CS224988B1 - The derivate of octanehydropyrrole (1,2- a)pyrazine and its methansulphonate - Google Patents
The derivate of octanehydropyrrole (1,2- a)pyrazine and its methansulphonate Download PDFInfo
- Publication number
- CS224988B1 CS224988B1 CS604682A CS604682A CS224988B1 CS 224988 B1 CS224988 B1 CS 224988B1 CS 604682 A CS604682 A CS 604682A CS 604682 A CS604682 A CS 604682A CS 224988 B1 CS224988 B1 CS 224988B1
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- pyrazine
- octanehydropyrrole
- methansulphonate
- derivate
- methanesulfonate
- Prior art date
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- GXWNSJYVSIJRLS-UHFFFAOYSA-N 6-bromo-8-methylimidazo[1,2-a]pyrazine Chemical compound CC1=NC(Br)=CN2C=CN=C12 GXWNSJYVSIJRLS-UHFFFAOYSA-N 0.000 title description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical class C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 claims description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 206010003591 Ataxia Diseases 0.000 description 1
- 208000009132 Catalepsy Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010047853 Waxy flexibility Diseases 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000002903 catalepsic effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Vynález se týká nového derivátu oktahydropyrrolo(1,2-a)pyrazinu vzorce IThe invention relates to a novel octahydropyrrolo (1,2-a) pyrazine derivative of the formula I
a jeho methansulfonátu. Látce I přísluší název 2-chlor-11-/oktahydropyrrolo(1,2-a)pyrazin-2-yl/-10,11-dihydrodibenzo(b,f)thiepinu. Tato látka a její methansulfonát jsou newroleptiky použitelnými v therapii psychos schizofrenního typu. Je to doloženo vlast nostmi zjištěnými v testech na pokusných zvířatech.and its methanesulfonate. Compound I is designated 2-chloro-11-octahydropyrrolo (1,2-a) pyrazin-2-yl) -10,11-dihydrodibenzo (b, f) thiepine. This substance and its methanesulfonate are newroleptics useful in the therapy of schizophrenic psychoses. This is evidenced by the properties found in the tests on the experimental animals.
Testován byl methansulfonát látky I, při^čemž uváděné dávky jsou přepočty na basi. Akutní toxicita na myších, LDjq » 34 mg/kg i.v. Diskoordinační účinek v testu rotující tyčky na myších, ED^q (střední účinná dávka vyvolávající ataxii u 50 % zvířat) je 0,45 mg/kg i.v. Kataleptický účinek u krys, ED^q (střední účinná dávka vyvolávající katalepsii u 50 % zvířat) je 3,6 mg/kg i.p.Compound (I) methanesulfonate was tested, the dosages reported being calculated on a basis. Acute toxicity in mice, LDjq »34 mg / kg i.v. The discoordination effect in the rotating rod test in mice, ED 50 (mean effective dose inducing ataxia in 50% of animals) is 0.45 mg / kg i.v. The cataleptic effect in rats, ED 50 (mean effective dose inducing catalepsy in 50% of animals) is 3.6 mg / kg i.p.
Látku vzorce I lze připravit substituční reakcí 2,11-dichlor-10,11-dihydrodibenzo(b,f)thiepinu (Jílek J.O. a spol., Collect.Czech.Chem.Commun. 33. 1θ31, 1968) s oktahydropyrrolo(1,2-a)pyrazinem /1,4-diazabicyklo(4,3,0)nonanem/ (Razarova L.S. a spol., Chim.-Parm.Žurnál 10(1), 88, 1976) ve vroucím chloroformu. Produkt má dvě centra chirality, takže lze předpokládat vznik stereoisomerní směsi. Base sice dobře krystaluje, avšak její NMR spektrum není dobře rozlišené, což naznačuje přítomnost ~ίτThe compound of formula (I) may be prepared by substitution reaction of 2,11-dichloro-10,11-dihydrodibenzo (b, f) thiepine (Jílek JO et al., Collect.Czech.Chem.Commun. 2-a) pyrazine (1,4-diazabicyclo (4.3.0) nonane) (Razarova LS et al., Chim.-Parm. Journal 10 (1), 88, 1976) in boiling chloroform. The product has two centers of chirality so that the formation of a stereoisomeric mixture can be expected. Although the base crystallizes well, its NMR spectrum is not well resolved, suggesting the presence of ίττ
224 988 obou stereoisomerů. Neůtralisací kyselinou methansulfonovou se získá amorfní methansulfonát, který je výborně rozpustný ve vodě a vhodný k provádění farmakologických testů i k výrobě lékových forem. Látka vzorce I se tedy připraví takto :224,988 both stereoisomers. By non-purification with methanesulfonic acid, an amorphous methanesulfonate is obtained which is perfectly water-soluble and suitable for pharmacological testing and for the manufacture of dosage forms. Thus, a compound of formula I is prepared as follows:
Směs 2,8 g 2,11-dichlor-10,11-dihydrodibenzo(b,f)thíepinu,A mixture of 2,8 g of 2,11-dichloro-10,11-dihydrodibenzo (b, f) thiepine,
1,9 g oktahydropyrrolo(1,2-a)pyrazinu a 4 ml chloroformu se vaří 7 h pod zpětným chladičem. Potom se odpaří ve vakuu, zbytek se smísí s 30 ml vody a 5 ml hydroxidu amonného a extrahuje se benzenem. Extrakt se protřepe s 10 ml 3M-HC1, vyloučený hydrochlorid se zfiltruje, promyje se benzenem a suspenduje se v 30 ml vo dy. Suspense se zalkalisuje 10 ml hydroxidu amonného a base se isoluje extrakcí benzenem. Zpracováním extraktu se získá 2,55 g (69 %) sklovitého produktu, který krystaluje z ethanolu, t.t.1.9 g of octahydropyrrolo [1,2-a] pyrazine and 4 ml of chloroform are refluxed for 7 h. It is then evaporated in vacuo, the residue is treated with 30 ml of water and 5 ml of ammonium hydroxide and extracted with benzene. The extract is shaken with 10 ml of 3M-HCl, the precipitated hydrochloride is filtered, washed with benzene and suspended in 30 ml of water. The suspension is basified with 10 ml of ammonium hydroxide and the base is isolated by extraction with benzene. Work-up of the extract gave 2.55 g (69%) of a glassy product which crystallized from ethanol, m.p.
145 až 150 °C. Neůtralisací této krystalické base (700 mg) methansulfonovou kyselinou (180 mg) ve 3 ml ethanolu a odpařením roztoku se získá 880 mg amorfního methansulfonátu, který je výborně rozpustný ve vodě a vhodný k provádění farmakologických testů.Mp 145-150 ° C. Failure to purify this crystalline base (700 mg) with methanesulfonic acid (180 mg) in 3 ml of ethanol and evaporation of the solution gave 880 mg of amorphous methanesulfonate, which is perfectly water soluble and suitable for pharmacological testing.
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Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS604682A CS224988B1 (en) | 1982-08-17 | 1982-08-17 | The derivate of octanehydropyrrole (1,2- a)pyrazine and its methansulphonate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS604682A CS224988B1 (en) | 1982-08-17 | 1982-08-17 | The derivate of octanehydropyrrole (1,2- a)pyrazine and its methansulphonate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS224988B1 true CS224988B1 (en) | 1984-02-13 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS604682A CS224988B1 (en) | 1982-08-17 | 1982-08-17 | The derivate of octanehydropyrrole (1,2- a)pyrazine and its methansulphonate |
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| CS (1) | CS224988B1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996018630A1 (en) * | 1994-12-12 | 1996-06-20 | Allelix Biopharmaceuticals Inc. | Bicyclic nonane and decane compounds having dopamine receptor affinity |
-
1982
- 1982-08-17 CS CS604682A patent/CS224988B1/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996018630A1 (en) * | 1994-12-12 | 1996-06-20 | Allelix Biopharmaceuticals Inc. | Bicyclic nonane and decane compounds having dopamine receptor affinity |
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