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WO1991010661A1 - DERIVES DE 5-AMINO-8-CHLORE-DIBENZO[b,e][1,4]-DIAZEPINE ET PREPARATION PHARMACEUTIQUE DE TRAITEMENT DE L'EPILEPSIE AINSI QUE D'ETATS EPILEPTIQUES A BASE DESDITS DERIVES - Google Patents

DERIVES DE 5-AMINO-8-CHLORE-DIBENZO[b,e][1,4]-DIAZEPINE ET PREPARATION PHARMACEUTIQUE DE TRAITEMENT DE L'EPILEPSIE AINSI QUE D'ETATS EPILEPTIQUES A BASE DESDITS DERIVES Download PDF

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Publication number
WO1991010661A1
WO1991010661A1 PCT/SU1991/000001 SU9100001W WO9110661A1 WO 1991010661 A1 WO1991010661 A1 WO 1991010661A1 SU 9100001 W SU9100001 W SU 9100001W WO 9110661 A1 WO9110661 A1 WO 9110661A1
Authority
WO
WIPO (PCT)
Prior art keywords
diazepine
compound
dibenzo
connection
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/SU1991/000001
Other languages
English (en)
Russian (ru)
Inventor
Grigory Semenovich Chernov
Zhanna Nikolaevna Khlienko
Galina Mikhailovna Mekhova
Tatyana Viktorovna Susekova
Viktor Eduardovich Kolla
Alexandr Vladimirovich Suldin
Svetlana Alexandrovna Shelenkova
Alexandr Leonidovich Tregubov
Tatyana Valerievna Pilipchuk
Evgeny Vasilievich Nikushkin
Natalya Alexandrovna Krupina
Valery Grigorievich Kucheryanu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novokuznetsky Nauchno-Issledovatelsky Khimiko-Farmatsevtichesky Institut
Original Assignee
Novokuznetsky Nauchno-Issledovatelsky Khimiko-Farmatsevtichesky Institut
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SU4797175/04A external-priority patent/SU1713245A1/ru
Application filed by Novokuznetsky Nauchno-Issledovatelsky Khimiko-Farmatsevtichesky Institut filed Critical Novokuznetsky Nauchno-Issledovatelsky Khimiko-Farmatsevtichesky Institut
Publication of WO1991010661A1 publication Critical patent/WO1991010661A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings

Definitions

  • the present invention is concerned with the search for new drugs for the treatment of epilepsy and epilepticus status at the present time.
  • 15 Izves ⁇ en ⁇ yad ⁇ iv ⁇ sud ⁇ zhny ⁇ s ⁇ eds ⁇ (an ⁇ i ⁇ nvul- san ⁇ v) is ⁇ lzuemy ⁇ the purpose ⁇ u ⁇ i ⁇ vaniya e ⁇ ile ⁇ iches ⁇ i ⁇ sud ⁇ zhny ⁇ ⁇ i ⁇ ad ⁇ v, ⁇ a ⁇ ie ⁇ a ⁇ ⁇ en ⁇ ba ⁇ bi ⁇ al, val ⁇ a ⁇ na ⁇ iya, and ⁇ a ⁇ bamaze ⁇ in d ⁇ ugie ( ⁇ .D. ⁇ ash ⁇ vs ⁇ y, Le ⁇ a ⁇ s ⁇ - governmental s ⁇ eds ⁇ va, 1984, ⁇ editsina ( ⁇ s ⁇ va), p. 27-28, 148, 20 153-154).
  • the indicated medium is more effective for the purchase of an epilepticus status and temporal epileptic lesions and tonic cardiomyopathic disease; Infectious diseases are more resistant to treatment. 35
  • the high efficiency of the diazepam when it comes to buying an epilepticus status in a number of cases its use does not prevent; in such cases, use is made of sharp medications (separately, either in combination with diazepam).
  • the improved complex of mediators is effective in case of epileptic - 2 - the status is 6-19 ⁇ .
  • a well-known compound is 8-chloro- ⁇ - ( ⁇ -methyl pyperazin-4-yl) - dibenzo [b, e] [ ⁇ , 4] diazepine, which is a disintegrant of the drug, is a ⁇ réelle On the quality of the neurological medicine ( ⁇ .D. ⁇ asko ⁇ réelleskiy, Medicinal products, 1984, Medicine (Yoscva), pp. 67-68).
  • Clozapine in clinical practice is chemically strong with a sedative heart rate of 10 nents. It is advantageously distinguished from other neuroleptic drugs in the absence of extraneous natural phenomena. It does not cause severe general oppression, such as chlorpromazine (and other aliphatic phenothiazines), and in some cases it is ineffective.
  • the basic task of the invention is to create new 25 compounds with a high effective trial, low physical injuries, and low
  • ZEYA- new compounds are produced - derivatives of 5-amine-8- ⁇ loo-di-30 benzo [b, e] [ ⁇ , 4] diazepine in general:
  • the inventive compound is found to have a high impairment of activity, which increases the effectiveness of the vessel and has a good health outcome.
  • the inventive compound in connection with the effect on the central nervous system is close to the treatment of the neuropathy - klezapine (lepros) - 4 - considering that there is a negative presence of a pronounced court action.
  • This connection provides a penny system for the biological sycis (non-therapeutic and non-judicial active). 5
  • the most active of the claimed compounds finds application in the scope of the active substance of the drug.
  • the inventive drug may be approximately 15 non-pharmaceutical in any pharmaceutical program.
  • a preferable product is used in the form of a battery with a content of 0.05-0, 1 g per one tablet.
  • the fair ship activity of the interested people was studied at the test of the maximum power supply for white - 6 - step, weighing 18-23 grams.
  • the shipping agent used a variable electric speed of 50 g: ⁇ and a power of 50 m.
  • the rat was administered with an internal dose of 100 mg / kg in the form of a fresh-water solution. This dose in all mice develops spasms, and the latent transition of the cortex increases 1.7–2 minutes.
  • the compliant active activity (test of the maximum electric shock) is in the process of being in disarray.
  • the number of occupied compounds is substantially lower than that of the phenobital, karbamazepin and the claimed compound ⁇ b, but higher than that of the Kaluga nation.
  • ⁇ ) 50 compound is equal to karbamazepinu
  • the inventive compound is subject to the claimed compound at a magnitude of a protective index of 25.9 times, and 20 at a conditional speed of 4.5 hours. - 9 -
  • Chart 2 Beneficial shipworthiness and easy access to connected connections
  • the claimed compound is 30.0 25.0 I a (24.3-36.9) (122, 1–28, 3)
  • the claimed compound is 25.0 27.5 based Market s (18.5-33.8) (14.1-53.6)
  • the claimed compound is 33.0 33.5 I ⁇ (25.0-43.6) (30.2-37.2)
  • the claimed compound is 30.0 66.0 I e (22.2-40.5) (48.2-90.4)
  • connection I 6 there is a maximum electric connection of 20 connection I 6 as well as the declared connection of the United States, and the remaining declared connections of the connection are 1.5-1.
  • the only claimed connection is that it fails to connect to other connections.
  • ⁇ z ⁇ sn ⁇ vanii ⁇ vedenny ⁇ is ⁇ y ⁇ any us ⁇ an ⁇ len ⁇ , ch ⁇ 35 zayavlyaeshe s ⁇ edineniya ⁇ n ⁇ sya ⁇ sya ⁇ mal ⁇ sichny ⁇ l s ⁇ edine- niyay Lg lyshey for 5 d ( ⁇ nu ⁇ ) s ⁇ s ⁇ avlyayu ⁇ ⁇ 254 mg / ⁇ g d ⁇ 1182 mg / ⁇ g, ⁇ ⁇ ⁇ emya ⁇ a ⁇ s) 50 ⁇ en ⁇ ba ⁇ bi ⁇ ala - II - 175 mg / kg, karbamazepine 550 mg / kg, and 155 mg / kg.
  • the hypothetical effect of the claimed compound is observed in the dose, equal to 1/5 of the name, and in the case of a decrease to 1/40, it is less than 5 days long.
  • the claimed compound is 500 120 36.3 N ° 30 36.8 15 36.5 6 36.4
  • Clozapine will have a significant effect on the dynamic response of low-dose and alternative reactions ( ⁇ ) 50, respectively 5.9 and 5.4 mg / kg).
  • the claimed connection is 20 I have a medicament sleep. But, in doses of 30-120 mg / kg, it is 3-7 times that you get more sleep, caused by malignant hydrochloride. And so on - 14 - Africa with small doses of the medal, the claimed compound has the potential to act on the last, with a 50 dose of 13.5 mg / kg.
  • the claimed compound is char- acterized by a neuroleptic and judicial activity.
  • the separation of the components and the privacy of the connected connection to the external and external control unit has shown the following.
  • the claimed connection is 205.9 124, 4 ⁇ _
  • Nia ⁇ a been studied ⁇ ⁇ yadu ⁇ bsche ⁇ inya ⁇ y ⁇ e ⁇ s ⁇ e ⁇ imen ⁇ al- ny ⁇ sud ⁇ shsh ⁇ ⁇ es ⁇ on bely ⁇ msh ⁇ a ⁇ ⁇ i ⁇ nu ⁇ ib ⁇ yushin- n ⁇ m and ⁇ e ⁇ aln ⁇ m ⁇ u ⁇ ya ⁇ administration.
  • the most useful products are the ones you have studied. They have been studied at the test of the smallest power supply. In this form of court
  • the claimed Primary Compound is 60 ' mg / kg 35. • " ⁇ ⁇ ⁇
  • the numerator is the number of mice without a ship
  • the denominator is the number of mice in the group. From the official table II, it is visible that the claimed connection is simple and secure, and there is no need for any kind of disruption.
  • the division of the product is a prod- uctive matter of the highest electrical safety factor in the case of a maximum electrical shock Comparative data
  • the claimed compound is ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • test should be waited for.
  • Diazepam ⁇ DILI ⁇ - is itself not muscle in a dose of 2 ig / kg.
  • the active diazepam was studied in a uniformly effective way for a given dose of 2 mg / ml. ⁇ ved-
  • the activities of the claimed compounds were studied in doses of 5.10 and 30 ig / kg. Introduction of the claimed compound in doses of ⁇ 5 and 10 ml / kg after 25-70 minutes after application of the penis
  • Diazepam used in the clinic for the treatment of the status of the epilepticus and the treatment of the status of the abscesses, indicates various types of therapies for the onset of the disease
  • the claimed compound is an active substance for the treatment of epilepsy and epilepticus status.
  • the claimed drug is indicated for 10 generalized epilepsies, partial symptoms of different localization, serial symptoms and epileptic systems.
  • the inventive preparation may be used in any other medicinal product.
  • a preliminary declaration of 15 preparations is in the form of a tablet with the contents of the active substance 0, 05-0, 1 g per one tablet.
  • the highest direct dose of the drug is 0.4-0.6 g, the highest daily dose is 2.0-2.4 g.
  • the drug has minor injuries: there is no
  • the reactive mixture is stirred for 1 hour, then the undisturbed sediment is washed off and washed off on a 50-water filter. Filtration eliminates the risk of stirring and cooling.
  • ⁇ YPARISHI The plant is equipped with filters, they wash 500 ml of water on the filter with water up to 8 and dry it on the air.
  • P ⁇ sle 30 ⁇ e ⁇ e ⁇ is ⁇ allizatsii of me ⁇ il ⁇ g ⁇ s ⁇ i ⁇ a ⁇ luchayu ⁇ ⁇ esches ⁇ - ⁇ , ne ⁇ as ⁇ shd ⁇ e ⁇ ⁇ de, ⁇ as ⁇ im ⁇ e ⁇ atse ⁇ ne, ⁇ l ⁇ - ⁇ yu ⁇ me, ⁇ ED ⁇ Y ⁇ ⁇ isl ⁇ a ⁇ , ⁇ em ⁇ e ⁇ a ⁇ u ⁇ a ⁇ la. ⁇ 39- ⁇ 4 ⁇ ° ⁇ .
  • connection is lower than 4-minutes.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dérivés de 5-amino-8-chlore-dibenzo[b,e][1,4]-diazépine de la formule générale (I), dans laquelle R = H ou -COR', dans laquelle R' = CH3, C2H5, C3H7, C4H9, C5H11 and CH(CH3)2. Les composés de l'invention présentent une activité anti-convulsive. Une préparation pharmaceutique de traitement de l'épilepsie et d'états épileptiques comprend, à titre de substance active, les composés de l'invention les plus efficaces: 5-acétylamino-8-chlore-11-(1-méthylpipérazine-4-yl)-dibenzo[b,e][1,4]-diazépine.
PCT/SU1991/000001 1990-01-11 1991-01-10 DERIVES DE 5-AMINO-8-CHLORE-DIBENZO[b,e][1,4]-DIAZEPINE ET PREPARATION PHARMACEUTIQUE DE TRAITEMENT DE L'EPILEPSIE AINSI QUE D'ETATS EPILEPTIQUES A BASE DESDITS DERIVES Ceased WO1991010661A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SU4781552 1990-01-11
SU4781552/04 1990-01-11
SU4797175/04A SU1713245A1 (ru) 1990-01-11 1990-01-11 5-АЦЕТИЛАМИНО-8-ХЛОР-11-(1-МЕТИЛПИПЕРАЗИН-4-ИЛ)ДИБЕНЗО[b,e][1,4]ДИАЗЕПИН, ОБЛАДАЮЩИЙ ПРОТИВОСУДОРОЖНОЙ АКТИВНОСТЬЮ
SU4797175/04 1990-01-11

Publications (1)

Publication Number Publication Date
WO1991010661A1 true WO1991010661A1 (fr) 1991-07-25

Family

ID=26666226

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SU1991/000001 Ceased WO1991010661A1 (fr) 1990-01-11 1991-01-10 DERIVES DE 5-AMINO-8-CHLORE-DIBENZO[b,e][1,4]-DIAZEPINE ET PREPARATION PHARMACEUTIQUE DE TRAITEMENT DE L'EPILEPSIE AINSI QUE D'ETATS EPILEPTIQUES A BASE DESDITS DERIVES

Country Status (1)

Country Link
WO (1) WO1991010661A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2557241C1 (ru) * 2014-07-31 2015-07-20 Общество с ограниченной ответственностью "Валентек" (ООО "Валентек") Способ синтеза фторклозапина и его производных

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4096261A (en) * 1977-02-23 1978-06-20 Abbott Laboratories Dibenzodiazepines
CH601288A5 (en) * 1976-06-09 1978-07-14 Sandoz Ag 11-Piperazino-5H-di:benzodiazepine derivs.
GB1554275A (en) * 1975-09-24 1979-10-17 Sandoz Ltd Dibenzo(b,e)-(1,4)diazepines
US4208207A (en) * 1975-10-15 1980-06-17 Tareh El Gammal Carrier body and method for introduction of a reaction agent into metal melts
SU920055A1 (ru) * 1979-01-11 1982-04-15 Новокузнецкий научно-исследовательский химико-фармацевтический институт Способ получени 8-хлор-11-/4-метилпиперазино/-5н-дибензо/в,е,//1,4-/диазепина
US4388237A (en) * 1979-05-10 1983-06-14 Basf Aktiengesellschaft 6(1-Piperazinyl), piperidino and (1(homopiperazinyl)11-cyanomethylene morphanthridines

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1554275A (en) * 1975-09-24 1979-10-17 Sandoz Ltd Dibenzo(b,e)-(1,4)diazepines
US4208207A (en) * 1975-10-15 1980-06-17 Tareh El Gammal Carrier body and method for introduction of a reaction agent into metal melts
CH601288A5 (en) * 1976-06-09 1978-07-14 Sandoz Ag 11-Piperazino-5H-di:benzodiazepine derivs.
US4096261A (en) * 1977-02-23 1978-06-20 Abbott Laboratories Dibenzodiazepines
SU920055A1 (ru) * 1979-01-11 1982-04-15 Новокузнецкий научно-исследовательский химико-фармацевтический институт Способ получени 8-хлор-11-/4-метилпиперазино/-5н-дибензо/в,е,//1,4-/диазепина
US4388237A (en) * 1979-05-10 1983-06-14 Basf Aktiengesellschaft 6(1-Piperazinyl), piperidino and (1(homopiperazinyl)11-cyanomethylene morphanthridines

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2557241C1 (ru) * 2014-07-31 2015-07-20 Общество с ограниченной ответственностью "Валентек" (ООО "Валентек") Способ синтеза фторклозапина и его производных
WO2016018173A1 (fr) * 2014-07-31 2016-02-04 Общество С Ограниченной Ответственностью "Валентек" Procédé de synthèse de fluoro clozapine et de ses dérivés

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