DE2134118A1 - Chinazohnones, process for their manufacture and medicinal preparations - Google Patents

Description

¹¹ quinazolinones, process for their production and medicinal preparations "

Priority: July 13, 1970

October 30, 1970

November 5, 1970 December 23, 1970

No. 61618/70, Japan

No. 96306/70, Japan

No. 98IO7 / 7O, Japan

No. II8332 / 70, Japan

The invention relates to new quinazolinones of the general formula I.

in which R ₁ and R _{3 are} hydrogen or halogen atoms, lower alkyl,

Alkoxy, alkylthlo or alkylsulfonyl radicals, nitro or TrI-.

fluoromethyl groups mean, R, a radical of the general formula II ff

is, in the H ₁ . represents a hydrogen or halogen atom, a lower alkyl or alkoxy radical or a trifluoromethyl group, or R represents a maphthyl group, a lower cycloalkyl radical, a lower cycloalkenyl radical, a pyridyl, pyrro-IyI, thienyl or furyl group, R represents a lower cycloalkylrene , a trihalomethyl radical, a lower one

109884/1891 _ϊΛ

Alkoxy, alkylthio or alkanoyloxy radical or a group of the general formula III or IV

^R 5 ^R 5

~~ ^{N <} s _D or - COM <^ - ^R 6 ^ R ₆

means in which R ₁ - and Rg represent lower alkyl radicals or Rc- and R / - together with the nitrogen atom form an unsubstituted or substituted 5- or 6-membered heterocyclic ring which optionally contains a further nitrogen, oxygen or sulfur moiety, and η is an integer from 1 to 3.

Specific examples of lower alkyl radicals are the methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl or tert-butyl groups. Specific examples of lower alkoxy radicals are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, Isobutoxy and tert-butoxy groups. Specific examples of lower ones Cycloalkyl radicals are the cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, methylcyclopropyl and dimethylcyclopropyl groups. Specific examples of lower alkanoyloxy groups are the acetoxy and propionyloxy groups. Specific examples of the trihalomethyl group are the trifluoromethyl, trichloromethyl and chloro-difluoromethyl group. As halogen atoms fluorine, chlorine, bromine and iodine atoms are possible. Examples of the alkylene radical C H_ are the methylene, ethylene, 1-Me-

nail "- ,

ethylethylene, 2-methylethylene and tr! methylene group.

10988W1891

The quinazolinones of the general formula I are according to the invention prepared by either (a) a compound of the general formula V

^C n ^H 2n

in which R ₁ , R ₂ , R ^, R and η have the above meaning reduced or

(b) a compound of the general formula VI

in which R ₁ , R ₂ , R 1, R and η are as defined above, reacts with phosgene, N, N * -carbonyldiimidazole or a lower halo genformic acid alkyl ester or

(c) a compound of the general formula VII

R I

in which R ₁ , Ro »R and η had the above meaning with an aldehyde of the general formula VIII

109884/1891

R ₃ - CHO (VIII)

In which R has the preceding meaning, condensed, or (d) a compound of the general formula IX

^R 2 I.

"* 3 in which R ₁ , R ₀ , R ,, R and η have the above meaning, heated or

(e) a compound of the general formula X

R '■

in which R ₁ , R ₂ , R and η have the above meaning, with a compound of the general formula XI

R3 - Y (XI)

inidi er ~ TC has the above meaning and Y represents a lithium atom or the remainder MgCl ₉ MgBr or MgJ, condensed and then subjected to hydrolysis or

(f) a compound of the general formula XII

R 1

109884/1891

ORIGINAL INSPECTED

. in which R 1, R ₃₁ , R 1, R and η are as defined above and X is a sulfur atom or an imino group which is subjected to hydrolysis.

The compound of the general formula V is preferably used in Presence of an inert solvent or solvent mixture with a reducing agent, e.g. a complex metal hydride such as sodium borohydride, lithium borohydride, lithium aluminum hydride, Diispbutyl -: - aluminum hydride or mixed metal hydrides, reduced. The reduction can also be carried out with hydrogen in the presence of a hydrogenation catalyst such as nickel, palladium, Platinum oxide, copper or cobalt. Customary processes for reducing a carbon-nitrogen double bond can be used can be applied.

The type of solvent used depends on the type of reducing agent used. Examples of suitable solvents are methanol, ethanol, isopropanol, ethyl acetate, acetic acid, water, methylene chloride, chloroform, carbon tetrachloride, Diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, diglycol methyl ether and dimethylformamide. The implementation is progressing usually at room temperature. If necessary, higher or lower temperatures can be used.

The reaction of the compound of the general formula VI is preferably carried out in the presence of an inert solvent and an acid acceptor. Examples of suitable νv-ev: ^.,, 109884/1891 _BAD original

- O -

Solvents are benzene, toluene, xylene, chloroform, Diftthyläther, Tetrahydrofuran, dioxane and dimethylformamide. Examples of suitable acid acceptors are tert. organic bases, such as TriMthylamin, Tri-n-Propylamin, Pyridine, Dimethylariilin and N-methylpiperidine, alkali metal salts of organic acids, such as Sodium acetate and potassium acetate, or inorganic bases such as sodium or potassium hydroxide or carbonate.

The implementation d <= r Ve * · connection of the general formula VII with the aldehyde of the general formula VIII is preferably in the presence of an anhydrous inert solvent and more catalytic Quantities of a dehydrating agent performed. Examples of usable inert solvents are benzene and toluene. Examples of dehydrating agents are aryl sulfonic acids, such as benzenesulfonic acid and p-toluenesulfonic acid, alkyl

sulfonic acids, such as methanesulfonic acid and trichloromethanesulfonic acid, Trifluoroacetic acid, a solution of hydrogen chloride in an alcohol such as methanol or ethanol. The reaction is preferably carried out at temperatures from 60 ° C. to the boiling point of the used solvent carried out.

The reaction of the compound of the general formula IX is preferably carried out in the presence of an acid. As the acids, mineral acids such as sulfuric acid and hydrochloric acid or organic acids such as acetic acid can be used. The reaction is preferably carried out at temperatures of 90 to 120 ⁰ C.

^ 109884/1891

The reaction of the compound of the general formula X with a compound of the general formula XI is carried out in an anhydrous inert solvent carried out. Examples of suitable Solvents are benzene, toluene, diethyl ether, dimeth-

oxyethane, tetrahydrofuran, dioxane or mixtures thereof. The compound of the general formula XI is preferably used in excess used. The hydrolysis of the reaction product is preferably carried out under alkaline conditions.

The hydrolysis of the compound of general formula XII will preferably carried out in the presence of a solvent with the aid of an acid or a base with heating. Examples suitable solvents are methanol, ethanol, isopropanol, Dioxane and dimethyl sulfoxide. Examples of usable Acids are mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid. Examples of bases that can be used are alkali metal hydroxides and carbonates, alkaline earth metal hydroxides and ammonium hydroxide. Specific examples of usable bases are sodium and potassium hydroxide or carbonate as well as calcium hydroxide and barium hydroxide.

The quinazolinones of general formula I are excellent anti-inflammatory and analgesic because of their excellent properties Properties and their low toxicity are valuable medicinal substances and valuable intermediates for the manufacture of others Medicinal substances. The anti-inflammatory effects of these compounds is higher than that of l, 2-diphenyl-3,5-dioxo-4-n-butyl- '

109884/1891

pyrazolidines (phenylbutazone), while their acute, subacute and chronic toxicity is much lower.

The examples illustrate the invention. -

109884/1691

example 1

A suspension of 6.22 g of 1-cyclopropylmethyl-4-phenyl-6-chloro-2 (1H) -quinazolinone in 150 ml of isopropanol is mixed with 0.8 g of sodium borohydride in portions. The mixture is stirred for 2 hours at room temperature. The solvent is then distilled off under reduced pressure. The residue is washed with water and filtered. After drying, 6.25 S of 1-cyclopropylmethyl-4-phenyl-6-chloro-3,4-dihydro-2 (1H) -quinazolinone are obtained. After recrystallization from ethanol colorless needles melting at 166.0 to 167 are obtained O ⁰ C.

Example 2

A solution of 3.11 g of 1-cyclopropylmethyl- ^ - phenyl-o-chloro-2 (1H) ~ quinazolinone 0.40 g of a platinum oxide catalyst are added to 50 ml of acetic acid. The mixture is at ' Shaken room temperature against hydrogen until 1 mole of hydrogen has been absorbed. After filtering off of the catalyst, the filtrate is evaporated to dryness under reduced pressure. The residue is recrystallized from ethanol, sated. There are 2.90 g of 1-cyclopropylmethyl- ^ i-phenyl-o-chloro-3,4-dihydro-2 (1H) -quinazolinori obtained from m.p. 165.0 to 166.0 ° C.

Example 3

In a manner similar to that described in Example 1 or 2, the quinazolinones listed below are prepared from the corresponding Output connections made:

109884/1891

.1-cyclopropylmethyl-4-phenyl-6-fluoro-3,4-dihydro-2 (IH) -quinazolinone, m.p. 158.0 to 159.0 ⁰ C; 1-Cyclopropylmethyl-4-phenyl-6,7-dichloro-5,4-dihydro-2 (1H) -quinazolinone, P. 170.5 to 171.5 ° C; 1-Cyclopropylraethyl-4-phenyl-6-methyl-5,4-dihydro-2 (IH) -quinazolinone, P. IJl, 0 to 1 ^ 2, O ⁰ Cj

lC./Glopropylmethyl-4-phenyl-6-raethoxy-3,4-dihydro-2(lH) -quinazolinone, P. 157.0 to 138, O ⁰ Cj

1-Cyclopropylmethyl-4-phenyl-6-nitro-5,4-dihydro-2 (1H) -quinazolinone, mp 159.5 to 16o.5 ° C; 1-Cyclopropylmethyl - ^ - phenyl-o-trifluoromethyl-j ^^ - dihydro-2 (1H) -quinazolinone, m.p. 16l, 5 to 162.5 ° C; 1- (2'-Ethoxyethyl) -4-phenyl-6-chloro-3,4-dihydro-2 (1H) -quinazolinone, F. 127.0 to 128.5 ⁰ Cj l- (2'-Ethoxyethyl) - 4- (o-fluorophenyl) -6-chloro-3,4-dihydro-2 (1H) -quinazolinone, m.p. 110.0 to 110.5 ° C; 1- (2 '- diethylaminoethyl) -4- (of luophenyl) ~ 6-chloro-3,4-dihydro-2 (1H) -quinazolinone hydrochloride, mp 193 ° C (decomposition); 1- (2 ', 2', 2'-trifluoroethyl) -4-phenyl-6-chloro-3,4-dihydro-2 (IH) -quinazolinone, mp 171.0 to 172.0 ° C; "l cyclopropylmethyl-4-cyclohexyl-6-ehlor-3,4-rdihydro-2 (lH) -quinazolinone, m.p. 176.5 to 177.5 ⁰ C; l-cyclopropylmethyl-4- (2'-pyridyl) -6 -chlor-5,4-dihydro-2 (-1H) -quinazolinone, F. 152.0 to 153.0 ⁰ C and l-cyclopropylmethyl - ^ - (2'-thienyl) -6-chloro-3,4- dihydro-2 (IH) -quinazolinone, F, 140.0 to 141, O ⁰ C.

109884/1891

Example 4

A mixture of 5.6 g of 2-cyclopropylmethylamino-5-chloro-benzhydrylamine dihydrochloride and 15 ml of triethylamine in 100 ml of benzene is added dropwise, with stirring, to 70 ml of a 10 percent strength Solution of phosgene in benzene added, the mixture with

the

Ice is cooled. After the addition is complete, the mixture is obtained Further stirred for JO minutes at room temperature. Afterward the solvent is distilled off to dryness under reduced pressure. The residue is diluted with 100 ml of a aqueous sodium carbonate solution and mixed with 100 ml of chloroform and thoroughly stirred. Thereafter, the chloroform layer is separated and the aqueous layer is extracted with chloroform. The combined chloroform layers are washed with water and dried over anhydrous sodium sulfate. After distilling off of the chloroform under reduced pressure, the residue is recrystallized from ethanol. The 1-cyclopropylmethyl-4-phenyl-6-chloro-3,4-dihydro-2 (1H) -ehlnazolinone obtained has a P. 166.0 to 167.0 ° C.

Example 5

A solution of 25.5 g of p-chloroaniline in 100 ml of benzene is made 8.15 g of 64 percent sodium hydride are added in portions. The mixture is refluxed for 2 hours and then cooled to room temperature. Thereafter, the mixture is 3.7 g Cyclopropylmethylbromid added. This mixture is refluxed for 9 hours. After cooling, the reaction mixture becomes washed with dilute hydrochloric acid and then with water and then dried over anhydrous sodium sulfate. ·

109884/1891

The solvent is distilled off under reduced pressure, whereby N-cyclopropylmethyl - ^ - chloroaniline is obtained.

A solution of N-cyclopropylmethyl - ^ - chloraniline in 150 ml Acetic acid is mixed with 15.0 g of sodium isoyanate. That The mixture is stirred for 20 hours at room temperature. The reaction mixture is poured into 700 ml of water and the mixture obtained is extracted with ether. The ether extract is washed with water and dried over anhydrous sodium sulfate. After distillation, Ren of the ether under reduced pressure, the oily brown residue is dissolved in einöm n-hexane-isopropyl ether mixture and cooled down. The precipitated crystals are filtered off, washed with an n-hexane-ether mixture and dried. It will 20.0 g of N-cyclopropylmethyl-N- (p-chlorophenyl) urea were obtained. After recrystallization from an ethanol-isopropyl ether mixture, colorless crystals with a P. 103.0 to 105.0 ° C. are obtained.

A mixture of 4.2 * g of N-cyclopropylmethyl-N- (p-chlorophenyl) urea, 2.0 g of benzaldehyde and 0.1 g of p-toluenesulfonic acid in 100 ml of anhydrous benzene is refluxed for 20 hours. After cooling, the reaction mixture is washed with water and dried over anhydrous sodium sulfate. To The solvent is distilled off under reduced pressure

the residue recrystallized from ethanol to give 1-cyclopropylmethyl-4-phenyl-6-chloro-3,4-dihydro-2 (lH) -chinazo3inon from P. 166.0 to 167, O C ⁰ is obtained.

109884/1891

Example 6

A solution of 2.9 g of 2- (2 ^! -Fithoxyäthylamino) -5-chlorobenzhydrol is mixed with 0.9 g of potassium isocyanate. The mixture is stirred and refluxed. After cooling, the reaction mixture is poured into water. The resulting mixture is extracted with chloroform. The chloroform extract is washed with dilute sodium hydroxide solution and then with water and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue is recrystallized from ethanol, and l- (2 ^- ethoxyethyl) - ¹ t-phenyl-6-chloro ^ ^J l-dihydro-2 (lH) -quinazolinone from j ?. 127.0 to 128.5 ° C is obtained.

Example 7

A solution of 5.0 S of 1-cyclopropylmethyl-6-chloro-2 (1H) -chynazolinone in 400 ml of anhydrous tetrahydrofuran, a solution of 50 ml of phenyllithium in ether is added. (The phenyllithium was obtained by reacting 25 * 0 g of bromobenzene and 2.1 g of lithium prepared in the usual way.) The resulting mixture is stirred at room temperature, then concentrated and then slowly mixed with cold water. The resulting mixture is extracted with chloroform. The chloroform extract is washed with water and dried over anhydrous Dried sodium sulfate. After the solvent has been distilled off under reduced pressure, the residue is extracted from ethanol recrystallized, whereby l-cyelopropylmethyl-H-phenyl-6-chloro-2,4-dihydro-2 (lH) -quin fizolinone at the front F. 165.0 to 166.0 ° C is obtained.

109884/189 1

Example

A solution of 1.62 g of l-cyclopropylmethyl ■ ^! J-phenyl-6-methoxy-3,4-dihydro-2 (1H) -quinazolinethione in 50 ml of methanol is treated with a solution of I ₃ 2 g of sodium hydroxide in 20 ml of water. The mixture is refluxed for 2 hours and then concentrated. Water is added to the residue. The deposited precipitate is filtered off, washed with water and dried, l-Cyclopropylmethyl - ^ - phenyl-ö-methoxy-2,4-dihydro-2 (1H) -quinazolinone from P. 136.0 to 1 ^ 7.0 ° C is obtained.

109884/1891

Claims (1)

Today patent application G 295 C "Chinazolinone, process: see below manufacturing and medicinal products" Sumitomo Chemical Company, Limited ,, ^ c _ Osaka / Japan Claims 9 1 * 3 Λ 1 IO 1. Quinazolinones of the general formula I. in which R ₁ and Rp are hydrogen or halogen atoms, lower alkyl,. Alkoxy, alkylthio or alkylsulfonyl radicals, nitro or trifluoromethyl groups, R is a radical of the general formula II is where R ₁ . represents a V / water or halogen atom, a lower alkyl or alkoxy radical or a trifluoromethyl group, or R represents a naphthyl group, a lower cycloalkyl radical, a lower cycloalkenyl radical, a pyridyl, pyridyl, thienyl or furyl group, R is a lower cycloalkyl radical, a trihalogeniethyl radical, a lower one Alkoxy, alkylthio or alkanoyloxy radical or a group of the general formula TIT. or IV ~ N <or - COM <^. ^R 6 ^ ^R 6 means in which Rp. and Rg represent lower alkyl radicals or R _c and R _r together with the nitrogen atom form an unsubstituted substance th or substituted 5- or 6-membered heterocyclic Form ring, which may contain a further nitrogen, oxygen or Contains sulfur atom, and η is an integer with a fourth from 1 to 3. .109884 / 1891 '- BAD ORIGINAL 2. quinazolinones according to claim 1, characterized in that R is a cyclopropyl, trifluoromethyl or trichloromethyl group or an alkoxy radical with 1 or 2 carbon atoms or η is an integer of 1 or 2. 109884/1891 ORIGINAL INSPECTED fc hm --- -If- J5. Process for the preparation of the quinazolinones according to claim 1, by rejecting either (a) a compound of the general formula V. in which R ₁ , Rp, R. ,, R and η have the above meaning, reduced or (b) a compound of the general formula VI in which H ₁ , R ₂ * R ^> R and η have the above meaning, with phosgene, Ν, Ν'-carbonyldiimida '/. ol or a lower halo GenarneisensäurealkylEster brings pder (c) a compound of the general formula VII R. H. in which R., R ₂ , R and η have the above meaning, with an aldehyde of the general formula VIII R, CHO (VIII) _{:> H1} 10 9 8 8 4/1891 BAD OBlOLNAl. In the R-, which has the preceding meaning, condensed, or (d) a compound of the general formula IX CO-Wf.-, in which R ₁ , R ₂ * R ,, R and η have the above meaning, heated or (e) a compound of the general formula X in which R ^, R ₂ , R and η have the above meaning with a compound of the general formula XI (XI) in the R-. has the above meaning and Y is a lithium atom or represents the remainder of MgCl =, MgBr or MgJ, "condenses and then subjected to hydrolysis or (f) a compound of the general formula XII 1 0988A / 189 1 - I ₉ - in which R ^, Rp, R ^, R und.η have the above meaning and X is a sulfur atom or an imino group which is subjected to hydrolysis. 109884/1891 H. Process according to claim 1, characterized in that the reduction is carried out with sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride or a mixed metal hydride or hydrogen in the presence of a hydrogenation catalyst. 5. The method according to claim jb, characterized in that the reaction in the presence of an inert solvent and fc of an acid reaceptor. G. Method according to claim 3c, characterized in that the reaction in the presence of an anhydrous inert solvent and catalytic amounts of a dehydrating agent Carries out means. 7 «Method according to claim 3d, characterized in that the reaction is carried out in the presence of an acid. δ. Method according to each claim, characterized in that the reaction is carried out in the presence of an anhydrous inert solvent. 9. The method according to claim Jf, characterized in that the hydrolysis in the presence of a solvent and a Acid or a base. 10. Medicinal preparations consisting of a quinazolinone according to claim 1 and customary carriers and / or excipients. 109884/1891