DE2015771B2 - 3- (2'-Fluoro-phenyl) -4 (3H) -quinazolone - Google Patents
3- (2'-Fluoro-phenyl) -4 (3H) -quinazoloneInfo
- Publication number
- DE2015771B2 DE2015771B2 DE19702015771 DE2015771A DE2015771B2 DE 2015771 B2 DE2015771 B2 DE 2015771B2 DE 19702015771 DE19702015771 DE 19702015771 DE 2015771 A DE2015771 A DE 2015771A DE 2015771 B2 DE2015771 B2 DE 2015771B2
- Authority
- DE
- Germany
- Prior art keywords
- fluoro
- quinazolone
- phenyl
- animals
- effect
- 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
Links
- UQQDBFGCCOCPAG-UHFFFAOYSA-N 3-(2-fluorophenyl)quinazolin-4-one Chemical compound FC1=CC=CC=C1N1C(=O)C2=CC=CC=C2N=C1 UQQDBFGCCOCPAG-UHFFFAOYSA-N 0.000 title claims description 6
- 230000001262 anti-secretory effect Effects 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 4
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical class OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 230000001078 anti-cholinergic effect Effects 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 241000416162 Astragalus gummifer Species 0.000 description 5
- 229920001615 Tragacanth Polymers 0.000 description 5
- 239000000196 tragacanth Substances 0.000 description 5
- 235000010487 tragacanth Nutrition 0.000 description 5
- 229940116362 tragacanth Drugs 0.000 description 5
- 230000037396 body weight Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 210000003736 gastrointestinal content Anatomy 0.000 description 3
- 210000003097 mucus Anatomy 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- JEYCTXHKTXCGPB-UHFFFAOYSA-N Methaqualone Chemical compound CC1=CC=CC=C1N1C(=O)C2=CC=CC=C2N=C1C JEYCTXHKTXCGPB-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- -1 anthranil-o-fluoroaniline Chemical compound 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 210000001747 pupil Anatomy 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 1
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 101150065082 NRM1 gene Proteins 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 235000013736 caramel Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000001179 pupillary effect Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000004260 weight control Methods 0.000 description 1
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
- C07D239/91—Oxygen atoms with aryl or aralkyl 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
(D(D
das dadurch gekennzeichnet isi, daß man in an sich bekannter Weise (siehe z. B. R. H. C1 a r k und E. C. Wagner; J. Org., Chemistry 8, 55 [1943]) Anthranil-o-fluor-anilid mittels Orthoameisensäureestern in Gegenwart einer katalytischen Menge einer starken, wasserfreien Säure bei Temperaturen zwischen 100 und 1700C cyclisiert. Das als Ausgangsstoff benötigte Anthranil-o-Fluoranilin kann in bekannter Weise dargestellt werden.which is characterized in that anthranil-o-fluoro-anilide is produced in a manner known per se (see, for example, BRH C1 ark and EC Wagner; J. Org., Chemistry 8, 55 [1943]) by means of orthoformic acid esters in the presence of a catalytic amount a strong, anhydrous acid at temperatures between 100 and 170 0 C cyclized. The anthranil-o-fluoroaniline required as a starting material can be prepared in a known manner.
Die Erfindung betrifft schließlich ein Arzneimittel, das neben den üblichen Trägerstoffen die erfindungsgemäße Verbindung allein oder in Kombination mit anderen üblichen Hilfsmitteln enthält. Als Hilfsmittel in diesem Sinne sind für die trockene Applikationsform und Tabletten nachfolgende Kombinationen als Trägerstoffe geeignet:The invention finally relates to a medicament that in addition to the usual carriers, the compound according to the invention alone or in combination with contains other common tools. The following combinations are used as aids in this sense for the dry application form and tablets suitable as a carrier:
a) Magnesium-Stearat,
Talkum,
Lactose,
Saccharose,
Maisstärke,
Cellulose oder
Mg.-Stearat,
Polyvinylpyrrolidon,
Gelatine,
Lactose,
Maisstärke.a) magnesium stearate,
Talc,
Lactose,
Sucrose,
Corn starch,
Cellulose or
Mg stearate,
Polyvinylpyrrolidone,
Gelatin,
Lactose,
Cornstarch.
Als Hilfsmittel für die flüssige Applikationsform ist beispielsweise eine Lösung bzw. Suspension vonA solution or suspension of, for example, is an aid for the liquid application form
Carboxymethylcellulose,
Cellulose,
Saccharose,
ZuckercouleurCarboxymethyl cellulose,
Cellulose,
Sucrose,
Caramel
und von Aromastoffen in Wasser geeignet.and suitable for flavorings in water.
Es wurde gefunden, daß die erlindungsgemäße Verbindung antisekretorische Wirkung besitzt.It has been found that the compound according to the invention has an antisecretory effect.
Ein sehr bedeutender therapeutischer Vorteil derA very significant therapeutic benefit of the
erfindungsgemäßen Verbindung besteht darin, daßThe compound of the invention is that
sie praktisch frei von anticholinergen Effekten ist.it is practically free from anticholinergic effects.
Die Verbindung übt demnach ihre antisekretorischeThe connection thus exercises its anti-secretory
Aktivität ohne die typischen Nebenwirkungen vonActivity without the typical side effects of
Anticholinergica aus. Gerade diese NebenwirkungenAnticholinergica from. Just these side effects
stellten aber bisher ein bedeutendes Hindernis Türbut have so far presented a significant obstacle to the door
ίο die Anwendung antisekretorischer Arzneimittel dar.ίο the use of antisecretory drugs.
Die Erfindung betrifft 3 - (2' - Fluor - phenyl)-4(3H)-chinazolon. The invention relates to 3 - (2 '- fluoro - phenyl) -4 (3H) - quinazolone.
Die Erfindung betrifft ferner ein Verfahren zur Herstellung des 3-(2'-Fluor-phenyl)-4(3H)-chinazolons der Formel IThe invention also relates to a process for the preparation of 3- (2'-fluoro-phenyl) -4 (3H) -quinazolone of formula I.
57,5 g Anthranil-o-fluor-anilid (0,25 Mo!) werden mit 50 ecm o-Ameisensäure-tri-äthylester und 0,4 ml cone. H2SO4 vermischt und im Kolben einer Destillationsapparatur mittels eines Ölbades auf 120 C (Badtemperatur) erhitzt. Durch langsames Steigern der Badtemperatur auf 1400C erreicht man eine weitgehende Entfernung des Äthanols ohne Verluste an Orthoester.57.5 g of anthranil-o-fluoro-anilide (0.25 Mo!) Are mixed with 50 ecm of tri-ethyl o-formate and 0.4 ml of cone. H 2 SO 4 mixed and heated to 120 C (bath temperature) in the flask of a distillation apparatus by means of an oil bath. By slowly raising the bath temperature to 140 0 C to reach a substantial removal of the ethanol without loss of Orthoester.
Nach dem Abkühlen wird der Kolbeninhalt in heißem Isopropanol aufgenommen und durch Abkühlen kristallin ausgeschieden. Ausbeute 38 g (69% der Theorie); Schmp. 124 bis 125°C.After cooling, the contents of the flask are taken up in hot isopropanol and then allowed to cool precipitated in crystalline form. Yield 38 g (69% of theory); M.p. 124 to 125 ° C.
C14H9FN2O (240,24):C 14 H 9 FN 2 O (240.24):
Berechnet ... C 70.00, H 3,78, N 11,65;
gefunden .... C 70,25, H 3,73, N 11.82.Calculated ... C 70.00, H 3.78, N 11.65;
found .... C 70.25, H 3.73, N 11.82.
Pharmakologische WirksamkeitPharmacological effectiveness
1. Akute ToxiziiSt1. Acute ToxiziiSt
Die Versuche wurden an männlichen Mäusen (NRMl-Stamm) im Gewicht von 18 bis 23 g durchgeführt. Die Tiere wurden 16 Stunden vor Versuchsbeginn nüchtern gesetzt, Wasser stand ad libitum zur Verfügung. Die Tiere erhielten die Substanz in logarithmisch gesteigerter Dosierung von 50 bis 1600 mg/kg intragastral mit der Schlundsonde. Die Substanz war in l%igem Traganthschleim suspendiert. Die Beobachtungszeit betrug 48 Stunden. Ergebnis: LD50 = 1600 mg/kg, i. g.The experiments were carried out on male mice (NRM1 strain) weighing 18 to 23 g. The animals were fasted 16 hours before the start of the experiment, water was available ad libitum. The animals received the substance in a logarithmically increased dose of 50 to 1600 mg / kg intragastrically with the gavage. The substance was suspended in 1% tragacanth mucus. The observation time was 48 hours. Result: LD 50 = 1600 mg / kg, ig
2. Antisekretorische Wirkung2. Antisecretory effect
Die Versuche wurden nach der von S h a y angegebenen Methode durchgeführt. Versuchstiere waren männliche Ratten (SIV) im Gewicht von 140 bis 180 g. Die Tiere saßen 48 Stunden vor Versuchsbeginn in Einzelkäfigen, das Futter wurde entzogen und Wasser ad libitum angeboten. Durch die Ver-Wendung großmaschiger Drahtkäfige beugten wir einer eventuellen Kotaufnahme vor.The tests were carried out according to the method given by S h a y. Were experimental animals male rats (SIV) weighing 140 to 180 g. The animals sat in individual cages 48 hours before the start of the experiment, and the food was withdrawn and water offered ad libitum. By using large-mesh wire cages, we bowed a possible droppings before.
Zur Durchführung der Pylorusligatur erhielten die Tiere eine kurze Äthernarkose. Die Testsubstanz wurde in l%igem Traganthschleim suspendiert 1 Stunde vor der Pylorusligatur intragastral mit der Schlundsonde verabreicht. Das Flüssigkeitsvolumen betrug in allen Versuchen 1 ml/100 g Körpergewicht. Jede Versuchsgruppe bestand aus 12 Tieren. ZurTo perform the pyloric ligature, the animals were given a brief ether anesthetic. The test substance was suspended in 1% tragacanth mucus 1 hour before the pyloric ligature intragastrically with the Gavage administered. The liquid volume in all experiments was 1 ml / 100 g body weight. Each experimental group consisted of 12 animals. To the
gleichen Zeit liefen mindestens ein Kontroll- und zwei Substanzgruppen. 4 Stunden nach der Pylorusligatur wurden die Tiere getötet, der Magen nach Cardialigatur entnommen und geöffnet. Gemessen wurden Volumen und pH-Wert des Mageninhalts. Die Ergebnisse dieser Versuche sind der folgenden Tabelle zu entnehmen.At least one control group and two substance groups ran at the same time. 4 hours after pyloric ligation the animals were sacrificed, the stomach removed after cardiac ligature and opened. Were measured Volume and pH of the stomach contents. The results of these tests are shown in the table below remove.
i substance
i
rung
mg/kgDosie
tion
mg / kg
inhalt
ml, 1(M) g
Körper
gewichtstomach
contents
ml, 1 (M) g
body
weight
40
80
16020th
40
80
160
2,0
1.7
1.0
0,162.9
2.0
1.7
1.0
0.16
3-(2'-Fluor-phenyl)-
4(3H)-chinazolon Tragacanth
3- (2'-fluoro-phenyl) -
4 (3H) -quinazolone
pH-WortpH word
1.81.8
2,4 2,3 2,52.4 2.3 2.5
Wie aus diesen Befunden hervorgeht, wird die Magensekretion durch die Substanz gehemmt. Für den Effekt bestehen ausgezeichnete Dosiswirkungsbeziehungen. Maximale pH-Effekte sind bereits bei 40 mg/kg erreicht.As can be seen from these findings, gastric secretion is inhibited by the substance. For the effect are excellent dose-response relationships. Maximum pH effects are already at 40 mg / kg reached.
Da Sekretionshemmer ohne anticholinerge Wirkung noch nicht zur Verfugung stehen, mußten die pharmakologischen Ergebnisse ohne positive Vergleichssubstanz angeführt werden. Die enorme Bedeutung des o-Halogen-substituenten zur Erzielung des gewünschten therapeutischen Effektes geht aus der Tatsache hervor, daß das im Handel als Sedativum erhältliche 2-Methyl-3-(o-tolyl)-4(3H)-chinazolon (II) keinen dosisabhängigen Effekt auf die Sekretion und keine Wirkung auf den pH-Wert des Magens ausübt. Die Verbindung Π wurde zu Vergleichsuntersuchungen herangezogen, da sie, absolut gesehen, die therapeutisch wirksamste der 3-Aryl-4(3H)-chinazolone ist.Since secretion inhibitors without an anticholinergic effect are not yet available, they had to pharmacological results are given without a positive comparison substance. The enormous importance of the o-halogen substituent to achieve the desired therapeutic effect is based on the The fact that 2-methyl-3- (o-tolyl) -4 (3H) -quinazolone (II), which is commercially available as a sedative has no dose-dependent effect on secretion and no effect on gastric pH. The compound Π was used for comparative studies because, viewed in absolute terms, it is therapeutic the most potent of the 3-aryl-4 (3H) -quinazolones.
,N:, N:
über die antisekretorische Wirkung der Vergleichs verbindung Π gibt die folgende Tabelle Aufschluß:about the antisecretory effect of the comparison connection Π provides information on the following table:
Aus diesen Ergebnissen geht hervor, daß die bekannte Verbindung II zwar anusekrctonsche Eigenschaften besitzt, jedoch bereits ab 40 mg/kg keine Dosisabhängigkeit mehr besteht. ....From these results it can be seen that the well-known Compound II has anusecrotic properties, but none from 40 mg / kg There is more dose dependency. ....
Di' maximal erreichbaren EfTekte stehen in keinem Vergleich zu denen der erfindungsgemäßen Substanz. Interessant ist auch, daß der pH-Wert bei Anwendung der Vergleichsverbindung II sinkt, was auf eine unspezifische Wirkung hindeutet. Bei 40 mg/kg der ,o Verbindung II zeigten die Tiere bereits Sedation und Scitenlage, nach 80 mg/kg narkoseähnliche Zustande.The maximum achievable effects do not exist in any Comparison to those of the substance according to the invention. It is also interesting that the pH value when applied the comparison compound II drops, which indicates a non-specific effect. At 40 mg / kg the , o Compound II, the animals already showed sedation and Scitical position, after 80 mg / kg anesthesia-like conditions.
2 von 12 Tieren starben.2 out of 12 animals died.
Der LD50-Wert von 2-Methyl-3-o-tolyl-4(3H)-chinazolon(Ii) an der Maus beträgt nach J. R. Bos-,5 s i e r (Therapie XIII, 30 [1958]) 680 mg/kg, >■ g·The LD 50 value of 2-methyl-3-o-tolyl-4 (3H) -quinazolone (Ii) in the mouse is, according to JR Bos-, 5 sier (Therapy XIII, 30 [1958]) 680 mg / kg, > ■ g ·
3 Bestimmung der anticholinergen Wirkung von 3-(2'-Fluor-phenyl)-3H-chinazolon-(4) 1 und Vergleiclissubstanzen durch Ermittlung der Puplilcn-3 Determination of the anticholinergic effect of 3- (2'-fluorophenyl) -3H-quinazolone- (4) 1 and comparison substances by determining the public
weite bei !".dttenwiden at! ". dtten
a) Methodika) methodology
Versuchstiere waren männliche Ratten (SIV 50» mit einem Körpergewicht von 100 bis 120 g. Die P'üpillenweite wurde mit einem Auflichtmikroskop mit Okularmikrometereinrichtung viermal vor Substanzverabreichung im Abstand von 15 Minuten und dann in zunächst 15minutigen, nach 90 Minuten in 30minuti2en Abständen bis zu 5 Stunden bestimmt. Die Applikation der Testsubstanzen erfolgte als Trasianthschleim-Suspension intragastral. Zu jeder Gruppe gehörten sechs Tiere. Aus den Pupillenwciten in Mikrometereinheiten dieser sechs Tiere wurden Durchschnitte berechnet. Die Ergebnisse dieser Untersuchung wurden graphisch dargestellt.Test animals were male rats (SIV 50 »with a body weight of 100 to 120 g. The The pupil size was determined with a reflected light microscope with an ocular micrometer device four times before the substance was administered determined every 15 minutes and then initially at 15-minute intervals, and after 90 minutes at 30-minute intervals for up to 5 hours. The test substances were applied as a Trasianth mucus suspension intragastric. There were six animals in each group. From the pupillary tissues Averages were calculated in micrometer units from these six animals. The results of this investigation were shown graphically.
Vergleichssubstanzen
Atropin:Comparison substances
Atropine:
Als Vertreter mit starker anticholinerger Wirkung (Dosis: 5 mg/kg).As a representative with a strong anticholinergic effect (dose: 5 mg / kg).
Dicyclopentyl-essigsaure-zMriathylammoniumäthylestcrbromid (III):Dicyclopentyl-acetic acid-methylammonium ethyl ester bromide (III):
Als bekanntes Gastro-Therapeuticum
(Dosis: 200 mg/kg).As a well-known gastro-therapeutic
(Dose: 200 mg / kg).
Vgl. B. H e 1 w i g, »Moderne Arzneimittel«
(Stuttgart 1967), S. 515.See B. H e 1 wig, "Modern Medicines"
(Stuttgart 1967), p. 515.
50 Vehikel:50 vehicles:
Traganthschleim l%ig.Tragacanth slime low.
Substanzsubstance
Kontrollecontrol
Traganth
Verbindung ΠTragacanth
Connection Π
desgl the same
desgl the same
desgl the same
160160
Mageninhalt ml/100 g Körpergewicht Stomach content ml / 100 g body weight
b) Ergebnisseb) Results
Wie aus der folgenden Abbildung zu entnehmen pH-Wert ist, besitzt die erfindungsgemäße Verbindung I keinerlei mydiiatische Aktivitäten an der Rattenpupille. Da die geprüften Dosen von 100 und 200 mg/kg stark antisekretorisch wirksam sind, kann dieser 1.8 60 Effekt nicht über eine anticholinerge Wirkung dieser Verbindung zustande kommen.As the pH value can be seen in the following figure, the compound I according to the invention has no mydiatic activities whatsoever on the rat pupil. Since the tested doses of 100 and 200 mg / kg have a strong antisecretory effect, this 1.8 60 effect cannot come about through an anticholinergic effect of this compound.
Die Versuche beweisen somit, daß der erfindungsgemäßen Substanz praktisch keine unerwünschte anticholinerge Aktivität zukommt; daß jedoch ein den gegenwärtigen Stand der Ulcustherapie repräsennicht mehr tierendes Produkt III noch beträchtliche anticho-The tests thus show that the substance according to the invention is practically not undesirable has anticholinergic activity; however, that one does not represent the current state of ulcer therapy more animal product III still considerable anticho-
durchführbar linerge: Nebenwirkungen aufweist.feasible linerge: has side effects.
2,92.9
1,9 1,2 1,21.9 1.2 1.2
1.91.9
1.5 1.71.5 1.7
Hierzu 1 Blatt Zeichnungen1 sheet of drawings
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19702015771 DE2015771B2 (en) | 1970-04-02 | 1970-04-02 | 3- (2'-Fluoro-phenyl) -4 (3H) -quinazolone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19702015771 DE2015771B2 (en) | 1970-04-02 | 1970-04-02 | 3- (2'-Fluoro-phenyl) -4 (3H) -quinazolone |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE2015771A1 DE2015771A1 (en) | 1972-02-17 |
| DE2015771B2 true DE2015771B2 (en) | 1974-01-31 |
| DE2015771C3 DE2015771C3 (en) | 1974-09-05 |
Family
ID=5766938
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19702015771 Granted DE2015771B2 (en) | 1970-04-02 | 1970-04-02 | 3- (2'-Fluoro-phenyl) -4 (3H) -quinazolone |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE2015771B2 (en) |
-
1970
- 1970-04-02 DE DE19702015771 patent/DE2015771B2/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| DE2015771C3 (en) | 1974-09-05 |
| DE2015771A1 (en) | 1972-02-17 |
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