CS209899B2 - Method of making the new substituted 1-piperazinyl-4h-s-triazolo /3,4c/ thieno/2,3e/ -1,4-diazepines - Google Patents
Method of making the new substituted 1-piperazinyl-4h-s-triazolo /3,4c/ thieno/2,3e/ -1,4-diazepines Download PDFInfo
- Publication number
- CS209899B2 CS209899B2 CS801312A CS131280A CS209899B2 CS 209899 B2 CS209899 B2 CS 209899B2 CS 801312 A CS801312 A CS 801312A CS 131280 A CS131280 A CS 131280A CS 209899 B2 CS209899 B2 CS 209899B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- triazolo
- thieno
- bromo
- diazepine
- formula
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- 238000002844 melting Methods 0.000 claims description 3
- 230000008018 melting Effects 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000005059 halophenyl group Chemical group 0.000 claims 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- -1 carboxylic acid halide Chemical class 0.000 description 10
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 231100000111 LD50 Toxicity 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000949 anxiolytic effect Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000000701 neuroleptic effect Effects 0.000 description 3
- 229930192474 thiophene Natural products 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003176 neuroleptic agent Substances 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- 125000003541 2-chlorobenzoyl group Chemical group ClC1=C(C(=O)*)C=CC=C1 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 240000000425 Chaenomeles speciosa Species 0.000 description 1
- 235000005078 Chaenomeles speciosa Nutrition 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 1
- 208000027520 Somatoform disease Diseases 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 238000010876 biochemical test Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 208000027753 pain disease Diseases 0.000 description 1
- 238000011302 passive avoidance test Methods 0.000 description 1
- VUNXBQRNMNVUMV-UHFFFAOYSA-N phenyl(piperazin-1-yl)methanone Chemical compound C=1C=CC=CC=1C(=O)N1CCNCC1 VUNXBQRNMNVUMV-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
ČESKOSLOVENSKA SOCIALISTICKÁ REPUBLIKA (19) POPIS VYNALEZU K PATENTU 209899 (11) (B2) É (22) Přihlášeno 19 07 78 (21) (PV 1312-80) (32) (31) (33) Právo přednosti od 21 07 77(P 27 32 921.1) Německá spolková republika (40) Zveřejněno· 31 03 81 (51) Int. Cl.3 C 07 D 495/14 OftAD PRO VYNÁLEZY A OBJEVY (45) Vydáno 15 06 84 WEBER KARL-HEINZ dr., LANGBEIN ADOLF dr., GAU-ALGESHEIM,(72) SCHNEIDER CLAUS dr., INGELHEIM/R., LEHR ERICH dr.,CZECHOSLOVAK SOCIALIST REPUBLIC (19) DESCRIPTION OF THE PATENT 209899 (11) (B2) É (22) Registered 19 07 78 (21) (PV 1312-80) (32) (31) (33) Priority from 21 07 77 ( P 27 32 921.1) Federal Republic of Germany (40) Published · 31 03 81 (51) Int. Cl.3 C 07 D 495/14 OFTAD FOR INVENTIONS AND DISCOVERIES (45) Published 15 06 84 WEBER KARL-HEINZ dr., LANGBEIN ADOLF dr., GAU-ALGESHEIM, (72) SCHNEIDER CLAUS dr., INGELHEIM / R., LEHR ERICH dr.
Autor vynalezu WALDALGESHEIM, BOKE KARIN dr., INGELHEIM/R. a KUHN FRANZ JOSEF dr., BINGEN (NSR) 173)The inventor of WALDALGESHEIM, BOKE KARIN dr., INGELHEIM / R. and KUHN FRANZ JOSEF dr., BINGEN (NSR) 173)
Majitel patentu C. H. BOEHRINGER SOHN, INGELHEIM/R. (NSR) (54) Způsob výroby nových substituovaných l-píperazinyl-4H-s-triazolo-[ 3,4c 1 thieno (2,3e ] -1,4-diazepinů 1Patent of C. H. BOEHRINGER SOHN, INGELHEIM / R. (NSR) (54) Method for the production of new substituted 1-piperazinyl-4H-s-triazolo- [3,4c1 thieno (2,3e] -1,4-diazepines 1)
Vynález popisuje nové substituované 1--piperazmyl-4H-s-triazolo [ 3,4c ] thieno[ 2,3 e ] --1,4 diazepiny obecného vzorce IThe present invention provides novel substituted 1-piperazinyl-4H-s-triazolo [3,4-c] thieno [2,3e] -1,4 diazepines of formula I
2 jich použití jako· účinných látek v léčivech. Z přímých nebo· rozvětvených alkylovýchskupin s 1 až 17 atomy uhlíku, ve významusymbolu R4, jsou výhodné příslušné skupinys 1 až 6 atomy uhlíku. Výrazem „halogen“ se označují atomy fluo-ru, chloru, bromu a jodu.2 of them as active ingredients in medicines. Of the straight or branched alkyl groups having 1 to 17 carbon atoms, in the meaning of R4, the preferred groups are 1 to 6 carbon atoms. The term "halogen" refers to fluorine, chlorine, bromine and iodine atoms.
Substituent na fenylovém kruhu může za-ujímat polosu o-, m- nebo p-.The substituent on the phenyl ring may include the o-, m-, or p- radius.
Pyridyloivý zbytek může být napojen na du-síkový atom piperazinového jádra polohou2, 3 nebo 4.The pyridyloid residue may be attached to the piperazine core of the piperazine core at position 2, 3 or 4.
V souhlase s vynálezem je možno shorauvedené nové sloučeniny připravit tak, že seacyluje sloučenina obecného vzorce IIAccording to the invention, the novel compounds can be prepared by salifying a compound of formula (II)
209899 ve kterém R1 znamená zbytek vzorce R4—CO—, R2 představuje atom fluoru, chloru nebobromu, R3 znamená atom chloru, atom bromu ne-bo alkylovou skupinu s 1 nebo 2 atomy uhlí-ku a R4 představuje atom vodíku, alkylovou skupinu s 1 až 17 atomy uhlíku, alkoxyskupi- nu s 1 nebo' 2 atomy uhlíku, fenylovou sku- pinu, MOgenfenylOVOU skupinu nebo pyri- dylovou skupinu, způsob jejich výroby a je- 209899 ve kterém R2 a R3 mají shora uvedený význam, půso-bením halogenidu nebo anhydridu odvoze-ného od karboxylové kyseliny obecného vzor-ce R4COOH, ve kterém R4 má shora uvedený význam.Wherein R 1 is a radical of formula R 4 -CO 2, R 2 is fluoro, chloro or bromo, R 3 is chloro, bromo or alkyl having 1 or 2 carbon atoms and R 4 is hydrogen, alkyl of 1 C 1 -C 17 alkoxy, phenyl group, MO 2 phenyl group or pyridyl group, a process for the preparation thereof, and is 209899 wherein R 2 and R 3 are as defined above for halide; or an anhydride derived from a carboxylic acid of formula R 4 COOH, wherein R 4 is as defined above.
Acylaci sloučenin obecného vzorce II pů-sobením halogenidu nebo anhydridu karbo-xylové kyseliny je možno provádět za po-užití nadbytku acylačního činidla nebo takéve vhodném inertním rozpouštědle, jako vdioxanu, tetrahydrofuranu, benzenu, tolue-nu nebo xylenu. V četných případech se u-kázalo jako užitečné přidávat anorganickounebo organickou bázi, například pyridin, tri-ethylamin, uhličitan draselný nebo kyselýuhličitan sodný, která má za úkol vázat ky-selinu. Reakční teplota a reakční doba semohou, v závislosti na používaných výcho-zích látkách, pohybovat v širokých mezích.Tak se může reakční teplota pohybovat me-zi teplotou místnosti a teplotou varu použi-tého rozpouštědla a reakční doba může činitněkolik minut až několik hodin.The acylation of the compounds of formula (II) with a carboxylic acid halide or anhydride can be carried out using an excess of the acylating agent or also in a suitable inert solvent such as dioxane, tetrahydrofuran, benzene, toluene or xylene. In many cases, it has been found useful to add an inorganic or organic base such as pyridine, triethylamine, potassium carbonate or sodium bicarbonate to bind the acid. Depending on the starting materials used, the reaction temperature and reaction time can be varied within wide limits. Thus, the reaction temperature can be varied between room temperature and the boiling point of the solvent used and the reaction time can be from a few minutes to several hours.
Shora popsaným způsobem je možno vyro-bit například následující finální produkty: 8-brom-6- (o-chlorfenyl J-1-N-f or-mylpiperazino-4H-s-itriazolo-[ 3,4c jthieno] 2,3e ] -1,4-diazepin, 1- (N-acetylpiperazino) -8-brom--6- (o-chlorfenyl j -4H-s-triazolo-[ 3,4c jthieno] 2,3e ] -1,4-diazepin, l-( N-acetylpiperazino) -8-ethyl-6- - (o-chlorfenyl) -4H-s-triazolo- [ 3,4c jthieno] 2,3e ] -1,4-diazepin, 1- (N-acetylpiperazino) -8-chlor-6- - (o-chlorfenyl j -4H-s-triažolo- [ 3,4c jthieno [ 2,3e ] -1,4-diazepin, 1- (N-acetylpiperazino) -8-br om-6--(o-f luor f eny l)-4H-s-triazolo-[ 3,4c jthieno ] 2,3e ] -1,4-diazepin, 1- (N-acetylpiperazino) -8-brom-6- - (o-bromf enyl j -4H-s-triazolo- [ 3,4c jthieno ] 2,3e ] -1,4-diazepin, 8-brom-6- (o-chlorfenyl )-1-( N-ste-arylpiperazino)-4H-s-triazolo-[ 3,4c jthieno] 2,3e ] -1,4-diazepin, 8-brom-l- (N-kapr oy lpiperazino j -6- - (o-chlorfenyl j -4H-s-triazolo- [ 3,4c jthiénof 2,3e ] -1,4-diazepin, 8-brom-6-( o-ohlorfenyl )-1-(N-ben- zoylpiperazino j -4H-s-triazolo- [ 3,4c jthieno] 2,3e j -1,4-diazepin, 8-br om-6-(o-chlorf ehyl)-l-[N-(p--fluorbenzoyljpiperazinoj-4H-s-triazolo-' [ 3,4c jthieno] 2,3e j -1,4-diazepin, 8-brom-6-( o-chlorfenyl) -1- [ N- (o--chlorbenzoyl) piiper azino ] -4H-s-triazolo-[ 3,4c jthieno] 2,3e ] -l,4-diazeí)in, 8-br om-6-(o-chlorfenyl )-l-(N-niko- 'tinoylpiperazino j -4H-s-triázólo-[ 3,4c jthieno] 2,3e ]-1,4-diazejňn, 8-brcm-6-(o-chlorfenyl)-l-(N-pi- -kolinoylpiperazino J -4H-s-triazolo-[ 3,4c jthieno] 2,3e ] -1,4-diazepin, 1- (N-ethoxykarbonylpiperazino) -8--brom-6- (o-chlorf enyl) -411-s-triazolo-[ 3,4c ]thieno]2,3e ] -1,4-diazepin, Výchozí látky obecného vzorce II je mož-no získat například reakcí příslušně substi-tuovaného l-halogen-4H-s-triazolo [ 3,4c ] -thieno] 2,3e]-l,4-diazepinu s piperazinem ne-bo dehydroigenací l-piperazinyl-4H-s-triazo-lo] 3,4c ] thieno] 2,3e j -5,6-dihy dro-l,4-diaze-pinu. Výsledné látky shora uvedeného obecné-ho vzorce I mají cenné terapeutické vlastnos-ti a lze je používat jako anxiolytika, trankvi-lizační činidla, sedativa a neuroleptika.Hlavní účinek může být u jednotlivých lá-tek odlišný, takže některé z těchto slouče-nin se používají převážně jako neurolepti-ka, jiné potom převážně jako uspávači pro-středky apod.For example, the following final products can be produced by the method described above: 8-bromo-6- (o-chlorophenyl-1-N-orylpiperazino-4H-s-itriazolo- [3,4c] thieno) 2,3e] -1 , 4-diazepine, 1- (N-acetylpiperazino) -8-bromo-6- (o-chlorophenyl) -4H-s-triazolo- [3,4c] thieno] 2,3e] -1,4-diazepine, 1 - (N-acetylpiperazino) -8-ethyl-6- (o-chlorophenyl) -4H-s-triazolo [3,4-d] thieno] 2,3e] -1,4-diazepine, 1- (N-acetylpiperazino) -8-chloro-6- (o-chlorophenyl) -4H-s-triazolo [3,4-thieno [2,3e] -1,4-diazepine, 1- (N-acetylpiperazino) -8-bromo- 6 - (fluorophenyl) -4H-s-triazolo [3,4c] thieno] 2,3e] -1,4-diazepine, 1- (N-acetylpiperazino) -8-bromo-6- ( o-bromophenyl] -4H-s-triazolo- [3,4c] thieno] 2,3e] -1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- (N-s-arylpiperazino) -4H-s-triazolo- [3,4c] thieno] 2,3e] -1,4-diazepine, 8-bromo-1- (N-caproylpiperazino-6 - (o-chlorophenyl) -4H-s -triazolo- [3,4c] thiophene 2,3e] -1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- (N-benzoylpiperazine j -4H-s-triazolo [3,4c] thieno] 2,3e-1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- [N- (p-fluorobenzoylpiperazinoj-4H -s-triazolo- [3,4c] thieno [2,3-d] -1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- [N- (o-chlorobenzoyl) piiper azino] - 4H-s-triazolo [3,4c] thieno] 2,3e] -1,4-diazoline, 8-bromo-6- (o-chlorophenyl) -1- (N-nicotinoylpiperazin-4H) -s-triazolo- [3,4c] thieno] 2,3e] -1,4-diazinine, 8-bromo-6- (o-chlorophenyl) -1- (N-pi-colinoylpiperazin-4H-s-triazolo) - [3,4c] thieno] 2,3e] -1,4-diazepine, 1- (N-ethoxycarbonylpiperazino) -8-bromo-6- (o-chlorophenyl) -411-s-triazolo- [3,4c] thieno] 2,3e] -1,4-diazepine The starting materials of the formula II can be obtained, for example, by reaction of appropriately substituted 1-halo-4H-s-triazolo [3,4-c] thieno] 2,3e 1,4-diazepine with piperazine or 1-piperazinyl-4H-s-triazol-1-yl] 3,4-thieno] -2,3e-5,6-dihydro-1,4-diazepine with piperazine . The resulting compounds of formula (I) have valuable therapeutic properties and can be used as anxiolytics, tranquilizers, sedatives and neuroleptics. The main effect may be different for individual substances, so that some of these compounds are they use predominantly as neuroleptics, others predominantly as sleepers and the like.
Tyto sloučeniny vykazují vedle vyslovenětrankvilizační a anxiolytické složky účirikurovněž dobrý účinek při testu na krysách,při němž se zvířata aktivně vyhýbají nepři-'jemným podnětům, přičemž oba tyto typy ú-činku mají časově posunutá maxima. Nej-prve se totiž projevuje neuroleptický účineka teprve později účinek anxiolytický. Rovněžz biochemických testů je možno usuzovatna neuroleptické vlastnosti acylpiperaziny-lových derivátů.These compounds, in addition to the pronetrancquilizing and anxiolytic components of the curicus, have a good effect on the rat test, in which the animals are actively avoiding unpleasant stimuli, both of which have time-shifted peaks. First, the neuroleptic effect only appears later on the anxiolytic effect. Neuroleptic properties of acylpiperazinyl derivatives can also be deduced from biochemical tests.
Nové sloučeniny jsou proto zvlášť vhodnék odstraňování psychomotorických stavůvzrušení a úzkosti, jaké se vyskytují napří-klad při schizofrenii, a dále k léčbě bolesti-vých stavů a poruch spánku různého půvo-du. Následujícími metodami byla testovánaantikonvulzivní účinnost, trankvilizační ú-činnost a toxicita sloučenin podle vynále-zu. 1. Antagonizování účinku pentetrazolú ; [Μ. I. Gluckmann, Curr. Ther. Res. 7, 721(1965)).The novel compounds are therefore particularly suitable for the removal of psychomotor disturbances and anxiety such as occur in schizophrenia and for the treatment of pain and sleep disorders of various origins. The following methods were used to test the anticonvulsant efficacy, tranquilization activity and toxicity of the compounds of the invention. 1. Antagonizing the effect of pentetrazoles; [Μ. I. Gluckmann, Curr. Ther. Res. 7, 721 (1965).
Zjišťuje se střední účinná dávka (EDso) testované sloučeniny, která ruší smrtící ú- čínek dávky 125 nig/kg pontylentotrazolu ů 50 % pokusných zvířat. Pentyleňtotrazol se ' podává intraperitoneálně za 1 hodinu po ap-likaci testované sloučeniny. 2. Konfliktní situace (Inhibition of Passive Avoidance Test) [J. Geller, Arch. Int. Pharmacodyn. 149,243 (1964)]. 3. Dobrinův test (Discriminative Active Avoidance) [P. B. Dobrin, Arch. Int. Pharmacodyn. 178,351—356 (1969)],The mean effective dose (ED 50) of the test compound is determined, which abolishes a lethal effect of 125 µg / kg of pontylentotrazole in 50% of the test animals. Pentyltotrazole is administered intraperitoneally 1 hour after the test compound is administered. 2. Inhibition of Passive Avoidance Test [J. Geller, Arch. Int. Pharmacodyn. 149, 243 (1964)]. 3. Discriminative Active Avoidance [P. B. Dobrin, Arch. Int. Pharmacodyn. 178,351—356 (1969)]
Tento test dokládá možnou neuroleptickouúčinnost testovaných sloučenin.This test demonstrates the possible neuroleptic efficacy of the test compounds.
Krysy se nacvičí tak, aby po· varovném sig-nálu stiskly tlačítko. Pokud tlačítko nestisk-nou, dostanou do tlapek krátký bolestivý e-lektrický šok. Po aplikaci určité dávky neu- roleptického činidla zvířata necítí potřebutisknout tlačítko i když vědí, že bude násle-dovat bolestivý podnět. V následující tabulce je uvedena dávkatestované sloučeniny v mg/kg, po jejíž apli-kaci je četnost stisků tlačítka snížena o 50procent. 4. Toxicita [Litchfield and Wilcoxon, ]. Pharmacol.Exp. Therap. 96, 99 (1949)].The rats are trained to press a button on the warning signal. If the button is not depressed, a short painful electric shock will get into the paws. When a certain dose of neuroleptic agent is administered, the animals do not feel the need to press a button even if they know that there will be a painful stimulus. The following table shows the dosed compound in mg / kg, after which the keystroke rate is reduced by 50%. 4. Toxicity [Litchfield and Wilcoxon,]. Pharmacol.Exp. Therap. 96, 99 (1949)].
Zjišuje se střední letální dávka (LDso).The median lethal dose (LD 50) is determined.
Jako pokusná zvířata se používají bílé my-ši (NMRI) o tělesné hmotnosti 20' až 25 gnebo bílé krysy (FW-49) o tělesné hmotnosti140 až 200 g. Testovaná sloučenina se podá-vá orálně v suspenzi v olivovém oleji za po-moci jícnové sondy. Výsledky shora popsaných testů (hodnotyzjišťovány graficky ) jsou uvedeny v následu-jící tabulce. testovaná látka antagonizování Geller Dobrin LDso účinku (krysa) (krysa) (myš) pentetrazolu mg/kg (myš) mg/kg mg/kg mg/kg 1- (N-acetylpiperazino) --8-brom-6- (o-chlorf enyl) --4H-s-triazolo [ 3,4c ]- thieno[2,3e]-l,4-diazepin 0,5 5,1 <30 1280*’White mice (NMRI) weighing 20-25 g or white rats (FW-49) weighing 140-200 g are used as experimental animals. The test compound is administered orally in suspension in olive oil under the esophageal probes. The results of the above described tests (graphically determined) are shown in the following table. Geller antagonist tested Dobrin LD 50 effect (rat) (rat) (mouse) pentetrazole mg / kg (mouse) mg / kg mg / kg mg / kg 1- (N-acetylpiperazino) -8-bromo-6- (o- chlorophenyl) -4H-s-triazolo [3,4-c] thieno [2,3e] -1,4-diazepine 0.5 5.1 <30 1280 ° -1.
Legenda: *’ tato hodnota je přibližná, protože při dané dávce žádné zvíře neuhynuloLegend: * 'This value is approximate because no animal died at a given dose
Jednotková dávka sloučenin podle vynále-zu činí 0,05 až 50 mg, s výhodou 0,1 až 25miligramů (při orálním podání), denní dáv-ka se potom pohybuje od 5 do 150 mg.The unit dose of the compounds of the invention is 0.05 to 50 mg, preferably 0.1 to 25 milligrams (by oral administration), and the daily dose is then from 5 to 150 mg.
Vynález ilustrují následující příklady pro-vedení, jimiž se však rozsah vynálezu v žád-ném směru neomezuje. Příklad 1 1- (N-acetylpiperazino) -8-brom--6- (o-chlorfenyl) -H-s-triazolo-[ 3,4c ] thienoj 2,3e ] -1,4-diazepin 4,6 g (0,01 mol) 8-brom-6-( o-chlorfenyl )--l-piperazino-4H-s-triazolo [ 3,4c ] thieno-[2,3e]-diazepinu se 20' minut míchá ve 100'mililitrech acetanhydridu. Reakční směs sevylije na led a zalkalizuje se amoniakem.Vzniklý acetylderivát se vyjme methylen-chloridem, methylenchloridová fáze se vy-suší a zbytek se přidáním etheru přivede kekrystalizaci. Výtěžek titulní sloučeniny tající při 247 až249 °C činí 3,8 g (76 % teorie). Příklad 2 8-brom-6- (o-chlorfenyl) -1- (N-etho- xyKarbonylpiperaáiiiuHH-s-triazolo- [ 3,4c ] thienof 2,3e ] -1,4-diazepin 4,6 g (0,01 mol) 8-brom-6-(o-chlorfenylj--l-piperazino-4H-s-tiriazolo[3,4c]thieno'-[2,3e]-l,4-diazepinu se ve 100 ml tetrahyd-rofuranu 30s minut míchá při teplotě míst-nosti s 2 ml ethylesteru kyseliny chlormra-venčí. Reakční směs se ochladí, přidá se kní voda a methylenchlorid, výsledná směsse zalkalizuje amoniakem, methylenchlori-dová fáze se vysuší, odpaří se a zbytek sepodrobí chromatografii. Výtěžek produktu tajícího při 216 až 218stupních Celsia činí 4,8 g (91% teorie).Příklad 3 1- (N f ormylpiperazino) -8-brom--6- (o-chlorfenyl) -H-s-triazolo-[ 3,4c ] thienoj 2,3e ] -1,4-diazepin 4,6 g (0,01 mol) 8-brom-6-(o-chlorfenylj--l-piperazino-4H-s-triazolo[3,4c]thieno-[2,3e]-l,4-diazepinu se ve 100 ml kyselinymravenčí 3 hodiny vaří pod zpětným chla-dičem. Reakční směs se vylije na led, zalka-lizuje se 2 N louhem sodným, vzniklý for-mylderivát se vyjme methylenchloridem azpracuje se analogickým způsobem jako vpříkladu 1.The invention is illustrated by the following non-limiting Examples. Example 1 1- (N-acetylpiperazino) -8-bromo-6- (o-chlorophenyl) -H-triazolo [3,4-c] thiophene 2,3e] -1,4-diazepine 4.6 g (0, 01 mol of 8-bromo-6- (o-chlorophenyl) -1-piperazino-4H-s-triazolo [3,4-b] thieno [2,3e] -diazepine was stirred in 100 ml of acetic anhydride for 20 minutes. The reaction mixture is poured onto ice and made alkaline with ammonia. The acetyl derivative is taken up in methylene chloride, the methylene chloride phase is dried and the residue is brought to crystallization by addition of ether. The yield of the title compound melting at 247-249 ° C was 3.8 g (76% of theory). Example 2 8-bromo-6- (o-chlorophenyl) -1- (N-ethoxycarbonylpiperazineHH-s-triazolo- [3,4-c] thiophene 2,3e) -1,4-diazepine 4.6 g (0, 01 mol) 8-bromo-6- (o-chlorophenyl-1-piperazino-4H-s-thiazolo [3,4-c] thieno [2,3e] -1,4-diazepine in 100 ml tetrahydrofuran The mixture is stirred for 30 minutes at room temperature with 2 ml of ethyl chloroformate, cooled, water and methylene chloride are added, the mixture is basified with ammonia, the methylene chloride phase is dried, evaporated and the residue is chromatographed. m.p. 216 DEG-218 DEG C., 4.8 g (91% of theory). EXAMPLE 3 1- (N-methylpiperazino) -8-bromo-6- (o-chlorophenyl) -H-triazolo [3,4-c] thienoic acid 2,3e] -1,4-diazepine 4.6 g (0.01 mol) 8-bromo-6- (o-chlorophenyl-1-piperazino-4H-s-triazolo [3,4-d] thieno [2,3-d] -1,4-diazepine; 3e] -1,4-diazepine is refluxed in 100 ml of formic acid for 3 hours, poured into ice, made alkaline with 2 N sodium hydroxide solution. The resulting formate is taken up in methylene chloride and worked up in an analogous manner to Example 1.
Výtěžek produktu tajícího při 203 až 215 °C činí 3,9 g (80 % teorie).The yield of the product melting at 203-215 ° C is 3.9 g (80% of theory).
Shora popsanými postupy se připraví rov- něž následující sloučeniny obecného vzorceThe following compounds of formula (I) are also prepared by the procedures described above
IAND
Claims (1)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS801312A CS209899B2 (en) | 1977-07-21 | 1980-02-26 | Method of making the new substituted 1-piperazinyl-4h-s-triazolo /3,4c/ thieno/2,3e/ -1,4-diazepines |
| CS131282A CS226583B1 (en) | 1980-02-26 | 1982-02-26 | Coupling,especially for tubular scaffolding |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772732921 DE2732921A1 (en) | 1977-07-21 | 1977-07-21 | 1-Piperazino-triazolo-thieno-diazepine derivs. - useful as anxiolytics, tranquillisers, sedatives and neuroleptics |
| CS784821A CS209897B2 (en) | 1977-07-21 | 1978-07-19 | Method of making the new substituted 2-piperazinyl-4h-s-triazolo /3,4c/ thieno /2,3c/-1,4-diazepines |
| CS801312A CS209899B2 (en) | 1977-07-21 | 1980-02-26 | Method of making the new substituted 1-piperazinyl-4h-s-triazolo /3,4c/ thieno/2,3e/ -1,4-diazepines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS209899B2 true CS209899B2 (en) | 1981-12-31 |
Family
ID=25746063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS801312A CS209899B2 (en) | 1977-07-21 | 1980-02-26 | Method of making the new substituted 1-piperazinyl-4h-s-triazolo /3,4c/ thieno/2,3e/ -1,4-diazepines |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS209899B2 (en) |
-
1980
- 1980-02-26 CS CS801312A patent/CS209899B2/en unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0091241B1 (en) | Condensed pyrrolinone derivatives, and their production | |
| JPH085895B2 (en) | New hetrazepine and its manufacturing method | |
| US5001130A (en) | Psychotropic heterobicycloalkylpiperazine derivatives | |
| PL101248B1 (en) | METHOD OF MAKING NEW PYROLINE DERIVATIVES | |
| HU218950B (en) | Condensed imidazo pyridine derivatives, pharmaceutical compositions containing them and process for their preparation | |
| DK157868B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF TETRACYCLIC COMPOUNDS | |
| CZ410791A3 (en) | Amides of thieno-triazolo-1,4-diazepino-2-carboxylic acid, process of their preparation and pharmaceutical preparation based thereon | |
| EP0230942A2 (en) | Thieno-1,4-diazepines | |
| WO1999043682A9 (en) | 2-(het-)aryl-4-(cyclic amino substituted) heteroaryl fused pyridine derivatives, their preparation and their use as (ant-)agonists for gaba (a) brain receptors | |
| SK33995A3 (en) | Imidazodiazepines | |
| ES2309398T3 (en) | DERIVATIVES 3,4-DIHIDRO-TIENO (2,3-D) PIRIMIDIN-4-ONA-3-SUBSTITUTED, PRODUCTION AND ITS USES. | |
| HU196403B (en) | Process for production of condensated tricyclic and heterocyclic compositions and medical preparatives containing them as active substance | |
| WO1997003986A1 (en) | Fused triazole compounds | |
| EP0318682A2 (en) | Tricyclic thiazole derivatives | |
| CA1304381C (en) | 3-(piperidin-1-yl)-carbonylmethyl-isoindolin-1-one | |
| IL25447A (en) | Benzothiazepines and benzothiazocines and their preparation | |
| CA2157231A1 (en) | Oxa- or thia-aliphatically bridged quinoxaline-2,3-diones | |
| US20030158245A1 (en) | Fused heterocyclic derivatives, their production and use | |
| HU196210B (en) | Process for producing 1,3,4,9-tetrahydropyrano/3,4-b/ indole-1-acetic acid derivatives and pharmaceutics comprising such compounds | |
| WO1993013105A1 (en) | Condensed thiophene compound and pharmaceutical use thereof | |
| PL114541B1 (en) | Process for preparing novel,substituted in position 2,4a,9b-trans-5-aryl-2,3,4,4a,5,9b-hexahydro-1h-pyrido/4,3-b/indoles | |
| Sharma et al. | Synthesis of thienopyrimidines and their antipsychotic activity | |
| SK37394A3 (en) | 1,8-benzonaphthyridine derivatives, method of their preparation and compositions containing these derivatives | |
| CS209899B2 (en) | Method of making the new substituted 1-piperazinyl-4h-s-triazolo /3,4c/ thieno/2,3e/ -1,4-diazepines | |
| HUT71488A (en) | Process for the production of neuroleptic 2-substituted perhydro-1-h-pyrido[1,2a]pyrazines and pharmaceuticals compositions containing the same |