DK154296B - 4H-BENZOCYCLO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN-4-ONER USED AS INTERMEDIATE PRODUCTS FOR THE PREPARATION OF THERAPEUTIC EFFECTIVE 4-PIPERIDYLIDEEN-4H-BENZO (4,5) CYCLOHEPTA THIOPHEN-10 (9H) -ONER AND A PROCEDURE FOR MANUFACTURING THESE INTERMEDIATES - Google Patents
4H-BENZOCYCLO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN-4-ONER USED AS INTERMEDIATE PRODUCTS FOR THE PREPARATION OF THERAPEUTIC EFFECTIVE 4-PIPERIDYLIDEEN-4H-BENZO (4,5) CYCLOHEPTA THIOPHEN-10 (9H) -ONER AND A PROCEDURE FOR MANUFACTURING THESE INTERMEDIATES Download PDFInfo
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- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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Description
DK 154296 BDK 154296 B
Den foreliggende opfindelse angår hidtil ukendte 4H-benzo[4,5]-cyclohepta[l,2-b]thiophen-4-oner med den almene formel VThe present invention relates to novel 4H-benzo [4,5] -cyclohepta [1,2-b] thiophen-4-ones of the general formula V
33
OROR
o hvor R1 betegner hydrogen eller i 6- eller 7-stillingen siddendeo where R1 represents hydrogen or in the 6- or 7-position
OISLAND
5 halogen eller alkoxy med 1-4 carbonatomer, og RJ betegner alkyl med 1-4 carbonatomer, til anvendelse som mellemprodukter ved fremstilling af terapeutisk virksomme 4-piperidyliden-4H-benzo[4,5]cyclohepta-[l,2-b]thiophen-10(9H)-oner med den almene formel I5 halogen or alkoxy of 1-4 carbon atoms, and RJ represents alkyl of 1-4 carbon atoms, for use as intermediates in the preparation of therapeutically effective 4-piperidylidene-4H-benzo [4,5] cyclohepta- [1,2-b] thiophene-10 (9H) -ones of general formula I
9 10 hvor r! har den ovenfor anførte betydning, og R^ betegner alkyl med 1-4 carbonatomer, eller syreadditionssalte deraf.9 10 where r! has the meaning given above and R 1 represents alkyl of 1-4 carbon atoms, or acid addition salts thereof.
Opfindelsen angår endvidere en særlig fremgangsmåde til fremstilling af forbindelserne med formlen V.The invention further relates to a particular process for preparing the compounds of formula V.
Mellemprodukterne med formlen V fremstilles ifølge opfindelsen ved 15 omsætning af forbindelser med den almene formel IIThe intermediates of formula V are prepared according to the invention by reaction of compounds of general formula II
hvor r1 har den ovenfor anførte betydning, og X betegner chlor eller brom, med alkanoler med den almene formel IIIwherein R1 is as defined above and X is chlorine or bromine with alkanols of the general formula III
R3OH IIIR3OH III
22
DK 154296 BDK 154296 B
hvor R3 har den ovenfor anførte betydning, og HX-fraspaltning fra de vundne forbindleser med den almene formel IVwherein R 3 is as defined above and HX cleavage from the obtained compounds of the general formula IV
X OR3X OR3
R1--I HR1 - I H
-’ IV- 'IV
o 5 hvor r1, R3 og X har den ovenfor anførte betydning.o 5 where R1, R3 and X have the meaning given above.
Til indføring af ethergruppen i forbindelserne med formlen II omsættes disse med forbindelserne med formlen III, hensigtsmæssigt under opvarmning, fortrinsvis under tilbagesvalings temperatur.For introduction of the ether group into the compounds of formula II, these are reacted with the compounds of formula III, conveniently under heating, preferably under reflux temperature.
Ved omsætningen dannes som eneste reaktionsprodukt forbindelser med 10 formlen IV: Ethergruppen indføres overraskende nok praktisk taget kvantitativt i 10-stillingen i tricyclen.By reaction, as the only reaction product, compounds of Formula IV are formed: surprisingly, the ether group is introduced almost quantitatively into the 10-position of the tricycle.
Til omsætning af forbindelserne med formlen IV til enoletheme med formlen V fraspaltes syren HX under alkaliske betingelser, fx ved behandling af forbindelserne med formlen IV med en opløsning af 15 kaliumhydroxid i et under de herskende betingelser inert organisk opløsningsmiddel såsom methanol.To react the compounds of formula IV into the enol ethers of formula V, the acid HX is decomposed under alkaline conditions, for example by treating the compounds of formula IV with a solution of potassium hydroxide in an organic solvent inert under the prevailing conditions such as methanol.
Forbindelserne med formlen V er værdifulde mellemprodukter. De kan under Grignard-reaktionsbetingelser omsættes med forbindelser med den almene formel VIThe compounds of formula V are valuable intermediates. Under Grignard reaction conditions, they can be reacted with compounds of general formula VI
R2-N y-MgHalR2-N y-MgHal
20 \_/ VI20 \ _ / VI
DK 154296 BDK 154296 B
3 hvor K.2 har den ovenfor anførte betydning, og Hal betegner chlor, brom eller iod, til dannelse af forbindelser med den almene formel VI1 3 oir *‘-QpVi3 wherein K.2 has the meaning given above and Hal represents chlorine, bromine or iodine to form compounds of the general formula VI1 3
OHOH
5 VIIVII
l2L2
RR
hvor R1, og R^ har den ovenfor anførte betydning, og forbindelserne med formlen VII kan ved hydrolyse af enolethergruppen og vandfraspaltning omdannes til forbindelser med den almene formel Iwherein R 1 and R 1 are as defined above, and the compounds of formula VII can be converted into compounds of general formula I by hydrolysis of the enol ether group and water decomposition.
dTdT
1212
ITIT
hvor R·*· og R^ har den ovenfor anførte betydning. Forbindelserne med formlen I er beskrevet i dansk patentskrift nr. 134.404.where R · and · R are as defined above. The compounds of formula I are described in Danish Patent Specification No. 1344.404.
Forbindelserne med formlen I udmærker sig ved histaminolytiske egenskaber, som det fremgår af resultaterne i histamin-toxicitetsfor-15 søg på marsvin, og de kan på grund af disse egenskaber anvendes ved allergiske lidelser af forskelligste oprindelse. Den histaminolytiske virkning af disse forbindelser er specifik, da der ved hjælp af serotonin-toxicitetsforsøg og acetylcholin-toxicitetsforsøg på marsvin ikke kunne fastslås signifikante serotoninantagonistiske og 20 anticholinerge egenskaber.The compounds of formula I are distinguished by histaminolytic properties as evidenced by the results of histamine toxicity studies in guinea pigs, and because of these properties they can be used for allergic disorders of various origins. The histaminolytic effect of these compounds is specific as significant serotonin antagonistic and anticholinergic properties could not be determined by serotonin toxicity and acetylcholine toxicity tests on guinea pigs.
Ved en fra dansk patentskrift nr. 134.404 kendt fremgangsmåde til fremstilling af forbindelserne med formlen I omsættes forbindelserBy a process known from Danish Patent No. 134,404, for the preparation of the compounds of formula I, compounds are reacted.
DK 154296BDK 154296B
44
med formlen II med alkanoler til dannelse af forbindelser med den almene formel VIIIof formula II having alkanols to form compounds of general formula VIII
XX
R1 —1 vin o 5R1 –1 wine o 5
hvor κΛ og X har den ovenfor anførte betydning, de vundne reaktionsprodukter omdannes- ved hjælp af forbindelser med den almene formel VI til forbindelser med den almene formel IXwherein κΛ and X are as defined above, the reaction products obtained are converted by compounds of general formula VI into compounds of general formula IX
XX
- hl, I 2- hl, I 2
i o Ri o R
10 hvor ΚΛ, Rr og X har den ovenfor anførte betydning, forbindelserne med formlen IX omdannes ved hjælp af aminer og/eller kaliumalkohol-ater til forbindelser med den almene formel XWherein ΚΛ, Rr and X are as defined above, the compounds of formula IX are converted by compounds of the formula X by amines and / or potassium alcohol ats.
ϊ '2 R* hvor R·*- og har den ovenfor anførte betydning, og Y betegner en 15 aminorest eller alkoxy, denne forbindelse hydrolyseres, og den vundne blanding af 9-ketoner og 10-ketoner (2:1) adskilles. Denne adskillelse af isomere ketoner foretages med fraktioneret krystallisation af deres fumarater.2 '2 R * where R · * - and is as defined above, and Y represents a 15 amino residue or alkoxy, this compound is hydrolyzed and the resulting mixture of 9-ketones and 10-ketones (2: 1) is separated. This separation of isomeric ketones is done by fractional crystallization of their fumarates.
55
DK 154296 BDK 154296 B
Det kritiske trin i denne fremgangsmåde er omsætningen mellem forbindelserne med formlen IX og aminerne og/eller alkoholaterne, som intermediært forløber via en tredobbeltbinding, hvorved der hovedsagelig dannes 9-enolethere eller 9-enaminer ud over en mindre andel 5 af de ønskede 10-enolethere eller 10-enaminer. Sådanne bireaktioner konstateres ikke ved anvendelse af forbindelserne med formlerne IV og V til fremstilling af forbindelserne med formlen I. Især forløber Grignard-reaktionen mellem forbindelserne med formlen V og forbindelserne med formlen VI glat og giver mindre anledning til 10 bireaktioner end den tilsvarende omsætning mellem forbindelserne med formlen VIII og forbindelserne med formlen VI ifølge fremgangsmåden i dansk patentskrift nr. 134.404.The critical step in this process is the reaction of the compounds of formula IX with the amines and / or alcoholates, which intermediate proceeds via a triple bond, thereby forming mainly 9-enol ethers or 9-enamines in addition to a minor proportion of the desired 10-enol ethers. or 10-enamines. Such side reactions are not found using the compounds of formulas IV and V to prepare the compounds of formula I. In particular, the Grignard reaction between the compounds of formula V and the compounds of formula VI proceeds smoothly and gives less cause for 10 reaction than the corresponding reaction between the compounds of formula VIII and the compounds of formula VI according to the method of Danish Patent Specification No. 1344.404.
Totaludbyttet ved denne fremgangsmåde (ud fra forbindelser med formlen II), hvor forbindelsen med formlen V anvendes, som mel-15 lemprodukt, ligger på 45-60%. Totaludbyttet af 10-ketoner (ud fra forbindelser med formlen II) ved den i dansk patentskrift nr. 134.404 beskrevne fremgangsmåde ligger på 10-15%.The total yield of this process (from compounds of formula II), wherein the compound of formula V is used as an intermediate, is 45-60%. The total yield of 10-ketones (based on compounds of formula II) by the method described in Danish Patent Specification No. 1344.404 is 10-15%.
Opfindelsen belyses nærmere ved nedenstående eksempler, hvor eksempel 1 belyser fremstillingen af mellemprodukterne ifølge opfindelsen, og 20 eksempel A belyser omdannelsen af mellemprodukterne til biologisk virksomme slutprodukter med formlen I.The invention is further illustrated by the following Examples, wherein Example 1 illustrates the preparation of the intermediates of the invention and Example A illustrates the conversion of the intermediates into biologically active end products of formula I.
jEESHSFELIjEESHSFELI
10-Me'dhoxy-^~%enzo[4,5]cycldheptaipl.^^b']thiophen-4-on (forbindelse med formlen V) 25 a) 9-Brom-9,10-dihydro-10-methoxy-4H-benzo[4,5]cyclohepta[l,2-b]-thiophen-4-on (forbindelse med formlen IV).10-Hydroxy-1% enzo [4,5] cycloheptaipl. B) b] thiophen-4-one (compound of formula V) a) 9-Bromo-9,10-dihydro-10-methoxy-4-one 4H-benzo [4,5] cyclohepta [1,2-b] -thiophen-4-one (compound of formula IV).
En suspension af 20 g 9,10-dibrom-9,10-dihydro-4H-benzo[4,5]cyclohep-ta[l,2-b]thiophen-4-on i 400 ml methanol koges i 5 timer under tilbagesvaling. Der fås 9-brom-9,10-dihydro-10-methoxy-4H-benzo[4,5]-30 cyclohepta[l,2-b]thiophen-4-on (smeltepunkt 103-106°C).A suspension of 20 g of 9,10-dibromo-9,10-dihydro-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one in 400 mL of methanol is refluxed for 5 hours . 9-Bromo-9,10-dihydro-10-methoxy-4H-benzo [4,5] -30 cyclohepta [1,2-b] thiophen-4-one is obtained (mp 103-106 ° C).
66
DK 154296 BDK 154296 B
b ) 10 -Me thoxy- 4H -benzo [4,5] cyclohep ta [ 1,2 -b ] thiopben- 4 - on ( forbindelse med formlen V).b) 10-Me thoxy-4H-benzo [4,5] cyclohep ta [1,2-b] thiopben-4-one (compound of formula V).
Til en opløsning af 17,5 g 9-brom-9,10-dihydro-10-methoxy-4H-ben-zo[4,5]cyclohepta[l,2-b]thiophen-4-on (smeltepunkt 103-106°C) i 400 5 ml methanol sættes 9 g kaliumhydroxid, og opløsningen koges under tilbagesvaling i 6 timer. Efter afkøling til 0-5°G frafiltreres det udfældede krystallisat og omkrystalliseres af methanol. På denne måde fås rent 10-methoxy-4H-benzo[4,5]cyclohepta[l,2-b]thiophen-4-on, som smelter ved 164-166°C. Mikroanalysen stemmer overens med formlen 10 ^14^10^2^.To a solution of 17.5 g of 9-bromo-9,10-dihydro-10-methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one (m.p. 103-106 ° C) in 400 5 ml of methanol are added 9 g of potassium hydroxide and the solution is refluxed for 6 hours. After cooling to 0-5 ° G, the precipitated crystallate is filtered off and recrystallized from methanol. In this way pure 10-methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one is obtained, which melts at 164-166 ° C. The microanalysis corresponds to the formula 10 ^ 14 ^ 10 ^ 2 ^.
Analogt med den i eksempel 1 a) beskrevne fremgangsmåde fås under anvendelse af de relevante udgangsforbindelser forbindelser med formlen IVAnalogous to the process described in Example 1 (a), compounds of formula IV are obtained using the relevant starting compounds.
9-Brom-6-chlor-9,10-dihydro-10-methoxy-4H-benzo[4,5]cyclohepta-15 [l,2-b]thiophen-4-on (smeltepunkt 134-136°C); 9- brom-7-chlor-9,10-dihydro-10-methoxy-4H-benzo[4,5]cyclohepta-[l,2-b]thiophen-4-on (smeltepunkt 135-137°C); og 9 -brom-10-butoxy-9,10 - dihydro-4H-benzo [4,5 ] cyclohepta[l, 2-b] thiophen-4-on (smeltepunkt 90-91°C).9-Bromo-6-chloro-9,10-dihydro-10-methoxy-4H-benzo [4,5] cyclohepta-15 [1,2-b] thiophen-4-one (mp 134-136 ° C); 9- bromo-7-chloro-9,10-dihydro-10-methoxy-4H-benzo [4,5] cyclohepta- [1,2-b] thiophen-4-one (m.p. 135-137 ° C); and 9-bromo-10-butoxy-9,10-dihydro-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one (m.p. 90-91 ° C).
20 Analogt med eksempel 1 b) fås de nedenfor anførte forbindelser med formlen V: 6- Chlor-10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-on (smel-tepunkt 220-222°C); 7- chlor-10-methoxy-4H-benzo[4,5]cyclohepta[l,2-b]thiophen-4-on (smel-25 tepunkt 216-218°C); 10- butoxy-4H-benzo[4,5]cycloheptaf1,2-b]thiophen-4-on (smeltepunkt 83-85bC); og 7Analogously to Example 1 b), the following compounds of formula V: 6- Chloro-10-methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one (melting point 220) are obtained. -222 ° C); 7- chloro-10-methoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one (m.p. 216-218 ° C); 10-butoxy-4H-benzo [4,5] cycloheptaf1,2-b] thiophen-4-one (m.p. 83-85bC); and 7
DK 154296 BDK 154296 B
10-ethoxy-4H-benzo[4,5]cyclohepta[l,2-b]thiophen-4-on (smeltepunkt 127-129eC).10-Ethoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one (mp 127-129 ° C).
EKSEMPEL AEXAMPLE A
4-(l-Methyl-4-piperidyliden)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-5 10(9H)-on (forbindelse med formlen I) 3,07 g med iod aktiviserede magnesiumspåner overhældes med 25 ml absolut tetrahydrofuran og tilsættes ca. 1/10 af en opløsning af 17,7 g 4-chlor-l-methylpiperidin-base i 70 ml absolut tetrahydrofuran. Ved tilsætning af nogle dråber 1,2-dibromethan sættes Grignard-reaktionen 10 i gang. Den resterende mængde 4-chlor-l-methylpiperidin-opløsning dryppes nu så hurtigt til magnesiumet, at reaktionsblandingen stadig koger under tilbagesvaling uden ydre varmetilførsel. Blandingen koges derefter i yderligere 1 ti'me under tilbagesvaling. Derefter tilsættes ved 20°C og under let afkøling 15,3 g 10-methoxy-4H-benzo[4,5]-15 cyclohepta[l,2-b]thiophen-4-on portionsvis i løbet af 40 minutter.4- (1-Methyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophen-5 (9H) -one (compound of formula I) 3.07 g with iodine activated Magnesium shavings are poured with 25 ml of absolute tetrahydrofuran and added approx. 1/10 of a solution of 17.7 g of 4-chloro-1-methylpiperidine base in 70 ml of absolute tetrahydrofuran. By adding a few drops of 1,2-dibromoethane, Grignard reaction 10 is started. The remaining amount of 4-chloro-1-methylpiperidine solution is now dropped so rapidly to the magnesium that the reaction mixture still boils under reflux without external heat supply. The mixture is then refluxed for a further 1 hour. Then, at 20 ° C and under slight cooling, 15.3 g of 10-methoxy-4H-benzo [4,5] -15 cyclohepta [1,2-b] thiophen-4-one are added portionwise over 40 minutes.
Efter 1 1/2 times omrøring ved 20“C hældes reaktionsopløsningen ud på en blanding af 180 g is og 20 g ammoniumchlorid. Den frie base ekstraheres med chloroform. Chloroformopløsningen inddampes, og remanensen omkrystalliseres af 270 ml absolut ethanol. På denne måde 20 fås den rene 10-methoxy-4-(l-methyl-4-piperidyl)-4H-benzo[4,5]-cyclohepta[l,2-b]thiophen-4-ol-base, som smelter ved 194-196eC.After stirring for 1 1/2 hours at 20 ° C, the reaction solution is poured onto a mixture of 180 g of ice and 20 g of ammonium chloride. The free base is extracted with chloroform. The chloroform solution is evaporated and the residue is recrystallized from 270 ml of absolute ethanol. In this way, the pure 10-methoxy-4- (1-methyl-4-piperidyl) -4H-benzo [4,5] -cyclohepta [1,2-b] thiophen-4-ol base is obtained which melts at 194-196eC.
Mikroanalysen stemmer overens med formlen C20H23NO2S.The microassay corresponds to the formula C20H23NO2S.
En blanding af 3,4 g 10-methoxy-4-(l-methyl-4-piperid.yl)-4H-ben-zo[4,5]cyclophepta[l,2-b]thiophen-4-ol-base og 40 ml 3N saltsyre 25 holdes i et kogende vandbad i 1 time ved 95-100°C. Derpå indstilles blandingen på alkalisk reaktion ved hjælp af koncentreret natriumhydroxidopløsning under afkøling til 20°C, og den frie base ekstraheres med chloroform. Chloroformopløsningen inddampes, og remanensen omkrystalliseres af ethanol/vand i forholdet 1:1. På denne 30 måde fås den rene 4-(l-methyl-4-piperidyliden)-4H-benzo[4,5]cyclohep-ta[l,2-b]thiophen-10(9H)-on-base, som smelter ved 152-153°C.A mixture of 3.4 g of 10-methoxy-4- (1-methyl-4-piperidyl) -4H-benzo [4,5] cyclophepta [1,2-b] thiophen-4-ol base and 40 ml of 3N hydrochloric acid 25 are kept in a boiling water bath for 1 hour at 95-100 ° C. Then, the mixture is adjusted to alkaline reaction by means of concentrated sodium hydroxide solution under cooling to 20 ° C and the free base is extracted with chloroform. The chloroform solution is evaporated and the residue is recrystallized from ethanol / water in a 1: 1 ratio. In this way, the pure 4- (1-methyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophene-10 (9H) -one base is obtained which melts at 152-153 ° C.
Mikroanalysen stemmer overens med formlen C^gH^gNOS.The microassay corresponds to the formula C C ^HH gNOS.
Analogt med eksempel A fås under anvendelse af:Analogously to Example A is obtained using:
Claims (3)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH98572 | 1972-01-24 | ||
| CH98572A CH568312A5 (en) | 1972-01-24 | 1972-01-24 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK555680A DK555680A (en) | 1980-12-29 |
| DK154296B true DK154296B (en) | 1988-10-31 |
| DK154296C DK154296C (en) | 1989-04-03 |
Family
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK555680A DK154296C (en) | 1972-01-24 | 1980-12-29 | 4H-BENZOCYCLO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN-4-ONER USED AS INTERMEDIATE PRODUCTS FOR THE PREPARATION OF THERAPEUTIC EFFECTIVE 4-PIPERIDYLIDEEN-4H-BENZO (4,5) CYCLOHEPTA THIOPHEN-10 (9H) -ONER AND A PROCEDURE FOR MANUFACTURING THESE INTERMEDIATES |
| DK238090A DK161324C (en) | 1972-01-24 | 1990-10-02 | METHOD FOR PREPARING 4- (1-SUBSTITUTED-4-PIPERIDYLIDE) -4H-BENZO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN-10 (9H) -ONDERIVATIVES |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK238090A DK161324C (en) | 1972-01-24 | 1990-10-02 | METHOD FOR PREPARING 4- (1-SUBSTITUTED-4-PIPERIDYLIDE) -4H-BENZO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN-10 (9H) -ONDERIVATIVES |
Country Status (29)
| Country | Link |
|---|---|
| JP (2) | JPS566997B2 (en) |
| KR (1) | KR780000049B1 (en) |
| AR (1) | AR202094A1 (en) |
| AT (1) | AT334897B (en) |
| AU (1) | AU477308B2 (en) |
| BE (1) | BE794370A (en) |
| CA (1) | CA1006523A (en) |
| CH (1) | CH568312A5 (en) |
| CS (1) | CS183674B2 (en) |
| DD (1) | DD104084A5 (en) |
| DE (2) | DE2302970C3 (en) |
| DK (2) | DK154296C (en) |
| ES (1) | ES410855A1 (en) |
| FI (1) | FI60396C (en) |
| FR (2) | FR2169091B1 (en) |
| GB (2) | GB1422444A (en) |
| HK (1) | HK53480A (en) |
| HU (1) | HU164966B (en) |
| IE (1) | IE38148B1 (en) |
| IL (1) | IL41374A (en) |
| LU (1) | LU66876A1 (en) |
| NL (1) | NL178970C (en) |
| NO (1) | NO136978C (en) |
| PL (1) | PL83921B1 (en) |
| RO (1) | RO63566A (en) |
| SE (1) | SE395696B (en) |
| SU (1) | SU509237A3 (en) |
| YU (1) | YU36173B (en) |
| ZA (1) | ZA73494B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0821909A2 (en) * | 2008-01-30 | 2018-07-17 | Nippon Zoki Pharmaceutical Co., Ltd. | piperidine derivative |
| AU2009277496B2 (en) * | 2008-08-01 | 2013-09-26 | Nippon Zoki Pharmaceutical Co., Ltd. | Aminopropylidene derivative |
| JP5083989B2 (en) * | 2008-11-20 | 2012-11-28 | 日本臓器製薬株式会社 | Medicaments containing piperidine derivatives |
| CN104817532B (en) * | 2015-03-04 | 2017-07-25 | 浙江工业大学 | A kind of preparation method of the ketone of 10 methoxyl group 4H benzos [4,5] cycloheptatriene [1,2 b] thiazole 4 |
-
1972
- 1972-01-24 CH CH98572A patent/CH568312A5/xx not_active IP Right Cessation
-
1973
- 1973-01-12 FI FI89/73A patent/FI60396C/en active
- 1973-01-15 SE SE7300504A patent/SE395696B/en unknown
- 1973-01-16 NO NO185/73A patent/NO136978C/en unknown
- 1973-01-19 NL NLAANVRAGE7300797,A patent/NL178970C/en not_active IP Right Cessation
- 1973-01-19 FR FR7301856A patent/FR2169091B1/fr not_active Expired
- 1973-01-22 CA CA161,801A patent/CA1006523A/en not_active Expired
- 1973-01-22 DD DD168384A patent/DD104084A5/xx unknown
- 1973-01-22 GB GB2921475A patent/GB1422444A/en not_active Expired
- 1973-01-22 BE BE794370D patent/BE794370A/en not_active IP Right Cessation
- 1973-01-22 PL PL1973160372A patent/PL83921B1/pl unknown
- 1973-01-22 GB GB311973A patent/GB1422443A/en not_active Expired
- 1973-01-22 IE IE90/73A patent/IE38148B1/en unknown
- 1973-01-22 KR KR7300110A patent/KR780000049B1/en active
- 1973-01-22 ES ES410855A patent/ES410855A1/en not_active Expired
- 1973-01-22 LU LU66876A patent/LU66876A1/xx unknown
- 1973-01-22 DE DE2302970A patent/DE2302970C3/en not_active Expired
- 1973-01-22 AT AT47873*#A patent/AT334897B/en not_active IP Right Cessation
- 1973-01-22 DE DE2366394A patent/DE2366394C1/en not_active Expired
- 1973-01-22 HU HUSA2446A patent/HU164966B/hu unknown
- 1973-01-22 RO RO7300073573A patent/RO63566A/en unknown
- 1973-01-23 IL IL41374A patent/IL41374A/en unknown
- 1973-01-23 ZA ZA730494A patent/ZA73494B/en unknown
- 1973-01-23 AU AU51378/73A patent/AU477308B2/en not_active Expired
- 1973-01-23 CS CS7300000503A patent/CS183674B2/en unknown
- 1973-01-23 JP JP922773A patent/JPS566997B2/ja not_active Expired
- 1973-01-23 SU SU1874878A patent/SU509237A3/en active
- 1973-01-27 AR AR246230A patent/AR202094A1/en active
- 1973-04-22 YU YU178/73A patent/YU36173B/en unknown
-
1978
- 1978-10-04 FR FR7828336A patent/FR2401153A1/en active Granted
-
1980
- 1980-02-29 JP JP2420780A patent/JPS55129282A/en active Granted
- 1980-09-25 HK HK534/80A patent/HK53480A/en unknown
- 1980-12-29 DK DK555680A patent/DK154296C/en not_active IP Right Cessation
-
1990
- 1990-10-02 DK DK238090A patent/DK161324C/en not_active IP Right Cessation
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| Date | Code | Title | Description |
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| PUP | Patent expired |