is Ar'-(CH2)n-R8,
R1 is -Y-(CH2)m-R5, -Y-(CH2) n-Ar' -(CH2) o-R6 or
-Y-(CH2) n-Ar' -(CH2) o-R 11 and is 1 or 2;
in Iv R is H,
R2 is Ar, R8 or Ar ' - (CH2) n-R8,
R1 is -Y-(CH2)m-R5, or -Y- (CH2) n-Ar' - (CH2) 0-R6 and i is 1 or 2.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben- eyl, ethoden 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 HC1 in dioxane at 15-30°C, the Fmoc group using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°C.
Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst (e.g. of a noble metal catalyst such as palladium, expediently on a support such as carbon) . Suitable solvents in this case are those indicated above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. As a rule, the hydrogenolysis is carried out at temperatures between approximately 0 and 100 °C and pressures between approximately 1 and 200 bar, preferentially at 20-30°C and 1-10 bar. Hydrogenolysis of the CBZ group takes place readily, for example, on 5 to 10% Pd/C in methanol or ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°C.
Compounds of the formula I can also preferably be obtained by reacting compounds of the formula II with compounds of the formula III. As a rule, the starting compounds of the formulae II and III are known or commercially available. The unknown compounds, however, can be prepared by methods known per se. The compounds of the formula II are naphthalene- 1, 8-dicarboxylic anhydride derivatives. They can be prepared in a conventional manner from appropriately substituted 1, 8-naphthalenedicarboxylic acids or corresponding derivatives. It is furthermore possible to introduce appropriate substituents into the aromatic by conventional electrophilic or alternatively nucleophilic substitutions.
The compounds of the formula III are primary amines, which, as a rule, are also commercially available. Furthermore, syntheses for the preparation of primary amines, such as, for example, the Gabriel synthesis, can be used.
As a rule, the reaction is carried out in an inert solvent. Depending on the conditions used, the reaction time is between a few minutes and a number of days, the reaction temperature between approximately 0° and 150°C, normally between 20° and 130°C. The reactions can be carried out in analogy to the methods indicated in Eur. J. Chem. Chim. Ther. 1981, 16, 207- 212 and in J. Med. Chem. 1982, 25, 714-719. Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol) , ethylene glycol dimethyl ether (diglyme) ; ketones such as acetone or butanone; amides such as acetamide, N-methylpyrrolidone (NMP) , dimethylacetamide or dimethylformamide (DMF) ; nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO) ; carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or mixtures of the solvents mentioned. For the preparation of compounds of the formula I in which R11 is H2N-C (=NH) -NH-, an appropriate amino-substituted compound can be treated with an amidinating agent. The preferred amidinating agent is 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'-Het and/or -CONH- (CH2) α-Ar, 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)4, in the presence of a base such as potassium carbonate in an inert solvent or solvent mixture, e.g. DMF at temperatures between 0° and 150°, preferably between 60° and 120°. Depending on the conditions used, the reaction time is between a few minutes and a number of days. The boronic acid derivatives can be prepared by conventional methods or are commercially available. The reactions can be carried out in analogy to the methods indicated in Suzuki et al., J. Am. Chem. Soc. 1989, 111 , 314ff. and Suzuki et al., Chem. Rev. 1995, 95, 2457ff. The compounds of the formula IV are derived from the anhydrides of the formula II and can be prepared from these by reaction with ammonia under conditions known per se. As a rule, the imides of the formula IV, however, are known and commercially available. The substituent R1 can preferably be introduced into the aromatic by substitution. In many cases, it is expedient to introduce this substituent before the reaction with ammonia. As a rule, the alcohols, activated alcohols or halides of the formula V are known and their preparation is familiar to the person skilled in the art, so that a description of the syntheses is unnecessary here. The reaction of the compounds of the formula IV with compounds of the formula V is preferably carried out in an inert solvent, with addition of a base and at temperatures and with reaction times as indicated beforehand. Suitable acid-binding agents are preferably alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates or other salts of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium, calcium or caesium. The addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the amine component of the formula IV may also be favourable.
Derivatives having a free primary or an additional secondary amino group are expediently employed in protected form. Possible protective groups are those mentioned beforehand.
For the esterification, an acid of the formula I (R1 = COOH or -Y- (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. In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.
The entire disclosure of all applications, patents and publications, cited above and below, is hereby incorporated by reference.
EXAMPLES
Example 1
A suspension of 4 g of 6-chlorobenzo [de] iso- chromene-1, 3-dione in 100 ml of toluene is treated with 0.8 g of methylamine and heated under reflux. After reaction is complete, the reaction mixture is allowed to cool and is worked up as is customary. 6-Chloro- 2-methylbenzo [de] isoquinoline-1, 3-dione is obtained. This compound is then heated in morpholine until conversion is complete. After cooling the reaction mixture, it is worked up as is customary and 2-methyl- 6-morpholin-4-ylbenzo [de] isoquinoline-1, 3-dione is obtained.
Analogously, by reaction of 6-chloro-2- methylbenzo [de] isoquinoline-1, 3-dione with R1-H, the following compounds of the formula la are obtained:
Figure imgf000049_0001
Example 2
A suspension of 4 g of 6-chlorobenzo [de] iso- chromene-1, 3-dione in 100 ml of dichloromethane is treated with 3.2 g of 2-aminoethanol and heated under reflux. After reaction is complete, the reaction mixture is allowed to cool and is worked up as is customary. 6-Chloro-2- (2-hydroxyethyl) benzo [de] 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-hydroxyethyl) -6-morpholin-4-yl- benzo [de] isoquinoline-1, 3-dione is obtained.
Analogously, by reaction of 6-chloro- 2- (2-hydroxyethyl) benzo [de] isoquinoline-1, 3-dione with R1-H, the following compounds of the formula lb are obtained
Figure imgf000050_0001
Figure imgf000051_0001
Example 3
Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with methyl 3-aminopropionate and then with R1-H. The following compounds of the formula Ic are obtained:
Figure imgf000051_0002
Figure imgf000052_0001
Example 4
Analogously to Example 2, 6-chloro- benzo [de] isochromene-1, 3-dione is reacted with benzylamine and then with Rx-H. The following compounds of the formula Ida are obtained:
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Example 5
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with phenylethylamine and then with R1-H. The following compounds of the formula Idb are obtained:
Figure imgf000055_0002
Figure imgf000056_0001
Figure imgf000057_0001
Example 6
A suspension of 4 g of 6-chlorobenzo [de] isoquinoline-1, 3-dione and 7 g of
Figure imgf000057_0002
in 100 ml of DMF is heated under reflux with 6 g of phenylethyl chloride. After conversion is complete, the mixture is allowed to cool, and is filtered and worked up as is customary. 6-Chloro-2- (2-phenylethyl) benzo [de] isoquinoline-1, 3-dione is then heated in morpholine until conversion is complete. After cooling of the reaction mixture, it is worked up as is customary and 2- (2-phenylethyl- 6-morpholin-4-ylbenzo [de] isoquinoline-1, 3-dione is obtained. MS: calculated: 386; found: 387. Example 7
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with C- cyclohexylmethylamine and then with Rx-H. The following compounds of the formula Idc are obtained:
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Example 8
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with (3- chlorophenyl) methylamine and then with R1-H. The following compounds of the formula Idd are obtained:
Figure imgf000060_0002
Figure imgf000061_0001
Example 9
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with 4-(2- aminoethyl) benzenesulfonamide and then with R1-H. The following compounds of the formula Ide are obtained:
Figure imgf000062_0001
Example 10
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with C-pyridin-4- ylmethylamine and then with Rx-H. The following compounds of the formula lea are obtained:
Figure imgf000062_0002
Figure imgf000063_0001
Figure imgf000064_0001
Example 11
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with C- benzo [b] thiophen-3-ylmethylamine and then with R1-H. The following compounds of the formula leb are obtained:
Figure imgf000064_0002
Example 12
10 ml of TFA are added at room temperature to a solution of 2 g of tert-butyl [3- (2-benzo [b] thiophen- 3-ylmethyl-l , 3-dioxo-2, 3-dihydro-lH-benzo [de] iso- quinolin-6-ylamino) propyl] carbamate in 40 ml of dichloromethane [obtainable by reaction of 6-chlorobenzo [de] isochromene-1, 3-dione with C-benzo[b]- thiophen-3-ylmethylamine and H2N- (CH2) 3-NH-BOC] and the reaction mixture is stirred until removal is complete. After customary work-up 6- (3-aminopropylamino) - 2-benzo [b] thiophen-3-ylmethylbenzo [de] isoquinoline- 1, 3-dione is obtained. MS: calculated: 415; found: 416.
Example 13
Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with H2N- (CH2) 2-Het1 and then with Rx-H. The following compounds of the formula Iec are obtained:
Figure imgf000065_0001
Figure imgf000066_0001
Example 14
Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with 1, 3-propanediamine and then with R1-H. The following compounds of the formula If are obtained:
Figure imgf000067_0001
Figure imgf000068_0001
Example 15
Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with 3-amino-2- methylpropionamide and then with R1-H. The following compounds of the formula Iga are obtained:
Figure imgf000069_0001
Example 16
Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with 2-aminoacetamide and then with R1-H. The following compounds of the formula Igb are obtained:
Figure imgf000070_0001
Figure imgf000071_0001
Example 17
Analogously to Example 2 , 6-chlorobenzo [de] isochromene-1 , 3-dione is reacted with 3-aminopropionamide and then with Rx-H . The following compounds of the formula Igc are obtained :
Figure imgf000072_0001
Figure imgf000073_0001
Example 18 Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with 6-amino-hexanoamide and then with R1-H. The following compounds of the formula Igd are obtained:
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Example 19
Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with H2N- (CH2) ι-CONH2 and then with Rx-H. The following compounds of the formula Ige are obtained:
Figure imgf000076_0002
Figure imgf000077_0001
Example 20
Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with H2N- (CH2) 2-CONH (R10) and then with R1-H. The following compounds of the formula Igf are obtained:
Figure imgf000077_0002
R1 in Ri-H and in Igf R1U MS calcul ated found
C3H7 438 439
-NH- ( CH2 ) 7-NH C5H11 466 467
-
Figure imgf000078_0001
Example 21
Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with H2N- (CH2) 2-CONH- (CH2)0-Ar and then with R1-H. The following compounds of the formula Iha are obtained:
Figure imgf000078_0002
Figure imgf000079_0001
Example 22
Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with H2N- (CH2) 2-CONH- (CH2)0-R5 and then with Rx-H. The following compounds of the formula Ihb are obtained:
Figure imgf000080_0001
CONH- (CH2) o-R3 R1 in R1-H and in Ihb MS calc. fnd.
-NH- (CH2)7-NH2 467 468
CONH-(CH2)4-NH2
Figure imgf000080_0002
-NH-(CH2)7-NH 539 540
CONH-(CH2)2-NH
Figure imgf000080_0003
Example 23
Analogously to Example 2 , 6-chlorobenzo [de] isochromene-1 , 3-dione is reacted with H2N- ( CH2) 2-CONH- (CH2 ) 0-Het and then with R1-H . The following compounds of the formula Ihc are obtained :
Figure imgf000080_0004
C0NH-(CH2)o-Het R1 in Rx-H and in Ihc MS calc. fnd.
-NH-(CH)7-NH2 487 488
Figure imgf000081_0001
Example 24
Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with 3- aminomethylbenzylamine and then with R1-H. The following compounds of the formula Iia are obtained:
Figure imgf000081_0002
Figure imgf000082_0001
Figure imgf000083_0001
Example 25
Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with H2N-CH2-Ar' - (CH2) n- CONH2 and then with R1-H. The following compounds of the formula lib are
Figure imgf000083_0002
Ar'-(CH2)n-CONH2 R1 in Rx-H and in lib MS calc. fnd.
Figure imgf000083_0003
CONH-
Figure imgf000083_0004
Ar'-(CH2)n-CONH2 R1 in R"-H and in lib MS calc. fnd.
Figure imgf000084_0001
CONH- 405 406
Figure imgf000084_0002
Ar'-(CH2)n-CONH2 R1 in Rx-H and in lib MS~ calc. fnd.
V ■CONH2 -NH-(CH2) 2-COOMe 31 432
Figure imgf000085_0001
V CONH — N CH- // w
H
CONH- 441 442
Figure imgf000085_0002
CONH2 455 456
Figure imgf000085_0003
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Ar'-(CH2)n-CONH2 R1 in Rx-H and in lib MS calc. fnd.
Figure imgf000091_0001
-NH-(CH2)2-NH-(CH2)2-OH 432 433
Figure imgf000091_0002
CONHo 438 439
-NH-(CH2)2-NH(C3H7) 430 431
Figure imgf000091_0003
CONH2 436 437
) 4-0- (CH2) 3-
Figure imgf000091_0004
CONHo 538 539
Figure imgf000091_0005
Figure imgf000091_0006
CONHo 490 491
Figure imgf000091_0007
CONHo 476 477
Figure imgf000092_0001
Example 26
Analogously to Example 2, 6-nitrobenzo [de] isochromene-1, 3-dione is reacted with H2N-CH2-Ar' - (CH2) n _ CONH-(CH2)0-NH2 and then with Rx-H. The following compounds of the formula lie are obtained:
Figure imgf000092_0002
H2)0-NH2
Figure imgf000093_0001
Example 27
Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with H2N-CH2-Ar' - (CH2) n- CONH-(CH ) o-Het and then with Rx-H. The following compounds of the formula lid are obtained:
Figure imgf000093_0002
H2)0-Het Ar'-(CH2)n-CONH- R1 in Rx-H and lid MS
(CH2)0-Het calc. fnd.
— ( — CONH — CH2 — £ ) -NH-(CH2)3-N(CH3)2 -NH-(CH2)7-NH2 555 556
-
Figure imgf000094_0001
— < — CONH — CH2 — £ > -NH-(CH2)3-N(CH3)2 521 522
-NH-(CH2)7-NH2
Figure imgf000094_0002
Example 28
Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with HN-CH-Ar' - (CH2) n- CONHA and then with R1-H. The following compounds of the formula lie are obtained:
Figure imgf000094_0003
Figure imgf000094_0004
Figure imgf000095_0001
Example 29
Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with H2N-CH2-Ar' - (CH2) n- C0NH-(CH2)o-Ar and then with R^H. The following compounds of the formula Iif are obtained:
Figure imgf000095_0002
Ar,-(CH2)n-CONH- R1 in R'-H and Iif MS
(CH2)0-Ar calc. fnd.
— ( — CONH — CH2 — ( -NH-(CH2)3-N(CH3)2 -NH-(CH2)7-NH2
Figure imgf000095_0003
— _J> — CONH — CH2 — ( ) -NH-(CH2)7-NH2 554 555
Figure imgf000095_0004
Figure imgf000096_0001
Example 30
Analogously to Example 2, 6-chlorobenzo [de] isochromene-1, 3-dione is reacted with H2N-CH (R) -CONH2 and then with Rx-H. The following compounds of the formula Ik are obtained:
Figure imgf000097_0001
Example 31 :
Analogously to Example 2, 6-chlorobenzo- [de] isochromene-1, 3-dione is reacted with H2N-Ar and then with R1-H. The following compounds of the formula II are obtained:
Figure imgf000098_0001
(CH2), Ar
Figure imgf000098_0002
Figure imgf000099_0001
Example 32:
Equimolar amounts of 6- (3-amino-propylamino) -2- (3, 4 , 5- trimethoxy-benzyl) -benzo [de] isoquinoline-1, 3-dione (according to example 31, page 96, table line 4) and methanesulfonic acid are reacted according to known procedures to give the acid addition salt 6- (3-amino- propylamino) -2- (3, 4, 5-trimethoxy-benzyl) - benzo [de] isoquinoline-1, 3-dione, methane sulfonate.
'H-nrar (DMSO-d6) :
8.74 (dd, J = 0.8 and J = 8.5 Hz, 1H) , 8.46 (dd, J =
0.8 and J = 7.3 Hz, 1H) , 8.29 (d, J = 8.5 Hz, 1H) , 7.81
(t, J = 5.5 Hz, 1H(NH)), 7.77-7.68 (m, 4H (3xNH)), 6.86
(d, J = 8.7 Hz, 1H), 6.66 (s, 2H) , 3.75 (s, 3H) , 3.74
(s, 3H) , 3.53-3.47 (m, 2H) , 3.02-2.94 (m, 2H) , 2.31 (s, 3H) , 2.04-1.96 (m, 2H) . Abbreviations of the nnmmrr--_signals (nmr nuclear magnetic resonance) : s singlet, d doublet, dd double doublet, t triplet, sbr broad singlet, m multiplet, q quadruplet,
J coupling constant J in Hz
Example 33:
Analogously to Example 2, 6-chlorobenzo-
[de] isochromene-1, 3-dione is reacted with H2N-CH2-Ar'-
(CH2)n-C0NH-(CH2)o-Ar and then with R^H. The following compounds of the formula Iif are obtained:
R1
Figure imgf000100_0001
Ar'-(CH2)n-CONH-(CH2)0-Ar
Figure imgf000100_0002
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Example 34 :
Analogously to Example 2, 6-chlorobenzo-
[de] isochromene-1, 3-dione is reacted with H2N-CH2-Ar'-
(CH2) n-CONH- (CH2)0-Het and then with Rx-H. The following compounds of the formula lid are obtained:
R1
Figure imgf000112_0001
Ar'-(CH2)n-CONH-(CH2)0-Het
Figure imgf000112_0002
- Ill
Figure imgf000113_0001
Figure imgf000114_0002
Example 35 :
Analogously to Example 2, 6-chlorobenzo-
[de] isochromene-1, 3-dione is reacted with H2N-CH2-Ar'-
(CH2) n-CONH- (CH2) o-CH (Ar1) -Ar2 and then with Rx-H. The following compounds of the formula 12 are obtained:
R1
Figure imgf000114_0001
Ar'-(CH2)n-CONH-(CH2)0-CH(Ar1)-Ar
Figure imgf000114_0003
Figure imgf000115_0002
Example 36 :
Analogously to Example 2, 6-chlorobenzo-
[de] isochromene-1, 3-dione is reacted with H2N-CH2-Ar'-
(CH2) n-CONH- (CH2) o-CH (A) -Ph and then with Rx-H. The following compounds of the formula 13 are obtained:
R1
Figure imgf000115_0001
Ar'-(CH2)n-CONH-(CH2)0-CH(A).Ph
Figure imgf000115_0003
Example 37 :
Analogously to Example 2, 6-chlorobenzo-
[de] isochromene-1, 3-dione is reacted with H2N-CH2-Ar'-
(CH2)n-C0NHA and then with R1-H. The following compounds of the formula lie are obtained:
R1
Figure imgf000116_0001
Ar'-(CH2)n-CONHA
Figure imgf000116_0002
Example 38: Analogously to Example 2, 6-nitrobenzo-
[de] isochromene-1, 3-dione is reacted with H2N-(CH2)2- CONH- (CH2)0-Ar and then with R^H. The following compounds of the formula Iha are obtained:
Figure imgf000117_0001
CONH-(CH2)0-Ar
Figure imgf000117_0002
Figure imgf000118_0001
Figure imgf000119_0001
Example 39 :
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 2-amino-N- (4-iodo-phenyl) -acetamide and the mixture is heated under reflux. After reaction is complete, the reaction mixture is allowed to cool and is worked up as is customary. N- (4-Iodo-phenyl) -2- ( 6- nitro-1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl) - acetamide 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, N-biphenyl-4-yl-2- (6-nitro-l, 3-dioxo-lH,3H- benzo [de] isoquinolin-2-yl) -acetamide is heated with 3- aminomethyl-benzylamine until conversion is complete. After cooling the reaction mixture, it is worked up as is customary and 2- [6- (3-aminomethyl-benzylamino) -1, 3- dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] -N-biphenyl-4-yl- acetamide is obtained.
Analogously, by reaction of N-(4-iodo-3- methoxyphenyl) -2- ( 6-nitro-l, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl) -propionamide with Ph-B-(OH)2 and 3-aminomethyl-benzylamine, 3- [6- (3-aminomethyl- benzylamino) -1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2- yl] -N- (2-methoxy-biphenyl-4-yl) -propionamide is obtained.
Analogously, by reaction of N- (4-iodo-benzyl) - 3- (6-nitro-l, 3-dioxo-lH, 3H-benzo[de] isoquinolin-2-yl) - propionamide with Ph-B-(OH)2 and 3-aminomethyl- benzylamine, 3- [6- (3-aminomethyl-benzylamino) -1, 3- dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] -N-biphenyl-4- ylmethyl-propionamide is obtained. Example 40 :
Analogously to example 39, by reaction of 6- nitro-2- (4-iodophenyl) benzo [de] isoquinoline-1, 3-dione with R12-B-(OH)2 and 3-aminomethyl-benzylamine, the following compounds of the formula 14 are obtained:
Figure imgf000120_0001
Figure imgf000120_0002
Figure imgf000121_0002
Example 41 :
Analogously to Example 2, 6-nitrobenzo-
[de] isochromene-1, 3-dione is reacted with H2N-(CH2)2_
C0NH-(CH2)o-Het and then with R1-H . The following compounds of the formula Ihc are obtained:
R1
Figure imgf000121_0001
Figure imgf000122_0001
Example 42:
Analogously to example 2, by reaction of 6- nitro-benzo [de] isochromene-1, 3-dione with 3-amino-N- (3, 3-diphenyl-propyl) -propionamide and 3-aminomethyl- benzylamine, 3- [6- (3-aminomethyl-benzylamino) -1, 3- dioxo-lH, 3H-benzo [de] isoquinolin-2-yl] -N- (3, 3-diphenyl- propyl) -propionamide is obtained.
Example 43:
Analogously to example 2, by reaction of 6- nitro-benzo [de] isochromene-1, 3-dione with N-[4-(3- amino-propionylamino) -2-methoxy-phenyl] -2-methoxy- benzamide and 3-aminomethyl-benzylamine, N- (4-{ 3- [6- (3- Aminomethyl-benzylamino) -1, 3-dioxo-lH, 3H- benzo [de] isoquinolin-2-yl] -propionylamino}-2-methoxy- phenyl) -2-methoxy-benzamide is obtained.
Example 44:
Analogously to example 2, 6-nitrobenzo- [de] isochromene-1, 3-dione is reacted with H2N-(CH2)2- CONH-Ar'-Het and then with 3-aminomethyl-benzylamine. The following compounds of the formula 15 are obtained:
Figure imgf000123_0001
Figure imgf000123_0002
Figure imgf000124_0002
Example 45 :
Analogously to example 2, 6-nitrobenzo-
[de] isochromene-1, 3-dione is reacted with 3, 3-diphenyl- propylamine and then with R1-H. The following compounds of the formula 16 are obtained:
Figure imgf000124_0001
Figure imgf000124_0003
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
Figure imgf000127_0001
in which
R is H, A or CH2-Ph,
R1 is -Het, -N-[ (CH2)s-OH]2, -N-[ (CH2)s-OA]2,
-NA-(CH2)S-Ar, -NA-(CH2)ra-R5, -Y-(CH2)m-R5, -Y-(CH2)2-NHA, -Y-(CH2) -NH-(CH2)s-OH, -Y- (CH2) 2~NA2,
-Y- (CH2)m-OH, -Y- (CH2) n- (CHR4) -R3, -Y- (CH2) n~ R i R i
-Y-(CH2) n-Het- (CH2) ■R -Y-(CH2)n-Ar' (CH2)0-RC
-Het- (CH2) n-Ar, -Het-Het, -Y- (CH2) S-Ar' - (CH2) 0~R 11 -Y-[X-0]t-[X1-0]u-X2-R5 or -Y-(CH2)n-NA-(CH2)0-R5,
R< is H, OH, OA, COOH, COOA, CH(Ph)-Ph, Ar, Het1, RD R7 or R8
RJ is CH3,
R" is -CH=CH2, -Ar, COOA, COOH
Figure imgf000127_0002
Rc is NH2, NHA, NA2, NHAr, -NH- (CH2) n~OH or
-NH-(CH2)n-OA,
Rfc is H or R5 R7 is -Ar'-(CH2)n-R8 or -Ar' - (CH2) n"R5
Rb is CONH2, CONHA, CONA2, CONH- (CH2) o-Ar,
CONH- (CH2) o-Het, CONH- (CH2) o" 5, CONH- (CH2) 0~CH (Ar1) -
Ar2, CONH-(CH2)0-CH(A)-Ph, CONH- (CH2) 0~Ar ' -NH-CO-Ar,
CONH-Ar'-Het or CHA-CONH2, R11 is -NH- ( C=NH ) -NH2 , -NH- ( C=NH ) -NHA, -NH- ( C=NH) -NA2 ,
-NA- (C=NH) -NH2, -NA- (C=NH) -NHA or -NA- (C=NH) -NA2, Ar' is phenylene, cycloalkylene or biphenylene, which is unsubstituted or mono- or disubstituted by A, OH, OA, Hal, CN, NH2, NHA, NA2, N02, CF3, CO-A, S02NH2, S02NAH or S02NA2, Ar is phenyl, cycloalkyl, naphthyl, cyclohex-1-enyl, biphenyl, bicyclohexyl, 4-cyclohexyl-phenyl, benzo [1, 3] dioxol-5-yl or indanyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, O-Ph, 0-CH2-Ph, 0-PH-CH3, 0 (cycloalkyl) , Hal, CN, NH2, NHA, NA2, NH-C(0)A, (CH2)n-NH2, (CH2)n-NHA, (CH2)n-NA2, N02, CF3, C(0)A, S02-Ph, S02NH2, S02NAH, S02NA2 or S02NA-Ph, Ar1 and Ar2 are each independently phenyl, Het is a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by CN, Hal, OH, OA, CF3, A, N02, CO, CO-A or R5, Het1 is an unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or 0 atoms can be present and/or can be mono- or disubstituted by Hal, OH, OA, A is unbranched or branched alkyl having 1-6 C atoms, Hal is F, Cl, Br or I,
X,
X^X2 in each case independently of one another are alkylene having 1 to 12 C atoms, Y is 0, S or NH, i is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, m is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, n,o in each case independently of one another are 0,
1, 2, 3 or 4, s is 1, 2, 3 or 4, t is 0, 1 or 2, u is 1 or 2, where if R2 is Ar or H, R1 is not
Figure imgf000129_0001
and their pharmaceutically tolerable salts and solvates.
2. Compound of the formula I according to Claim 1 a) methyl 3- (1, 3-dioxo-6-piperidin-l-yl-3a, 9b- dihydro-lH-3H-benzo [de] isoquinolin-2- yl ) propionate; b) 6- (3-amino-propylamino) -2- (3, 4 , 5-trimethoxy- benzyl) -benzo [de] isoquinoline-1, 3-dione; and its physiologically acceptable salts and solvates.
3. Process for the preparation of the compounds of the formula I according to Claim 1 and their salts or solvates, characterized in that a) a compound of the formula I is liberated from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent, or b) a compound of the formula II
Figure imgf000129_0002
in which
R9 is Cl, Br, N02 or R1, where
R1 has the meaning indicated in Claim 1 is reacted with a compound of the formula III
H2N—(CHR)i R2 III in which R, R2 and i have the meanings indicated in Claim 1, and, if necessary, the radical R9 is converted into a radical R1, or (c) a compound of the formula IV
Figure imgf000130_0001
in which
R9 is Cl, Br, N02 or R1, where
R1 has the meaning indicated in Claim 1 is reacted with a compound of the formula V L (CHR)i R2 V in which L iiss CCll,, BBrr,, oorr I, OH or a reactive esterified OH group and R, R and i have the meanings indicated in Claim 1 and, if appropriate, the radical R9 is converted into a radical R1, or (d) a radical R and/or R2 and/or R9 is converted into another radical R and/or R2 and/or R9 by, for example
- converting an amino group into a guanidino group by reaction with an amidinating agent,
- reacting an aryl bromide or iodide to give the corresponding coupling products by means of a Suzuki coupling with boronic acids,
- reducing a nitro group, sulfonyl group or sulfoxyl group,
- etherifying an OH group or subjecting an OA group to ether cleavage,
- alkylating a primary or secondary amino group,
- partially or completely hydrolysing a CN group,
- cleaving an ester group or esterifying a carboxylic acid radical,
- or carrying out a nucleophilic or electrophilic substitution, and/or (e) a base or acid of the formula I is converted into one of its salts or solvates.
4. A pharmaceutical composition comprising an effective amount of a compound of formula I of claim 1 or a physiologically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
5. A pharmaceutical composition of claim 4 which is effective as a glycoprotein 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 pharmaceutical active compound.
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.
PCT/EP1999/008560 1998-11-25 1999-11-09 Substituted benzo[de]isoquinoline-1,3-diones WO2000031039A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
MXPA01005228A MXPA01005228A (en) 1998-11-25 1999-11-09 Substituted benzo[de]isoquinoline-1,3-diones.
BR9915611-3A BR9915611A (en) 1998-11-25 1999-11-09 Benzo [de] substituted isoquinoline-1,3-diones
PL99347766A PL347766A1 (en) 1998-11-25 1999-11-09 Substituted benzo[de]isoquinoline-1,3-diones
SK701-2001A SK7012001A3 (en) 1998-11-25 1999-11-09 Substituted benzo[de]isoquinoline-1,3-diones
HU0104469A HUP0104469A3 (en) 1998-11-25 1999-11-09 Substituted benzo[de]isoquinoline-1,3-diones, process for preparation of the compounds and medicaments containing them
CA002351348A CA2351348A1 (en) 1998-11-25 1999-11-09 Substituted benzo[de]isoquinoline-1,3-diones
AU15049/00A AU1504900A (en) 1998-11-25 1999-11-09 Substituted benzo(de)isoquinoline-1,3-diones
EP99957291A EP1133475A1 (en) 1998-11-25 1999-11-09 Substituted benzo de]isoquinoline-1,3-diones
JP2000583867A JP2002530379A (en) 1998-11-25 1999-11-09 Substituted benzo [de] isoquinoline-1,3-diones
NO20012543A NO20012543L (en) 1998-11-25 2001-05-23 Substituted benzo [de] isoquinoline-1,3-dione

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US19940998A 1998-11-25 1998-11-25
US40099299A 1999-09-21 1999-09-21
US09/199,409 1999-09-21
US09/400,992 1999-09-21

Publications (1)

Publication Number Publication Date
WO2000031039A1 true WO2000031039A1 (en) 2000-06-02

Family

ID=26894739

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/008560 WO2000031039A1 (en) 1998-11-25 1999-11-09 Substituted benzo[de]isoquinoline-1,3-diones

Country Status (15)

Country Link
EP (1) EP1133475A1 (en)
JP (1) JP2002530379A (en)
CN (1) CN1328549A (en)
AR (1) AR029152A1 (en)
AU (1) AU1504900A (en)
BR (1) BR9915611A (en)
CA (1) CA2351348A1 (en)
CZ (1) CZ20011792A3 (en)
HU (1) HUP0104469A3 (en)
ID (1) ID29425A (en)
MX (1) MXPA01005228A (en)
NO (1) NO20012543L (en)
PL (1) PL347766A1 (en)
SK (1) SK7012001A3 (en)
WO (1) WO2000031039A1 (en)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6559306B2 (en) 2001-02-21 2003-05-06 Clariant Finance (Bvi) Limited Dye compounds
WO2006027628A2 (en) * 2004-09-07 2006-03-16 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Naphthalimide derivatives as antiviral agents
WO2006058778A2 (en) * 2004-12-03 2006-06-08 Roche Diagnostics Gmbh Luminescent indicator dye and optical sensor
US7087677B2 (en) 2001-02-21 2006-08-08 Mitchell A. Winnik Copolymer composition having pigment like properties
WO2012115945A1 (en) * 2011-02-21 2012-08-30 The Board Of Regents Of The University Of Texas System Viral inhibitors
CN103848787A (en) * 2012-12-06 2014-06-11 中国科学院大连化学物理研究所 Fluorescence probe and application thereof in reversible detection of hypochlorous acid
WO2014149198A1 (en) * 2013-03-15 2014-09-25 Alumend, Llc Compositions and methods of using the compositions for plaque softening
US20160106728A1 (en) * 2013-05-01 2016-04-21 Academia Sinica Methods and compositions for treating beta-thalassemia and sickle cell disease
WO2018212355A1 (en) * 2017-05-19 2018-11-22 株式会社同仁化学研究所 Fluorescent compound and autophagy detection reagent using same
CN111777557A (en) * 2020-07-28 2020-10-16 中国科学院上海有机化学研究所 Novel anti-tumor lead compound with aromatic biphenyl alkene as skeleton and application thereof
WO2023166531A1 (en) * 2022-03-04 2023-09-07 Jawaharlal Nehru Centre For Advanced Scientific Research Amyloid and associated pathology modulators and methods thereof
WO2024042539A1 (en) * 2022-08-22 2024-02-29 Jawaharlal Nehru Centre For Advanced Scientific Research Modulators of tau liquid-liquid phase separation and methods thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111253368B (en) * 2018-11-30 2020-12-25 沈阳药科大学 Stable nitroxide radical modified naphthalimide compound and application thereof
CN113087702B (en) * 2021-03-29 2022-07-12 苏州大学 Multifunctional perchloroethylene derivative and preparation method and application thereof

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3821383A (en) * 1972-07-10 1974-06-28 Ayerst Mckenna & Harrison Compositions for and a method of treating diabetic complications
FR2253744A1 (en) * 1973-12-06 1975-07-04 Hoechst Ag 4-Amino-naphthalene-1,8-dicarboxylic acid N-substd. imide derivs. - used in fluorescent pigments
JPS54160977A (en) * 1978-06-09 1979-12-20 Kawasaki Steel Corp Functioning speed changing method by means of operating lever
US4200752A (en) * 1978-02-16 1980-04-29 Bertelson Robert C 4-Disubstituted amino, N-substituted naphthalimide dyestuffs
GB2183667A (en) * 1985-10-29 1987-06-10 Univ Brunel Synthesis of naphthalimide derivatives
EP0243841A1 (en) * 1986-04-29 1987-11-04 Knoll Ag Benzo[d,e]isoquinoline-1,3 diones, their preparation and use
US5308773A (en) * 1992-11-16 1994-05-03 Microbiomed Corp. Non-azo 1,8-naphthalimide dyes for the detection and quantitation of a paramagnetic metal cation in a non-aqueous medium
DE19505941A1 (en) * 1995-02-21 1996-08-22 Bayer Ag 1,8-naphthalimide derivatives, process for their preparation and their use as intermediates
WO1998017278A1 (en) * 1996-10-21 1998-04-30 Allelix Biopharmaceuticals Inc. Neurotrophin antagonist compositions

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3821383A (en) * 1972-07-10 1974-06-28 Ayerst Mckenna & Harrison Compositions for and a method of treating diabetic complications
FR2253744A1 (en) * 1973-12-06 1975-07-04 Hoechst Ag 4-Amino-naphthalene-1,8-dicarboxylic acid N-substd. imide derivs. - used in fluorescent pigments
US4200752A (en) * 1978-02-16 1980-04-29 Bertelson Robert C 4-Disubstituted amino, N-substituted naphthalimide dyestuffs
JPS54160977A (en) * 1978-06-09 1979-12-20 Kawasaki Steel Corp Functioning speed changing method by means of operating lever
GB2183667A (en) * 1985-10-29 1987-06-10 Univ Brunel Synthesis of naphthalimide derivatives
EP0243841A1 (en) * 1986-04-29 1987-11-04 Knoll Ag Benzo[d,e]isoquinoline-1,3 diones, their preparation and use
US5308773A (en) * 1992-11-16 1994-05-03 Microbiomed Corp. Non-azo 1,8-naphthalimide dyes for the detection and quantitation of a paramagnetic metal cation in a non-aqueous medium
DE19505941A1 (en) * 1995-02-21 1996-08-22 Bayer Ag 1,8-naphthalimide derivatives, process for their preparation and their use as intermediates
WO1998017278A1 (en) * 1996-10-21 1998-04-30 Allelix Biopharmaceuticals Inc. Neurotrophin antagonist compositions

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 103, no. 24, 16 December 1985, Columbus, Ohio, US; abstract no. 197364w, A.T.PETERS ET AL: "Amino derivatives of 1,8-naphtalic anhydride and derived dyes for synthetic-polymer fibers" page 68; XP002132396 *
CHEMICAL ABSTRACTS, vol. 115, no. 2, 15 July 1991, Columbus, Ohio, US; abstract no. 10854p, page 110; XP002132397 *
CHEMICAL ABSTRACTS, vol. 123, no. 4, 24 July 1995, Columbus, Ohio, US; abstract no. 35244t, TZWETANKA PHILIPOVA ET AL: "Absorption spectra of some N-substituted-1,8-naphthalimides" page 113; XP002132398 *
CHEMICAL ABSTRACTS, vol. 123, no. 7, 14 August 1995, Columbus, Ohio, US; abstract no. 83189a, T.FILIPOVA: "Synthesis of 4-substituted-N-(beta-hydroxyethyl)naphthalimides" page 1026; XP002132399 *
CHEMICAL ABSTRACTS, vol. 77, no. 22, 27 November 1972, Columbus, Ohio, US; abstract no. 141485p, page 76; XP002132400 *
CHEMICAL ABSTRACTS, vol. 93, no. 1, 7 July 1980, Columbus, Ohio, US; abstract no. 2247v, page 226; XP002132394 *
CHEMICAL ABSTRACTS, vol. 99, no. 17, 24 October 1983, Columbus, Ohio, US; abstract no. 139735f, B.M.KRASOVITSKII ET AL: "Synthesis and luminescent properties of 4-substituted derivatives of naphtalic anhydride and naphthalimide" page 580; XP002132395 *
DOKL.BULG.AKAD.NAUK, vol. 47, no. 4, 1994, pages 49 - 52 *
DYES PIGM., vol. 28, no. 2, 1995, pages 91 - 99 *
DYES PIGM., vol. 6, no. 5, 1985, pages 349 - 375 *
ZH.ORG.KHIM., vol. 19, no. 61983, pages 1305 - 1308 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7087677B2 (en) 2001-02-21 2006-08-08 Mitchell A. Winnik Copolymer composition having pigment like properties
US6559306B2 (en) 2001-02-21 2003-05-06 Clariant Finance (Bvi) Limited Dye compounds
WO2006027628A2 (en) * 2004-09-07 2006-03-16 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Naphthalimide derivatives as antiviral agents
WO2006027628A3 (en) * 2004-09-07 2006-05-04 Eletti Spa Istituto Di Ricerch Naphthalimide derivatives as antiviral agents
WO2006058778A2 (en) * 2004-12-03 2006-06-08 Roche Diagnostics Gmbh Luminescent indicator dye and optical sensor
WO2006058778A3 (en) * 2004-12-03 2006-08-10 Roche Diagnostics Gmbh Luminescent indicator dye and optical sensor
US8097725B2 (en) 2004-12-03 2012-01-17 Roche Diagnostics Operations, Inc. Luminescent indicator dye and optical sensor
WO2012115945A1 (en) * 2011-02-21 2012-08-30 The Board Of Regents Of The University Of Texas System Viral inhibitors
CN103848787A (en) * 2012-12-06 2014-06-11 中国科学院大连化学物理研究所 Fluorescence probe and application thereof in reversible detection of hypochlorous acid
US10131635B2 (en) 2013-03-15 2018-11-20 Alumend, Llc Compositions and methods of using the compositions for plaque softening
WO2014149198A1 (en) * 2013-03-15 2014-09-25 Alumend, Llc Compositions and methods of using the compositions for plaque softening
US20160106728A1 (en) * 2013-05-01 2016-04-21 Academia Sinica Methods and compositions for treating beta-thalassemia and sickle cell disease
US9662324B2 (en) * 2013-05-01 2017-05-30 Academia Sinica Methods and compositions for treating β-thalassemia and sickle cell disease
WO2018212355A1 (en) * 2017-05-19 2018-11-22 株式会社同仁化学研究所 Fluorescent compound and autophagy detection reagent using same
CN110650946A (en) * 2017-05-19 2020-01-03 株式会社同仁化学研究所 Fluorescent compound and autophagy detection reagent using same
JPWO2018212355A1 (en) * 2017-05-19 2020-03-19 株式会社同仁化学研究所 Fluorescent compound and autophagy detection reagent using the same
JP7301259B2 (en) 2017-05-19 2023-07-03 株式会社同仁化学研究所 Fluorescent compound and autophagy detection reagent using the same
CN111777557A (en) * 2020-07-28 2020-10-16 中国科学院上海有机化学研究所 Novel anti-tumor lead compound with aromatic biphenyl alkene as skeleton and application thereof
CN111777557B (en) * 2020-07-28 2022-11-22 中国科学院上海有机化学研究所 Novel anti-tumor lead compound with aromatic biphenyl alkene as framework and application thereof
WO2023166531A1 (en) * 2022-03-04 2023-09-07 Jawaharlal Nehru Centre For Advanced Scientific Research Amyloid and associated pathology modulators and methods thereof
WO2024042539A1 (en) * 2022-08-22 2024-02-29 Jawaharlal Nehru Centre For Advanced Scientific Research Modulators of tau liquid-liquid phase separation and methods thereof

Also Published As

Publication number Publication date
AU1504900A (en) 2000-06-13
HUP0104469A2 (en) 2002-04-29
CA2351348A1 (en) 2000-06-02
CN1328549A (en) 2001-12-26
AR029152A1 (en) 2003-06-18
BR9915611A (en) 2001-08-14
CZ20011792A3 (en) 2001-09-12
NO20012543D0 (en) 2001-05-23
ID29425A (en) 2001-08-30
JP2002530379A (en) 2002-09-17
SK7012001A3 (en) 2001-11-06
MXPA01005228A (en) 2002-06-21
EP1133475A1 (en) 2001-09-19
NO20012543L (en) 2001-05-23
PL347766A1 (en) 2002-04-22
HUP0104469A3 (en) 2003-06-30

Similar Documents

Publication Publication Date Title
AU693496B2 (en) 4-amino-1-piperidylbenzoylguanidine
JP4023841B2 (en) Heterocyclyl-benzoylguanidine compounds
JP4202438B2 (en) Adhesive receptor antagonist compound
EP1133475A1 (en) Substituted benzo de]isoquinoline-1,3-diones
WO2007003934A2 (en) 17beta-hydr0xyster0id dehydrogenase type 3 (17beta-hsd3 ) inhibitors
CZ300127B6 (en) Process for preparing retroviral protease inhibiting intermediates
SK279363B6 (en) Indole derivatives, method of preparation thereof, pharmaceutical agent containing thereof and its use
WO2000032577A2 (en) Substituted benzo[de]isoquinoline-1,3-diones
CZ290984B6 (en) Oxazolidinone carboxylic acid derivatives, process of their preparation and pharmaceutical preparations based thereon
WO2000026212A1 (en) Chromenone and chromanone derivatives as integrin inhibitors
KR20040065233A (en) 2-guanidino-4-heterocyclylquinazolines
WO2001023364A1 (en) Quinazolinones
ZA200202284B (en) alphavbeta3 integrin inhibitors.
KR20010087399A (en) Substituted benzo[de]isoquinoline-1,3-diones
US6521646B1 (en) Dibenzoazulene derivatives for treating thrombosis, osteoporosis, arteriosclerosis
EP1216235A1 (en) Quinazolinones
US6890930B1 (en) Quinazolinones
SK2282002A3 (en) Integrin alpha&#39;v&#39;beta&#39;3&#39; inhibitors, process for the preparation and use thereof and pharmaceutical composition comprising same
WO2002012193A1 (en) Tetrahydroisoquinoline-3-carboxylic acid alkoxyguanidines as integrin antagonists
CZ2002298A3 (en) Fluorene derivative, process of its preparation, use and pharmaceutical preparation in which the derivative is comprised
MXPA01004272A (en) Chromenone and chromanone derivatives as integrin inhibitors
MXPA01005227A (en) Substituted benzo[de]isoquinoline-1,3-diones

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 99813608.5

Country of ref document: CN

ENP Entry into the national phase

Ref document number: 2000 15049

Country of ref document: AU

Kind code of ref document: A

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 1999957291

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 7012001

Country of ref document: SK

WWE Wipo information: entry into national phase

Ref document number: PV2001-1792

Country of ref document: CZ

ENP Entry into the national phase

Ref document number: 2351348

Country of ref document: CA

Ref document number: 2351348

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/a/2001/005228

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2000 583867

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1020017006546

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: IN/PCT/2001/646/KOL

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 200105199

Country of ref document: ZA

Ref document number: 15049/00

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 1200100594

Country of ref document: VN

WWP Wipo information: published in national office

Ref document number: PV2001-1792

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1020017006546

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 1999957291

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWW Wipo information: withdrawn in national office

Ref document number: 1999957291

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1020017006546

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: PV2001-1792

Country of ref document: CZ