DD139715A1 - PROCESS FOR PREPARING 1-SUBSTITUTED 4-ARYL-S-TRIAZOLO (4,3-A) CHINAZOLONES (5) - Google Patents

Abstract

The invention relates to a process for the preparation of the abovementioned compounds of general formula I. The object of the invention is to prepare biologically active 1-substituted 4-aryl-s-triazolo (4,3-a) quinazolone- (5). According to the invention, the compounds are prepared by reacting 2-hydrazino-3-arylquinazolone- (4) with optionally activated Säurederivatan under oxidative cyclization or melting conditions or in organic solvents. The field of application of the invention is the pharmaceutical industry, - formula I.

Description

-Ί-

Title: '"Process for the preparation of 1-substituted

the invention

The invention relates to a process for the preparation of 1-substituted 4-aryl-s-triazoloC ^ - ^ - a ^ hinazolonen-C !?) of general formula I,

in which R ₁ = H, CH, OCH,

, F, Cl ₉ Br, J, and R _g β CH

- (CK) -COOC ₉ H ₁ . (η = 0-2), SH, OH, S-alkyl, SCS, aryl. The invention is applicable in the pharmaceutical industry »

Characteristic of the known technical solutions

It is well known that heterocyclic hydrazino compounds whose hydrazino nucleus is adjacent to the ring nitrogen atom react with various agents to join a 1,2,4-triazole ring (Houben-¥ eyl, Methoden der organischen Chemie, B. X / 2, Georg Thieme Verlag, Stuttgart 1967).

Some 1-substituted 4-aryl ~ s ~> triazolo (4,3-a) -quinazolone- (5) are known in the literature (N, N * ¥ ereschtschagina and I "Yes" Posstowski, Z, obsc "Chim J, 4, 1, 45 (1964), Kottke & _e H * Kiihmstedt, Pharmaceutics 3J, _9, 19, 124, 125, 462, 50 (19-8).

Thus, from the corresponding 2-hydrazino ~ 3-allyl ~, 3-phenyl ~ and 3-o ~ toiylchinazolones ~ (4) with orthoformic acid triethylester 4 ~ aryl (or ₀ 4 ~ allyl) -s-triazolo (4, 3-a) quinazolone- (5), with acetic anhydride 1-methyl-4-aryl (bzv / 4-allyl) -s-triazolo (4,3-a) quinazolone- (5) and with 1: 1 carbon monoxide. Mercapto-aryl (or _e 4-allyl) -s-triazolo (4,3-a) quinazolone "(5) herge"

Significant biological effects of these enumerated compounds are not known "It is further known from ^{2-hydrazino-3-a} llyl and 3- ⁱ z * ylchinazolonen- (4) with nitrous acid 4-" alkyl and ~ 4 ~ Aryltetrasolo (1, 5-a) quinazolones ~ (5) (H.Bowie, J _e M, Cox, G _e M _e Farrell and M »C _e Shephard, BRD-OS 2539396).

i o. υ U i ι. ί J fw · ^: ic ·, w ι. ί tf ·.,

3- ζ υ β 2

Object of the invention

The aim of the invention is to produce biologically active 1-substituted 4-aryl-s-triazolo (4,3-a) quinazolone- (5).

Explanation of the nature of the invention

According to the invention, compounds of the formula I are prepared by reacting 2-hydrazino-3-aryl-quinazolone- (4 ·) of the general formula II Q.

HH-HH ₁

R ₁ = H ₉ CH, OCH, OC ₂ H, F, Cl, Br, J denote with, if necessary,

activated acid derivatives of the formula

where X, Y, R

formic acid X = OH, Y _s O, (OC = H 2 · ^R 2 ⁼ H Orthoameisen- säuretriäthyl- ester X = OC ₂ H ₅ , V - = O  V, = CK Acetic anhydride X s OOC-CH 3 »Y ^! 2 = ^{9 E} 2 acetaldehyde X: = H, Y = Oj I CH ₃

Äcetylchlorid X s Cl ίϊ = O * ^ ₂ = CH ₃ benzoyl chloride X a Cl ; υ = 0, , R ₂ = ^c gV benzaldehyde X = H; Y s O; R ₂ = ^C 6 ^H 5 urea X, Rg = NHg, Y: = 0 Chlorine ants · »· Acid ethyl ester X a Cl, Y = O, R ₂ = OC ₂ H ₅ CSG = S ; υ = S Phenyl = S ; υ = ^C 6 ψ, - Malonic acid ethyl ester X = OCg H * Y: 2 = ( ^C «2> _n -C °° C ₂ H _{5 n = 0} _ ₂

mean, under oxidative cyclization or * melting conditions or in organic solvents, preferably under reflux conditions, implemented «

The compounds listed in Tab. 1 (I, R _? = H) are prepared by reacting the corresponding 2-hydrazino-3-arylquinazolones (4) with formic acid under reflux or else with triethyl orthoformate in a water bath.

The 1-ethyl-4-ariasol (A, 3-a) quinazolone- (5) (I, Rp = CH,), listed in Tables 2 and 3, are prepared by reaction of the corresponding 2-hydrazine O. "-3 ~ arylchinazolone- (4) with acetic anhydride and Äcetylchlorid produced" you can also by the oxidation of acetaldehyde 3-arylchinazoion -> (4 -) - yl - (-) - ~ hydrazones are made with lead tetraacetate _β

The reaction of hydrazino compounds with excess acetic anhydride is carried out at h A water bath temperature under reflux "The yields vary in the individual derivatives (Table" 2) _e proceeds with high yields, the reaction

ι η m ' ^v ' -Ό ι Ώ : '/! " \. {i '.; t /

  - 5. -

the Hydrazinoderivate with acetyl chloride in glacial acetic acid ^1/2 h under reflux (Tab. 2).

In the oxidation of acetaldehyde-3-aryl-quinazolone- (4) -yl- (2) -hydrazones with lead tetraacetate, the hydrazones are dissolved in glacial acetic acid and the lead tetraacetate is added at room temperature »The reaction mixture heats spontaneously, after cooling the methyltriazolo compounds fall into 60 ~ 70% yield (Table 3). The reaction of 2-hydrazino-3-arylquinazolone- (4) with benzoyl chloride in glacial acetic acid under reflux and the oxidation of benzaldehyde-3-arylquinazolone- (4) -yl are also successful - (2) -hydrazones with lead tetraacetate in glacial acetic acid to give 1,4-diaryl-triazolo (4,3-a) quinazolone- (5) (I, R ₂ = aryl, Tab, 3), The 1-hydroxy »4- aryl-s-triazolo (4,3-a) quinazolone- (5) (I, R ₂ = OH, Tab, 4 ·) v / earth by reacting the corresponding 2-hydrazino ~ 3 ~ arylchinazolone- (4 ·) with Urea at 1 ° -18 ° C. in the melt and with ethyl chloroformate in dioxane / sodium carbonate. The yields are good »

The ^ -aryl-i-athoxycarbonyimethyl-s-triazoles (4-, 3-a) quinazolones ~ (5) are obtained by reaction of the hydrazine derivatives with malonic acid ethyl ester under reflux (I, Rp-CH ₂ COOC ₂ H ₅ , Tab , 5), The "I-mercapto-A-aryl-s-triazolo (4,3-a) quinazolone- (5) (1, R ₂ = SH Tab.6) can be derived from the corresponding hydrazino compounds in alcohol-sodium hydroxide alkaline Prepare solution with carbon disulfide but also with carbon disulfide in pyridine under reflux in a water bath.

The compounds (I, Rp = SH) can also be prepared from the N, ₁ ~ (3-arylquinazolone- (4) -yl- (2)) - N, = phenylthi © semicarbazides. "The 2-kydrazino-3 ~ Arylchinazolone- (4-) reacted with phenyl isothiocyanate in ethanol under reflux to the Thiosemicarbazidderivaten (Tab.7), which after isolation by thermal cyclization at 14-0 C and Anilinabspaltung the compounds (I, Rp = SH) form. The compounds (I, R = SH) prepared according to the invention can then be further modified. They can be used directly to cyanogen bromide nascierendeci -1-thiocyanate-4-aryl-triazolo (4, 3-a) chinazclonen ~ (5) (I, Rp = SCN) cyanating _o Here

.kv / η

f. g ^ · Φ% ff em v & % «p

5, the mercaptans are dissolved or suspended with sodium cyanide in KBr-saturated methanol with stirring. With cooling on * ^ 5 C a solution of bromine is hinzugetsopft "The intermediate resulting Broracyan reacts with the likewise formed as intermediates Natriunmiercaptidea to the compounds (I, R = SCN) The compounds (I ₁ Rp = SH) react in Natriummethylatlosung with ethyl bromide under reflux to the corresponding 1-ethyl-mercapto-4-aryl-s-triaaolo (4,3-a) quinazolone- (5) s The compounds prepared according to the invention exhibit biological activity, in particular antianaphyic effects. For example, 1-hydroxy-4-m-bromophenyl-s-triazolo (4-, 3'-a -) - chiria-zolone ~ (5)

(I, R = m-Br, R_ = OH) at a single local dose of 3 · Ί0 mol / kg, an eternal 5O / 5 inhibition of rat passive cutaneous anaphylaxis «

The invention will now be explained in more detail by way of examples.

embodiments

1, 4-aryl-s-triazolo (4,3-a) quinazolone ^ 5)

a) 5g 2 ~ hydrazino-3-arylchinazolone- (4) are heated with 98 #iger Araeisensäure in excess (30 - 50 rai) for 2h under reflux »Then the reaction mixture is stirred into water» sucked the precipitated substance, washed with water and dried (Tab, 1),

b) 5 g of 2-hydrazino-3-arylquinazolone (4-) are refluxed with ethyl cetroformate (20 to 30 μl) in a water bath for 4 hours. The reaction mixture is mixed with 30 ml of methanol. After storage in the refrigerator, the precipitate is filtered off with suction Tab.1).

Table 1 4-Aryl-s-triazolo (4-, 3-a) china2olone- (5) (I, Rp = H)

M.p. (C) (solvent) Yield (%) formic acid Orthoironic acid ethyl ester H 325 - 328 (n ~ propanol) 86 83 o-CH - 238-240 (Lit.235-236) (ethanol) 76 45 P-CH ₃ - 335 - 339 (n-butanol) 95 90 0-F 206-208 (n-propanol) 63 57

Schmp, (C) (solvent)

Yield (, ft) of formic acid Orthotric acid triethyl ester 74 62 88 76 95 80 90 85 96 86 58 60 93 89 92 90 67 90 57 79 89 84

m ~ F-p-F-o-Cl-m-Cl-Clo-.P-Br-K-Brp-Br

o-CH 0 m-CH 0

P-CHO

263-266 (n-Bu tanol)

318 - 322 (n-butanol)

225-230 (n-propanol)

268-271 (n-butanol)

285 - 290 (glacial acetic acid)

260 - 265 (glacial acetic acid)

280-285 (n-butanol)

301-305 (n-butanol)

205-209 (n-propanol)

223 - 225 (ethanol)

300 - 302 (ethanol)

2 β 1rSubstituted _i -4 ~ aryl-s-triazolo (4 _g 3'-a) quinagiolone (5.) (I, R ₂ = CH, aryl)

Implementation; with acetic anhydride

a) 0.01 Hol 2-hydrazino-3-arylquinazolone- (4) are heated with excess acetic anhydride for 4- h on your water bath under reflux then the Reaktionsgernisch is mixed with methanol and evaporated to dryness (Tab.2) _e

bjl_ Reaction with acid chlorides 0.005 H 2-hydrazino-3-arylquinazolone- (4) are dissolved in 20% glacial acetic acid and refluxed with 0.005 mol of acid chloride (acetyl chloride or * or benzotrichloride) for 30 min. 0025 mol of acid chloride added »The reaction mixture is then added to ice-water, and the precipitated substance xärd aspirated (Tab. 2 and 3);

c) Reaction of Ifydrazones with Lead Tetraacetate 0.01 mol of hydrazone is dissolved in anhydrous acetic acid and admixed with 0.015 mol of lead tetraacetate. On cooling, the reaction products crystallize out as white crystals (Table 3).

Table 2; 1-methyl-4-aryl-s-triazolo (4,3-a) quinazolone (5) (I, R ₂ = CH ₃ , aryl)

Schrap.CC) Yield (%) (n-butanol) acetic acid

anhydride (a) acetyl chloride (b) (A) 93 (a) (b) 60 90 (A) 90 Ca) 61 Ca) / 84 Ca) 81 (a) (b) 53 90

H 317-318

m ~ CH 27A- - 277

P-CH ₃ 333-337

0-CH ₃ O 323-325

Egg CH 0 265-266

P-CK 0 308-310

o-COTCO. 262-265

L · ν ο £> ^ *

- ίο -

Y Mp _e (C) (nB-utanol) Yield (#) Acetic anhydride (a) Acetyl chloride (b) EC ₂ H ₅ O 28Q - 284 46 (a) 85 Cb) o-F 257 -. 258 62 (a) 90 (b) m-F 314 - 316 36 (a) 88 (b) p-F 292-295 76 (a) o ~ Cl 205-210 76 (a) E-Cl , 252 - 253 64 (a) 90 (b) P-Cl 338-340 98 (a) 90 (b) o-Br 296 - 301 40 (a) 85 Cb) m-Br 208-210 56 (a) 90 (b) p-Br 342 - 345 70 (a) 90 (b) p ~ J 310 - 314 80 Ca)

Table 3

R ¹ R ² yield (JS) mp. ( ⁰ C)

(N-butanol)

P-Br CH ⁺⁺ 72 (a) + cf. Table 2

P-Cl ^c c ^H c ⁺⁺ + 47 (a) 263-266

, ^ 60 (b) +

P-Cl P-Cl-C ₆ H ^ ++++ 70 (a) 254 · 258

p-Br P-Cl-C ₆ H ₄ ++++ 40 (a) 248-253

+ (a) oxidation of hydrazones with lead tetraacetate; Ob) 'reacting the hydrazino compound with benzoyl chloride ++ acetaldehyde (3 ~ p-bromphenylchinazolon - (4 -) - yl- (2) hydrazone: mp. 219-221 ⁰ C, yield: 88%

Bonsai dehyd- (3 - p-bromphenylchinazolon- (4 -) - yl- (2) -hydrason. Mp 258-262 ⁰ C, yield: 72 ^c, i

p "Chlorbenzaldehyd- (3" -p ~ broraphenylehinazolon- (4) 'yl ~ (2) "hydrazone: Schrap": 295-299 ⁰ C, yield: OJ5

3 x 4-aryl-1-hydroxy-s-triazipo (4,3a) china2olone (

a) 0.01 mol of 2-hydrazino-3-arylquinazolone (4) are triturated with 0.03 mol of urea. The mixture is heated to 170-18O ⁰ C for 2 h. The reaction product is dissolved in NaOH, possibly with the addition of C_H OH, the solution is filtered and acidified with HCl. The precipitate is filtered off with suction, washed with H ₃ O and dried,

b) 0.01 mol of 2-Hydraüino ~ 3-arylchinazoloh- (4) in 20 ml of dioxane with 0.05 mol of ethyl chloroformate and 0.02 mol of Na ^ Cö- 8 h in a water bath under reflux for reaction The reaction solution is allowed The work-up of the residue is carried out as described under a) (Tab _e 4-) _e

4'-1-yl -oxycarbonyl-diethyl-4'-aryl-s-triazo- lo (4,3-a) china zolone- (5) (I, R ₂ = 'CH

5 g 2 ~ hydrazino-3 "~ ^ar ylchinazolon- (4) are heated with diethyl malonate in excess 6 h at 1ÖO-18O ° C under reflux. After cooling, admixing the reaction mixture with CH_OH and the precipitate is suctioned off (Table 5 )

Table 4: 1-Hydroxy- 4-aryl-s-triazolo (4 *, 3-a) quinolone- (5) (I, E

p-Cl o -Br n -Br p -Br

Melting point (solvent) (C) Yield (%) 316 - 321 (n-butanol) 82 345 - 349 (ethanol) 90 312-315 (n-butanol) 80 323 - 328 (n-butanol) 85 329 - 333 (n-butanol) 94 29? - 301 (glacial acetic acid) 73 338 - 343 (glacial acetic acid) 86 > 330 (glacial acetic acid) 75 312-316 (n-butanol) 90 ^! 339 - 345 (glacial acetic acid) 85 347 - 349 (glacial acetic acid) 70

Q YHr; 137i ^ VO ^ o, k. <

R melting point yield (? Ί)

(Solvents C)

o-CHO 300 - 304 ·

*. (Ethanol)

M-CHO 299-305

* (Ethanol)

P-CH 0 312-315

* (Ethanol)

Table 3 '· 1 ~ 4 * Äthoxycarbonylmethyl-aryl ~ s-triazolo (4 _<3-a) ⁱ chinazolone- (5) (I ₁ R ₂ = CH ₂

Melting point (solvent) (C) Yield (#) 219 - 222 (n-butanol) 71 252 - 258 (methanol) 40 239 - 242 (glacial acetic acid) 85 278-286 Zers _e . (N-Propanol) 20 198-204 (n ~ propanol) 95 233 - 23? (N-butanol) 94 360 Zers, (n-butanol) 39 220 - 223 (n-butanol) 49

1B-CH ₃ O

p-CH 0

Melting point yield

(Solvent) (° C)

P-P 232 - 237 64

(N-.Butanol)

m-Br 219 - 222 50

(Methanol)

p-Br 225-228 95

.- (n ~ butanol)

_5> ^ - _i Ar _i Yl-1- »me rcapto-s ^ triagolo (4, 3-- a) china2olone- (5.) ._, (I _i, Rp.

a) 0.01 mol of 2-hydrazino-3 ~ a.i'yl-quinazolone- (4) (2) is dissolved in 40 ml of pyridine and 10 ml of CS _? given. The yellow solution is refluxed in a water bath for 3 h. The cooled reaction solution is poured into 1 1 of ice water, the precipitate is sucked off, with H _? 0 washed and dried (Tab.6).

b) 0.01 mol of 2-hydrazino-3-aryl-quinazolone (4), 0.4 g of NaOH, 20 ml of C ₅ H OH and 30 ml of CS_ are reacted in a water bath for 2 h at reflux. Subsequently, with H _? 0 diluted, acidified, dia precipitated substance sucked off, with H _? 0 washed and dried (Tab, 6).

Table 6: 4 ~ Ar: _v d-5-oxo "1 ~ thioxo ~ 1.2.4 ₀ 5-tetrahydro-s-tria zplo j (4, 3-a) quinazol i ne (4 ~ aryl-1! nercapto-s-triazolo ( ^/ i, 3-a) china, olone- (5)) (1, R ₂

^R 1 Melting point (solvent) (C) Yield (f *) H 310 - 315 (n-propanol) 94 m-CH 308-311 (n-butanol) 98 P-CH ₃ > 3OO Zers, (pyridine / methanol) 83 P-F 3.25 - 328 (ethanol) 83 B-F 305-310 (pyridine / methanol) 88 p ~ P 321-326 (n-butanol) 78 o-Cl 224- ~ 227 (glacial acetic acid) 63 m-Cl 197-201 (n-propanol) 65 P-Cl 322 - 324- (ethanol) 68 o-Br 207 - 212 (n-butanol) 83 m-Br 308-312 (n-butanol) 89 p "Br 315 - 321 (glacial acetic acid) V5 o-CH 0 305-310 (n-butanol) 78 m -CH _o 0 312 ~ 314 · (Fisetig) 76

~ 16 c) Preparation of N - (3-arylquinazolone- (4) -yl- (2)) - N.-

phenylthiosemicarbazide

0.01 mol of 2-hydrazino-3-aryl-quinazolone (4) is reacted with 1.4 g of phenyl isothiocyanate in 100 ml of ^C ₂ ^H ₅ ^OH 1 under reflux for reaction. The mixture is allowed to cool and the precipitate is filtered off with suction (Tab. ) · The compounds listed in Tab «7 are heated in a metal bath at 140 - 150 C until the aniline elimination is complete. The corresponding compounds of Tab, 6 are formed. Yields: 50-60- / 5.

Table 7: N, .- (3-Arylquinazolone- (4-) - yl- (2)) -N, -phenylthiosemi-

carbazides

^R 1 melting point H 303-307 (n-butanol) 0-CH ₃ 286-291 (n-butanol) P-CH ₃ 312-315 (n-butanol) P-Br 329 - 332 (n-butanol) o -Cl. 270-274 (n-butanol) ci-Cl 313 ~ 317 (n-butanol) p-Cl ' 315-320 (n-butanol) 0-CH ₃ O : 288-294 (n ~ propanol) B-CH 0 285 - 290 (n-propanol) P-CH ₃ O 330 - 336 (n ~ butanol)

62 58 80 60 71 52 47 82

58 67

J l \\. '

6. 4-phenyl-1-rhodan-s-triazolo (4 ₊ 3-a) quinazolone (5) (I, R ₂ =

0.01 mol of i-M

is dissolved or "suspended" with 2 g of sodium cyanide in 50 ml of KBr-saturated methanol with stirring. After cooling to -5 C, 0.9 b * 1 of bromine are added dropwise with stirring. Subsequently, the reaction mixture is added to water.

Pale yellow crystals, mp: 230-233 ° (Sers', n-butanol) Yield: 60 %

C ₁₆ H ₉ N ₅ OS (319.3)

Her: K 21,93

Gef .: N 21.81

zolon- (5) (I, R ₂ = SC ₂ H)

0.02 mole of 4-4 ^{t of} fluorophenyl 1-niercapto-s-triazolo (4,3-a) quinazolone (5) are dissolved in I50 of the CH_ONa solution (0.5 g of Na in 150 mL of CH OH) , After addition of 2 g of C Fi Br, the reaction mixture is refluxed for 2 h in a water bath. »The mixture is allowed to crystallize out in the cold *

Yield: 55 ? >, Melting point 238 - 242 ⁰ C (n-butanol). C ₁₇ H ₁₃ FN ^ OSC 340.4 ·) Calc .: N 16.4-6 Found: N 16.40

Ausführungsb EISP iel 8

In rats antianaphylactic effects are found for the compounds I (testing by known methods). In passive cutaneous anaphylaxis (PCA). IgE-containing antiserum and after 48 hours latency, the corresponding antigen cormatting be applied. The leakage of intravenously-labeled dye in the region of the antigen-antibody reaction indicative of the increased capillary permeability as a result of the immunologically-induced mediator release is suppressed by Compound I.

This leads, for example, to a dose-dependent inhibition of PCA in the case of a single local application of 1-hydroxy-4-m-bromophenyl-s-triazolo (4,3-a) quinazolone (5):

3 * 10 ~ ⁵ mol / kg 50%

3 x 10 ^"6 mol / kg 26% *

3 x 10 ~ ⁷ mol Ag 10%

If the substance is given orally, a ca 20% inhibition of the PCA is to be determined at 5 x 10 -10 mol / kg after a 1-hour exposure.

Suppression of histamine release by substances I is also achieved in passive peritoneal anaphylaxis (PPA). Here, the IgE-containing antiserum is administered intraperitoneally, after a latency period of 2 hours the dye is administered intravenously and immediately thereafter the substance I to be tested and the antigen intraperitoneally After a reasonable time, after the abdominal cavity has been opened, the peritoneal fluid is aspirated off and the dye output is determined spectrophotometrically. By 1-hydroxy-4-m-bromophenyl-striazolo (4,3 - a) -quinazolone- (5) in a concentration of 1 x 10 -9 mol / kg, a 50% suppression of Kistaminfreisetzung is achieved.

In vitro, these substances are also active, as can be determined by measuring the suppression of histamine release from isolated rat mast cells. "

Claims (1)

2 08 205 Claim for invention A process for the preparation of 4- ~ aryl-s-triazolo (4-, 3-a) china ~ zolonen- (5) of general formula I. in the R ^ s H, CH, OCH OCgH, F ₁ -Cl ₁ Br, J = .Η * * CH ₃ , - (CHg) _n - COOC ₂ H ₅ (n = 0-2), OH, SH, - S-alkyl-, SCIi, aryl, d »d» k ,, that ^ - = hydrazino-3 "-arylchina2olone- (4) of the general Forrael II in the E ₁ = H, CH ₃ , OCH ₃ , ₂ H ₅ , F, CJL, Br, J, with optionally activated acid derivatives of the formula in which
χ H _r (CH ₉ ) -COOCpH (dicarboxylic acid-η = 0-2 diethyl) CGH _r (benzaldehyde) under oxidative cyclization under sulfuric or organic solvents, preferably under reflux conditions.