FI64161B - SUBSTITUTES 5-PHENYL-THIENO- (2,3-E) -1,4-OXAZEPINONE- (1) -ER SOM AER MELLAN PRODUCTS WITH FRAMSTATING OF PHARMACOLOGICAL PROPERTIES 6-PHENYL-4H-S-TRIAZOLO- (3,4-C ) -TIENO- (2,3-E) -1,4-IAZEPINE SAMT FOERFARANDE FOER DERAS FRAMSTAELLNING - Google Patents

Description

[B] ANNOUNCEMENT

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Federal Republic of Germany-Förbundsrepuhliken Tyskland (DE) P 2531677-2 (71) C.ii. Boehringer Sohn, D-Ö5C7 Ingelheim am Rhein, Federal Republic of Germany Förbundsrepubliken Tyskland (DE) v72) Karl-Heinz Weber, Gau-Algeshoim, Adolf Langbein, Ingelheim / Rhein,

Adolf Bauer, Ingelheim / Rhein, Federal Republic of Germany-Förbunds-republiken riyskland (DE) (7'0 Leitzinger Oy (5 ^ +) new substituted 5-phenyl-thieno- [2,3-e. - (1) - which are intermediates in the preparation of pharmacologically valuable 6-phenyl-1 + Hs-triazolo - [3,1 + -e] -thieno- [2,3-e] -diazepine and a process for their preparation - · This substituent is 5 "phenyl-thieno - [2,3-e] -1, L-oxazepinone- (1) -er, which is a product of the pharmacologically active 6-phenyl-i * Hs-triazolo- / 3, ^ _ c / - thieno - / '2,3 ~ e / -1, i-diazepine as described above for the preparation

The present invention relates to novel substituted 5-phenyl-thieno [2,3-e] -1,4-oxazepinones (1), which are intermediates in the preparation of pharmacologically valuable 6-phenyl-4H-s-triazolo [3,4-b] cJ-thieno-C2,3-eJ-1,4-diazepine and a process for the preparation of these new compounds.

The compounds of the invention have the formula I

H ^ 0 'W S N - C C.

I_1 = H2 R1 ^ CH - O '^ containing hydrogen, halogen or lower alkyl having .1-2 carbon atoms, 2,641 61

R 1 is hydrogen or forms a 6-membered ring on the alkyl chain with ** 1, and and which may be the same or different represent hydrogen, fluorine, chlorine or bromine.

A conventional way to prepare thieno-triazolol-diazepine is to use 2-haloacetylamino-3-benzoyl-thiophene as starting material. In this method, the corresponding amine is prepared first, then the ring is closed to a diazepine, the carbonyl function is activated, the compound is reacted with a hydrazine derivative to give the final product (DAS 24 10 030). Although there are two fewer steps in this synthesis than in the process of the present invention, the latter process yields almost twice as much as known processes. It has now surprisingly been found that if ring closure occurs in the oxazepine molecule, apparently for sterile reasons, the reaction proceeds spontaneously and almost quantitatively, whereas the corresponding reaction in the diazepine molecule requires longer treatment, most often with heating. The new method thus gives a yield almost twice as high as the known methods.

According to the invention, novel thieno-1,4-oxazepines of the general formula I can be obtained by reacting a compound of the general formula II

B

R 3 s N - CO - CH 2 -X

RX-X, m R 2 C = 0 641 61 3 in which the groups - R 1 have the same meaning as above, and X is a halogen atom, reduced with sodium borohydride in dimethylformamide or dimethylacetamide at temperatures between 0 and + 10 ° C to the corresponding carbinol of formula III

B

R,. _ - CO - CH- - X

iV / S 2

J-J

R2 ^ CH - OH

R4 R3

XX

wherein the groups R 1 - R 2 and X have the same meaning as above and the carbinol is treated with suitable ring closures such as sodium isopropylate or sodium t-butylate. Surprisingly, there is hardly any reductive cleavage of the group X or hydrolytic cleavage of the group - CO - CH2 - X, while in other solvents, for example in a lower alcohol, the cleavage reactions overcome the formation of carbinol.

The following reaction scheme illustrates the use of intermediates of the invention in the preparation of known 4H-s-triazolo [3,4-c] -thieno-t2,3-eJ-1,4-diazepines.

64161 * 4

B

R, S N-CO-CHo-X

TT

r2 ^ ^ r = 0 wXXi *, Λ JL Rl s N-C "'tr" XX / ¾ R2 ^ ^ CH — 0 R5 ~ X |] - Ri *

R., S N C ^ 5 ^ I

XX X

R2 ^ ^ CH-O ^ j T ^ T4 R1> -vN _c ^ li / ** IV R2 ^ ^ CH - </ R5-ArR4 * 0 XX ^ v r3- \ x

Ri χ-, ^ I T Λ X! \ R ^ CH — N R3 “Cv n * I H r \ / y JL R1 S N — c

T - ^ 2¾¾. I | V

| j

VII

vi 5 64161

A detour via a functional derivative of an aminoketone of formula I proved necessary in the present case because it surprisingly proved that, in contrast to readily reducing 2-aminobenzophenones (see for example DOS 15 45 639), the corresponding 2-aminobenzoylthiophenes cannot be reduced directly to carbinols.

The carbinols III obtained as described above, in contrast to the hydrolysable ketone compounds II, are surprisingly very stable against alkalis. This is a prerequisite for the high yields obtained in the described sodium borohydride reduction.

The reduction of the carbinol III ring to the oxazepine of formula I associated with the reduction is performed with a suitable alkali alcoholate or sodium hydride; sodium isopropylate and sodium t-butylate are best used to seal the ring. As the solvent, alcohols, tetrahydrofuran, dioxane, dimethylformamide or inert solvents such as benzenes and its homologues can be used. The reaction temperature depends on the starting material used in each case and is between 0 ° C and the boiling point of the solvent used in each case.

The starting materials of the general formula II are known from the literature and can be prepared, for example, by the following method: Monatscheften der Chemie, Band 104, page 704 (1973).

The final products of general formula I are valuable intermediates in the preparation of tranquilizing and enticonvulsively effective substituted thieno-triazolo-1,4-diazepines. Such compounds are described in German patent publications (German patent applications P 24 10 030, P 24 35 041, P 24 45 430, P 24 60 776) and in DOS 2,229,845.

These compounds are obtained from an intermediate of formula IV by reaction with a carboxylic acid hydrazide to give the corresponding thieno [2,3-e] -triazolo [3,4-c] -1,4-oxazepine, opening the oxazepine ring with hydrohalic acids, converting the resulting 4-t3 -phenyl-halomethyl) -thienyl- (2) -5-6 641 61 hydroxymethyl-1,2,4-triazole to the corresponding 5-halomethyl compound, by closing the ring with ammonia and dehydrating.

The compounds disclosed in said patents have been shown to be effective as anxiolytic, stress-relieving and muscle relaxant agents using various pharmacological test methods and, in addition, have a strong anticonvulsant effect. In addition, they significantly increase feed consumption in mammals. In addition, their very low toxicity is noteworthy.

The following examples illustrate the invention:

Example 1 5- (o-Chlorophenyl) -thieno-C2,3-e1,4-oxazepinone- (1) a) 2-chloroacetylamino-3- [(o-chlorophenyl) -hydroxymethyl] thiophene 1 mol = 314 g 2-Chloroacetylamino-3- (o-chlorobenzoyl) -thiophene is dissolved in 500% dimethylformamide and 36 g of ground sodium borohydride are added over 1 hour with stirring at 0 ° C.

It is then poured into 2 liters of ice water to form an oily precipitate. The aqueous phase is separated by decantation, the oil is washed 2-3 times with water and taken up in methylene chloride. After drying and evaporation of the methylene chloride phase, 300 g of oil are obtained, which gradually solidifies and recrystallizes from methanol-ether. 253 g (80.1% of theory) of the title compound are obtained, melting point 118-120 ° C. Oil can also be used directly to close the tire.

b) 0.08 mol = 253 g of 2-chloroacetylamino-3- (o-chlorophenyl) hydroxymethyl) thiophene dissolved in 200 ml of isopropanol are added to a boiling solution containing 52 g (2.25 mol) of sodium and 1.8 liters of isopropanol, and boil at reflux for 5 minutes.

I.

641 61 7

The brownish suspension is then poured into 1.5 liters of ice water and acidified with concentrated hydrochloric acid. The precipitated crystals are filtered off with suction and washed with water. The wet residue is then dissolved in 2 liters of methylene chloride, dried over magnesium sulphate, evaporated and the residue is recrystallized from methanol.

140 g (62% of theory) of the title compound are obtained, m.p. 175-176 ° C.

Example 2 7-Bromo-5- (o-chlorophenyl) -thieno-C2,3-e3-1,4-oxazepinone 0.1 mol = 27.9 g of 5- (o-chlorophenyl) -thieno [2,3-g] -eJ-1,4-oxazepinone- (1) is dissolved in a mixture of 300 ml of chloroform and 8.5 ml of pyridine. A solution of 5.5 ml of bromine in 50 ml of chloroform is added over 10 to 15 minutes at room temperature. The color disappears immediately. The title compound precipitates, is filtered off with suction and washed with ether. The yield is 30 g (83% of theory), m.p. 178-180 ° C (decomposes)

By reduction and closure of the ring according to Example 1 and optionally Example 2, the following final products were further prepared via the corresponding carbinols: R 1 R 2 R 3 R 4 Sp. ° C M.p. ° C Ex.

____________carbinol_ C2H5 H Cl H 148-150 oil 1 CH2 CH2 Cl H 263-264 192-194 1 NCH2 - CH2 H H Br H 168-170 Oil 1

Br H Br H 176 (dec.) Oil 2

Cl H Cl H 223-225 oil 2

Br H PH 145-150 oil 2 (dec.)

Br H Cl Cl 180-182 Oil 2

The preparation of therapeutically valuable 6-phenyl-4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepines is described in more detail in the following examples: 8 64161

Example 3 8-Bromo-6- (o-chlorophenyl) -1-methyl-4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepine ____ a) 0 , 1 mole = 35.8 g of 7-bromo-5- (O-chlorophenyl) -thieno- [2,3-e] -1,4-oxazepinone, 350 ml of diglyme, 24 g of 2 ^ 5 3a ^ 9 g The MaHCO 3 is heated together for 30 minutes at 60 ° C. The mixture is then poured into about 1 liter of ice water to form a crystalline precipitate which is filtered off with suction, washed with water and dried. 37 g or 99% of theory of 7-bromo-5- (o-chlorophenyl) -thieno [2,3-e] -4,1-oxazepine-2-thione are obtained, m.p. From 200 ° C (decomposes).

b) 0.1 mol = 37.5 g of 7-bromo- (o-chlorophenyl) -thieno [2,3-e] -1,4-oxazepin-2-thione are dissolved in 370 ml of tetrahydrofuran and 10 ml are added. of hydrazine hydrate. The reaction stops after 5 minutes at room temperature. The solution is evaporated, the residue is taken up in 200 ml of ethanol and 50 ml of o-acetic acid triethyl ester are added. Boil for 30 minutes at reflux, evaporate in vacuo and crystallize the residue from ether.

Yield of 8-bromo-6- (o-chlorophenyl) -1-methyl-thieno [2,3-e] -triazolo [3,4-c] -1,4-oxazepine: 34.5 g = 87% of theory, m.p. 146-148 ° C.

c) 0.1 mol = 39.6 g of 8-bromo-6- (o-chlorophenyl) -1-methyl-thieno [2,3-e] triazolo [3,4-c] -1, 4-oxazepine, m.p. 146 DEG-148 DEG C., suspended in 250 ml of concentrated hydrobromic acid. As soon as a clear solution is obtained (after 15 to 20 minutes), dilute with 300 ml of ice water and shake with methylene chloride. The methylene chloride phase is dried and evaporated. The residue is crystallized from ether. 52 g of 3-methyl-4- [3- (o-chlorophenyl-bromoethyl)] - 5-bromothienyl- (2) -5-hydroxymethyl-1,2,4-triazole hydrobromide (94% of theory) are obtained. , sp. 200 ° C (decomposes).

9 64161 d) 0.05 mol = 27.9 hydrobromide is stirred together with 110 ml of thionyl chloride for 30 minutes at room temperature. The excess thionyl chloride was then distilled off in vacuo, the residue taken up in methylene chloride and washed with ice water and dilute ammonia. The dried methylene chloride phase is evaporated and the residue is triturated with ether. Yield: 24.2 g of 3-methyl-4-C3-Co-chlorophenyl-bromomethyl) -5-bromothienyl (2) -5-chloromethyl-1,2,4-triazole, m.p. 167-169 ° C.

e) 12.4 g of this compound are dissolved in 270 parts of methanol and 100 ml of liquid ammonia are added. It is then heated for 30 minutes at 100 ° C in an autoclave. The reaction mixture is evaporated, the residue is taken up in methylene chloride, washed with water, the methylene chloride phase is dried, evaporated and the residue is recrystallized from methanol. Yield of 8-chromo-6- (o-chlorophenyl) -1-methyl-thieno [2,3-d] triazolo [1,4-c] -5,6-dihydro-1,4-diazepine: 9 , 0 g = 91% of theory,

Sp. 160-162 ° C.

f) 39.5 g = 0.1 mol of 8-bromo-6- (o-chlorophenyl) -1-methyl-4H-s-triazolo-C3,4-cJ-thieno [2,3-d] 5 , 6-dihydro-1,4-diazepine, m.p. 162 ° C, is dissolved in a mixture of 500 ml of methylene chloride and 15 ml of pyridine, and a solution of 10 ml of bromine in 50 ml of methylene chloride is added to the solution over 10 minutes with stirring at room temperature. The solution, from which the color disappears immediately, is stirred for 30 minutes, then shaken several times with water, dried, evaporated and the residue is recrystallized from ethanol. Yield of 8-bromo-6- (o-chlorophenyl) -1-methyl-4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepine: 36.9 g = 94 % of theoretical, Sp. 208-210 ° C.

Claims (2)

64161 ίο Novel substituted 5-phenyl-thieno-C2,3-eJ-1,4-oxazepinones (1), which are intermediates in the preparation of pharmacologically valuable 6-phenyl-4H-s-triazolo-3,4-cJ -thieno-? 2,3-eJ-1,4-diazepine, characterized in that the compounds have the formula 1H o Ri s. N - c ^ TY R, ^ - \ / (I) 2 CH - O XX ”wherein R 1 is hydrogen, halogen or lower alkyl of 1-2 carbon atoms, R 2 is hydrogen or forms a 6-membered ring with R 1 to form an alkylene chain, and R 1 and R 4 which may be be the same or different, mean hydrogen, fluorine, chlorine or bromine. Process for the preparation of novel thieno-1,4-oxazepines according to Claim 1, characterized in that the compound of the general formula II H R 1 v / N - c ° - ch 2 - X XY * 2 ^ N: = O j (II) wherein the groups R 1 - R 2 have the same meaning as above, X is a halogen atom, reduced with sodium borohydride in dimethylformamide or dimethylacetamide at temperatures between 0 and + 10 ° C to the corresponding carbinol of formula III 11 64161 H ~ XTT r / X m)