WO2004065390A1 - Process and intermediates for the preparation of olanzapine - Google Patents
Process and intermediates for the preparation of olanzapine Download PDFInfo
- Publication number
- WO2004065390A1 WO2004065390A1 PCT/EP2004/000299 EP2004000299W WO2004065390A1 WO 2004065390 A1 WO2004065390 A1 WO 2004065390A1 EP 2004000299 W EP2004000299 W EP 2004000299W WO 2004065390 A1 WO2004065390 A1 WO 2004065390A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- benzodiazepine
- mmol
- olanzapine
- reaction
- dichloromethane
- Prior art date
Links
- SMJOWOWYVULWSW-UHFFFAOYSA-N CC(C)CC(C1C(N2CCN(C)CC2)=Nc(cccc2)c2N=C1N1CCN(C)CC1)O Chemical compound CC(C)CC(C1C(N2CCN(C)CC2)=Nc(cccc2)c2N=C1N1CCN(C)CC1)O SMJOWOWYVULWSW-UHFFFAOYSA-N 0.000 description 1
- HEPWKRXLUSZLEJ-DJFIPANJSA-N CC/C=C1/C(N2CCN(C)CC2)=NC(/C=C\C)=C(C)N=C1N1CCN(C)CC1 Chemical compound CC/C=C1/C(N2CCN(C)CC2)=NC(/C=C\C)=C(C)N=C1N1CCN(C)CC1 HEPWKRXLUSZLEJ-DJFIPANJSA-N 0.000 description 1
- XOINBKIDYXJYFM-UHFFFAOYSA-N CN(CC1)CCN1C(C1)=Nc(cccc2)c2N=C1N1CCNCC1 Chemical compound CN(CC1)CCN1C(C1)=Nc(cccc2)c2N=C1N1CCNCC1 XOINBKIDYXJYFM-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N CN1CCNCC1 Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- CQPTVHYZSDDQLT-UHFFFAOYSA-O Cc1cc(C(N2CCN(C)CC2)=NC(C=CC=C2)C2=[NH+]2)c2[s]1 Chemical compound Cc1cc(C(N2CCN(C)CC2)=NC(C=CC=C2)C2=[NH+]2)c2[s]1 CQPTVHYZSDDQLT-UHFFFAOYSA-O 0.000 description 1
- TWIPZRDLVIKTEE-UHFFFAOYSA-O NC(C1)=Nc2ccccc2N=C1[NH3+] Chemical compound NC(C1)=Nc2ccccc2N=C1[NH3+] TWIPZRDLVIKTEE-UHFFFAOYSA-O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic 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
- C07D495/04—Ortho-condensed systems
-
- 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
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
Definitions
- Olanzapine is a serotonin (5-HT 2 ) and dopamine (O 1 /O 2 ) receptor antagonist with anticholinergic activity. It is useful in treat- ing psychotic conditions such as schizophrenia, schizophreniform disorders, acute mania, states of mild anxiety and psychosis.
- R and R represent various substituents, e.g. hydrogen
- R c represents amine substituents, e.g. 4-methylpiperazinyl
- T represents thiophene rings fused to the [1, 5] -benzodiazepine ring.
- R and R represent various substituents, e.g. hydrogen
- R c represents amine substituents, e.g. 4-methylpiperazinyl
- T represents thiophene rings fused to the [1, 5] -benzodiazepine ring.
- An example of these derivatives is 2-methyl-10ff-thieno-
- this thiophene is then (c) reduced and cyclised to a benzodiazepine-4-amine hydrochloride .
- Replacement of the amine group by 1-methylpiperazine (d) leads to the desired Olanzapine.
- the thiophene is catalytically hydrogenated to an amino-ester (e) , which is then transformed into an amino-amide (f) , and this amino-amide is subsequently cyclised (g) to give Olanzapine.
- This second approach requires chromatographic purification in each step, because the reactions
- X is CN and in path 2, X is COOR, e.g. COOC 2 H 5 .
- the reagents used in the respective steps of the reactions were as follows: (a) Et 3 N, DMF; (b) NaH, THF; (c) SnCl 2 , HCI; (d) DMSO, toluene; (e) H 2 , Pd/C, EtOH-EtOAc; (f) TiCl 4 , anisole; (g) TiCl 4 , anisole.
- a preferred leaving group R3 is -OR .
- R4 can preferably be H, so that the leaving group R3 is preferably an alkohol group.
- the compound to be converted is the diazepine-alcohol of the following formula VI:
- R4 can also be selected from the group of acyl, sulfonyl, pre- ferably trifluoroacetyl and methane sulfonyl, so that the leaving group R3 is an ester group, and the compound to be converted is the benzodiazepine-ester of the following formula VII:
- R4 being preferably selected from the group of acyl, sulfonyl, and with R4 most preferably being trifluoroacetyl or methane sulfonyl.
- the reagents used in the respective steps are preferably as follows :
- the use of symmetrical intermediates according to the present invention is particularly advantageous because the possibility of obtaining undesired regioisomeres is exluded.
- Olanzapine can be produced in a reaction (e) of the propylidene- benzodiazepine of formula III with a source of sulphur [S] , preferably elementary sulphur or sodium poiysuiphide, which is usually base mediated.
- a source of sulphur [S] preferably elementary sulphur or sodium poiysuiphide, which is usually base mediated.
- An appropriate base can be chosen among secondary or tertiary alkylamines of formula R NR R , in which R is H or R 2 , and R 2 is a C x - to C 5 -alkyl or cyclic amine such as morpholine, piperidine, piperazine or 1-methyl-piperazine .
- the base is chosen from tertiary alkyl-amines and the most preferable base is triethylamine .
- Acceptable solvents for the reaction are N-methyl- imidazole, dimethyl sulfoxide (DMSO) , C]_- to C 5 -aliphatic alcohols, alcoholamines, diols, polyols or mixtures thereof, preferably mixtures of dimethyl sulfoxide and alcohols .
- An appropriate reaction temperature range is from room temperature to the boiling point of the reaction mixture, preferably from 50°C to 150°C and most preferably is a reaction temperature of about 100°C.
- the reaction can also be mediated with a salt AHB.
- This salt is composed of an acid AH and an amine B.
- the acid AH can be chosen among organic or anorganic acids .
- Preferred are organic car- boxylic or sulfonic acids, such as acetic acid, ' trifluoroacetic acid, benzoic acid, 4-nitrobenoic acid, 4-chlorobenzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzene- sulfonic acid or p-toluenesulfonic acid and most preferred are p-toluenesulfonic acid or methanesulfonic acid.
- the amine B can be chosen among secondary or tertiary aliphatic or aromatic amines.
- Preferred aromatic amines are pyridine picoline, luti- dine, quinoline, 2-methylquinoline or 1-methylimidazole and most preferred are pyridine or quinoline.
- Either part of the salt AHB can be polymer bound.
- Acceptable solvents for the reaction are high boiling point solvents. They can be hydrocarbons, ethers, esters, nitriles or alcohols or mixtures thereof.
- aromatic ethers, esters, or nitriles such as anisole, di- methoxybenzene, diphenyl ether, methyl benzoate, ethyl benzoate and benzonitrile and most preferred is benzonitrile .
- An appro- priate reaction temperature range is from 80°C to 220°C, preferably from 100°C to 180°C and most preferred is a reaction temperature of about 140°C.
- the propylidene-benzodiazepine of formula III can preferably be synthesised via step (b) from the benzodiazepine of formula IV.
- the benzodiazepine IV is firstly transformed to an alkali salt using strong bases such as alkali amides, alkali alkyls or alkali silazanes.
- strong bases such as alkali amides, alkali alkyls or alkali silazanes.
- LDA lithium diisopropylamide
- butyl-lithium is used and most preferably lithium diisopropylamide is used.
- the alkali salt of the benzodiazepine IV to propionaldehyde .the benzodiazepine-alcoholate of the alcohol of formula VI is formed.
- the solvent for this reaction should be inert to strong bases and it is in particular chosen from ethers or aromatic hydrocarbons. Water miscible ethers are preferred, with the most preferable solvent being THF. Usual reaction temperatures range from -50 °C to room temperature, preferably from -30 °C to 0 °C.
- the benzodiazepine-alcoholate is than transformed to a benzodiazepine-ester of formula VII, in which R4 is in particular selected from the group of acyl or sulfonyl, preferably acetyl trifluoroacetyl or methane sulfonyl, with trifluoroacetyl being most preferred.
- the elimination of said ester group to produce the propylidene-benzodiazepine of formula III is accomplished by adding of an aqueous solution of alkali hydroxide salts such as lithium hydroxide, sodium hydroxide or potassium hydroxide and preferably is an aqueous solution of sodium hydroxide.
- alkali hydroxide salts such as lithium hydroxide, sodium hydroxide or potassium hydroxide and preferably is an aqueous solution of sodium hydroxide.
- the reaction can be catalysed with quarternary ammonium salts, such as tetraalkylammonium chlorides, bromides, fluorides, hydroxides or cyanides, wherein "alkyl” represents groups having 1 to 8 carbon atoms.
- the reaction is catalysed with tetrabutylammonium bromide or hydroxide and most preferably with tetrabutylammonium bromide. It is most preferable that the sequence of these reactions is conducted as a one pot reaction.
- the propylidene-diazepine of formula III can be prepared via step (d) starting from the benzodiazepine-alcohol of formula VI.
- the procedure is similar to the second part of step (b) .
- the benzodiazepine-alcohol is first transformed to a diazepine-ester of formula VII, in which R4 is in particular selected from the group of acyl or sulfonyl, preferably acetyl, trifluoroacetyl or methane sulfonyl, with trifluoroacetyl being most preferred.
- R4 is in particular selected from the group of acyl or sulfonyl, preferably acetyl, trifluoroacetyl or methane sulfonyl, with trifluoroacetyl being most preferred.
- the elimination of the ester group to produce the propylidene-benzodiazepine of formula III is preferably carried out in a one
- the organic solvent can be chosen from ethers, halogenated hydrocarbons or aromatic or aliphatic hydrocarbons and is preferably chosen from tetrahydrofuran, dichloromethane or toluene, with the most preferable solvent being tetrahydrofuran.
- the second solvent can be an aqueous solution of alkali hydroxide salts such as lithium hydroxide, sodium hydroxide, or potassium hydroxide and preferably is an aqueous solution of sodium hydroxide .
- the reaction can be catalysed with quarternary ammonium salts such as tetraalkylammonium chlorides, bromides, fluorides, hydroxides or cyanides, wherein "alkyl” represents groups having 1 to 8 carbon atoms.
- the reaction is catalysed with tetrabutylammonium bromide or hydroxide and most preferably with tetrabutylammonium bromide. It is most preferable that esterification and subsequent elimination of the resulting ester group are conducted as a one pot reac- tion.
- the benzodiazepine-alcohol of formula VI is preferably obtained via step (c) in an addition reaction of an alkali salt of the benzodiazepine of formula IV to propionaldehyde .
- the alkali salt can be prepared using strong bases such as alkali amides, alkali alkyls or alkali silazanes.
- strong bases such as alkali amides, alkali alkyls or alkali silazanes.
- Preferably lithium diisopropylamide (LDA) or butyl-lithium is used and most preferably lithium diisopropylamide is used. Due to this po.ssible use of strong bases the benzodiazepine-alcohol of formula VI can also be present in its deprotonized form, i.e. the corresponding benzodiazepine- alcoholate is present.
- the solvent for this reaction should be inert to strong bases and is in particular chosen from ethers or aromatic hydrocarbons. Ethers are preferred, with the most preferable solvent being THF. Usual reaction temperatures range from -50 °C to room temperature, preferably from -30 °C to 0 °C.
- the benzodiazepine of formula IV can be synthesised by reacting 3H- [1, 5] benzodiazepine-2, 4-diamine (J. Chem. Soc . , Chem. Commun. 1973, 367-368) and 1-methylpiperazine.
- the reaction can be carried out in a mixture of solvents comprising toluene and dimethyl sulfoxide.
- the reaction temperature may vary from 60°C to 180°C, preferably from 90°C to 150°C and is most preferably about 120 °C.
- the compounds according to formulae III to VII mentioned hereinbefore or salts thereof as well as their use for the manufacture of Olanzapine are further objects of the invention.
- or salts thereof is meant that the compound can not only be present in the form as is shown by formulae I to VII but can also be present in the form of a salt e.g. a salt formed of an organic or inorganic base and an acidic part of the compound such as the alcohol group or a salt formed of an organic or inorganic acid and a basic part of the compound such as the amino-groups .
- a salt e.g. a salt formed of an organic or inorganic base and an acidic part of the compound such as the alcohol group or a salt formed of an organic or inorganic acid and a basic part of the compound such as the amino-groups .
- the conversion of one of the substances claimed into its salt or back into the form as is shown by formulae I to VII is within the scope of the invention. This also applies, when this conversion is performed as part of another reaction.
- the solution was made acidic at ph of 1 and extracted with dichloromethane (3 x 25 ml) .
- the water phase was made alkalic at a pH of 10 and extracted with diethyl ether (15 x 25 ml) . After each extraction water phase was adjusted ' to pH of 10.
- the ether phase was dried over anhydrous Na 2 S0 4 and ether was evaporated at reduced pressure to give 1, 701 g (89 %) of the title compound as a yellow resin.
- Trifluoroacetacetic anhydride (93.1 ml, 667 mmol) was added over a period of 50 min, maintaining the temperature at -10°C.
- the reaction mixture was stirred for 1 h and allowed to warm to -5°C.
- Methanol (213 ml) and while strongly agitated NaOH (5M, 200 ml, 1.000 mol) were added maintaining the tempera-
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
YUP-2005/0543A RS51033B (en) | 2003-01-17 | 2004-01-16 | Process and intermediates for the preparation of olanzapine |
SI200430996T SI1594879T1 (en) | 2003-01-17 | 2004-01-16 | Process and intermediates for the preparation of olanzapine |
EA200501137A EA007950B1 (en) | 2003-01-17 | 2004-01-16 | Process and intermediates for the preparation of olanzapine |
US10/541,604 US7498433B2 (en) | 2003-01-17 | 2004-01-16 | Process and intermediates for the preparation of olanzapine |
EP04702675A EP1594879B1 (en) | 2003-01-17 | 2004-01-16 | Process and intermediates for the preparation of olanzapine |
DE602004017281T DE602004017281D1 (en) | 2003-01-17 | 2004-01-16 | PROCESS AND INTERMEDIATE PRODUCTS FOR THE PRODUCTION OF OLANZAPINE |
NO20053829A NO331720B1 (en) | 2003-01-17 | 2005-08-15 | Process and Intermediates for the Preparation of Olanzapine. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10301923.5 | 2003-01-17 | ||
DE10301923A DE10301923B3 (en) | 2003-01-17 | 2003-01-17 | Process and intermediates for the production of olanzapine |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2004065390A1 true WO2004065390A1 (en) | 2004-08-05 |
WO2004065390A8 WO2004065390A8 (en) | 2004-12-16 |
Family
ID=32747459
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2004/000299 WO2004065390A1 (en) | 2003-01-17 | 2004-01-16 | Process and intermediates for the preparation of olanzapine |
Country Status (11)
Country | Link |
---|---|
US (1) | US7498433B2 (en) |
EP (1) | EP1594879B1 (en) |
AT (1) | ATE411999T1 (en) |
DE (2) | DE10301923B3 (en) |
EA (1) | EA007950B1 (en) |
ES (1) | ES2316955T3 (en) |
NO (1) | NO331720B1 (en) |
PT (1) | PT1594879E (en) |
RS (1) | RS51033B (en) |
SI (1) | SI1594879T1 (en) |
WO (1) | WO2004065390A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005063771A1 (en) * | 2003-12-22 | 2005-07-14 | Teva Pharmaceutical Industries Ltd | Methods of preparing olanzapine |
US7323459B2 (en) | 2002-12-24 | 2008-01-29 | Teva Pharmaceutical Industries Ltd. | Crystal forms, methods for their preparation and method for preparation of olanzapine |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1533235A (en) * | 1974-11-26 | 1978-11-22 | Lilly Industries Ltd | Benzodiazepine derivatives |
EP0454436A1 (en) * | 1990-04-25 | 1991-10-30 | Lilly Industries Limited | Pharmaceutical compounds |
-
2003
- 2003-01-17 DE DE10301923A patent/DE10301923B3/en not_active Expired - Fee Related
-
2004
- 2004-01-16 SI SI200430996T patent/SI1594879T1/en unknown
- 2004-01-16 US US10/541,604 patent/US7498433B2/en not_active Expired - Fee Related
- 2004-01-16 DE DE602004017281T patent/DE602004017281D1/en not_active Expired - Lifetime
- 2004-01-16 RS YUP-2005/0543A patent/RS51033B/en unknown
- 2004-01-16 EA EA200501137A patent/EA007950B1/en not_active IP Right Cessation
- 2004-01-16 PT PT04702675T patent/PT1594879E/en unknown
- 2004-01-16 WO PCT/EP2004/000299 patent/WO2004065390A1/en active Application Filing
- 2004-01-16 EP EP04702675A patent/EP1594879B1/en not_active Expired - Lifetime
- 2004-01-16 ES ES04702675T patent/ES2316955T3/en not_active Expired - Lifetime
- 2004-01-16 AT AT04702675T patent/ATE411999T1/en not_active IP Right Cessation
-
2005
- 2005-08-15 NO NO20053829A patent/NO331720B1/en not_active IP Right Cessation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1533235A (en) * | 1974-11-26 | 1978-11-22 | Lilly Industries Ltd | Benzodiazepine derivatives |
EP0454436A1 (en) * | 1990-04-25 | 1991-10-30 | Lilly Industries Limited | Pharmaceutical compounds |
Non-Patent Citations (1)
Title |
---|
CALLIGARO, D.O. ET AL.: "The Synthesis and Biological Activity of some known and Putative Metabolites of the Atypical Antipsychotic Agent Olanzapine (LY170053)", BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 7, no. 1, 1997, pages 25 - 30, XP002279427 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7323459B2 (en) | 2002-12-24 | 2008-01-29 | Teva Pharmaceutical Industries Ltd. | Crystal forms, methods for their preparation and method for preparation of olanzapine |
WO2005063771A1 (en) * | 2003-12-22 | 2005-07-14 | Teva Pharmaceutical Industries Ltd | Methods of preparing olanzapine |
US7425627B2 (en) | 2003-12-22 | 2008-09-16 | Teva Pharmaceutical Industries Ltd. | Methods of synthesizing olanzapine |
Also Published As
Publication number | Publication date |
---|---|
ATE411999T1 (en) | 2008-11-15 |
RS20050543A (en) | 2007-06-04 |
NO20053829D0 (en) | 2005-08-15 |
NO331720B1 (en) | 2012-03-05 |
PT1594879E (en) | 2008-11-14 |
DE602004017281D1 (en) | 2008-12-04 |
NO20053829L (en) | 2005-10-12 |
EP1594879B1 (en) | 2008-10-22 |
EA200501137A1 (en) | 2006-02-24 |
SI1594879T1 (en) | 2009-04-30 |
DE10301923B3 (en) | 2004-09-16 |
US7498433B2 (en) | 2009-03-03 |
ES2316955T3 (en) | 2009-04-16 |
EP1594879A1 (en) | 2005-11-16 |
EA007950B1 (en) | 2007-02-27 |
RS51033B (en) | 2010-10-31 |
US20060040921A1 (en) | 2006-02-23 |
WO2004065390A8 (en) | 2004-12-16 |
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