EP0000718A2 - Dérivés de la quinazoline, procédé pour leur préparation, préparations pharmaceutiques et leur préparation - Google Patents

Dérivés de la quinazoline, procédé pour leur préparation, préparations pharmaceutiques et leur préparation Download PDF

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Publication number
EP0000718A2
EP0000718A2 EP78100471A EP78100471A EP0000718A2 EP 0000718 A2 EP0000718 A2 EP 0000718A2 EP 78100471 A EP78100471 A EP 78100471A EP 78100471 A EP78100471 A EP 78100471A EP 0000718 A2 EP0000718 A2 EP 0000718A2
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EP
European Patent Office
Prior art keywords
lower alkyl
formula
compounds
hydrogen
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP78100471A
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German (de)
English (en)
Other versions
EP0000718B1 (fr
EP0000718A3 (en
Inventor
Madhukar Subraya Dr. Chodnekar
Ado Dr. Kaiser
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Publication of EP0000718A2 publication Critical patent/EP0000718A2/fr
Publication of EP0000718A3 publication Critical patent/EP0000718A3/xx
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Publication of EP0000718B1 publication Critical patent/EP0000718B1/fr
Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to new tricyclic compounds, namely imidazo-quinazolines of the formula wherein R 1 and R 2 are hydrogen, lower alkyl, hydroxy, lower alkoxy, hydroxy lower alkyl, lower alkoxy lower alkyl, halogen, phenyl, phenoxy, amino, lower alkylamino or di-lower alkylamino, and R 1 and R 2 on adjacent carbon atoms also together methylenedioxy; R is hydrogen, lower alkyl or phenyl; and R 4 is lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, aryl lower alkyl or aryl, their tautomers and salts of such compounds.
  • alkyl radicals can be straight-chain or branched. Examples of alkyl radicals are: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl.
  • Aryl means in particular phenyl or phenyl substituted by halogen, lower alkyl, hydroxy and / or lower alkoxy.
  • R and R are hydrogen
  • R 2 is halogen in the 6- or 7-position or lower alkyl in the 6-position, in particular 6-chloro, 7-bromo or 6-methyl
  • R 4 lower alkyl, especially methyl are preferred.
  • the invention further relates to a process for the preparation of the compounds mentioned and pharmaceutical preparations based on the compounds mentioned.
  • the compounds of formula I can exist in various tautomeric forms.
  • the invention is therefore not limited to compounds of the formula I shown above, but also includes the tautomers, for example those of the formula and
  • the compounds of formula I and their tautomers e.g. Ia and Ib can also be present in the form of racemates or in optically active form, all of which are the subject of the invention.
  • physiologically compatible salts are mineral acid salts, such as hydrochlorides, hydrobromides, sulfates and phosphates; Salts of organic sulfonic acids such as alkyl sulfates and aryl sulfonates; and carboxylic acid salts such as succinates, citrates, tartrates and maleates.
  • reaction of a compound of formula II with cyanogen bromide is conveniently carried out with heating in a solvent such as a lower alcohol, e.g. Ethanol performed.
  • reaction of a compound of formula III with ammonia is conveniently carried out with heating in a solvent such as a lower alcohol, e.g. Ethanol, and water.
  • a compound of the formula I in which R 1 and / or R 2 is hydrogen can be halogenated in a manner known per se. For example, you can find a solution in the React positions 6, 7, 8 and 9 of unsubstituted compound in acetic acid with bromine to the 7-bromo compound.
  • R 1 and R 2 are different from an optionally alkylated amino group
  • R 11 and R 21 have the same meanings as R 1 and R 2 with the exception of optionally alkylated amino and R 3 and R 4 have the above meaning.
  • the compounds of the formula I can furthermore be prepared according to the formula scheme II given below, in which Z represents oxygen or sulfur, M ammonium, potassium or sodium and the remaining symbols have the above meaning.
  • the compounds of the formula I, their tautomers and physiologically tolerable salts of such compounds are to be used as medicaments. They inhibit e.g. platelet aggregation and can therefore be used to prevent thrombosis. They are also effective in the circulation. Because of their positive inotropic effects, they can be used without significant tachycardia for the treatment and prophylaxis of heart failure and heart failure.
  • the compounds of formula I and their tautomers can be used as medicaments e.g. in the form of pharmaceutical preparations which they or their salts are mixed with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration, such as e.g. Contain water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc.
  • the pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules; in semi-solid form, e.g. as ointments; or in liquid form, e.g. as solutions, suspensions or emulsions.
  • auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances. Oral administration of the compounds according to the invention is preferred. For adults, an oral daily dose of 0.5 to 30 mg / kg and a parenteral daily dose of 0.05 to 10 mg / kg are possible.
  • the aggregation-inhibiting effect was determined by the aggregometer method of BORN [Nature 194, 927 (1962)] and MICHAL and BORN [Nature 231, 220 proven.
  • the maximum rate of aggregation was taken as the test parameter and the effective concentration (EC 50 ) was determined from dose-response curves.
  • Human plasma was obtained from venous blood decomposed with citrate (10.6 mM) by centrifugation. 0.18 ml of plasma were mixed with 10 ⁇ l of aqueous suspension of the test compounds, incubated for 10 minutes at 37 ° C., whereupon the aggregation was initiated by adding 10 ⁇ l of collagen-fibril suspension.
  • Rabbit plasma was obtained from arterial blood decomposed with citrate (9 mM) by centrifugation. 1 ml of plasma was mixed with 10 ⁇ l of test solution and incubated for 1 minute at 37 ° C., whereupon 8 ⁇ l of collagen-fibril suspension or 10 ⁇ l of adenosine diphosphate (ADP) in 10 ⁇ 4 M saline solution were added. Plasma incubated with dimethyl sulfoxide was used as a control value.
  • ADP adenosine diphosphate
  • the positive inotropic effect was measured after oral administration of the test substances to awake German shepherds.
  • the animals are equipped with an implanted pressure telemetry system, the pressure sensor being fixed in the left ventricle.
  • the left ventricular pressure is transmitted from the animal via the implanted radio transmitter and received, demodulated and amplified via a suitable antenna and receiver system.
  • LVP left ventricular pressure
  • dLVP / dtmax maximum rate of pressure rise
  • the heart rate is recorded on a cardiotachograph.
  • Inotropy is the percentage. Change ( ⁇ %) of dLVP / dt max and the duration of action in minutes (min) are given.
  • Tachycardia shows the percentage changes in heart rate ( ⁇ %) after administration of the test substance and the duration of action in minutes (min). The results are shown in Table II below.
  • N- (2-amino-3-methylbenzyl) -D-alanine ethyl ester was used to convert D-1,5-dihydro-3,9-dimethylimidazo [2,1-b] quinazolin-2 (3H ) -On hydrochloride obtained. Melting point 270-275 ° (dec.). The free base melts at 262-265 °.
  • N- (2-amino-6-methylbenzyl) -L-alanine ethyl ester was converted into L-1,5-dihydro-3,6-dimethyl-imidazo [2, lb] quinazolin-2 (3H ) -On hydrochloride obtained. Colorless crystals with a melting point of 285-288 ° (dec.). The free base melts above 340 ° with decomposition.
  • N- (2-amino-6-methylbenzyl) -D-alanine ethyl ester became D-1,5-dihydro-3,6-dimethyl-imidazo [2,1-b] quinazolin-2 Obtained (3H) -one hydrochloride. Light yellow crystals with a melting point of 287-290 ° (Dec.). The free base melts above 340 °.
  • N- (2-amino-6-methylbenzyl) -L-serine ethyl ester became L-1,5-dihydro-3-hydroxymethyl-6-methylimidazo [2,1-b] quinazoline -2 (3H) -one hydrochloride obtained. Yellow crystals with melting point 320-325 ° (dec.).
  • N- (2-amino-6-methylbenzyl) -Da-phenylglycine-ethyl ester became D-1,5-dihydro-3-phenyl-6-methyl-imidazo [2,1-b] quinazoline Obtained -2 (3H) -one hydrochloride. Light yellow crystals with a melting point of about 320 ° (dec.).
  • N- (2-chloro-6-nitrobenzyl) -D-alanine ethyl ester was obtained analogously from ethyl D-alanine and a-bromo-2-chloro-6-nitrotoluene, .
  • N- (2-amino-6-chlorobenzyl) -D-alanine ethyl ester was obtained analogously by hydrogenation of N- (2-chloro-6-nitrobenzyl) - D-alanine ethyl ester, .
  • Gelatin capsules of the following composition are produced in the usual way:
  • a solution for injection of the following composition is prepared in the usual way:

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Hospice & Palliative Care (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP78100471A 1977-07-25 1978-07-21 Dérivés de la quinazoline, procédé pour leur préparation, préparations pharmaceutiques et leur préparation Expired EP0000718B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
LU77829 1977-07-25
LU77829 1977-07-25
CH5776/78 1978-05-26
CH577678 1978-05-26

Publications (3)

Publication Number Publication Date
EP0000718A2 true EP0000718A2 (fr) 1979-02-21
EP0000718A3 EP0000718A3 (en) 1979-06-13
EP0000718B1 EP0000718B1 (fr) 1982-03-24

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EP78100471A Expired EP0000718B1 (fr) 1977-07-25 1978-07-21 Dérivés de la quinazoline, procédé pour leur préparation, préparations pharmaceutiques et leur préparation

Country Status (29)

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US (1) US4256748A (fr)
EP (1) EP0000718B1 (fr)
JP (1) JPS5441894A (fr)
AR (1) AR218500A1 (fr)
AT (1) AT363479B (fr)
AU (1) AU519688B2 (fr)
BR (1) BR7804763A (fr)
CA (1) CA1094555A (fr)
CS (1) CS203014B2 (fr)
DE (2) DE2832138A1 (fr)
DK (1) DK144128C (fr)
ES (2) ES471981A1 (fr)
FI (1) FI63409C (fr)
FR (1) FR2398748A1 (fr)
GB (1) GB2001638B (fr)
GR (1) GR72968B (fr)
HU (1) HU177643B (fr)
IE (1) IE47280B1 (fr)
IL (1) IL55183A (fr)
IT (1) IT1097337B (fr)
MC (1) MC1199A1 (fr)
MY (1) MY8500249A (fr)
NL (1) NL7807507A (fr)
NO (1) NO150800C (fr)
NZ (1) NZ187921A (fr)
PH (1) PH14642A (fr)
PT (1) PT68342A (fr)
SE (1) SE7808111L (fr)
YU (1) YU177578A (fr)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0021338A1 (fr) * 1979-06-20 1981-01-07 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Dérivés de la quinazoline et préparations pharmaceutiques
EP0054180A3 (fr) * 1980-12-16 1982-12-01 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Procédé pour la préparation de dérivés de l'imidazoquinazoline
EP0116948A3 (en) * 1983-02-16 1984-12-19 Syntex (U.S.A.) Inc. (2-oxo-1,2,3,5-tetrahydroimidazo-(2,1-b)quinazolinyl)-oxyalkyl-amides
EP0129258A1 (fr) * 1983-06-21 1984-12-27 Daiichi Seiyaku Co., Ltd. Composé imidazoquinazolinique
EP0133234A3 (en) * 1983-07-14 1985-10-30 Daiichi Seiyaku Co. Ltd. Imidazoquinazolin-2-one compounds process for their production and pharmaceutical compositions containing said compounds
US4663320A (en) * 1983-02-16 1987-05-05 Syntex (U.S.A.) Inc. (2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinoazolinyl)oxyalkylamides, compositions and the use thereof
US4670434A (en) * 1985-11-14 1987-06-02 Syntex (U.S.A.) Inc. (2-oxo-3-methylene-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolinyl)oxyalkylamides useful as cyclic AMP phosphodiesterase inhibitors
EP0153152A3 (fr) * 1984-02-15 1987-07-15 Syntex (U.S.A.) Inc. (2-Oxo-1,2,3,5-tétrahydroimidazo[2,1-b]quinazolinyl)oxyalcoylamides, leur préparation, compositions les contenant et leur utilisaton pour la préparation de médicaments
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2012118972A2 (fr) 2011-03-01 2012-09-07 Synegy Pharmaceuticals Inc. Procédé de préparation d'agonistes du guanylate cyclase c
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014131024A2 (fr) 2013-02-25 2014-08-28 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et applications associées
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
WO2015021358A2 (fr) 2013-08-09 2015-02-12 Dominique Charmot Composés et procédés d'inhibition du transport de phosphate
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
US20170204492A1 (en) * 2014-08-08 2017-07-20 Jfe Steel Corporation Cold-rolled steel sheet having excellent spot weldability, and manufacturing method therefor
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2020237096A1 (fr) 2019-05-21 2020-11-26 Ardelyx, Inc. Combinaison pour baisser le phosphate sérique chez un patient
EP4201403A1 (fr) 2021-12-21 2023-06-28 Som Innovation Biotech, S.L. Composés tirapazamine et quazinone à utiliser dans le traitement des gangliosidoses gm2

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EP1216037A2 (fr) * 1999-09-21 2002-06-26 Emory University Procedes et compositions pour le traitement de troubles lies aux plaquettes au moyen d'agents inhibiteurs de trajet de mpl
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US20060030574A1 (en) * 2004-08-04 2006-02-09 Shire Holdings Ag Quinazoline derivatives useful for the treatment of peripheral arterial disease and as phosphodiesterase inhibitors
US7700608B2 (en) 2004-08-04 2010-04-20 Shire Holdings Ag Quinazoline derivatives and their use in the treatment of thrombocythemia
US8426429B2 (en) 2004-08-06 2013-04-23 Jansssen Pharmaceutica N.V. 2-amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE)
US8383637B2 (en) 2004-08-06 2013-02-26 Jansssen Pharmaceutica N.V. 2-amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE)
US8436006B2 (en) 2004-08-06 2013-05-07 Jansssen Pharmaceutica N.V. 2-amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE)
US7910597B2 (en) * 2006-11-28 2011-03-22 Shire Llc Substituted quinazolines
GB0623750D0 (en) * 2006-11-28 2007-01-10 Shire Llc Substituted quinazolines
US8304420B2 (en) 2006-11-28 2012-11-06 Shire Llc Substituted quinazolines for reducing platelet count
GB0808952D0 (en) * 2008-05-16 2008-06-25 Shire Llc Substituted quinazolines
GB0808967D0 (en) * 2008-05-16 2008-06-25 Shire Llc Substitute quinazolines
GB0808944D0 (en) * 2008-05-16 2008-06-25 Shire Llc Substituted quinazolines
GB0808968D0 (en) * 2008-05-16 2008-06-25 Shire Llc Substitute quinazolines
GB0808953D0 (en) * 2008-05-16 2008-06-25 Shire Llc substituted quinazolines
GB0808950D0 (en) * 2008-05-16 2008-06-25 Shire Llc Substituted quinazolines
GB0808948D0 (en) * 2008-05-16 2008-06-25 Shire Llc Substituted quinazolines
GB0808951D0 (en) * 2008-05-16 2008-06-25 Shire Llc Substituted quinazolines
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GB0810005D0 (en) * 2008-06-02 2008-07-09 Shire Llc Substituted quinazolines
GB0822970D0 (en) 2008-12-17 2009-01-21 Shire Llc Process for the preparation of anagrelide and analogues
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Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0021338A1 (fr) * 1979-06-20 1981-01-07 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Dérivés de la quinazoline et préparations pharmaceutiques
EP0054180A3 (fr) * 1980-12-16 1982-12-01 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Procédé pour la préparation de dérivés de l'imidazoquinazoline
EP0116948A3 (en) * 1983-02-16 1984-12-19 Syntex (U.S.A.) Inc. (2-oxo-1,2,3,5-tetrahydroimidazo-(2,1-b)quinazolinyl)-oxyalkyl-amides
US4663320A (en) * 1983-02-16 1987-05-05 Syntex (U.S.A.) Inc. (2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinoazolinyl)oxyalkylamides, compositions and the use thereof
EP0129258A1 (fr) * 1983-06-21 1984-12-27 Daiichi Seiyaku Co., Ltd. Composé imidazoquinazolinique
EP0133234A3 (en) * 1983-07-14 1985-10-30 Daiichi Seiyaku Co. Ltd. Imidazoquinazolin-2-one compounds process for their production and pharmaceutical compositions containing said compounds
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EP0000718B1 (fr) 1982-03-24
DE2861688D1 (en) 1982-04-29
ES471981A1 (es) 1979-10-16
NL7807507A (nl) 1979-01-29
GB2001638A (en) 1979-02-07
HU177643B (en) 1981-11-28
MY8500249A (en) 1985-12-31
AU3812778A (en) 1980-01-24
CS203014B2 (en) 1981-02-27
US4256748A (en) 1981-03-17
NO150800B (no) 1984-09-10
NO150800C (no) 1984-12-27
IL55183A (en) 1981-11-30
CA1094555A (fr) 1981-01-27
GB2001638B (en) 1982-02-10
BR7804763A (pt) 1979-04-10
EP0000718A3 (en) 1979-06-13
AU519688B2 (en) 1981-12-17
AR218500A1 (es) 1980-06-13
ES476955A1 (es) 1979-10-16
FI782248A7 (fi) 1979-01-26
JPS5441894A (en) 1979-04-03
DK144128B (da) 1981-12-14
NZ187921A (en) 1981-03-16
PH14642A (en) 1981-10-12
YU177578A (en) 1983-01-21
FR2398748B1 (fr) 1981-09-04
PT68342A (en) 1978-08-01
IL55183A0 (en) 1978-09-29
DK144128C (da) 1982-05-17
MC1199A1 (fr) 1979-03-19
AT363479B (de) 1981-08-10
DK328978A (da) 1979-01-26
FI63409B (fi) 1983-02-28
SE7808111L (sv) 1979-01-26
IE781478L (en) 1979-01-25
IT7826019A0 (it) 1978-07-24
ATA535178A (de) 1981-01-15
FR2398748A1 (fr) 1979-02-23
DE2832138A1 (de) 1979-02-08
NO782541L (no) 1979-01-26
IT1097337B (it) 1985-08-31
GR72968B (fr) 1984-01-20
FI63409C (fi) 1983-06-10
IE47280B1 (en) 1984-02-08

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