PL97275B1 - METHOD OF MAKING NEW DERIVATIVES OF THENOTRIIAZOLODUAZEPINE - Google Patents

Description

The subject of the invention is a process for the preparation of new thienotriazole diazepine derivatives of the general formula I, in which Ri is a halogen atom, R2 is a phenyl radical, o-trifluoromethylphenyl, o-halophenyl, o, o'-dihalophenyl, o-nitrophenyl or pyridyl, R3 represents a hydrogen atom, an alkyl radical, a hydroxyalkyl group, an alkoxycarbonyl group, a haloalkyl group, an alkoxyalkyl group, an alkylthioalkyl group, an alkoxycarbonylalkyl group, or an e-alkyl-Z group, in which Z represents a group of formula 3, and R4 and R5 independently represent a hydrogen atom or an alkyl radical, or also taken together with the nitrogen atom to denote a monocircle saturated 5-6 membered heterocyclic ring of at most one further nitrogen or oxygen atoms, optionally in the form of their acid addition salts. The term "alkyl radical" as used in this specification, alone or in in combination as in a hydroxyalkyl group, means a straight-chained or branched hydrocarbon radical with 1-4 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, tertiary butyl or the like. The expression "halogen" denotes an atom of one of the four elements bromine, chlorine, fluorine or iodine. The expression "alkoxy" denotes an oxygen-functional alkyl radical, such as, for example, methoxy, ethoxy, propoxy or the like. In the class of compounds of formula I indicated, Rt is halogen, with chlorine being particularly preferred, R2 is preferably E-o-halophenyl, o, o-dihalophenyl or 2-pyridyl group. For R2 in the meaning of the o-halophenyl group, fluorine or chlorine atoms are preferred as halogen atoms. In the case where R2 is present in the meaning of the 0.0-dihalophenyl group, They are preferably two halogen atoms that are the same, in particular two fluorine atoms. A preferred meaning of R3 is an alkyl radical, a hydroxyalkyl group and an aminoalkyl group. As is apparent from the above in the compounds of formula I, Ri is particularly preferably a chlorine atom, R2 is a group o- chlorophenyl or o-fluorophenyl, and R3 is an aminoalkyl group. A particularly preferred compound is 2-chloro-4- (o-chlorophenyl) -9-aminoethyl-6H-thieno [3,2-f] * s-triazolo [4, 3 -a] -f1,4] diazepine Further representative compounds of formula I sa: 2 97 275 2-chforo-4- (o-chlorophyl) "9-methyl-6H-thieno [3,2-f] -s oxide -triazolo [4,3-a] [1,4] diazepine, 2-Chlaro-4- {o-chlorophenyio) -9-methyl-6H- thieno [3,2-f] -s- acid ethyl ester triazolo [4,3-a] [1,4] diarepinino-6-carboxylic, 2-ch-oro-9-methyl-4- (2-pyridyl) -6H-thieno [3,2-f] -s -triazolo [4,3-a] [1,4] diazepine, 2-chloro-9-methyl-4- {o-nitrophenyl-4- {o-nitrophenyl] -6H-teno [3,2-f] -s-triazolo [4/3-a ] [1/4] diazepine, 2-chloro-9-methyl-4-f8nyl, H -thieno [3,2-f] - α-triazolo [4,3-a] [M] diazepine, 2-chloro4- ( 'fluorophenyl) -9-methyl! o-6H-thieno [3,2-f] -s-triazolo [4,3-a] [1,4] diazepine, 2-chloro-4- (o, o'- difluoro) -9-methyl-6H-oxygen [3,2-f] -s-triazoio [4,3-a] [1,4] diazepine, 9-yl.pre-butyio-2-chJoro4- (o- chlorophenyl) -6H-thieno [3,2-tnazolo [4,3-a] [1,4] diazepine, 2-chloro-4- (o-chlorophenyl) -9-methylthiomethyl-6H-thieno [3 , 2-f] -s-triazolo [4,3-aj [1,4] diazepine, 2-collection * 4- (o-chlorophenes! O) -9-morpholinomethyl-6H-thieno [3,2-f] -s- triazolo [4,3-a] [1A] diazepine, 2 "Chloro4- (o-chlorophenyl} 9 * methoxymethyl-6H-thieno (3,2-f] -s-triazolo [4,3-a] [1 A] diazepine, 2-chloro-4- (o-chlorophenyl) -9-hydroxymethyl-6H-thieno [3,2-fj-s-triazo [4,3-a] [1,4] diazepine, 2-chloro -4-tochiordphenyl) -9-dimethylaminomethyl-6H-thieno [3,2-f] * - triazolo [4,3-a] [1,4] diazepine, 2-chloro-9-chlorom8tylO "4- (o- chlorophenyl) -6H-thieno [3,2'f] -s-triazolo [4,3-a] [1,4j diazepine, [2 * chloro-4- (o-chlorophenyl) -6H-thieno [3, 2-f] -s-triazolo [4,3-f] [1,4] diazepin-O-yl] -methyl, 2-chloro-4 * (o-chlorophenyio) -9- (1-hydroxyethyl) - 6H-thieno [3,2-f] -f-triazolo [4,3-a] [1,4-diazepine, 2-chloro-4- (o-chlorophenyl) -9-iodomethio-6H-thieno [3.2 -f] - α-triazolo [4,3-a] [M] diazepine, 2-chloro-9-ethoxymethyl Q4- (nitrophenyl) * 6H-thie4 [2-Chloro-4- (o-nitrophenyl) acid ethyl ester -6H-thieno [3,2-f] -s-triazolo [4,3-a] [1,4] 9-yl] -carboxy diasepin, 2-chloro-9 2-chloro-9'-methyl4- (o- trifluoromethics! -phenyl) -6H-thieno [3,2-f] -s-triazoJo {4,3-a] [1,4] - diazepine.Poc According to the invention, the cultivated thienotriazole-diazepines of the formula I and their acid addition salts can be prepared in such a way that a compound of the general formula II is cyclized in which R1, R2 and R3 have the above meaning. According to the invention, the cyclization is carried out by heating the compounds of the formula II in an organic environment, but in order to obtain satisfactory yields, in some cases it is advantageously operated in the presence of acid. For example, the cyclization can be carried out by heating the compound of formula II within a few hours to the reflux temperature in a solution of an aliphatic carboxylic acid, e.g. formic or acetic acid, walkanol, e.g. ethanol or n-propanol, or for a relatively short time, e.g. about 5 minutes to 1/2 hour, in an aliphatic carboxylic acid, e.g. acetic, isobutyric or pivalic. The compounds of formula 2 need not and may not be used in their isolated form in all cases, as they are often used in the conditions for their preparation undergo spontaneous cyclization. The preparation of starting compounds of formula 2 is shown in the attached reaction scheme, which shows the case where in formula 2, Ri is hydrogen, Ra is phenyl and R3 is as defined above. The 2-amino-3-benzothiophene of formula 4 is converted by treatment with an orthoester of formula R4-C (O * alkyl) 3 to the compound of formula 5. The reactions are expediently carried out in the presence of an inert organic solvent such as benzene, toluene, etc. the like, and acid catalyst, such as hydrochloric, sulfuric, acetic, propionic, benzenesulfonic, p-toluenesulfonic acid and the like. Temperature is not critical, however you usually work around 50 ° C to 60 ° C, but you can also work at warmer and cooler temperatures. Suitable solvents are hydrocarbons such as benzene or toluene and the like, or the excess orthoester used as a reaction component. The compound of the formula V thus obtained is reacted in an inert organic solvent with hydrazine, which is preferably used in the form of its hydrate. Aicanols such as methanol, ethanol, 1-propanol, 2-propanol and the like are particularly suitable as solvents. The reactions are carried out at a temperature from about 0 ° C to the reflux temperature of the reaction mixture, preferably from about 10 ° C to 30 ° C. The reactions can be accelerated by adding an acid catalyst, such as hydrochloric / hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid. , benzenesulfonic, p-toluenesulfonic and the like. The thus-obtained crude product is then reacted with an alpha-halogen acid chloranhydride such as chloroacetyl chloride, bromoacetyl bromide and the like in an inert organic solvent with ice cooling or keeping the reaction mixture below the boiling point to form the compound of formula 6.97 275 3. chloroform, methylene chloride, ether, pyridine, acetic acid, mono-chloroacetic acid, or mixtures thereof with water. When an inert solvent is used, the reactions are preferably carried out in the presence of an acid acceptor such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, pyridine / triethylamine, imidazole, 2-methylimidazole and the like. The compound of formula 6 is then treated with ammonia or hexamine hexamethylene tetra whereby the obtained compound of formula 2 can be cyclized into the corresponding compound of formula 1 without isolation. The cart of formula 3 does not require isolation before cyclization, that is, the closure of the ring to form the compound of formula 1 can be performed in the reaction mixture in which the compound of formula 1 was prepared 2, without isolating it, or without interrupting the course of the reaction. For example, a compound of formula VI can be added to an alcoholic, e.g. ethanolic or methanolic ammonia solution, or a compound of formula VI can be dissolved in an inert organic solvent and mixed with liquid ammonia or hexamethylene tetraamine, to obtain the compound of formula 2. Suitable for this reaction are as solvents: methylene chloride, carbon tetrachloride, ethers like tetrahydrofuran or dioxane, dimethylsulfoxide, dimethylformamide, alkanols like methanol, ethanol-propanol, 2-propanol, 1-butanol, 2-butanol and the like. The obtained compound of formula II, whether in a crude or purified state, can be cyclized in the above-mentioned manner to form a compound of formula 1. In the event that compounds of formula II are to be obtained, where Hx represents groups other than hydrogen atoms and R2 is a group other than a phenyl group, depending on the kind of the desired substituent, it is possible to start with the appropriately substituted compounds of the formula IV or introduce substituents by generally known methods or transform them into other substituents. Compounds of the formula 5 and 6 are new compounds. The compounds of formula I and their pharmaceutically usable acid addition salts are valuable medicaments and can be used as antispasmodics, calming, relaxing and anxiolytic agents. For example, the compound 2-chloro-4-fo-chlorophenyl-9-methyl-6H * thieno [3,2-f] -s-triazolo [413-a] [1,4] -diazepine in the antipentatetrazole test already mice exhibit an APR2 # 0 value of 0.03-0.1 mg / kg orally. The above-mentioned test is carried out according to the Orlaff method (Pros. Soc. Exp. Biol. Med. 70, 254-257, 1949). Thienodiazepines are known to have a similar effect from the German publication No. 2221623, but the antipentatetrazole test showed an unexpected superiority of the compounds obtained by this method. According to the invention, the new compounds of formula 1 exhibit much better pharmacological properties compared to known compounds of similar structure. The table gives comparative data obtained in the metrazol test, the results showing that the new compounds significantly exceed the known compounds for their activity. Table Compounds of formula 1, where n = O, R3 = H, and the meanings of Ri, Ra and R4 are given in the table Ri Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl a Cl Cl Cl Cl yz \ a R2 o -nitrophenyl o, o'-difluorophenyl phenyl o-fluorophenyl o-nitrophenyl o-nitrophenyl o-nitrophenyl o-chlorophenyl o-chlorophenyl o-nitrophenyl o-nitrophenyl o-chlorophenyl o-chlorophenyl o-chlorophenyl o-chlorophenyl o-chlorophenyl o-chlorophenyl 7 R4 -CH3 -CH3 -CHa -CHa -CHa-N (CH3) a -CO-O-CHa -CH3 -CHa-O-CH3 -CHa-OH -CHa -CH2-OH -CHa-N (CHi) a -CHa-N (CHi) a -CHa-NH-CH | -CHa-N (CaH |) a -CHa-NHa metrazol test (APR 2.0) 2.2 0.23 1.68 0.131 2.12 0.53 0.196 0.78 v 0.49 1.43 1, 33 0.494 0.189 0.58 0.173 52.34 97 275 The compounds of formula I as well as their pharmaceutically usable acid addition salts can be converted into pharmaceutical preparations by generally known methods, e.g. into tablets, dragees, suppositories, capsules, solutions, suspensions, emulsions and the like In addition to commonly used pharmacologically inert carriers, such as, for example, milk sugar, starch, talc, magnesium stearate, water, vegetable oils, polyethylene glycols and the like, these preparations may also contain preservatives, stabilizers, wetting agents and emulsifying agents, salts for changing the osmotic pressure, buffers or still other therapeutically valuable substances. If necessary, the mentioned preparations can be sterilized or also subjected to other operations accepted in the pharmaceutical industry. A suitable pharmaceutical dosage unit may contain from about 1 to 50 mg of a compound of the invention. Suitable daily doses for oral administration for mammals range from about QJ mg to about 30 mg / kg; for parenteral administration to mammals, a suitable daily dose is from about 0.1 mg / kg to about 10 mg / kg. These doses should only be taken as examples; the specific dosage must be adapted to individual needs in each case. 500 mg of crude sodium 2 - [(3.5 yl] -5-chloro-3-thiene dihydrochloride). The aqueous phase is extracted with methylene chloride. After drying over sodium sulphate and evaporating the organic phase, the residue is heated to the boiling point under a chiller. reflux in 5 ml of absolute alcohol for 30 minutes After evaporation, the crude base is chromatographed on alumina, bleached with chloroform and crystallized from ethyl acetate 9 (aminomethyl) -2-chloro-4- (o-chlorophenyl) -6H-thienoph-3,2-fj Mriazolo [4,3-a] {1,4] -dvuazepine has a melting point of 167-168 ° C. Recrystallized from ethyl acetate and petroleum ether, the sample melts at 170.5-171 ° C. 2 Formula 2 -n: \ , Formula 397 275 LX O -Alkii ó Formula A Formula 5 FL-C N, S ^ M — C No. C = 0 NH? FL-C N LX CH? Formula 2 Formula 6 Schem at 1 OL-C = Nx 3 IN DC ^ C = NT WZOR 7 Printing work UP PRL print 1/0 +! 8 Price PLN 45 PL

Claims (1)

Claim 1. Process for the preparation of new thienotriazole diazepine derivatives of general formula I, in which Rj is a halogen atom, R2 is a phenyl radical, o-trifluoromethylphenyl, o-halophenyl, o, o'-dihalophenyl, o-nitrophenyl or pyridyl group , Rj represents a hydrogen atom, an alkyl radical, a hydroxyalkyl group, Iowa alkoxycarbones, halogen halogen, alkoxyalkyl, alkylthioalkyl, alkoxycarbonylalkyl, or an e-alkyl-Z group, in which Z is a group of formula 3, and R4 and R5 independently of each other are a hydrogen atom or an alkyl radical, or also together with the nitrogen atom, represent a single ring, saturated 5-6-membered heterocyclic ring with at most one further nitrogen or oxygen atom, optionally in the form of acid addition salts, characterized in that a compound with the general general Formula 2, wherein Rt, R2 and R3 are as defined above and the resulting compound is optionally converted into an acid addition salt. '97 275 R - C9; n. 3 \ // 1 ^ C 5CH2 * 2 Formula 1 N N CHn C = 0 NhL 'I 2 * PL