DE1280874B - 2-methyl-3- (2-dimethylaminophenyl) -8-amino-3H-quinazolone- (4) - Google Patents
2-methyl-3- (2-dimethylaminophenyl) -8-amino-3H-quinazolone- (4)Info
- Publication number
- DE1280874B DE1280874B DEB73447A DEB0073447A DE1280874B DE 1280874 B DE1280874 B DE 1280874B DE B73447 A DEB73447 A DE B73447A DE B0073447 A DEB0073447 A DE B0073447A DE 1280874 B DE1280874 B DE 1280874B
- Authority
- DE
- Germany
- Prior art keywords
- methyl
- amino
- dimethylaminophenyl
- quinazolone
- general 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.)
- Pending
Links
Classifications
-
- 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
- C07D401/12—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 chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
BUNDESREPUBLIK DEUTSCHLANDFEDERAL REPUBLIC OF GERMANY
DEUTSCHESGERMAN
PATENTAMTPATENT OFFICE
AUSLEGESCHRIFTEDITORIAL
Int. Cl.:Int. Cl .:
C07dC07d
A 61kA 61k
Deutsche Kl.: 12 ρ-7/01
30 h-2/36German class: 12 ρ-7/01
30 h-2/36
Nummer: 1 280 874Number: 1 280 874
Aktenzeichen: P 12 80 874.1-44 (B 73447)File number: P 12 80 874.1-44 (B 73447)
Anmeldetag: 9. September 1963Filing date: September 9, 1963
Auslegetag: 24. Oktober 1968Opening day: October 24, 1968
Die Erfindung betrifft das 2-Methyl-3-(2-dimethylaminophenyl)-8-amino-3 H-chinazolon-(4) der Formel The invention relates to 2-methyl-3- (2-dimethylaminophenyl) -8-amino-3 H-quinazolone- (4) of the formula
N(CHj)2 N (CHj) 2
NH,NH,
sowie dessen physiologisch verträgliche Säureadditionssalze und Verfahren zur Herstellung derselben. Die Herstellung der neuen Verbindung der Formel I erfolgt nach den folgenden an sich bekannten Methoden:as well as its physiologically acceptable acid addition salts and processes for the preparation thereof. The preparation of the new compound of the formula I takes place according to the following per se known Methods:
a) Reduktion von Chinazolonen der allgemeinen Formela) Reduction of quinazolones of the general formula
2-Methyl-3-(2-dimethylaminophenyl)-8-amino-3H-chinazolon-(4) 2-methyl-3- (2-dimethylaminophenyl) -8-amino-3H-quinazolone- (4)
Anmelder:Applicant:
C. H. Boehringer Sohn, 6507 IngelheimC. H. Boehringer Sohn, 6507 Ingelheim
Als Erfinder benannt:Named as inventor:
Dr. Alex Heusner,Dr. Alex Heusner,
Dr. Karl Zeile, 6507 IngelheimDr. Karlzeile, 6507 Ingelheim
als auch organische Säuren geeignet. Beispielsweise seien die folgenden Säuren genannt: Salzsäure. Bromwasserstoff-, Phosphor-, Schwefel-, Essig-, Milch-, Salicyl-, Wein-, Methansulfon-, Benzoesäure. Die als Ausgangsstoffe verwendeten Nitro- bzw. Nitrosochinazolone der Formel II werden beispielsweise durch Kondensation einer Nitro- oder Nitrosoacetylanthranilsäure der allgemeinen Formelas well as organic acids. The following acids may be mentioned as examples: hydrochloric acid. Hydrobromic, phosphoric, sulfuric, acetic, lactic, salicylic, tartaric, methanesulphonic, benzoic acid. The nitro or nitrosoquinazolones of the formula II used as starting materials are, for example by condensation of a nitro or nitrosoacetylanthranilic acid of the general formula
IIII
N(CH3J2 N (CH 3 J 2
in der R eine Nitro- oder Nitrosogruppe bedeutet, mit katalytisch erregtem Wasserstoff oder mit Wasserstoff in statu nascendi, oder b) hydrogenolytische Abspaltung des Restes Z aus Verbindungen der allgemeinen Formelin which R is a nitro or nitroso group, with catalytically excited hydrogen or with hydrogen in statu nascendi, or b) hydrogenolytic cleavage of the radical Z from Compounds of the general formula
OO
IVIV
N(CH3),N (CH 3 ),
NH-ZNH-Z
in der Z den Carbobenzoxy- oder den Benzylrest bedeutet, oderin which Z denotes the carbobenzoxy or benzyl radical, or
c) Kondensation von 2-Acetylamino-3-aminobenzoesäure mit 2-Dimethylaminoanilin in Gegenwart wasserabspaltender Mittel.c) Condensation of 2-acetylamino-3-aminobenzoic acid with 2-dimethylaminoaniline in the presence dehydrating agents.
Die Verbindung der Formel I läßt sich in üblicher Weise in ihre physiologisch verträglichen Salze überfuhren. Zur Salzbildung sind sowohl anorganischeThe compound of the formula I can be converted into its physiologically tolerated salts in a customary manner. For salt formation are both inorganic
COOHCOOH
NH — COCH,NH - COCH,
in der R eine Nitro- oder Nitrosogruppe bedeutet, mit 2-Dimethylaminoanilin in Anwesenheit wasserabspaltender Mittel hergestellt.in which R is a nitro or nitroso group, with 2-dimethylaminoaniline in the presence of dehydrating agents Means made.
Die Herstellung der Ausgangsverbindungen der Formel IV kann z. B. durch Kondensation von N-geschützten Aminoacetylanthranilsäuren der allgemeinen FormelThe preparation of the starting compounds of the formula IV can, for. B. by condensation of N-protected aminoacetylanthranilic acids of the general formula
COOHCOOH
NH — COCH3 NH - COCH 3
NH-ZNH-Z
in der Z die obengenannte Bedeutung besitzt, mit 2-Dimethylaminoanilin in Gegenwart wasserabspaltender Mittel erfolgen.in which Z has the abovementioned meaning, with 2-dimethylaminoaniline in the presence of dehydrating agents Means done.
Das erfindungsgemäße Chinazolon der Formel I zeichnet sich durch wertvolle pharmakologische Eigenschaften aus. Es wirkt insbesondere stark sedierend bei geringer Toxizität. Besonders über-The quinazolone of the formula I according to the invention is distinguished by valuable pharmacological properties Properties. In particular, it has a strong sedating effect with low toxicity. Especially over-
- «("- 6?8 167f- «(" - 6? 8 167f
raschend ist die Tatsache, daß im Gegensatz zu bekannten Verbindungen des Standes der Technik die erfindungsgemäße Verbindung keinerlei zentralerregende Komponente besitzt.surprising is the fact that, in contrast to known compounds of the prior art the compound according to the invention does not have any central excitation component.
Das erfindungsgemäße 2-Methyl-3-(2-dimethylaminophenyl) - 3 H - 8 - amino - chinazolon - (4) wurde hinsichtlich der sedativen Wirkung mit dem bekannten 2 - Methyl - 3 - (2 - methylphenyl) - 3 H - chinazolone) (Methaqualone) und dem aus der britischen Patentschrift 916 139 bekannten 2-Methyl-3-(2-methyIphenyl)-3 H-o-amino-chinazolon-^) verglichen. Über eine sedierende Wirkung der zuletzt genannten Verbindung ist in der Patentschrift nichts vermerkt.The 2-methyl-3- (2-dimethylaminophenyl) according to the invention - 3 H - 8 - amino - quinazolone - (4) was known for its sedative effect with the 2 - Methyl - 3 - (2 - methylphenyl) - 3 H - chinazolone) (Methaqualone) and the one from the British Patent specification 916 139 known 2-methyl-3- (2-methylphenyl) -3 H-o-amino-quinazolone- ^) compared. The patent specification says nothing about a sedative effect of the last-mentioned compound noted.
Zur Prüfung auf sedative Wirkung wurden die »ataktische Dosis« (AD50), bei der die Bewegungen der Versuchstiere nicht mehr koordiniert sind, und die »Stellreflexdosis« (SD50), bei der die Tiere aus der Seitenlage sich nicht mehr selbständig auf die Beine stellen können, sowie die letale Dosis (LD50) bestimmt. Die therapeutische Breite (T) wurde als QuotientThe "atactic dose" (AD50) at which the movements of the test animals are no longer coordinated, and the "corrective reflex dose" (SD50) at which the animals the side position can no longer stand on their own feet, as well as the lethal dose (LD50) certainly. The therapeutic range (T) was expressed as a quotient
LDLD
r50 r 50
V2 (AD50 + SD50)V 2 (AD 50 + SD 50 )
errechnet. Die Substanzen wurden peroral in einer Öl-Wasser-Emulsion gegeben, als Versuchstiere dienten Mäuse. Folgende Werte wurden erhalten:calculated. The substances were given orally in an oil-water emulsion, as test animals Mice. The following values were obtained:
4545
Hinsichtlich der antikoavulsivsn Wirksamkeit ergibt sich für das erfindungsgemäSe Chinazoton gegenüber Methaqualone eine überraschend große Überlegenheit: With regard to the anticoavulsive effectiveness for the quinazotone according to the invention Methaqualone has a surprisingly great superiority:
Methaqualone ED»Methaqualone ED »
2-Methyt-3-{2-dimethyl-2-methyl-3- {2-dimethyl-
aminopbenyi)-aminopbenyi) -
3 H-8-ammo-chin-3 H-8-ammo-chin-
azoIon-(4) ED50azoIon- (4) ED50
154 mg/kg Maus154 mg / kg mouse
30 mg/kg Maus30 mg / kg mouse
5555
Es war nicht vorherzusehen, daß die erfiadungsgemäße Verbindung derart ausgeprägte sedative und überraschenderweise auch antikonvulsive Eigenschaften bei gleichzeitigem Fehlen einer zentralerregenden Komponente aufweisen würde.It was not foreseeable that the Compound such pronounced sedative and surprisingly also anticonvulsant properties in the absence of a central excitation component.
Die Erfahrungen bei der Synthese von substituierten Barbitursäuren (B. D ο r a η , Barbituric acid hypnotics, Medicinical Chemistry, Vol. IV, S. 34, Verlag Wiley and Sons, New York 1959) ließen vielmehr erwarten, daß durch die Einführung eines basischen Restes die «edierende Wirkung vermindert werden würde.Experience in the synthesis of substituted barbituric acids (B. D ο r a η, Barbituric acid hypnotics, Medicinical Chemistry, Vol. IV, p. 34, Verlag Wiley and Sons, New York 1959) on the contrary, one might expect that the introduction of a basic residue would reduce the edifying effect would be.
10,8 g 2 - Methyl - 3 - (2 - dimethylaminophenyl}-8-nitro-3 H-chinazolon-(4) werden mit etwa 10 g Raney-Nickel in 200 ml Dioxan bei Raumtemperatur und Atmosphärendruck hydriert; die Wasserstoffaufnahme ist nach einer Stunde beendet. Die vom Katalysator befreite Lösung wird im Vakuum eingedampft, wobei das Hydrierungsprodukt in kristalliner Form zurückbleibt; Ausbeute fast quantitativ; Schmelzpunkt nach dem Umkristallisieren aus Äthanol—Wasser 189 bis 1900C.10.8 g of 2 - methyl - 3 - (2 - dimethylaminophenyl} -8-nitro-3 H-quinazolone- (4) are hydrogenated with about 10 g of Raney nickel in 200 ml of dioxane at room temperature and atmospheric pressure; the hydrogen uptake is after The solution freed from the catalyst is evaporated in vacuo, the hydrogenation product remaining in crystalline form; yield almost quantitative; melting point after recrystallization from ethanol-water 189 to 190 ° C.
Die als Ausgangsprodukt verwendete Nitroverbindung. Schmelzpunkt 214 bis 216 0C, kann in üblicher Weise durch Umsetzung von 3-Nitroacetylanthranilsäura mit o-Amino-dimethylanilin in Gegenwart wasserabspaltender Mittel, wie Phosphoroxychlorid oder Phosphortrichlorid, oder durch direkte Umsetzung von 3-NitroacetylanthraniI mit 2-Dimeihylaminoanilin erhalten werden.The nitro compound used as the starting product. Melting point 214 to 216 ° C., can be obtained in the usual way by reacting 3-nitroacetylanthranilic acid with o-amino-dimethylaniline in the presence of dehydrating agents, such as phosphorus oxychloride or phosphorus trichloride, or by direct reaction of 3-nitroacetylanthraniI with 2-dimethylaminoaniline.
Claims (3)
b) aus Chinazolonen der allgemeinen Formelin which R is a nitro or nitroso group, reduced with catalytically excited hydrogen or with hydrogen m statu nasendi or that one
b) from quinazolones of the general formula
c) 2 - Acetyiamino - 3 - aminobenioesäure mit 2-Dimethylaminoanilin in Gegenwart wasserabspaltender Mittel kondensiert und daß man die erhaltene Verbindung gegebenenfalls in ihre physiologisch verträglichen Säureadditionssalze überführt.in which Z denotes the carbobenzoxy or benzyl radical, the radical Z is split off hydrogenolytically or that one
c) 2 - Acetyiamino - 3 - aminobenioesäure is condensed with 2-dimethylaminoaniline in the presence of dehydrating agents and that the compound obtained is optionally converted into its physiologically acceptable acid addition salts.
Britische Patentschrift Nr. 916 139.Considered publications:
British Patent No. 916 139.
Deutsch« Patent Nr. 1 232 152.Legacy Patents Considered:
German «Patent No. 1 232 152.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEB73447A DE1280874B (en) | 1963-10-09 | 1963-10-09 | 2-methyl-3- (2-dimethylaminophenyl) -8-amino-3H-quinazolone- (4) |
| CH1163164A CH443310A (en) | 1963-10-09 | 1964-09-07 | Process for the preparation of new 2-methyl-3-phenyl-3H-4-quinazolones |
| FR987530A FR4074M (en) | 1963-10-09 | 1964-09-09 | |
| FR987529A FR1412615A (en) | 1963-10-09 | 1964-09-09 | Process for making new 2-methyl-3-phenyl-3h-4-quinazolones |
| GB36951/64A GB1076747A (en) | 1963-10-09 | 1964-09-09 | Substituted quinazolones |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEB73447A DE1280874B (en) | 1963-10-09 | 1963-10-09 | 2-methyl-3- (2-dimethylaminophenyl) -8-amino-3H-quinazolone- (4) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1280874B true DE1280874B (en) | 1968-10-24 |
Family
ID=6977860
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEB73447A Pending DE1280874B (en) | 1963-10-09 | 1963-10-09 | 2-methyl-3- (2-dimethylaminophenyl) -8-amino-3H-quinazolone- (4) |
Country Status (4)
| Country | Link |
|---|---|
| CH (1) | CH443310A (en) |
| DE (1) | DE1280874B (en) |
| FR (2) | FR1412615A (en) |
| GB (1) | GB1076747A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3448109A (en) * | 1966-08-01 | 1969-06-03 | Boehringer Sohn Ingelheim | Certain amino-substituted 2-methyl-3-phenyl-4(3h)-quinazolinones |
| AU2004293310A1 (en) * | 2003-11-28 | 2005-06-09 | Aveo Pharmaceuticals, Inc. | Quinazoline derivative and process for producing the same |
| GB0412769D0 (en) * | 2004-06-08 | 2004-07-07 | Novartis Ag | Organic compounds |
| TW202045179A (en) | 2019-02-15 | 2020-12-16 | 瑞士商諾華公司 | Methods for treating ocular surface pain |
| JP6994061B2 (en) | 2019-02-15 | 2022-01-14 | ノバルティス アーゲー | Preparation of 4- (7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3-yl) -benzonitrile |
| US20230357165A1 (en) * | 2020-06-29 | 2023-11-09 | Council Of Scientific And Industrial Research | Quinazolinones derivatives for treatment of non-alcoholic fatty liver disease, preparation and use thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE916139C (en) * | 1949-09-04 | 1954-08-05 | Franz Seiffert & Co Ag | Seat ring fastening for gate valves |
-
1963
- 1963-10-09 DE DEB73447A patent/DE1280874B/en active Pending
-
1964
- 1964-09-07 CH CH1163164A patent/CH443310A/en unknown
- 1964-09-09 FR FR987529A patent/FR1412615A/en not_active Expired
- 1964-09-09 GB GB36951/64A patent/GB1076747A/en not_active Expired
- 1964-09-09 FR FR987530A patent/FR4074M/fr not_active Expired
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE916139C (en) * | 1949-09-04 | 1954-08-05 | Franz Seiffert & Co Ag | Seat ring fastening for gate valves |
Also Published As
| Publication number | Publication date |
|---|---|
| FR4074M (en) | 1966-04-12 |
| CH443310A (en) | 1967-09-15 |
| GB1076747A (en) | 1967-07-19 |
| FR1412615A (en) | 1965-10-01 |
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