WO2001023364A1 - Quinazolinones - Google Patents

Quinazolinones Download PDF

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Publication number
WO2001023364A1
WO2001023364A1 PCT/EP2000/008939 EP0008939W WO0123364A1 WO 2001023364 A1 WO2001023364 A1 WO 2001023364A1 EP 0008939 W EP0008939 W EP 0008939W WO 0123364 A1 WO0123364 A1 WO 0123364A1
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WO
WIPO (PCT)
Prior art keywords
formula
cyclohexylmethyl
aminomethyl
quinazolin
compounds
Prior art date
Application number
PCT/EP2000/008939
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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
Bertram Cezanne
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 CA002385918A priority Critical patent/CA2385918A1/fr
Priority to US10/089,167 priority patent/US7060706B1/en
Priority to AU74193/00A priority patent/AU7419300A/en
Priority to KR1020027003906A priority patent/KR20020047185A/ko
Priority to EP00962482A priority patent/EP1216233A1/fr
Priority to BR0014311-1A priority patent/BR0014311A/pt
Publication of WO2001023364A1 publication Critical patent/WO2001023364A1/fr
Priority to NO20021503A priority patent/NO20021503D0/no

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • 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
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—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
    • 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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
  • R and R 1 are independently of each other H, A, OH, OA, OCH 2 -Ar, Hal,
  • R 4 is Ar, phenylalkyl, cycloalkyl 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 , NO 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,
  • NA 2 , NO 2 , SO 2 NH 2 , SO 2 NAH or SO 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 , NO 2 ,
  • 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.
  • 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. 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.
  • the invention relates further to compounds of the formula I according to Claim 1 and their physiologically acceptable salts or solvates as pharmaceutical active compounds.
  • 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 compound of the formula I is liberated from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent, or b) in stage 1) a compound of the formula II
  • 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.
  • 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, cyclohexy
  • Y is absent
  • R 3 is H, Y is absent,
  • -COOH carry a group -COOR", in which R" is a hydroxyl protective group.
  • acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl groups, aryloxycarbonyl groups and especially aralkoxycarbonyi groups.
  • 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-butyldimethylsilyl (TBS) or triethylsilyl, trimethylsilylethyl, aralkylsilyl groups such as tert-butyldiphenylsilyl (TBDPS), cyclic acetals such as isopropylidene-, cyclopentylidene-, cyclohexylidene-, benzyliden
  • the solid phase with a carbonate moiety as terminal functional group can preferably be removed, for example, using TFA (50%) in dichloromethane.
  • 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.
  • 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, dicyclohexylcarbodiim.de (DCC), N-(3-dimethylaminopropyl)-N'-ethyl- carbodiimide-hydrochlo d (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, dicyclohexylcarbodiim.de (DCC), N-(3-dimethylaminopropyl)
  • a coupling agent such as TBTU (O-(benzotriazol-1-yl)-N,N,N',N'-bis-(tetramethylene)-uronium tetrafluoroborate) or O-(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 1-amidino-3,5-dimethylpyrazole (DPFN), which is employed, in particular, in the form of its nitrate, or pyrazole-1-carboxamidine.
  • DPFN 1-amidino-3,5-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.
  • 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.
  • 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 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.
  • R 2 and R 3 are H, excluding C-(3-aminomethyi-cyclohexyl)- methylamine, and n and m have the meanings indicated in Claim 1 the following resin bound bis amines are obtained: cyclohexane-1 ,3-diamine, resin bound;
  • 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' 4-CI in formula lla 3-(3-aminomethyl-cyclohexylmethyl)-2-styryl-7-chloro-3H-quinazolin-4-one;
  • Example 13 Analogously to example 2, by reaction of resin (2) with a compound of formula lla, cleavage of the Fmoc protecting group and reaction with benzofuran-5-carbaldehyde, oxidation and cleavage from the solid phase, the following compounds are obtained
  • R' 4-CI in formula lla 3-(3-aminomethyl-cyclohexylmethyl)-2-[2-(2,5-dimethyoxy-phenyl)-vinyl]-7- chloro-3H-quinazolin-4-one;
  • R' H in formula lla 3-(3-aminomethyl-cyclohexylmethyl)-2-(2',4'-dimethoxy-biphenyl-4-yl)-3H- quinazolin-4-one.
  • reaction is then treated with 1.62 mmol Cs 2 CO 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' 3-CH 3 in formula lla 3-(3-aminomethyl-cyclohexylmethyl)-2-[5-(2,4-dimethoxy-phenyl)-2- thiophenyl]-6-methyl-3H-quinazolin-4-one;
  • 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.
  • Example B Suppositories
  • a solution is prepared from 1 g of an active compound of the formula I,
  • 500 mg of an active compound of the formula I is mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • 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 active compound.

Abstract

La présente invention concerne des quinazolinones de formule (I) dans laquelle R, R?1, R2, R3, R4¿, Y, n et m sont tels que définis dans la revendication 1, leurs sels ou leurs solvates agissant comme antagonistes IbIX glycoprotéines.
PCT/EP2000/008939 1999-09-28 2000-09-13 Quinazolinones WO2001023364A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CA002385918A CA2385918A1 (fr) 1999-09-28 2000-09-13 Quinazolinones
US10/089,167 US7060706B1 (en) 1999-09-28 2000-09-13 Quinazolinones
AU74193/00A AU7419300A (en) 1999-09-28 2000-09-13 Quinazolinones
KR1020027003906A KR20020047185A (ko) 1999-09-28 2000-09-13 퀴나졸리논
EP00962482A EP1216233A1 (fr) 1999-09-28 2000-09-13 Quinazolinones
BR0014311-1A BR0014311A (pt) 1999-09-28 2000-09-13 Quinazolinonas
NO20021503A NO20021503D0 (no) 1999-09-28 2002-03-26 Kinazolinoner

Applications Claiming Priority (2)

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US40793999A 1999-09-28 1999-09-28
US09/407,939 1999-09-28

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WO2001023364A1 true WO2001023364A1 (fr) 2001-04-05

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EP (1) EP1216233A1 (fr)
KR (1) KR20020047185A (fr)
AR (1) AR025796A1 (fr)
AU (1) AU7419300A (fr)
BR (1) BR0014311A (fr)
CA (1) CA2385918A1 (fr)
NO (1) NO20021503D0 (fr)
WO (1) WO2001023364A1 (fr)

Cited By (13)

* 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
US7671200B2 (en) 1999-10-27 2010-03-02 Cytokinetics, Inc. Quinazolinone KSP inhibitors
US7687625B2 (en) 2003-03-25 2010-03-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7723344B2 (en) 2003-08-13 2010-05-25 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US7763628B2 (en) 1999-10-27 2010-07-27 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US7781584B2 (en) 2004-03-15 2010-08-24 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7790734B2 (en) 2003-09-08 2010-09-07 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7872124B2 (en) 2004-12-21 2011-01-18 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
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US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors

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US8008311B2 (en) 1999-10-27 2011-08-30 Cytokinetics, Inc. Methods and compostions utilizing quinazolinones
US6562831B1 (en) 1999-10-27 2003-05-13 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US6630479B1 (en) 1999-10-27 2003-10-07 Cytokinetics, Inc. Methods and compositions 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
US7763628B2 (en) 1999-10-27 2010-07-27 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US8470838B2 (en) 1999-10-27 2013-06-25 Cytokinetics, Incorporated Methods and compositions utilizing quinazolinones
US6545004B1 (en) 1999-10-27 2003-04-08 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US7687625B2 (en) 2003-03-25 2010-03-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7723344B2 (en) 2003-08-13 2010-05-25 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US7790736B2 (en) 2003-08-13 2010-09-07 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
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US8188275B2 (en) 2004-03-15 2012-05-29 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
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US7807689B2 (en) 2004-03-15 2010-10-05 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
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US8329900B2 (en) 2004-03-15 2012-12-11 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7781584B2 (en) 2004-03-15 2010-08-24 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7872124B2 (en) 2004-12-21 2011-01-18 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors

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EP1216233A1 (fr) 2002-06-26
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BR0014311A (pt) 2002-05-21
NO20021503L (no) 2002-03-26
KR20020047185A (ko) 2002-06-21
AU7419300A (en) 2001-04-30
NO20021503D0 (no) 2002-03-26

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