WO2005005410A1 - A method for the preparation of enantiomerically pure mirtazapine - Google Patents
A method for the preparation of enantiomerically pure mirtazapine Download PDFInfo
- Publication number
- WO2005005410A1 WO2005005410A1 PCT/EP2004/051357 EP2004051357W WO2005005410A1 WO 2005005410 A1 WO2005005410 A1 WO 2005005410A1 EP 2004051357 W EP2004051357 W EP 2004051357W WO 2005005410 A1 WO2005005410 A1 WO 2005005410A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- mirtazapine
- combination
- enantiomerically pure
- solvent
- Prior art date
Links
- 0 CN(CC1)CC(c2ccccc2)N1c1c(C*)cccn1 Chemical compound CN(CC1)CC(c2ccccc2)N1c1c(C*)cccn1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Definitions
- the present invention relates to a method for the preparation of enantiomerically pure mirtazapine comprising ring closure with an acid.
- 5 Mirtazapine, 1 ,2,3,4, 10, 14b-hexahydro-2-methyl-pyrazino[2, 1 -a]pyrido[2,3- c][2]benzazepine is a tetracyclic compound having the formula I:
- the compound is chiral and the racemic mixture finds widespread use as a medicine for 10 the treatment of depression.
- Other medical uses for mirtazapine have also been reported e.g., WO 99/25356 and WO 01/58453 disclose its use in the treatment of sleep disorders and apnea.
- Investigations into the biological effects of the enantiomers of mirtazapine e.g. O'Connor and Leonard, Neuropharmacology, 1986, vol. 25, pp. 267-270; Kooyman et al., 1994, vol. 33, pp. 501-507; De Boer et al., Neuropharmacology, 1988, vol. 27, pp. 15 399-408; Gower et al., 1988, vol.
- X can represent a leaving group, such as a hydroxyl group, an esterified or etherified hydroxyl group or a halogen, using a variety of ring closing reagents.
- reagents include acids such as sulfuric acid, concentrated hydrochloric acid, picric acid, trifluoroacetic acid, phosphoric acid, polyp hosphoric acid (PPA), phosphorus oxychloride, phosphorus trioxide, phosphorus pentoxide and Lewis Acids such as aluminium chloride, ferric chloride, zinc chloride, tin chloride, titanium chloride, boron trifluoride, antimony pentachloride and zirconium tetrachloride.
- acids such as sulfuric acid, concentrated hydrochloric acid, picric acid, trifluoroacetic acid, phosphoric acid, polyp hosphoric acid (PPA), phosphorus oxychloride, phosphorus trioxide, phosphorus pentoxide and Lewis Acids such as aluminiu
- the present invention therefore provides a method comprising a step of ring closure of a compound according to formula (11), wherein X is a leaving group, said step comprising treatment, wherein mirtazapine with enantiomeric excess is formed by the ring closure of the compound of formula (II) with enantiomeric excess by treatment with a suitable acid in the absence of a solvent or a suitable combination of an acid and an organic solvent.
- the alcohol according to formula II is preferably used as crystalline salt or solvate, such as the oxalate salt of (S) or (R) 1 -(3-hydroxymethyl-2-pyridyl)-4-methyl-2-phenylpiperazine.
- dicalite is added to the reaction mixture to prevent lump formation.
- mirtazapine is used here in its generic meaning commonly used to refer to the chemical compound as a base and, depending on the context, to the salts and solvates thereof and supplemented with the prefixes (R) or (S) and/or (+) or (-) to the enantiomers of the compound.
- the (S) configuration causes positive optical rotation in the usual solvents.
- enantiomeric excess in a compound refers to the difference between the amounts of each of the enantiomers present in a mixture, relative to the total amount of the compound in the mixture expressed as percentage. For example, in a 10 g mixture containing 9 g mirtazapine (90%), of which 4 g is (R)-mirtazapine and 5 g is (S)- mirtazapine the enantiomeric excess of the (S)-enantiomer is about 11%.
- mirtazapine or compound with enantiomeric excess refers to a mixture containing the mirtazapine or the compound with enantiomeric excess.
- the invention can provide enantiomerically pure mirtazapine if enantiomerically pure starting material is used and the ring closure is effected by treatment with a suitable acid in the absence of a solvent or a suitable combination of an acid and an organic solvent.
- Enantiomerically pure compound is one comprising less than 20 % of the other enantiomer, which is an enantiomeric excess of 60 %. Depending on the specific conditions of the invented method an enantiomerically pure compound having less than 10 % of the other enantiomer or less than 1 % of the other enantiomer can also be obtained.
- the yields of enantiomerically pure mirtazapine isolated are typically not less than 50 % but yields of not less than 70 % can also be obtained.
- a leaving group is a reactive function on a molecule which undergoes displacement from the molecule when a new bond is formed, as is commonly known in the art.
- a leaving group can be a hydroxyl group, an activated ester thereof, such as a carboxylate, a sulfonate or a phosphonate, or a halogen.
- an activated ester thereof such as a carboxylate, a sulfonate or a phosphonate, or a halogen.
- a suitable acid for the method of the present invention is defined to be a specific acid or acid/solvent combination as mentioned hereafter or an acid or acid/solvent combination not mentioned hereafter, but which is obtained by performing a test as to the suitability of the acid.
- the test is to perform the ring closure with an acid, being a candidate acid, and starting material, which is compound ll as defined above, or a salt or solvate thereof, in a predetermined enantiomeric purity, and determine after the reaction the enantiomeric excess of the resulting mirtazapine.
- the quantitative degree of loss of enantiomeric purity can be determined by simple calculation and expressed as difference between enantiomeric excess in the starting material before the reaction and the enantiomeric excess of the product mirtazapine after the reaction.
- the acid or acid/solvent combination is a suitable acid or acid/solvent combination.
- a more strict criterion for a suitable acid or acid/solvent combination can be applied by selecting those causing a loss less than a number anywhere between 0% and 40%, such as 35%, 30%, 25%, 20%, 15%, 10%, 5%, 2%, 1%, 0.5% and 0.3%. It is therefore an aspect of the invention to provide a method for the selection of an acid or acid/solvent combination suitable for the stereospecific ring closure leading to enantiomerically pure mirtazapine.
- the method comprises performing the ring closure reaction of an enantiomerically pure compound according to the formula II, or a salt or solvate thereof, with the meaning of X, as defined previously with any candidate acid or any candidate acid/solvent combination and determining a loss of enantiomeric excess by the reaction and identifying an acid or an acid/solvent combination, as suitable if it results in the loss of less than 40%.
- a stricter criterion as mentioned above can be applied for more suitable acids or acid/solvent combinations.
- a suitable acid used in the absence of solvent can be a protic acid or a protic acid derivative such as a protic acid anhydride.
- Concentrated sulfuric acid the prior art method of choice for the preparation of racemic mirtazapine, or aluminium trichloride is not suitable.
- the use of polyphosphoric acid or phosphorus pentoxide in phosphoric acid are particularly preferred. It is recommended to use polyphosphoric acid, or phosphorus pentoxide in phosphoric acid, in an amount of low excess over the starting alcohol defined as compound II above.
- the reaction will give better yield and better retention of enantiomeric excess if the ratio (w/w) of polyphosphoric acid over the alcohol (weight of base of compound II) is less than 10 to 1 (w/w), or better 5 to 1, even better if less than 2.5 to 1.
- polyphosphoric acid is introduced in amounts of pentoxide and phosphoric acid (possibly in weight (w/w) ratio of pentoxide over phosphoric acid of 1 : 1 to 1 :9) the weights of phosphorus pentoxide and phosphoric acid are added up to express as the total amount of polyphosphoric acid.
- a suitable acid and organic solvent combination can be a combination of a protic acid or a protic acid derivative such as a protic acid anhydride or a mineral acid and a polar coordinating solvent such as ethanol or higher alcohols, DMF, DMA or N- methylpyrrolidinone. More preferred is to use the combination of a protic acid derivative and /V-methylpyrrolidinone or DMF. Polyphosphoric acid and A-methylpyrrolidinone or DMF are particularly preferred.
- the acid/solvent combinations phosphorus pentoxide or polyphosphoric acid or sulfuric acid and xylene; phosphorus pentoxide or polyphosphoric acid and chlorobenzene; phosphorus pentoxide or polyphosphoric acid and toluene, and sulfuric acid and dichloromethane are not suitable.
- the ring closure reaction can take place at room temperature, the reaction can also be facilitated with additional heating. It is a further aspect of the invention therefore to include ring closure according to the methods of the present invention including additional heating.
- a compound of formula (II) can be prepared by the synthetic route shown in Scheme I which is described in US 4062848.
- compound (V) can be prepared by reaction of compound (IV) with chloronicotinitrile (III) in an organic solvent, such as tetrahydrofuran or dimethylformamide and in the presence of an equivalent of a base such as potassium fluoride.
- Compound (VI) can then be prepared by hydrolysis of compound (V) using an aqueous base such as potassium hydroxide in an alcohol such as ethanol, typically at reflux.
- an aqueous base such as potassium hydroxide in an alcohol such as ethanol, typically at reflux.
- WO 00/62782 it is described that the molar ratio of the base used to effectuate the nitrile hydrolysis can be reduced from 25 moles of base (as disclosed in the procedure of US patent 4062848) to around 12 moles of base.
- compound (II) can be prepared by reduction of compound (VI) again using a metal hydride such as lithium aluminium hydride in an organic solvent such as tetrahydrofuran. Conversion of the alcohol function to other leaving groups such as carboxylate and sulphonate esters and to halogens can be readily achieved by methods which are well known in the art.
- a metal hydride such as lithium aluminium hydride in an organic solvent such as tetrahydrofuran.
- enantiomerically pure compound (II) can then be achieved by using methods well known in the art.
- asymmetric synthesis methods e.g., synthesis with chiral induction, fractional crystallisation of diastereoisomeric salts formed upon reaction with a chiral acid or separation by chromatography on a chiral medium by normal or reverse phase chromatographic methods.
- Such methods are for example described in 'Chirality in Industry' (edited by A.N. Collins, G.N. Sheldrake and J. Crosby, 1992; John Wiley)
- the invention also includes enantiomerically pure mirtazapine produced by the method of the present invention and pharmaceutical compositions of such for use in therapy.
- Such compositions can comprise a therapeutically effective amount of enantiomerically pure mirtazapine in combination with pharmaceutically acceptable carriers and excipients which are well known in the art.
- Example 6 A solution of [S]-1-(3-Hydroxymethyl-2-pyridyl)-4-methyl-2-phenylpiperazine (1.0 g, 3.53 mmole) in dichloromethane was added to polyphosphoric acid prepared from 85% phosphoric acid (2.8 g) and phosphorouspentoxide (1.3 g). The reaction mixture was heated to 130°C for 18 hours. The reaction mixture was diluted with water (6.5 ml) and the pH was brought to 8 by adding 4N sodium hydroxide solution. The water layer was extracted with ethyl acetate. The organic layer was washed with water, dried with magnesium sulfate and evaporated. This provided the title compound (0.79 g, 84%) with e.e. of 83%.
- Example 7 To polyphosphoric acid (20 gram) was added (S)-1-(3-hydroxymethyI-2-pyridyl)-4-methyl- 2-phenylpiperazine oxalic acid salt (13.2 g, 35.3 mmole). The reaction mixture was stirred at 130°C for 18 hours. To the reaction mixture were added water (220 ml), ethyl acetate (220 ml), and 33% sodium hydroxide solution (65 ml). The aqueous layer was separated and extracted twice with ethyl acetate (220 ml). The combined organic fractions were washed three times with water (220 ml) and evaporated. This gave 7.9 g of (S)- Mirtazapine (84%) with an e.e. of 99.2%.
- Example 8 To polyphosphoric acid (4 gram) was added (S)-1-(3-hydroxymethyl-2-pyridyl)-4-methyl- 2-phenylpiperazine oxalic acid salt (1.32 g, 3.53 mmole). The reaction mixture was stirred at 130°C for 18 hours. To the reaction mixture were added water (22 ml), ethyl acetate (22 ml), and 33% sodium hydroxide solution (6.5 ml). The aqeous layer was separated and extracted twice with ethyl acetate (22 ml). The combined organic fractions were washed three times with water (22 ml), dried with MgS0 4 and evaporated. This gave 0.79 g of (S)-Mirtazapine (84%) with an e.e. of 83%.
Abstract
Description
Claims
Priority Applications (20)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
UAA200600274A UA83666C2 (en) | 2003-07-10 | 2004-05-07 | Method for the preparation of enantiomerically pure mirtazapine |
DK04741958T DK1656365T3 (en) | 2003-07-10 | 2004-07-05 | Process for the preparation of enantiomerically pure mirtazapine |
BRPI0412447-2A BRPI0412447A (en) | 2003-07-10 | 2004-07-05 | method for the preparation of enantiomerically pure mirtazapine; and, method for selecting an appropriate acid or solvent / acid combination for a stereospecifically ring-closing reaction of enantiomerically pure compound |
DE602004021605T DE602004021605D1 (en) | 2003-07-10 | 2004-07-05 | PROCESS FOR PREPARING ENANTIOMERIC MIRTAZAPINE |
CA2531165A CA2531165C (en) | 2003-07-10 | 2004-07-05 | A method for the preparation of enantiomerically pure mirtazapine |
JP2006518216A JP4668184B2 (en) | 2003-07-10 | 2004-07-05 | Process for the preparation of enantiomerically pure mirtazapine |
YUP-2005/0972A RS20050972A (en) | 2003-07-10 | 2004-07-05 | A method for the preparation of enantiomerically pure mirtazapine |
AT04741958T ATE433965T1 (en) | 2003-07-10 | 2004-07-05 | METHOD FOR PRODUCING ENANTIOMER PURE MIRTAZAPINE |
SI200431183T SI1656365T1 (en) | 2003-07-10 | 2004-07-05 | A method for the preparation of enantiomerically pure mirtazapine |
MXPA06000325A MXPA06000325A (en) | 2003-07-10 | 2004-07-05 | A method for the preparation of enantiomerically pure mirtazapine. |
EP04741958A EP1656365B1 (en) | 2003-07-10 | 2004-07-05 | A method for the preparation of enantiomerically pure mirtazapine |
PL04741958T PL1656365T3 (en) | 2003-07-10 | 2004-07-05 | A method for the preparation of enantiomerically pure mirtazapine |
AU2004255874A AU2004255874B2 (en) | 2003-07-10 | 2004-07-05 | A method for the preparation of enantiomerically pure mirtazapine |
US10/564,193 US8058436B2 (en) | 2003-07-10 | 2004-07-05 | Method for the preparation of enantiomerically pure mirtazapine |
NZ544360A NZ544360A (en) | 2003-07-10 | 2004-07-05 | A method for the preparation of enantiomerically pure 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,1-a]pyrido[2,3c][2]benzazepine |
IL172549A IL172549A0 (en) | 2003-07-10 | 2005-12-13 | A method for the preparation of enantiomerically pure mirtazapine |
IS8184A IS2674B (en) | 2003-07-10 | 2005-12-15 | Process for the production of enantiomerically pure myrtasapine |
HR20051019A HRP20051019A2 (en) | 2003-07-10 | 2005-12-22 | A method for the preparation of enantiomerically pure mirtazapine |
NO20056175A NO20056175L (en) | 2003-07-10 | 2005-12-23 | Method of preparing enantiomerically pure mirtazapine |
HK06109133.3A HK1086841A1 (en) | 2003-07-10 | 2006-08-17 | A method for the preparation of enantiomerically pure mirtazapine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03102095 | 2003-07-10 | ||
EP03102095.1 | 2003-07-10 |
Publications (1)
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WO2005005410A1 true WO2005005410A1 (en) | 2005-01-20 |
Family
ID=34042934
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---|---|---|---|
PCT/EP2004/051357 WO2005005410A1 (en) | 2003-07-10 | 2004-07-05 | A method for the preparation of enantiomerically pure mirtazapine |
Country Status (36)
Country | Link |
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US (2) | US8058436B2 (en) |
EP (1) | EP1656365B1 (en) |
JP (1) | JP4668184B2 (en) |
KR (1) | KR20060056315A (en) |
CN (1) | CN100558722C (en) |
AR (1) | AR046494A1 (en) |
AT (1) | ATE433965T1 (en) |
AU (1) | AU2004255874B2 (en) |
BR (1) | BRPI0412447A (en) |
CA (1) | CA2531165C (en) |
CO (1) | CO5640123A2 (en) |
CY (1) | CY1109327T1 (en) |
DE (1) | DE602004021605D1 (en) |
DK (1) | DK1656365T3 (en) |
EC (1) | ECSP066271A (en) |
ES (1) | ES2327123T3 (en) |
HK (1) | HK1086841A1 (en) |
HR (1) | HRP20051019A2 (en) |
IL (1) | IL172549A0 (en) |
IS (1) | IS2674B (en) |
LT (1) | LT5382B (en) |
LV (1) | LV13441B (en) |
MX (1) | MXPA06000325A (en) |
NO (1) | NO20056175L (en) |
NZ (1) | NZ544360A (en) |
PE (1) | PE20050323A1 (en) |
PL (1) | PL1656365T3 (en) |
PT (1) | PT1656365E (en) |
RS (1) | RS20050972A (en) |
RU (1) | RU2352566C2 (en) |
SG (1) | SG144914A1 (en) |
SI (1) | SI1656365T1 (en) |
TW (1) | TWI335915B (en) |
UA (1) | UA83666C2 (en) |
WO (1) | WO2005005410A1 (en) |
ZA (1) | ZA200600019B (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007035003A1 (en) * | 2005-09-26 | 2007-03-29 | Sumitomo Chemical Company, Limited | Process for producing optically active piperazine compound |
JP2007284416A (en) * | 2005-09-26 | 2007-11-01 | Sumitomo Chemical Co Ltd | Process for producing optically active piperazine compound |
WO2007135123A2 (en) * | 2006-05-22 | 2007-11-29 | N.V. Organon | Mirtazapine for the treatment of neuropathic pain |
WO2008099715A1 (en) * | 2007-02-09 | 2008-08-21 | Kaneka Corporation | Method for producing optically active 2-arylpiperazine derivative |
WO2008114691A1 (en) * | 2007-03-22 | 2008-09-25 | Sumitomo Chemical Company, Limited | Process for production of mirtazapine |
WO2008125578A2 (en) | 2007-04-11 | 2008-10-23 | N.V. Organon | A method for the preparation of mirtazapine |
JP2009539939A (en) * | 2006-06-16 | 2009-11-19 | ナームローゼ・フエンノートチヤツプ・オルガノン | Stereoselective synthesis of (S) -1-methyl-phenylpiperazine |
US7994314B2 (en) | 2007-04-11 | 2011-08-09 | N.V. Organon | Method for the preparation of an enantiomerically pure benzazepine |
Families Citing this family (3)
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---|---|---|---|---|
KR101485418B1 (en) * | 2013-05-29 | 2015-01-26 | 주식회사 메디켐코리아 | A synthetic method of high purity mirtazapine |
HUE055000T2 (en) | 2015-02-27 | 2021-10-28 | Dechra Ltd | Stimulation of appetite, management of weight loss, and treatment of anorexia in dogs and cats |
KR102540021B1 (en) * | 2020-12-02 | 2023-06-07 | (주)유케이케미팜 | Method for preparing mirtazapine suitable for mass production |
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US4062848A (en) * | 1975-04-05 | 1977-12-13 | Akzona Incorporated | Tetracyclic compounds |
WO2000062782A1 (en) * | 1999-04-19 | 2000-10-26 | Teva Pharmaceutical Industries Ltd. | Novel synthesis and crystallization of piperazine ring-containing compounds |
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US3959470A (en) * | 1972-11-28 | 1976-05-25 | Mikhail Davidovich Mashkovsky | Psychotropic medicinal preparation |
CA2026925A1 (en) * | 1989-10-05 | 1991-04-06 | Hiroshi Fukumi | Tetracyclic compounds having anti-allergic and anti-asthmatic activities, their preparation and use |
JPH11222407A (en) * | 1997-11-14 | 1999-08-17 | Sankyo Co Ltd | New microbicidal |
CA2309744A1 (en) | 1997-11-14 | 1999-05-27 | Akzo Nobel N.V. | Use of mirtazapine for treating sleep apneas |
US20030069417A1 (en) * | 1999-04-19 | 2003-04-10 | Claude Singer | Novel synthesis and crystallization of piperazine ring-containing compounds |
US6068695A (en) * | 1999-07-13 | 2000-05-30 | Bayer Corporation | Process for the continuous preparation of quinacridones |
AU6476300A (en) | 1999-09-30 | 2001-05-10 | Sumika Fine Chemicals Co., Ltd. | Process for the preparation of a piperazine derivative |
WO2001042239A1 (en) * | 1999-12-13 | 2001-06-14 | Sumika Fine Chemicals Co., Ltd. | Process for the preparation of a pyridinemethanol compound |
HUP0204391A3 (en) | 2000-02-11 | 2005-03-29 | Akzo Nobel Nv | The use of mirtazapine for the preparation of pharmaceutical composition suitable for the treatment of sleep disorders |
JP2001342188A (en) * | 2000-03-27 | 2001-12-11 | Takeda Chem Ind Ltd | Condensed pyrazole derivative, and its production method and use |
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2004
- 2004-05-07 UA UAA200600274A patent/UA83666C2/en unknown
- 2004-06-28 TW TW093118845A patent/TWI335915B/en not_active IP Right Cessation
- 2004-07-05 CA CA2531165A patent/CA2531165C/en not_active Expired - Fee Related
- 2004-07-05 RS YUP-2005/0972A patent/RS20050972A/en unknown
- 2004-07-05 PT PT04741958T patent/PT1656365E/en unknown
- 2004-07-05 BR BRPI0412447-2A patent/BRPI0412447A/en not_active IP Right Cessation
- 2004-07-05 SI SI200431183T patent/SI1656365T1/en unknown
- 2004-07-05 PL PL04741958T patent/PL1656365T3/en unknown
- 2004-07-05 DE DE602004021605T patent/DE602004021605D1/en active Active
- 2004-07-05 WO PCT/EP2004/051357 patent/WO2005005410A1/en active IP Right Grant
- 2004-07-05 CN CNB2004800194891A patent/CN100558722C/en active Active
- 2004-07-05 MX MXPA06000325A patent/MXPA06000325A/en active IP Right Grant
- 2004-07-05 SG SG200805127-8A patent/SG144914A1/en unknown
- 2004-07-05 KR KR1020067000511A patent/KR20060056315A/en active IP Right Grant
- 2004-07-05 NZ NZ544360A patent/NZ544360A/en not_active IP Right Cessation
- 2004-07-05 DK DK04741958T patent/DK1656365T3/en active
- 2004-07-05 ES ES04741958T patent/ES2327123T3/en active Active
- 2004-07-05 JP JP2006518216A patent/JP4668184B2/en active Active
- 2004-07-05 AT AT04741958T patent/ATE433965T1/en active
- 2004-07-05 US US10/564,193 patent/US8058436B2/en not_active Expired - Fee Related
- 2004-07-05 EP EP04741958A patent/EP1656365B1/en active Active
- 2004-07-05 AU AU2004255874A patent/AU2004255874B2/en active Active
- 2004-07-05 RU RU2006103992/04A patent/RU2352566C2/en not_active IP Right Cessation
- 2004-07-07 PE PE2004000653A patent/PE20050323A1/en not_active Application Discontinuation
- 2004-07-08 AR ARP040102412A patent/AR046494A1/en not_active Application Discontinuation
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2005
- 2005-12-12 LT LT2005107A patent/LT5382B/en not_active IP Right Cessation
- 2005-12-13 IL IL172549A patent/IL172549A0/en not_active IP Right Cessation
- 2005-12-15 IS IS8184A patent/IS2674B/en unknown
- 2005-12-22 HR HR20051019A patent/HRP20051019A2/en not_active Application Discontinuation
- 2005-12-23 NO NO20056175A patent/NO20056175L/en not_active Application Discontinuation
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2006
- 2006-01-03 ZA ZA200600019A patent/ZA200600019B/en unknown
- 2006-01-09 EC EC2006006271A patent/ECSP066271A/en unknown
- 2006-01-10 CO CO06001617A patent/CO5640123A2/en not_active Application Discontinuation
- 2006-02-10 LV LVP-06-21A patent/LV13441B/en unknown
- 2006-08-17 HK HK06109133.3A patent/HK1086841A1/en not_active IP Right Cessation
-
2008
- 2008-07-02 US US12/667,969 patent/US20100179319A1/en not_active Abandoned
-
2009
- 2009-08-25 CY CY20091100894T patent/CY1109327T1/en unknown
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US4062848A (en) * | 1975-04-05 | 1977-12-13 | Akzona Incorporated | Tetracyclic compounds |
WO2000062782A1 (en) * | 1999-04-19 | 2000-10-26 | Teva Pharmaceutical Industries Ltd. | Novel synthesis and crystallization of piperazine ring-containing compounds |
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