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EP0000718B1 - 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
EP0000718B1
EP0000718B1 EP78100471A EP78100471A EP0000718B1 EP 0000718 B1 EP0000718 B1 EP 0000718B1 EP 78100471 A EP78100471 A EP 78100471A EP 78100471 A EP78100471 A EP 78100471A EP 0000718 B1 EP0000718 B1 EP 0000718B1
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EP
European Patent Office
Prior art keywords
alkyl
ethyl ester
nitrobenzyl
dihydro
formula
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.)
Expired
Application number
EP78100471A
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German (de)
English (en)
Other versions
EP0000718A2 (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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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 'and R 2 are hydrogen, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, halogen, phenyl , Phenoxy, amino, C 1-6 alkylamino or di-C 1-6 alkylamino, and R 1 and R 2 together on adjacent carbon atoms also methylenedioxy; R 3 is hydrogen, C 1-6 alkyl or phenyl; and R 4 is C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, arylC 1-6 alkyl or aryl, their tautomers and salts of such compounds.
  • the present imidazoquinazolines contain a substituent in the 3-position.
  • Alkyl and alkoxy radicals preferably contain 1-4 carbon atoms.
  • 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, C 1-6 -alkyl, hydroxy and / or C 1-6 -alkoxy.
  • 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
  • the compounds of formula I and their tautomers, e.g. la and Ib can also be 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 bromo-cyan 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.
  • a solution of a compound which is unsubstituted in positions 6, 7, 8 and 9 in acetic acid can be reacted with bromine to give 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 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 for the circulation. Because of their positive inotropic effect, they can be used without significant tachycardia for the treatment and prophylaxis of heart failure and heart failure.
  • the compounds of the formula 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, Vaseline @, 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.
  • 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.
  • the maximum pressure rise rate (dLVP / dt max ) is calculated, which is considered a contractility parameter.
  • the heart rate is recorded on a cardiotachograph.
  • the percentage change ( ⁇ %) of dLVP / dt and the duration of action in minutes (min) are given under inotropy.
  • the percentage changes in heart rate ( ⁇ %) after administration of the test substance and the duration of action in minutes (min) are given under tachycardia.
  • Table II 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-5-methylbenzyl) -L-alanine ethyl ester became the L-1,5-dihydro-2,7-dimethyl-imidazo [2,1-b] quinazolin-2 Obtained (3H) -one hydrochloride. Light yellow crystals, melting point 173-176 °. The free base melts with decomposition above 300 °.
  • N- (2-amino-5-methylbenzyl) -D-alanine ethyl ester became D-1,5-dihydro-3,7-dimethyl-imidazo [2,1-b] quinazolin-2 Obtained (3H) -one hydrochloride. Light yellow crystals, melting point 173-176 ° (dec.). The free base melts with decomposition at 310-314 °.
  • N- (2-amino-6-methylbenzyl) -L-alanine ethyl ester became L-1,5-dihydro-3,6-dimethyl-imidazo [2,1-b] quinazolin-2 Obtained (3H) -one hydrochloride. 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 Obtained -2 (3H) -one hydrochloride. Yellow crystals with melting point 320-325 ° (dec.).
  • Example 2 Analogously to Example 1, the D-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride was obtained from 2-amino-benzyl-D-alanine ethyl ester . Yellow crystals with a melting point of 225-227 °. The free base melts at about 300 ° with decomposition.
  • D-6-chloro-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride was analogously made from N- (2-amino-6-chlorobenzyl) -D-alanine -ethyl ester obtained, mp. 263-266 °, [ ⁇ ] D -23.9 ° (DMSO); Mp of the free base 275-280 °.
  • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Claims (9)

1. Composés de formule générale I
Figure imgb0025
dans laquelle:
R1 et R2 représentent un hydrogène, C1-6-alkyle, un hydroxy, C1-6-alcoxy, hydroxy-C1-6-alkyle,
C1-6-alcoxy-C1-6-alkyle, un halogène, phényle, phénoxy, amino, C1-6-alkylamino ou di-C1-6- alkylamino, et R' et R2 représentent également ensemble un méthylènedioxy sur deux atomes de carbone voisins; R3 représente un hydrogène, C1-6-alkyle ou phényle; et R4 représente C1-6-alkyle, hydroxy-C1-6-alkyle, C1-6-alcoxy-C1-6alkyle, aryle-C1-6-alkyle ou aryle,
ainsi que leurs tautomères et les sels de ces composés.
2: La D-6-chloro-1,5-dihydro-3-méthylimidazo[2,1-b]quinazolin-2(3H)-one et ses sels.
3. Un composé selon l'une des revendications 1 et 2 en tant qu'agent inhibiteur de l'agrégation des plaquettes sanguines ou en tant qu'agent de renforcement de la contraction cardiaque sans tachycardie notable.
4. Procédé de préparation de composés de formule I
Figure imgb0026
dans laquelle:
R' et R2 représentent un hydrogène, C1-6-alkyle, un hydroxy, C1-6-alcoxy, hydroxy-C1-6-alkyle,
C1-6-alcoxy-C1-6-alkyle, un halogène, un phényle, un phénoxy, un amino, C1-6-alkylamino ou di-
C1-6-alkylamino, et R1 et R2 représentent également ensemble un méthylènedioxy sur deux atomes de carbone voisins; R3 représente un hydrogène, C1-6-alkyle ou phényle; et R4 représente
C1-6-alkyle, hydroxy-C1-6-alkyle, C1-6-alcoxy-C1-6-alkyle, aryle-C1-6-alkyle ou aryle,

ainsi que leurs tautomères et les sels de ces composés, caractérisé en ce que:
a) l'on fait réagir un composé de formule
Figure imgb0027
dans laquelle:
R' à R4 ont la signification donnée précédemment et R5 représente C1-6-alkyle, avec du bromocyanure, ou
b) l'on traite un composé de formule
Figure imgb0028
dans laquelle:
R' à R5 ont la signification donnée précédemment, avec de l'ammoniac.
5. Procédé selon la revendication 4, caractérisé en ce que l'on prépare la D-6-chloro-1,5-dihydro-3-méthylimidazo [2,1-b] quinazolin-2(3H)-one et ses sels.
6. Préparation pharmaceutique, caractérisée en ce qu'elle contient un composé de formule générale 1 selon la définition de la revendication 1, un tautomère ou un sel physiologiquement acceptable d'un tel composé.
7. Procédé de préparation de compositions pharmaceutiques, caractérisé en ce que l'on mélange un composé de formule générale 1 selon la définition de la revendication 1, un tautomère ou un sel physiologiquement acceptable d'un tel composé, à titre de substance active, avec des supports et/ou excipients liquides ou solides usuels, inertes, non toxiques et appropriés à l'administration théraneutique.
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 EP0000718A2 (fr) 1979-02-21
EP0000718A3 EP0000718A3 (en) 1979-06-13
EP0000718B1 true EP0000718B1 (fr) 1982-03-24

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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)

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AT363479B (de) 1981-08-10
IE47280B1 (en) 1984-02-08
ES476955A1 (es) 1979-10-16
MY8500249A (en) 1985-12-31
IL55183A0 (en) 1978-09-29
GR72968B (fr) 1984-01-20
CS203014B2 (en) 1981-02-27
HU177643B (en) 1981-11-28
GB2001638A (en) 1979-02-07
EP0000718A2 (fr) 1979-02-21
YU177578A (en) 1983-01-21
ES471981A1 (es) 1979-10-16
JPS5441894A (en) 1979-04-03
SE7808111L (sv) 1979-01-26
GB2001638B (en) 1982-02-10
AR218500A1 (es) 1980-06-13
NO782541L (no) 1979-01-26
FI63409B (fi) 1983-02-28
IL55183A (en) 1981-11-30
FI782248A (fi) 1979-01-26
AU3812778A (en) 1980-01-24
US4256748A (en) 1981-03-17
MC1199A1 (fr) 1979-03-19
NL7807507A (nl) 1979-01-29
DK144128B (da) 1981-12-14
PT68342A (en) 1978-08-01
EP0000718A3 (en) 1979-06-13
FR2398748A1 (fr) 1979-02-23
DE2832138A1 (de) 1979-02-08
DK328978A (da) 1979-01-26
DE2861688D1 (en) 1982-04-29
FI63409C (fi) 1983-06-10
NZ187921A (en) 1981-03-16
DK144128C (da) 1982-05-17
NO150800C (no) 1984-12-27
IT7826019A0 (it) 1978-07-24
AU519688B2 (en) 1981-12-17
NO150800B (no) 1984-09-10
PH14642A (en) 1981-10-12
IE781478L (en) 1979-01-25
FR2398748B1 (fr) 1981-09-04
IT1097337B (it) 1985-08-31
BR7804763A (pt) 1979-04-10
CA1094555A (fr) 1981-01-27
ATA535178A (de) 1981-01-15

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