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WO2001023365A1 - Quinazolinones - Google Patents

Quinazolinones Download PDF

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Publication number
WO2001023365A1
WO2001023365A1 PCT/EP2000/008940 EP0008940W WO0123365A1 WO 2001023365 A1 WO2001023365 A1 WO 2001023365A1 EP 0008940 W EP0008940 W EP 0008940W WO 0123365 A1 WO0123365 A1 WO 0123365A1
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WO
WIPO (PCT)
Prior art keywords
quinazolin
formula
phenyl
absent
formula lla
Prior art date
Application number
PCT/EP2000/008940
Other languages
English (en)
Inventor
Werner Mederski
Ralf Devant
Gerhard Barnickel
Sabine Bernotat-Danielowski
Guido Melzer
Daljit Dhanoa
Bao-Ping Zhao
James Rinker
Mark Player
Richard Soll
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 AU76548/00A priority Critical patent/AU7654800A/en
Priority to US10/089,166 priority patent/US6890930B1/en
Priority to KR1020027003907A priority patent/KR20020047186A/ko
Priority to CA002385921A priority patent/CA2385921A1/fr
Priority to EP00965991A priority patent/EP1216235A1/fr
Priority to BR0014294-8A priority patent/BR0014294A/pt
Publication of WO2001023365A1 publication Critical patent/WO2001023365A1/fr
Priority to NO20021502A priority patent/NO20021502D0/no

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to substituted quinazoiinones of the formula I
  • R and R 1 are independently of each other H, A, OH, OA, OCH 2 -Ar, Hal,
  • R 4 is Ar, cycloalkyl, phenylalkyl or Het, Y may be absent and, if present, is alkenyl having 2 to 4 carbon atoms,
  • Z may be absent and, if present, is phenylene, A is unbranched or branched alkyl having 1 to 6 carbon atoms, Ar is phenyl, naphthyl, biphenyl or benzofuranyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA,
  • CF 3 OCF 3l Hal, CN, COOH, COOA, NH 2 , NHA, NA 2 , N0 2 ,
  • 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 A,
  • the invention is based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments. It has been found that the compounds of the formula I and their salts or solvates have very valuable pharmacological properties together with good tolerability.
  • GPIblX inhibitors act especially as GPIblX inhibitors, in particular inhibiting the interaction of this receptor with the ligand von Willebrand factor (vWF).
  • vWF von Willebrand factor
  • This action can be demonstrated, for example, by a method which is described by S. Meyer et al. in J. Biol. Chem. 1993, 268, 20555-20562.
  • the property as 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).
  • the blocking action of GPIblX inhibitors exerts its maximum effect, as described by J.J. Sixma et al. in Arteriosclerosis, Thrombosis, and Vascular Biology 1996, 16, 64-71.
  • the compounds of the formula I can be characterized as GPIblX inhibitors in whole blood.
  • the inhibition of thrombus formation of the GPIblX inhibitors can be measured by a modified Born method (Nature 1962, 4832, 927-929) using botrocetin or ristocetin as an aggregation stimulant.
  • the compounds of the formula I according to the invention can therefore be employed as pharmaceutical active compounds in human and veterinary medicine. They act as adhesion receptor antagonists, in particular as glycoprotein IblX antagonists, and are suitable for the prophylaxis and/or therapy of thrombotic disorders and sequelae deriving therefrom.
  • adhesion receptor antagonists in particular as glycoprotein IblX antagonists
  • glycoprotein IblX antagonists are suitable for the prophylaxis and/or therapy of thrombotic disorders and sequelae deriving therefrom.
  • the preferentially best action is to be expected in the case of thrombotic disorders in the arterial vascular system, but GPIblX inhibitors also have an effect in the case of thrombotic disorders in the venous vascular bed.
  • the disorders are acute coronary syndromes, angina pectoris, myocardial infarct, peripheral circulatory disorders, stroke, transient ischaemic attacks, arteriosclerosis, reocclusion/restenosis after angioplasty/stent implantation.
  • the compounds can furthermore be employed as anti-adhesive substances where the body comes into contact with foreign surfaces such as implants, catheters or cardiac pacemakers.
  • R and R 1 are independently of each other H, A, OH, OA, OCH 2 -Ar, Hal,
  • Y may be absent and, if present, is alkenyl having 2 to 4 carbon atoms
  • Z may be absent and, if present, is phenylene
  • A is unbranched or branched alkyl having 1 to 6 carbon atoms
  • Ar is phenyl, naphthyl, biphenyi or benzofuranyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF 3 , OCF 3 , Hal, CN, COOH, COOA, NH 2 , NHA, NA 2 , N0 2 ,
  • S0 2 NH 2 , S0 2 NAH or S0 2 NA 2 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 A,
  • OA, CF 3 , OCF 3 , Hal, CN, COOH, COOA, NH 2 , NHA, NA 2 , N0 2 , S0 2 NH 2 , S0 2 NAH or S0 2 NA 2 Hal is F, Cl, Br or l, n is 1 , 2 or 3, m is 0, 1 , 2 or 3, with the proviso if Y is vinyl, R 4 is phenyl, Z is absent, n is 1 , m is 1 and R 2 and R 3 are ethyl, then R or R 1 is not NH 2 , if Z is absent, Y is absent or vinyl, R 4 is phenyl, phenylalkyl, alkoxyphenyl or pyridyl, R is H and R 1 is NH 2 , then R 2 and R 3 are not A, and if Z and Y are absent, then R 4 is not phenylalkyl and their physiologically acceptable salts or solvates as pharmaceutical active compounds.
  • the invention relates to compounds of the formula I according to Claim 4 and their physiologically acceptable salts or solvates as glycoprotein IblX antagonists.
  • the invention relates to the compounds of the formula I of claim 1 and their salts or solvates, and to a process for the preparation of the compounds of the formula I
  • R and R 1 are independently of each other H, A, OH, OA, OCH 2 -Ar, Hal,
  • R 4 is Ar, cycloalkyl, phenylalkyl or Het, Y may be absent and, if present, is alkenyl having 2 to 4 carbon atoms,
  • Z may be absent and, if present, is phenylene, A is unbranched or branched alkyl having 1 to 6 carbon atoms, Ar is phenyl, naphthyl, biphenyl or benzofuranyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF 3 , OCF 3 , Hal, CN, COOH, COOA, NH 2 , NHA, NA 2 , N0 2 , S0 2 NH 2 , S0 2 NAH or S0 2 NA 2 , 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 A, Hal, OH, OA, CF 3 , OCF 3 , NH 2 , NHA, NA 2 , COOH,
  • X is Cl, Br, OH or a reactive esterified OH group
  • Q is NH 2 or NHA, either of which optionally is protected, and R and R 1 are optionally protected when they are or contain NH 2 or NHA, is reacted with a compound of the formula III
  • R -Y-CHO V in which R 4 and Y have the meanings indicated in Claim 1 , or c) a radical R, R ⁇ R 2 , R 3 and/or R 4 is converted into another radical R, R 1 , R 2 , R 3 and/or R 4 by, for example converting an amino group into a guanidino group by reaction with an amidinating agent, - 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, reacting an aryl bromide, aryl iodide, heteroaryl bromide or heteroaryliodide to give the corresponding coupling products by means of a Suzuki coupling with boronic acids, or carrying out a nucle
  • 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.
  • the proviso excludes e.g. the following compounds: 3-(2-amino-ethyl)-2-p-tolyl-3H-quinazolin-4-one;
  • 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, 1-ethyl-2-methylpropyl, 1 ,1 ,2- or 1 ,2,2-trimethylpropyl.
  • A is preferentially methyl.
  • Alkenyl having 2 to 4 carbon atoms is preferably vinyl or buta-1 ,3-dienyl, vinyl is particularly preferred.
  • Ar is phenyl, naphthyl, biphenyl or benzofuranyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF 3 , OCF 3 , Hal, CN, COOH, COOA, NH 2 , NHA, NA 2 , N0 2 , S0 2 NH 2 , S0 2 NAH or S0 2 NA 2 .
  • Ar is preferentially phenyl, preferably - as indicated - mono- di- or trisubstituted phenyl, specifically preferentially phenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-ethylphenyl, 2-, 3- or 4-propylphenyl, 2-, 3- or 4-isopropylphenyl, 2-, 3- or 4-tert-butylphenyl, 2-, 3- or 4-aminophenyl, 2-, 3- or 4-N,N-dimethylaminophenyl, 2-, 3- or 4-sulfonamidophenyl, 2-, 3- or 4-nitrophenyl, 2-, 3- or 4-hydroxyphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4- trifluoromethoxyphenyl, 2-, 3- or 4-carboxyphenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or
  • Cycloalkyl preferably has 3-7 C atoms and is preferably cyclopropyl or cyclobutyl, furthermore preferably cyclopentyl or cyclohexyl, and further also cycloheptyl; cyclohexyl is particularly preferred .
  • Hal is preferably F, Cl or Br.
  • 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 A, Hal, OH, OA, CF 3 , OCF 3 , NH 2 , NHA, NA 2 , COOH, COOA, phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF 3 , OCF 3 , Hal, CN, COOH, COOA, NH 2 , NHA, NA 2 , N0 2 ,
  • S0 2 NH 2 , S0 2 NAH or S0 2 NA 2 or thiophenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF 3 , OCF 3 , Hal, CN, COOH, COOA, NH 2 , NHA, NA 2 , N0 2 , S0 2 NH 2 , S0 2 NAH or S0 2 NA 2 .
  • Het is preferably substituted by A, OH, OA, CF 3 , OCF 3 , Hal, CN, COOH, COOA, NH 2 , NHA, NA 2 , N0 2 , S0 2 NH 2 , S0 2 NAH or S0 2 NA 2 or thiophenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF 3 , OCF 3 , Hal, CN, COOH, COOA, NH 2 , NHA, NA 2 , N0 2 , S0 2 NH 2 , S0 2 NAH or S0 2 NA 2 or unsubstituted 2- or 3-furyl, 2- or 3-thiophenyl, 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-1-, -4- or -5-yl, 1 ,2,4-triazol-1-, -4- or -5-yl, 1- or 5-tetrazolyl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or
  • 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-1-, -2-, -3-, -4- or
  • Phenylalkyl preferably has 7, 8, 9 or 10 carbon atoms and is preferably phenylmethyl, phenylethyl, phenylpropyl or phenylbutyl; phenylethyl is particularly preferred .
  • solid phase indicates a resin for solid-phase chemistry, especially for combinatorial chemistry, i.e. by robot- and computer-assisted syntheses, and subjected to mass screening as indicated in 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 polymeric material of the solid phase is generally chosen from the group consisting of cross-linked polystyrene, cross-linked polyacrylamide or other resins, natural polymers or silicagels.
  • the group of cross-linked polystyrene, cross-linked polyacrylamide or other resins includes e.g. polyacrylamide, polymethacrylarnide, polyhydroxyethylmethacrylate, polyamide, polystyrene, (meth)acrylate copolymers, for instance from (methy)acrylic acid, esters of (meth)acryiic acid and/or 2-methylene-succinic acid, but-2-enoic acid or maleic acid, polyurethanes or other copolymers.
  • Suitable terminal functional groups or linkers on the surface of the resin have to be chosen to attach the compounds to the resin.
  • resins There exists a variety of commercially available resins, e.g. in Novabiochem - The Combinatorial Chemistry Catalog, March 99.
  • sutitable resins are carbonate resins with a modified carbonate group as terminal functional group like p-nitrophenylcarbonate resin, halogenated resins like Merrifield resin (chloromethylpolystyrene) or carboxy resins like carboxy polystyrene resin or NovaSyn ® TG Carboxy Resin.
  • p-Nitrophenylcarbonate resin is particularly preferred.
  • R and R 1 are independently of each other H, A, OH, OA, OCH 2 -Ar, Hal,
  • R is preferentially H.
  • R 1 is preferentially H, A, OA or Hal.
  • R 1 is the 6- or 7-position of the quinazolinone ring system.
  • R 2 is preferentially H.
  • R 4 is Ar, phenylalkyl, cycloalkyl or Het, where Ar, phenylalkyl, cycloalkyl or Het have a preferred meaning indicated beforehand.
  • R 4 is preferentially phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-tert- butylphenyl, 4-dimethylaminophenyl, 4-methoxyphenyl, 3-methoxyphenyl,
  • 3-chlorophenyl 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 2,5- dimethoxyphenyl, 3',5'-dimethoxybiphenyl-4-yl, 2',4'-dimethoxybiphenyl-4- yl, biphenyl-4-yl, naphthalen-1-yl, naphthalen-2-yl or benzofuran-5-yl, phenylethyl, cyclohexyl, 2-furyl, thiophen-2-yl, thiophen-3-yl, 5-(3,4- dimethoxyphenyl)-thiophen-2-yl or 5-[2,2']bithiophenyl.
  • Y may be absent and, if present, is alkenyl having 2 to 4 carbon atoms. Y is preferentially absent or vinyl.
  • Z may be absent and, if present, is phenylene.
  • n 1 , 2 or 3, particularly preferred 1.
  • m is 0, 1 , 2 or 3, particularly preferred 1.
  • R 1 is H, A, OA or Hal
  • R 1 is H, A, OA or Hal and Y is absent; in lc R is H,
  • R 1 is H, A, OA or Hal, Y is absent and Z is absent;
  • R 1 is H, A, OA or Hal
  • R 4 is Ar, cycloalkyl or Het
  • R 1 is H, A, OA or Hal
  • R 4 is Het
  • R 1 is H, A, OA or Hal
  • Z is phenylene
  • R 1 is H, A, OA or Hal
  • Y is alkenyl having 2 to 4 carbon atoms
  • R 1 is H, A, OA or Hal
  • Y is alkenyl having 2 to 4 carbon atoms and Z is absent;
  • R 1 is H, A, OA or Hal
  • Y is alkenyl having 2 to 4 carbon atoms and Z is phenylene;
  • R 1 is H. A, OA or Hal,
  • R 2 is H
  • R 4 is Ar
  • R 1 is H, A, OA or Hal
  • R 2 is H
  • R 4 is phenylalkyl
  • R 1 is H, A, OA or Hal
  • R 2 is H
  • R 4 is cycloalkyl
  • R is H, R 1 is H, A, OA or Hal, R 2 is H and R 4 is Het;
  • R 1 is H, A, OA or Hal
  • R 2 is H
  • R 3 is H
  • R 4 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4- tert-butylphenyl, 4-dimethylaminophenyl, 4-methoxyphenyl, 3- methoxyphenyl, 3-chlorophenyl, 3,4,5-trimethoxyphenyl, 3,4- dimethoxyphenyl, 2,5-dimethoxyphenyl, 3',5'-dimethoxy- biphenyl-4-yl, 2 , ,4'-dimethoxybiphenyl-4-yl, biphenyl-4-yl, naphthalen-1-yl, naphthalen-2-yl or benzofuran-5-yl, phenylethyl, cyclohexyl, 2-furyl, thiophen-2-yi, thiophen-3-yl,
  • Z is absent, n is 1 and m is 1 ;
  • R 4 s phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4- tert-butylphenyl, 4-dimethylaminophenyl, 4-methoxyphenyl, 3- methoxyphenyl, 3-chlorophenyl, 3,4,5-trimethoxyphenyl, 3,4- dimethoxyphenyl, 2,5-dimethoxyphenyl, 3',5'-dimethoxy- biphenyl-4-yl, 2',4'-dimethoxybiphenyl-4-yl, biphenyl-4-yl, naphthalen-1-yl, naphthalen-2-yl or benzofuran-5-yl, phenylethyl, cyclohexyl, 2-furyl, thiophen-2-yl, thiophen-3-yl, 5-(3,4-dimethoxyphenyl)-thiophen-2-yl or 5-[2,2']bith
  • Z is phenylene, n is 1 and m is 1;
  • R 4 s phenyl, 4-dimethylaminophenyl or 2,5-dimethoxyphenyl,
  • R 4 s phenyl, 4-dimethylaminophenyl or 2,5-dimethoxyphenyl,
  • R 1 is H, A, OA or Hal
  • R 2 is H
  • R 3 is H, Y is absent,
  • R 4 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4- tert-butylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3- chlorophenyl, 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 3',5'-dimethoxybiphenyl, 2',4'-dimethoxybiphenyl-4-yl, biphenyl-4-yl, naphthalen-1-yl, naphthalen-2-yl or benzofuran- 5-yl, phenylethyl, cyclohexyl, 2-furyl, thiophen-2-yl, thiophen- 3-yl, 5-(3,4-dimethoxyphenyl)-thiophen-2-yl or 5- [2,2']bithiophenyl,
  • Z is absent, n is 1 and m is 1 ;
  • R 4 s phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4- tert-butylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3- chlorophenyl, 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl,
  • Z is phenylene, n is 1 and m is 1 ; in lu
  • R and R 1 are independently of each other H, A, OH, OA, OCH 2 -Ar, Hal,
  • R 4 is Ar, cycloalkyl, phenylalkyl or Het, Y may be absent and, if present, is alkenyl having 2 to 4 carbon atoms,
  • A is unbranched or branched alkyl having 1 to 6 carbon atoms
  • Ar is phenyl, naphthyl, biphenyl or benzofuranyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA,
  • CF 3 OCF 3 , Hal, CN, COOH, COOA, NH 2 , NHA, NA 2 , N0 2 ,
  • 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 A,
  • NHA N0 2 , S0 2 NH 2 , S0 2 NAH or S0 2 NA 2 or thiophenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH,
  • R and R 1 are independently of each other H, A, OH, OA, OCH 2 -Ar, Hal,
  • Y may be absent and, if present, is alkenyl having 2 to 4 carbon atoms, A is unbranched or branched alkyl having 1 to 6 carbon atoms,
  • Ar is phenyl, naphthyl, biphenyl or benzofuranyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF 3 , OCF 3 , Hal, CN, COOH, COOA, NH 2 , NHA, NA 2 , N0 2 , S0 2 NH 2 , S0 2 NAH or S0 2 NA 2 ,
  • 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 A, Hal, OH, OA, CF 3 , OCF 3 , NH 2 , NHA, NA 2 , COOH, COOA, phenyl which is unsubstituted or mono-, di- or trisubstituted by by A, OH, OA, CF 3 , OCF 3 , Hal, CN, COOH, COOA, NH 2 , NHA, NA 2 , N0 2 , S0 2 NH 2 , S0 2 NAH or S0 2 NA 2 or thiophenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF 3 , OCF 3 , Hal, CN, COOH,
  • Hal is F, Cl, Br or l, n is 1 , 2 or 3, m is 0, 1 , 2 or 3, and their pharmaceutically tolerable salts and solvates.
  • 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- Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), namely under reaction conditions which are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se, but not mentioned here in greater detail.
  • the starting substances if desired, can also be formed in situ such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
  • the compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis or by hydrogenolysis.
  • Preferred starting substances for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxyl groups, in particular those which instead of an H-N- group carry an R'-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 (lit.: T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Chemistry, 2nd ed., Wiley, New York 1991 or P.J. Kocienski, Protecting Groups, 1st ed., Georg Thieme Verlag, Stuttgart - New-York, 1994).
  • 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; aryioxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl (MOZ), 4-Nitro- benzyloxycarbonyl oder 9-fluorenylmethoxycarbonyl (Fmoc); 2-
  • Preferred amino protective groups are BOC, furthermore CBZ, Fmoc, benzyl and acetyl; particularly preferred Fmoc.
  • 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, aroyl or acyl groups, furthermore also alkylgroups, alkyl-, aryl- or aralkylsilylgroups or 0,0- or 0,S-acetals.
  • 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, 4-methoxybenzyl oder 2,4-dimethoxybenzyl, aroyl groups such as benzoyl or p-nitrobenzoyl, acyl groups such as acetyl or pivaloyl, p-toluolsulfonyl, alkyl groups such as methyl or tert-butyl, but also allyl, alkylsilyl groups such as trimethylsilyl
  • TMS triisopropylsilyl
  • TIPS tert-butyidimethyisilyl
  • TBS tert-butyidimethyisilyl
  • TDPS triethylsiiyl
  • aralkylsilyl groups such as tert-butyldiphenylsilyl (TBDPS)
  • cyclic acetals such as isopropylidene-, cyclopentylidene-, cyclohexylidene-, benzylidene-, p-methoxybenzylidene- or o,p- dimethoxybenzylideneacetal
  • acyclic acetales such as tetrahydropyranyl (Thp), methoxymethyl (MOM), methoxyethoxymethyl (MEM), benzyloxymethyl (BOM) or methylthiomethyl (MTM).
  • Thip tetrahydropyranyl
  • MOM me
  • the groups BOC and O-tert-butyl can preferably be removed, for example, using TFA in dichloromethane or using approximately 3 to 5N HCI in dioxane at 15-30°C, the Fmoc group using an approximately 5 to 50% solution of dimethylamine, diethyiamine or piperidine in DMF at 15-30°C.
  • Preferred starting substances for the solvolysis or hydrogenolysis includes also those which otherwise correspond to the formula I, but are attached to a solid phase.
  • the liberation of the compounds of the formula I from the solid phase is known in the present literature such as Novabiochem - The Combinatorial Chemistry Catalog, March 99 and cited literature.
  • the solid phase with a carbonate moiety as terminal functional group can preferably be removed, for example, using TFA (50%) in dichloromethane.
  • the quinazoiinones of formula I can also preferably be prepared, using either solution or solid-phase techniques, by combining and reacting an anthranilic acid of formula II with an amine of formula III and if necessary deprotect the given formula IV in which Q is then NH 2 or NHA and reacting the compound of formul IV in which Q is NH 2 or NHA with an aldehyde of formula V.
  • the unknown compounds can be prepared by methods known per se.
  • the compounds of the formula II are anthranilic acids. It is furthermore possible to introduce appropriate substituents into the aromatic by conventional electrophilic or alternatively nucleophilic substitutions.
  • Fmoc protected anthranilic acids include, but are not limited to, Fmoc protected anthranilic acid, Fmoc protected 3-methyl anthranilic acid, Fmoc protected 3-methoxy anthranilic acid, Fmoc protected 3-chloro anthranilic acid or Fmoc protected 4-chloro anthranilic acid.
  • Solid-phase techniques may be employed to condense anthranilic acids of formula II and the amine component of formula III which is resin bound (R 2 or R 3 is solid phase).
  • amines of formula III in which R 2 or R 3 are H are also commercially available and can be attached to the suitable resin by coupling procedures well known in the art and as described in the ensuing Examples. Furthermore, syntheses for the preparation of amines of formula III, such as, for example, the Gabriel synthesis, can be used.
  • aldehydes of formula V are also commercially available. Furthermore, syntheses for the preparation of aldehydes of formula V, such as, for example, the oxidation of an alcohol, can be used.
  • the reactions and the attachment to the resin are 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.
  • 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), di
  • the reaction of the compounds of formula II with compounds of formula III is analoguesly to the coupling of peptides.
  • the condensation reaction of formula II with formula III is preferrably carried out in an inert solvent as indicated above in the presence of a dehydrating agent, such as, dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethyl- carbodiimide-hydrochlorid (EDC) or diisopropylcarbodiimide (DIC), further for instance in the presence af an anhydride of propanphosphonic acid (see Angew. Chem. 1980, 92, 129), diphenylphosphorylazide or 2-ethoxy- N-ethoxycarbonyl-1 ,2-dihydroquinoline.
  • a dehydrating agent such as, dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'
  • a coupling agent such as TBTU (0-(benzotriazol-1-yl)-N,N,N',N'-bis-(tetramethylene)-uronium tetrafluoroborate) or 0-(benzotriazol-1-yl)-N,N,N ⁇ N'-bis-(tetramethylene)- uronium hexafluorophosphate.
  • a compound of formula II in which X is a reactive esterified OH group can be synthesized by reacting a compound of formula II in which X is OH with HOBt (1-hydroxybenzotriazole) or N-hydroxysuccinimide(e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart).
  • a compond of formula I in which R 2 and R 3 are H can be treated with an amidinating agent.
  • the preferred amidinating agent is
  • DPFN 1-amidino-3,5-dimethylpyrazole
  • 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.
  • Pd(P(Ph) 3 ) 2 , Pd(ll)CI 2 dppf, PdOAc 2 + P(R*) 3 (R * phenyl, cyclohexyl, tert-butyl) etc. in the presence of a base such as potassium carbonate, caesium carbonate, DBU, NaOH, in an inert solvent or solvent mixture, e.g. DMF or 1 ,4-dioxane 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.
  • 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
  • R and R 1 are independently of each other H, A, OH, OA, OCH 2 -Ar, Hal,
  • R 4 is Ar, cycloalkyl, phenylalkyl or Het, Y may be absent and, if present, is alkenyl having 2 to 4 carbon atoms,
  • Z may be absent and, if present, is phenylene, A is unbranched or branched alkyl having 1 to 6 carbon atoms, Ar is phenyl, naphthyl, biphenyl or benzofuranyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA,
  • CF 3 OCF 3 , Hal, CN, COOH, COOA, NH 2 , NHA, NA 2 , N0 2 ,
  • 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 A, Hal, OH, OA, CF 3 , OCF 3 , NH 2 , NHA, NA 2 , COOH, COOA, phenyl which is unsubstituted or mono-, di- or trisubstituted by by A, OH, OA, CF 3 , OCF 3 , Hal, CN, COOH, COOA, NH 2 ,
  • NHA, NA 2 , N0 2 , S0 2 NH 2 , S0 2 NAH or S0 2 NA 2 or thiophenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF 3 , OCF 3 , Hal, CN, COOH, COOA, NH 2 , NHA, NA 2 , N0 2 , S0 2 NH 2 , S0 2 NAH or S0 2 NA 2 Hal is F, Cl, Br or l, n is 1 , 2 or 3, m is 0, 1 , 2 or 3, with the proviso if Y is vinyl, R 4 is phenyl, Z is absent, n is 1 , m is 1 and R 2 and R 3 are ethyl, then R or R 1 is not NH 2 , if Z is absent, Y is absent or vinyl, R 4 is phenyl, phenylalkyl, alkoxyphenyl or pyrid
  • 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 llbllla antagonist ReoPro® of preferably between approximately 1 and 500 mg, in particular between 5 and 100 mg, per dose unit.
  • the daily dose is preferably between approximately 0.02 and 10 mg/kg of body weight.
  • the specific dose for each patient depends, however, on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health and sex, on the diet, on the time and route of administration, and on the excretion rate, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Oral administration is preferred.
  • customary working-up for solution reactions 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.
  • resin bound bis amines methanediamine, resin bound; ethane-1 ,2-diamine, resin bound; butane-1 ,4-diamine, resin bound; pentane-1 ,5-diamine, resin bound and hexane-1 ,6-diamine, resin bound.
  • -aminoethyl-benzylamine resin bound; -aminopropyl-benzylamine, resin bound; -[3-(2-aminoethyl)-phenyl]-ethylamine, resin bound; -[3-(3-aminopropyl)-phenyl]-propylamine, resin bound; -aminomethyl-phenylamine, resin bound; -aminoethyl-phenylamine, resin bound; -aminopropyl-phenylamine, resin bound; -aminomethyl-benzylamine, resin bound; -aminoethyl-benzylamine, resin bound; -aminopropyl-benzylamine, resin bound; 2-[4-(2-aminoethyl)-phenyl]-ethylamine, resin bound and 3-[4-(3-aminopropyl)-phenyl]-propylamine, resin bound.
  • R' 4-CI in formula lla 3-(3-aminopropyl)-7-chloro-2-(2-methylphenyl)-3H-quinazolin-4-one;
  • R' 4-CI in formula lla 3-(3-aminopropyl)-7-chloro-2-(4-methylphenyl)-3H-quinazolin-4-one;
  • R' 4-CI in formula lla 3-(3-aminopropyl)-7-chloro-2-(3-chlorophenyl)-3H-quinazolin-4-one;
  • R' 4-CI in formula lla 3-(3-aminopropyl)-7-chloro-2-(3-methoxyphenyl)-3H-quinazolin-4-one;
  • R' 4-CI in formula lla 3-(3-aminopropyl)-7-chloro-2-(3,4,5-trimethoxyphenyl)-3H-quinazolin-4-one;
  • R' H in formula lla 3-(3-aminopropyl)-2-(3,4,5-trimethoxyphenyl)-3H-quinazolin-4-one.
  • Example 6 Analogously to example 2, by reaction of resin (2) with a compound of formula lla, cleavage of the Fmoc protecting group and reaction with 3- furan-2-yl-propenal, oxidation and cleavage from the solid phase, the following compounds are obtained
  • Example 7 Analogously to example 2, by reaction of resin (2) with a compound of formula lla, cleavage of the Fmoc protecting group and reaction with cyclohexanecarbaldehyde, oxidation and cleavage from the solid phase, the following compounds are obtained
  • R' 4-CI in formula lla 3-(3-aminopropyl)-7-chloro-2-cyclohexyl-3H-quinazolin-4-one;
  • R' 3-OCH 3 in formula lla 3-(3-aminopropyl)-6-methoxy-2-phenylethyl-3H-quinazolin-4-one;
  • R' H in formula lla 3-(3-aminopropyl)-2-biphenyl-4-yl-3H-quinazolin-4-one;
  • Example 11 Analogously to example 2, by reaction of resin (2) with a compound of formula lla, cleavage of the Fmoc protecting group and reaction with naphthalene-2-carbaldehyde, oxidation and cleavage from the solid phase, the following compounds are obtained
  • R' 3-CH 3 in formula lla 3-(3-aminopropyl)-2-naphthalen-1 -yl-6-methyl-3H-quinazolin-4-one;
  • Example 12 Analogously to example 2, by reaction of resin (2) with a compound of formula lla, cleavage of the Fmoc protecting group and reaction with 3- phenyl-propenal, oxidation and cleavage from the solid phase, the following compounds are obtained
  • R' H in formula lla 3-(3-aminopropyl)-2-[2-(2,5-dimethoxy-phenyl)-vinyl]-3H-quinazolin-4-one.
  • reaction is then treated with 1.62 mmol Cs 2 C0 3 , 1.62 mmol of 2,4- dimethoxyphenyl boronic acid and 10 mol% ([Pd 2 (dba) 3 ] + P(tert-Bu) 3 ).
  • the reaction is then allowed to shake at 80° until conversion is complete. After cooling the reaction mixture, it is worked up as is customary.
  • R' H in formula lla 3-(3-aminopropyl)-2-(3',5'-dimethoxy-biphenyl-4-yl)-3H-quinazolin-4-one.
  • R' 4-CI in formula lla 3-(3-aminopropyl)-2-[5-(2,4-dimethoxy-phenyl)-thiophen-2-yl]-7-chloro-3H- quinazolin-4-one;
  • R' 4-CI in formula lla 3-(3-aminomethyl-benzyl)-7-chloro-2-(3-methylphenyl)-3H-quinazolin-4- one;
  • R' 4-CI in formula lla 3-(3-aminomethyl-benzyl)-7-chloro-2-(4-methylphenyl)-3H-quinazolin-4- one;
  • R' 4-CI in formula lla 3-(3-aminomethyl-benzyl)-7-chloro-2-(4-tert-butylphenyl)-3H-quinazolin-4- one;
  • Example 18 Analogously to example 16, by reaction of resin (3) with a compound of formula lla
  • R' H in formula lla 3-(3-aminomethyl-benzyl)-2-(3,4,5-trimethoxyphenyl)-3H-quinazolin-4-one.
  • R' 3-OCH, 3 in formula lla 3-(3-aminomethyl-benzyl)-6-methoxy-2-(3,4-dimethoxyphenyl)-3H- quinazolin-4-one;
  • R' H in formula lla 3-(3-aminomethyl-benzyl)-2-(3,4-dimethoxyphenyl)-3H-quinazolin-4-one.
  • Example 23 Analogously to example 16, by reaction of resin (3) with a compound of formula lla, cleavage of the Fmoc protecting group and reaction with biphenyl-4-carbaldehyde, oxidation and cleavage from the solid phase, the following compounds are obtained
  • R' 4-CI in formula lla 3-(3-aminomethyl-benzyl)-2-biphenyl-4-yl-7-chloro-3H-quinazolin-4-one;
  • R' H in formula lla 3-(3-aminomethyl-benzyl)-2-thiophenyl-3-yl-3H-quinazolin-4-one;
  • Example 25 Analogously to example 16, by reaction of resin (3) with a compound of formula lla, cleavage of the Fmoc protecting group and reaction with naphthalene-2-carbaldehyde, oxidation and cleavage from the solid phase, the following compounds are obtained
  • Example 26 Analogously to example 16, by reaction of resin (3) with a compound of formula lla, cleavage of the Fmoc protecting group and reaction with 3- phenyl-propenal, oxidation and cleavage from the solid phase, the following compounds are obtained
  • R' 4-CI in formula lla 3-(3-aminomethyl-benzyl)-2-benzofuran-5-yl-7-chloro-3H-quinazolin-4-one;
  • Example 29 Analogously to example 16, by reaction of resin (3) with a compound of formula lla, cleavage of the Fmoc protecting group and reaction with 4- bromo-benzaldehyde, Suzuki-reaction with 2,4-dimethoxyphenyl boronic acid as indicated afterwards, oxidation and cleavage from the solid phase, the following compounds are obtained
  • R' 4-CI in formula lla 3-(3-aminomethyl-benzyl)-2-(2 ⁇ 4'-dimethoxy-biphenyl-4-yi)-7-chloro-3H- quinazolin-4-one;
  • reaction is then treated with 1.62 mmol Cs 2 C0 3 , 1.62 mmol of 2,4- dimethoxyphenyl boronic acid and 10 mol% ([Pd 2 (dba) 3 ] + P(tert-Bu) 3 ).
  • the reaction is then allowed to shake at 80° until conversion is complete. After cooling the reaction mixture, it is worked up as is customary.
  • 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 I of double-distilled water using 2N hydrochloric acid, sterile-filtered, dispensed into injection vials, lyophilized under sterile conditions and aseptically sealed. Each injection vial contains 5 mg of active compound.
  • a mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. 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 I and sterilized by irradiation. This solution can be used in the form of eye drops.
  • 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 E Analogously to Example E, tablets are pressed which are then coated with a coating of sucrose, potato starch, talc, tragacanth and colourant in a customary manner.
  • a solution of 1 kg of active compound of the formula I in 60 ml of double- distilled water is sterile-filtered, dispensed into ampoules, lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 10 mg of 0 active compound.

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Abstract

L'invention concerne des quinazolinones correspondant à la formule (I) dans laquelle R, R?1, R2, R3, R4¿, Y, Z, n et m possèdent les notations données dans la revendication 1. Elle concerne également des sels ou solvates de ces quinazolinones. Ces composés sont utiles en tant qu'antagonistes de la glycoprotéine IbIX.
PCT/EP2000/008940 1999-09-28 2000-09-13 Quinazolinones WO2001023365A1 (fr)

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KR1020027003907A KR20020047186A (ko) 1999-09-28 2000-09-13 퀴나졸리논
CA002385921A CA2385921A1 (fr) 1999-09-28 2000-09-13 Quinazolinones
EP00965991A EP1216235A1 (fr) 1999-09-28 2000-09-13 Quinazolinones
BR0014294-8A BR0014294A (pt) 1999-09-28 2000-09-13 Quinazolinonas
NO20021502A NO20021502D0 (no) 1999-09-28 2002-03-26 Kinazolinoner

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6545004B1 (en) 1999-10-27 2003-04-08 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
WO2003106435A1 (fr) * 2002-06-18 2003-12-24 Sankyo Company, Limited Derives de la pyrimidin-4(3h)-one a cycles fusionnes, spn procede de preparation et ses utilisations
WO2004013111A1 (fr) * 2002-08-01 2004-02-12 Euro-Celtique S.A. Composes benzoheterocycliques bicycliques substitues en 2 et leur utilisation en tant que bloqueurs du canal sodique
EP1558260A2 (fr) * 2002-11-04 2005-08-03 Nps Pharmaceuticals, Inc. Composes de quinazolinone utilises comme calcilytiques
US7009049B2 (en) 2002-02-15 2006-03-07 Cytokinetics, Inc. Syntheses of quinazolinones
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US8008311B2 (en) 1999-10-27 2011-08-30 Cytokinetics, Inc. Methods and compostions utilizing quinazolinones
US6831085B1 (en) 1999-10-27 2004-12-14 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US7671200B2 (en) 1999-10-27 2010-03-02 Cytokinetics, Inc. Quinazolinone KSP inhibitors
US6545004B1 (en) 1999-10-27 2003-04-08 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US6562831B1 (en) 1999-10-27 2003-05-13 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US7589098B2 (en) 1999-10-27 2009-09-15 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US7294634B2 (en) 1999-10-27 2007-11-13 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US7105668B1 (en) 1999-10-27 2006-09-12 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US7009049B2 (en) 2002-02-15 2006-03-07 Cytokinetics, Inc. Syntheses of quinazolinones
US7161002B2 (en) 2002-02-15 2007-01-09 Cytokinetics, Inc. Syntheses of quinazolinones
US7166595B2 (en) 2002-05-09 2007-01-23 Cytokinetics, Inc. Compounds, methods and compositions
US7214800B2 (en) 2002-05-09 2007-05-08 Cytokinetics, Inc. Compounds, compositions, and methods
US7528137B2 (en) 2002-05-09 2009-05-05 Cytokinetics, Inc. Compounds, compositions, and methods
US7332498B2 (en) 2002-05-23 2008-02-19 Cytokinetics, Inc. Modulation of KSP kinesin activity with heterocyclic-fused pyrimidinone derivatives
US7038048B2 (en) 2002-05-23 2006-05-02 Cytokinetics, Inc. 3H-pyridopyrimidin-4-one compounds, compositions, and methods of their use
US7041676B2 (en) 2002-06-14 2006-05-09 Cytokinetics, Inc. Compounds, compositions, and methods
WO2003106435A1 (fr) * 2002-06-18 2003-12-24 Sankyo Company, Limited Derives de la pyrimidin-4(3h)-one a cycles fusionnes, spn procede de preparation et ses utilisations
US7211580B2 (en) 2002-07-23 2007-05-01 Cytokinetics, Incorporated Compounds, compositions, and methods
WO2004013111A1 (fr) * 2002-08-01 2004-02-12 Euro-Celtique S.A. Composes benzoheterocycliques bicycliques substitues en 2 et leur utilisation en tant que bloqueurs du canal sodique
US7557115B2 (en) 2002-09-30 2009-07-07 Cytokinetics, Inc. Compounds, compositions, and methods
EP1558260A4 (fr) * 2002-11-04 2006-10-25 Nps Pharma Inc Composes de quinazolinone utilises comme calcilytiques
JP2006512315A (ja) * 2002-11-04 2006-04-13 エヌピーエス ファーマスーティカルズ インコーポレイテッド カルシリティックとしてのキナゾリノン化合物
EP1558260A2 (fr) * 2002-11-04 2005-08-03 Nps Pharmaceuticals, Inc. Composes de quinazolinone utilises comme calcilytiques
US7439254B2 (en) 2003-12-08 2008-10-21 Cytokinetics, Inc. Compounds, compositions, and methods

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BR0014294A (pt) 2002-05-21
AU7654800A (en) 2001-04-30
NO20021502L (no) 2002-03-26
AR025797A1 (es) 2002-12-11
NO20021502D0 (no) 2002-03-26
EP1216235A1 (fr) 2002-06-26
CA2385921A1 (fr) 2001-04-05

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