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SU626702A3 - Method of producing thieno/1,5/benzodiazepine or their salts - Google Patents

Method of producing thieno/1,5/benzodiazepine or their salts

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Publication number
SU626702A3
SU626702A3 SU762406250A SU2406250A SU626702A3 SU 626702 A3 SU626702 A3 SU 626702A3 SU 762406250 A SU762406250 A SU 762406250A SU 2406250 A SU2406250 A SU 2406250A SU 626702 A3 SU626702 A3 SU 626702A3
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SU
USSR - Soviet Union
Prior art keywords
benzodiazepine
salts
thieno
fluoro
ethyl
Prior art date
Application number
SU762406250A
Other languages
Russian (ru)
Inventor
Кумар Чакрабарти Джибан (Индия)
Эдвард Таппер Дэвид (Великобритания)
Original Assignee
Лилли Индастриз Лимитед (Фирма)
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

И обрртение отнсхзитс  к способу полу чени  новых THeHoj l,5j бензоаназепинов, обла/аюшнх венными фармакологЕгческнмн свойствами. С целью расширени  арсенала редст воздействн  на жнвой организм предлагаетс  основанный на известной реаконн N -алкнлнровани  ij способ получени  тие о 1,5 бензодназешгаов обшей фор1 4улы . т VT.xV ---- где 1 и R - водород нлн галоген; F - группа формулы где R С i - С -алкил, бензил или (CHjj) ОН, гае ц - 2 или 3, кольцо Т - тнофеновое кольао, сконденсированное с диазепиновым  дрс н незам ценвое или замешенное одной или дву.м  группами, выбранными нз С -С -влкн.ла , С21-С -алкеннла, С.-С/-галогенап«свла , С - -алкааоипа, нитрогруппы, галогена н фенила, или нх солей путем взаимоде ггвн  соединени  обшей формулы гае F. , R н кольцо Т имеют указанные значени  с алквлнруюшкм агентом обшей формулы . гае R имеет указанные Качени , X - еакаионноспособна  группа. Целевой продукт выдел ют нзвестнымн приемами в свободн(л состо ннн  лн в виде соли. 362 Новые TMeHo l,5J бензодиазепкны могут существовать в трех видах формул в. Радикал Ci-СА алкил - метил, этил, изопропил, Н бутил, втор.бутил, кзобутил и н-Йутил, Раднкал X - .реакционноспособный .атом, такой как хлор, бром йод, или реакнйонноспособна  групп фовка, така  как тоэил или мезил. t-«. 1,5 бенэодиазепины йвлаютс  полезными как в виде свободного основани , так и в форме их солей. Эти соли предпочтительно  вл ютс  фармацевтически приемлемыми, нетоксичными сол ми подход щих кислот, например неорга нических кислот, таких как сол на , . мистоводородна , азотна , серна  шш фосфорна , или органических кислот, таких как органические карбоновые кислотьч, например г лик о лева , малеинова , скск малеинова , фурмарова ,  блочна , винна  лимонна , салицилова , о -ацетоксйбен@ой«на , никотинова  или изоникотинова , или органические сульфоновые кислоты, например метансульфонова , этансульфоиовал 2-.оксиэтансульфонова , толуолсульфонова  или нафталиН 2 Сульфонова . Помим фар -. мацевтически приемлемых солей получают также соли пикриновой и щавелевой кисло ты, они могут служить- в качестве проме жуточных продуктов при очистке целевых соединений или при получении целевых фар мацевтически приемлемых солей, или  вл  ютс  полезнь ми при идентификации илй оч отке указанных оснований. Пример. 10-(4-п-хлорбензил -1-пиперазиш1л)2«-этил-7-фтор-4Н-тие но ,.5J бензодиазепин. Смесь 2-этил 7-фтор-1О( 1-41ипера-. зинил)-4Н тиено|2,3--Ъ1Г1.52бенэоаиазе гаша (1,0 г 0,ООЗ моль), п- лорбензилхлорида (0,38 г, 0,0033 моль) итриати амина (1,0 мл ) в этаноле . (25 мл) кип т т 16 ч с обратным холодильником , выпаривают досуха и цел т между водой и метиленхлори дом. С ганнческве экстракты промывают водой, суша над сульфатом мапш  ш шаривавл- в вакууме и получают целевой бензодназв ин в виде твердого вещества, т. пл, 66-168с (СН2;СЕ„гексан). Аналогично получают; 1(5„(4 бензил 1-пиперазинил)-2этил 4Н тиено 2 ,3-Ь1 1 iS бензодиаае ин , т. пл. 79-80 0. В данной реакции бензилбромид выстуает в качестве алкилирующего агента. 10( 4 бензил-1-пиперазинил) .. о L3,.5j бензодиазепин, т.-пл. 19800 0 (этилацетат); 7-фтор-10-.( 4 бензил 1-.пиперазин)4Н тиено|з ,,5J бензодиазепин, . пл. 180 1820С (СНСЕ). 10( 4-.нзил-1.пиперазинил)-4Н-тиео 3,,5 бензодиазепин, т. пл, 21-222, 7-фтор-2«-меткл 1О.( 4 1 1етил-.1-пипеa3HHHn ),3J(l ,5 бензодиаепин , т. пл, 7 фтор 2-этил 1О-( 4 метил-1 ипера иннл)4Н тиено 2 ,,5 бензойиазе-. га, т. пл., . П р и м е р 2. 2-Зтил-7-фтор-1О .4( 2 оксиэтил)-1-пипераз11Нкл1 4Н-тиеHo 2 ,,5 бензодказепин. Смесь 2-этил-7-фтзр-.10( 1-липеразкшш )4Н-.ткено 2.3-Ъ ,5 бензодиазе пина (1,65 г, О,О05 моль) и этиленбромгидрина (1,25 г, О,О1 моль) в 90%-ном этаноле (15О мл) и триэтиламине (2,О2г 0,О2 моль) кип т т 16 ч с обратньпу xoiлодильником в атмосфере азота, выпаривают Jjocyxa, дел т между водой и метиленхлоридом , метиленхлоридный экстракт промывают водой, сушат над сульфатом магни , выпаривают досуха и получают т,пл. 173-175 С целевое соединение, (СН СЕ -гексан). Аналогично получают следукхцие соединени : . , 7-фтор-10- 4 -(2 оксиэтил)-1-пиперазитш 4Н™тйено з , ,5 бензодиазепин , Т.ПЯ. (CHC%), 2«-этил--7-фтор-1О-.4-( 3.оксипропил) 1 Липеразшшп -4Н- .тиено 2,,5 бензодиааепин, т.пл. 145-148 С (С С2 -гексан ), бензодиазепин, т.пл. 172-17;ГС (этилацетат.гексан). 7-.фтор--1О 4- (3 оксипропил)-1 пиперазинил - Н-тиено 3,,б бензодиазепин , д.пл. 138-14ОС (CHCl ); (3-оксипропил)-1-пиперазинил - ™4Н-/гиено L3,,5J бензодиазепин, т.пл. 184°С. Строение полученных соединений подтверждено данными ЯМР- и УФ- спектров .And the attribution of attitudes to the method of obtaining new THeHoj l, 5j benzanoazepines, regional pharmacologists, their diagnostic properties. In order to broaden the arsenal, a reduction in the organism of a stubble organism proposes a method, based on the known N-alkylation reaction ij, of preparing about 1.5 benzene derivatives of the total form1 of oil. t VT.xV ---- where 1 and R is hydrogen nl halogen; F is a group of the formula where R С i is C alkyl, benzyl or (CHjj) OH, hee c is 2 or 3, the T ring is a tinophen colo condensed with diazepine drs n uncensored or mixed with one or two groups selected nz C-C -vlnla, C21-C-alkennla, C.-C / -halogenoplum, C -alkaoipa, nitro, halogen n phenyl, or nx salts by the interaction of the compound of the general formula hei F., R The ring T has the indicated meanings with an alkaline agent of general formula. R has the specified Rolling, X - active group. The target product is isolated by known methods in free form (as a salt. 362 New TMeHo, 5J benzodiazepcans can exist in three types of formulas in. Radical Ci-CA alkyl - methyl, ethyl, isopropyl, H butyl, sec. Butyl , ksobutyl and n-Yutyl, Radnkal X -. reactive. atom, such as chlorine, bromine, iodine, or reactive groups, such as tooyl or mesyl. t- ". 1,5 beneodiazepines are useful both as a free base and and in the form of their salts. These salts are preferably pharmaceutically acceptable, non-toxic salts. and suitable acids, for example, inorganic acids, such as hydrochloric, hydrosulfuric, nitric, sulfuric phosphoric, or organic acids, such as organic carboxylic acids, for example, oleukene, maleic, maleskin, furmarova, block, wine citric, salicylic, o-acetoxyben @ oi “on, nicotinic or isonicotinic, or organic sulfonic acids, for example methanesulfonic, ethanesulfonic 2-.-oxyethanesulfonic, toluenesulfonic or naphtaliN 2 sulfonic. Mark headlights -. salts of acceptable salts also receive salts of picric and oxalic acids, they can serve as intermediates in the purification of the target compounds or in the preparation of the target pharmaceutically acceptable salts, or they are useful in identifying these reasons. Example. 10- (4-p-chlorobenzyl -1-piperazisl) 2 "-ethyl-7-fluoro-4H-tie but .5J benzodiazepine. A mixture of 2-ethyl 7-fluoro-1O (1-41ipera-. Zinyl) -4H thieno | 2,3 - 1Г1.52beneoaiase gash (1.0 g 0, OOZ mol), p-lorbenzyl chloride (0.38 g, 0.0033 mol) itriate amine (1.0 ml) in ethanol. (25 ml) are refluxed for 16 hours, evaporated to dryness and intact between water and methylene chloride. From Hannescawe extracts are washed with water, dried over sulphate mumsh sharivavl- in vacuum and get the target benzodnane yn in the form of a solid, so pl. 66-168s (CH2; CE „hexane). Similarly receive; 1 (5 „(4 benzyl 1-piperazinyl) -2ethyl 4H thieno 2, 3-Ü1 1 iS benzodiaein, t. Pl. 79-80 0. In this reaction, benzyl bromide acts as an alkylating agent. 10 (4 benzyl-1 piperazinyl) .. about L3, .5j benzodiazepine, mp - 19800 0 (ethyl acetate); 7-fluoro-10 -. (4 benzyl 1-piperazine) 4H thieno | s ,, 5J benzodiazepine, pl. 180 1820С (СНСЕ). 10 (4-.snyl-1.piperazinyl) -4H-thieo 3,, 5 benzodiazepine, m.p., 21-222, 7-fluoro-2 "-metcl 1O. (4 1 1ethyl- .1-pipea3HHHn), 3J (l, 5 benzodiaepine, mp, 7 fluoro 2-ethyl 1O- (4 methyl-1 iper innl) 4H thieno 2, 5 benzoiaza ga, mp, pl. R u mme r 2. 2-Ztil-7-fluoro-1O .4 (2 hydroxyethyl) -1-piperaz11Nkl1 4N-tieHo 2 ,, 5 ba nzodkazepin. A mixture of 2-ethyl-7-ftzr-.10 (1-liperazshsh) 4H-.tkeno 2.3-b, 5 benzodiazine pina (1.65 g, O, O05 mol) and ethylene bromohydrin (1.25 g, O, O1 mol) in 90% ethanol (15 O ml) and triethylamine (2, O2 0, O2 mol) are boiled for 16 h with reverse nitrogen in a nitrogen atmosphere, evaporated with Jjocyxa, divided between water and methylene chloride, the methylene chloride extract is washed with water , dried over magnesium sulfate, evaporated to dryness and get t, pl. 173-175 C target compound, (CH CE-hexane). Similarly, the following compounds are prepared:. , 7-fluoro-10-4- (2 hydroxyethyl) -1-piperazitsh 4H ™ tyeno z, 5 benzodiazepine, T.PYA. (CHC%), 2 "-ethyl - 7-fluoro-1O-.4- (3.oxypropyl) 1 Liperase-4H-type 2, 5 benzodiaepine, 145-148 C (C 2 -hexane), benzodiazepine, so pl. 172-17; HS (ethyl acetate-hexane). 7-fluorine - 1O 4- (3 hydroxypropyl) -1 piperazinyl - H-thieno 3, b. Benzodiazepine, d. 138-14 ° C (CHCl); (3-hydroxypropyl) -1-piperazinyl - ™ 4H- / hyeno L3,, 5J benzodiazepine, m.p. 184 ° C. The structure of the compounds obtained was confirmed by NMR and UV spectra.

Claims (1)

1. Патент ФРГ N 1445888, кл. 12 р iO/01, 1971,1. Patent of Germany N 1445888, cl. 12 p iO / 01, 1971,
SU762406250A 1974-11-26 1976-10-07 Method of producing thieno/1,5/benzodiazepine or their salts SU626702A3 (en)

Applications Claiming Priority (1)

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GB51240/74A GB1533235A (en) 1974-11-26 1974-11-26 Benzodiazepine derivatives

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SU742191705A SU629879A3 (en) 1974-11-26 1974-11-25 Method of obtaining thieno(1,5)-benzodiazepines or salts thereof
SU762406250A SU626702A3 (en) 1974-11-26 1976-10-07 Method of producing thieno/1,5/benzodiazepine or their salts

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AR (1) AR221203A1 (en)
AT (1) AT351547B (en)
AU (1) AU506340B2 (en)
BE (1) BE835932A (en)
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Cited By (1)

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RU2125574C1 (en) * 1992-05-29 1999-01-27 Лилли Индастриз Лимитед Thienobenzodiazepines or pharmaceutically acceptable salts thereof, process for preparing thereof, and pharmaceutical composition

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IL62792A (en) * 1980-05-07 1985-02-28 Byk Gulden Lomberg Chem Fab Acylated dihydrothienodiazepinone compounds,process for their preparation,and medicaments containing them
GB8819059D0 (en) * 1988-08-11 1988-09-14 Lilly Industries Ltd Benzodiazepine compounds & their use as pharmaceuticals
GB9009229D0 (en) 1990-04-25 1990-06-20 Lilly Industries Ltd Pharmaceutical compounds
US6043358A (en) 1995-11-01 2000-03-28 Merck & Co., Inc. Hexahydro-5-imino-1,4-heteroazepine derivatives as inhibitors of nitric oxide synthases
JP3188715B2 (en) * 1995-11-01 2001-07-16 メルク エンド カンパニー インコーポレーテッド Hexahydro-5-imino-1,4-heteroazepine derivatives as inhibitors of nitric oxide synthase
HUP0003718A3 (en) * 1997-09-02 2002-11-28 Welfide Corp Fused thiophene derivatives, use thereof and pharmaceutical compositions containing them
RU2185383C1 (en) * 2001-05-22 2002-07-20 Институт молекулярной генетики РАН 2-methyl-4-(4-methyl-1-piperazinyl)-10h-thieno-[2,3-b][1,5]benzodiazepine high-labeled with tritium
PL199016B1 (en) * 2002-06-20 2008-08-29 Adamed Sp Z Oo Method of manufacture of alanzapine, new derivative of n-demethyl olanzapine and method of manufacture of new derivative of n-demethyl olanzapine
SI21270A (en) 2002-07-15 2004-02-29 Krka, Tovarna Zdravil, D.D., Novo Mesto Crystal forms of olanzapine and procedures for their preparation
DE10301923B3 (en) * 2003-01-17 2004-09-16 Krka Tovarna Zdravil, D.D. Process and intermediates for the production of olanzapine
AR047461A1 (en) * 2004-01-27 2006-01-18 Synthon Bv TRAINING, PURIFICATION AND USE OF N-FORMILOLANZAPINE
AR048272A1 (en) 2004-03-18 2006-04-12 Lek Pharmaceuticals SYNTHESIS OF 2 METHYL - 4- (4- METHYL -1- PIPERAZINIL) - 10 H- TIENO (2,3-B) (1,5) BENZODIAZEPIN AND ITS SALTS, METHODS FOR THEIR PREPARATION, PHARMACEUTICAL COMPOSITIONS CONTAINING IT AND ITS USE IN THE MANUFACTURE OF MEDICINES FOR THE TREATMENT OF MENTAL DISEASES.
EP1778243B1 (en) * 2004-06-30 2012-10-31 Athersys, Inc. Substituted azepine derivatives as serotonin receptor modulators
EP2292624A1 (en) 2009-07-20 2011-03-09 LEK Pharmaceuticals d.d. Process for the purification of olanzapine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2125574C1 (en) * 1992-05-29 1999-01-27 Лилли Индастриз Лимитед Thienobenzodiazepines or pharmaceutically acceptable salts thereof, process for preparing thereof, and pharmaceutical composition

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SU629879A3 (en) 1978-10-25
IL48502A (en) 1980-01-31
HK58681A (en) 1981-12-04
IE42564L (en) 1976-05-26
KE3163A (en) 1981-10-16
ATA898275A (en) 1979-01-15
NL7513833A (en) 1976-05-31
NL186088C (en) 1990-09-17
DE2552403A1 (en) 1976-08-12
ZA757344B (en) 1976-11-24
DD123343A5 (en) 1976-12-12
JPS6044314B2 (en) 1985-10-02
BE835932A (en) 1976-05-25
NZ179335A (en) 1978-11-13
AU8685875A (en) 1977-05-26
CS236753B2 (en) 1985-05-15
IL48502A0 (en) 1976-01-30
SE421209B (en) 1981-12-07
AR221203A1 (en) 1981-01-15
SE429045B (en) 1983-08-08
PH24534A (en) 1990-08-03
DK146887B (en) 1984-01-30
ES443011A1 (en) 1977-07-01
CA1075687A (en) 1980-04-15
IE42564B1 (en) 1980-09-10
FR2292479B1 (en) 1978-07-28
SE7812194L (en) 1978-11-27
CH613455A5 (en) 1979-09-28
DE2552403C2 (en) 1986-06-19
DK146887C (en) 1984-07-09
PH11669A (en) 1978-05-19
MY8200149A (en) 1982-12-31
AT351547B (en) 1979-07-25
CH613454A5 (en) 1979-09-28
JPS5176296A (en) 1976-07-01
AU506340B2 (en) 1979-12-20
NL186088B (en) 1990-04-17
BG29573A3 (en) 1980-12-12
HU172493B (en) 1978-09-28
FR2292479A1 (en) 1976-06-25
YU298375A (en) 1982-10-31
PL100135B1 (en) 1978-09-30
GB1533235A (en) 1978-11-22
RO69912A (en) 1980-08-15
SE7513185L (en) 1976-05-27
DK524175A (en) 1976-05-27

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