GB2063263A - A 1-isopropyl-4-phenyl-2(1H)- quinazolinone Derivative - Google Patents

A 1-isopropyl-4-phenyl-2(1H)- quinazolinone Derivative Download PDF

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Publication number
GB2063263A
GB2063263A GB8036362A GB8036362A GB2063263A GB 2063263 A GB2063263 A GB 2063263A GB 8036362 A GB8036362 A GB 8036362A GB 8036362 A GB8036362 A GB 8036362A GB 2063263 A GB2063263 A GB 2063263A
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United Kingdom
Prior art keywords
compound
formula
isopropyl
gt
lt
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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.)
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Application number
GB8036362A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sandoz KK
Original Assignee
Sandoz KK
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
Priority to CH1020179 priority Critical
Application filed by Sandoz KK filed Critical Sandoz KK
Publication of GB2063263A publication Critical patent/GB2063263A/en
Application status is Withdrawn legal-status Critical

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72Quinazolines; Hydrogenated quinazolines
    • C07D239/78Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80Oxygen atoms
    • C07D239/82Oxygen atoms with an aryl radical attached in position 4

Abstract

Compound of formula I, <IMAGE> is useful for treating phlogistic conditions and pain.i

Description

SPECIFICATION A 1 -lsopropyl-4Phenyl-2( 1 H)-Quinazol inone Derivative, Its Production and Pharmaceutical Compositions Containing it The present invention provides the compound of formula I, <img class="EMIRef" id="027282372-00010001" />

namely 1 -isopropyl-4-(4'-fluorophenyl)-5-methyl 2(1 H)-quinazolinone.

The compound of formula I falls under the scope of DAS 1 805 501, but is not specifically disclosed therein. It has now been found that the compound of formula I possesses valuable pharmacological activity whilst at the same time only exhibiting the ulcerogenicity normally associated with compounds of this type to a very limited extent.

The invention also provides a process for the production of the compound of formula I, characterised by cyclising the compound of formula II, <img class="EMIRef" id="027282372-00010002" />

with urea or a C,~5-alkyicarbamate in the presence of an aromatic acid.

The process may be effected in manner analogous to that described in DOS 2 753 970 and is conveniently carried out in the presence or absence of an inert organic solvent. Suitable temperatures lie between 120 and 1800 C, preferably 140 and 1600 C. Suitable aromatic acids include benzoic acid and o- or pmethylbenzoic acid. The aromatic acid is preferably employed in amount of at least 1 mol, preferably 3 to 6 mols per mol of 2aminobenzophenone derivative.

The compound of formula II may be prepared by reacting in liquid medium, a compound of formula Ill, <img class="EMIRef" id="027282372-00010003" />

with acetone, a borohydride and an acid, or the reaction product of a borohydride and an acid.

This process can be effected in manner analogous to that described in DOS 2 701 888.

The compound of formula I exhibits pharmacological activity. In particular the compound exhibits antiphlogistic activity, as indicated in standard tests, for example by inhibition of oedema formation in the carrageen paw oedema test in rats on pto. administration of from 10 to 100 mg/kg animal body weight of the compound [Winter, Proc. Soc. Exp. Biol. Med.

111,544(1962)j.

The compound is therefore indicated for use as an antiphlogisic agent. For this use an indicated daily dosage is from about 100 to about 1000 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing from about 25 mg to about 500 mg or in sustained release form.

The compound of formula I exhibit further analgesic activity as indicated in standard tests.

For example, in one standard test an inhibition of the phenyl benzoquinone syndrome is observed in mice on p.o. administration of from 10 to 50 mg/kg animal body weight of the compound.

The compound is therefore indicated for use as an analgesic agent. For this use an indicated daily dosage is from about 30 to about 350 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 7.5 mg to about 175 mg or in sustained release form.

The compound of formula I has surprisingly a low propensity to produce gastric erosions, as indicated in standard tests. For example in one test rats starved overnight were administered the compound orally and sacrificed 6 hours later. The stomachs were examined for superficial erosions.

The dose-responsecurves were estimated using probit-analysis. The UDso was taken as the dose which induced petechial hemorrhages in 50% of the rats. The UD50 mg/kg p.o. is 91.1.

The present invention also provides a pharmaceutical composition comprising the compound of formula I in association with a pharmaceutical carrier or diluent. Such composition may be in the form of, for example, a solution or a tablet. The invention concerns in addition the use of the compound of formula I as a pharmaceutical in particular as an analgesic or antiphlogistic and in the treatment of the human or animal body by therapy.

In the following Example all temperatures are in degrees Centigrade.

Example 1 -Isopropyl-4-(4'-fluorophenyl)-5-methyl- 2(1 H)-quinazolinone a) 2-Amino-6-methyl-4'-fluorobenzophenone To a solution of 53.6 g m-toluidine in 160 ml 1,2-dichloroethane 64.8 g borontrichloride are added at 600 over a period of 1 hour. 121 g of 4fluorobenzonitrile in 40 ml dichloroethane and 73.4 g of aluminium chloride are then added at the same temperature. The mixture is heated for 4 hours under reflux and the resulting imine hydrolised to the ketone with hydrochloric acid.

The phases are separated at pH 3. The organic phase is evaporated and the residue dissolved in 360 ml ethanol. The solution is cooled to 0 and filtered off to remove unwanted 2-amino4methyl-4'-fluorobenzophenone. The filtrate is then concentrated, dissolved in 60 ml xylene and extracted with 10% aqueous hydrochloric acid.

After addition of aqueous sodium hydroxide the title compound is obtained as a brown oil.

b) 2-N-lsopropylamino-6-methyl-4'- fluorobenzophenone To a solution of 50 g 2-amino-6-methyl-4'fluorobenzophenone in 250 ml acetone are added 44.8 g o-phthalic acid. The mixture is heated to 450 and 8.5 g of sodium borohydride added portionwise over a period of 1 hour. The temperature is then raised to 550 and maintained for 1 hour. The mixture is then cooled at 400, 140 ml of 20% aqueous sodium hydroxide is added and the phases separated. The water phase is extracted vvlth toluene. The combined acetone and toluene phases are concentrated and distilled in vacuo to give the title compound, b.p.

136/0.06 Torr.

C) I -lsopropyl-4-(4'-fluorophenyl)-5-methyl- 2!1 H)-quinazolinone A solution of 45.0 g 2-N-isopropylamino-6 rnethyl-4'-fluorobenzophenone in 60 ml of xylene is heated to 800. 88.5 g of benzoic acid and 34.0 g of methyl carbamate are added and the mixture is heated to 1 550 for 10 hours, during which time xylene-water is distilled off. The mixture is then cooled to 900, diluted with 170 ml xylene and washed with aqueous sodium hydroxide. The hot xylene solution is dehydrated and cooled to 0 to give the title compound, m.p. 183.5-184.5.

Claims (6)

Claims
1. A process for the production of the compound of formula <img class="EMIRef" id="027282373-00020001" />
which comprises cyclising the compound of formula II <img class="EMIRef" id="027282373-00020002" />
with urea or an C,,-alkylcarbamate in the presence of an aromatic acid.
2. Compound of formula I as defined in claim 1.
3. Compound of formula I for use as a pharmaceutical.
4. Compound of formula I for use as an antiphlogistic or analgesic agent.
5. A pharmaceutical composition which comprises the compound of formula I in association with a pharmaceutical carrier and/or diluent.
6. A method for treating phlogistic conditions and pain which comprises administering a therapeutically effective amount of the compound of formula I to a subject in need of such treatment.
GB8036362A 1979-11-15 1980-11-12 A 1-isopropyl-4-phenyl-2(1H)- quinazolinone Derivative Withdrawn GB2063263A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CH1020179 1979-11-15

Publications (1)

Publication Number Publication Date
GB2063263A true GB2063263A (en) 1981-06-03

Family

ID=4360522

Family Applications (1)

Application Number Title Priority Date Filing Date
GB8036362A Withdrawn GB2063263A (en) 1979-11-15 1980-11-12 A 1-isopropyl-4-phenyl-2(1H)- quinazolinone Derivative

Country Status (5)

Country Link
JP (1) JPS5686173A (en)
DE (1) DE3041678A1 (en)
FR (1) FR2469407A1 (en)
GB (1) GB2063263A (en)
IT (1) IT8050159D0 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4645836A (en) * 1983-09-12 1987-02-24 Ortho Pharmaceutical Corporation Process for the preparation of 6,7-dihydroxy-4-alkyl-2(1H) quinazolinone-1-propionic acids

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE792942A (en) * 1972-03-09 1973-06-18 Sandoz Sa New derived quinazolinone, its preparation and its application in therapeutic

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4645836A (en) * 1983-09-12 1987-02-24 Ortho Pharmaceutical Corporation Process for the preparation of 6,7-dihydroxy-4-alkyl-2(1H) quinazolinone-1-propionic acids

Also Published As

Publication number Publication date
JPS5686173A (en) 1981-07-13
DE3041678A1 (en) 1981-05-27
IT8050159D0 (en) 1980-11-13
FR2469407A1 (en) 1981-05-22

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WAP Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1)