NZ542603A - Synthesis of 2-chloromethyl-6-methylbenzoic acid esters - Google Patents
Synthesis of 2-chloromethyl-6-methylbenzoic acid estersInfo
- Publication number
- NZ542603A NZ542603A NZ542603A NZ54260304A NZ542603A NZ 542603 A NZ542603 A NZ 542603A NZ 542603 A NZ542603 A NZ 542603A NZ 54260304 A NZ54260304 A NZ 54260304A NZ 542603 A NZ542603 A NZ 542603A
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkyl
- formula
- aryl
- cycloalkyl
- compounds
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Disclosed are 2-Haloalkyl benzoic acid derivatives of formula (I), methods of their production and use in the synthesis of PPAR agonists.
Description
New Zealand Paient Spedficaiion for Paient Number 542603
I
2004/085377 PCT/EP2004/002579
Synthesis of 2-chloromethyM>-methylbenzoic add esters Description
2-Haloalkylbenzoic acid derivatives are used as building blocks for the synthesis of active pharmaceutical ingredients. For various reasons, it is desirable for the use to have storage-stable compounds which can additionally be prepared and purified in a simple manner. These reasons include, for example, the ensuring of a constant quality, the avoidance of 10 frequent checks on the materials to record the product quality, the . avoidance of the necessity of cold storage and/or cold transport, easy transfer to production plants and also simple cleaning of used vessels,
2-Bromomethyl-6-methytbenzoic esters (A1 and A2) are known, for 15 example, from WO 00/64888 (R = iBu (A1)) and WO 00/64876 (R = Me (A2)). These compounds are not storage-stable at room temperature, since they cyclize spontaneously to the lactone (B) and in the process, as is well t
known, release mutagenic alkyl bromides as a by-product.
(A1) (A2) (B)
, The use of these thermally labile substances on the industrial scale is therefore associated with occupational. hygiene risks, difficulties and additional costs.
.
Among other uses, the 2-bromomethyl-6-methylbenzoic esters are of interest as starting materials for the preparation of PPAR agonists, as described, for example, in WO 00/64888, WO 00/64876 and WO 03/020269. Particular mention should be made here of the compounds of 30 the formula (C):
IPONZ
1 0 APR 2006
2
-•R'
c°2r
(C)
where
R is H, Ci-Ci2-alkyl. c3-Cs-cycloalkyI, C6-Ci2-aryl, Ci-C4-alkyl-C6-Ci2-5 aryl or Cs-C-io-heteroaryl, where, in alkyl and cycloalkyl, one or more CH2 groups may be replaced by -0- and alkyl, cycloalkyl and aryl may be substituted by halogen,
Y is -(CH2)3-, 1,3-phenylene, 1,3-cyclohexanediyl;
R' is H, F, Br, cf3, (C-|-c6)-alkyl, 0-(C-|-C6}-alkyl, phenyl;
R" is H, (Gi-c6)-alkyl, (Ci-c3)-alkylphenyl, (c5-c6)-cycloalkyl, phenyl,
Preference is given to the compounds of formula (C) in which the phenyl ring is substituted by R' in the m- or p-position.
It is thus an object of the invention to find more stable compounds than (A1) and (A2) which do not have the above-outlined disadvantages. In addition, the compounds which can occur in a purity which is not yet sufficient when they are prepared even from a crude product should, in 20 contrast to the compounds of the formulae (A1) and (A2), be purifiable.
This is achieved by the compounds of the formula (I) described below.
The present invention provides the compounds of formula (I)
CF3.
C02R
3
where
R is H, Ci-Ci2-alkyl, c3-c8-cycloalkyl, Cg-012-aryl, Ci-c4-alkyl-5 C6-Ci2-aryl or Cs-C-iO-heteroaryl, and, in alkyl and cycloalkyl, one or more CH2 groups may be replaced by -0-, and alkyl, cycloalkyl and aryl may be substituted by halogen.
Preference is given to the compounds of the formula (I) in which
R is C1-C8 alkyl, c3-c6-cycloalkyl or C-|-c4-alkyl-c6-ci2-aryl, each of which may optionally be substituted by halogen and in which one or two CH2 groups may be replaced by -0-.
Particular preference is given to the compounds of the formula (I) in which
R is C1-C6 alkyl or Ci-c4-alkyl-c6-ci2-aryl, each of which may optionally be substituted by halogen and in which one CH2 group may be replaced by -0-.
Very particular preference is given to the compounds of the formula (I) in which
R is methyl, ethyl, propyl, i-propyl, t-butyl, phenyl, 2-methoxyethyl or 25 benzyl.
Alkyl may be branched or unbranched. Halogen is CI, Br, I, preferably CI. In this context, heteroaryl refers to 5- to 10 membered aromatic rings which contain from one to four identical or different heteroatoms from the group of 30 N, O, S, for example pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, triazole, tetrazole, triazine, tetrazine, preference is given to: pyrrole, imidazole, oxazole, thiazole and pyridine.
The present invention also provides a process for preparing the compounds of the formula (I)
4
CI
C02R
where
R is H, Ci-Ci2-alkyl, C3-C8-cycloalkyl, C6-Ci2-aryl, C-|-C4-alkyl-C6-Ci2-aryl or Cg-Cio-heteroaryl, and, in alkyl or cycloalkyl, one or more CH2 groups may be replaced by -0-, and alkyl, cycloalkyl and aryl may be substituted by halogen,
which comprises reacting dimethylbenzoic esters of the formula (II)
where R is as defined above with a chlorinating reagent, for example sulfuryl chloride, N-chloro-succinimide (NCS), 1,3-dichloro-5,5-dimethylhydantoin (NDDH) ortrichloro-20 isocyanuric acid [Org Process Research & Development 2002,6,384-393], in an inert solvent, for example cci4, chlorobenzene, or without solvents above 40°C and subsequently optionally purifying.
Preference is given to carrying out the reaction at 60-90°C, while 25 chlorination on the aromatic ring is observed at lower temperatures than 40°C. The purification is preferably distillative or by a silica gel filtration.
The chlorine „ compounds of the formula (I) are only obtainable very inefficiently, if at all, by a ring-opening chlorination of the lactones (B), since 30 the lactone structure is very stable. In addition, the 2-chloromethylbenzoic
C02R
(II)
acid derivatives can surprisingly be distilled, can be isolated by this method in excellent chemical purity and do not react spontaneously in the course of storage to give the lactones.
A conversion of the chlorine compounds of the formula (I) to more reactive bromine or iodine compounds may likewise be advantageous, in order to increase the reactivity of this molecular building block in the further synthesis (for example to give PPAR agonists (C)). However, these compounds then have the "technical" disadvantages mentioned in the 10 introduction. The conversion of the chlorine into the bromine or iodine compound is effected with alkali metal halides in inert solvents, preferably with sodium bromide or iodide in acetone under reflux. Alternatively, the transhalogenation and the further synthesis can also be carried out as a one-pot method with catalytical or stoichiometric amounts of alkyl halide, 15 based on the chlorine compound used.
The present invention further provides a process for preparing the compounds of the formula (C)
co2r
(C)
in which
R is H, Ci-Ci2-alkyl, Ca-Cs-cyctoalkyl, C6-Ci2-aryl, Ci-C4-alkyl-C6-25 Ci2-aryl or Cs-C-io-heteroaryl and, in alkyl and cycloalkyl, one or more CH2 groups may be replaced by -O- and alkyl, cycloakyi and aryl may be substituted by halogen,
Y is -(CH2)3-, 1,3-phenylene, 1,3-cyclohexanediyl,
R' is Hr F^Br, CF3, (Ci-CeJ-alkyl, 0-(Ci-C6)-alkyl, phenyl; 30 R" is H, (Ci-C6)-alkyl, (Ci-C3)-alkylphenyl, (C5-C6)-cycloalkyl, phenyl, CF3;
which comprises reacting compounds of the formula (C1)
HO^
Y
\—'
(CI)
where Y, R' and R" are each as defined above
with compounds of the formula (I)
C02R (I)
where R is as defined above in toluene, NMP or other aprotic solvents, in the presence of a suitable 15 base, preferably with potassium tert-butoxide, at from -78 to +50°C, preferably at from -30 to +20°C, and subsequently working up extractively and optionally crystallizing the end product.
The compounds of the formula (I) are notable for high stability compared to 20 the corresponding bromine compounds. When the stability of methyl 2-bromomethyl-6-methylbenzoate is compared to that of the analogous chlorine compound, the following result is obtained: methyl 2-chloromethyl-6-methylbenzoate can be distilled without decomposition at 66-77°C/0.1 mbar, and only a bottom temperature of above 120°C leads to significant 25 lactone formation. At room temperature, it can be stored stably over several months. The "storage stability of methyl 2-bromomethyl-6-methylbenzoate differs distinctly from this. At room temperature, the content of the bromine
7
compound reduces sharply within a few days, within one week from 92.6 to 81.0%, within 2 weeks to 67.8% and within 2 months to 7.8%. At the same time, the lactone content rises from 1.9% via 13.9% after 1 week and 89.5% in 2 months.
The following examples are cited without restriction to them:
Example 1:
Synthesis of methyl 2-chloromethyl-6-methylbenzoate
11.9 g of methyl 2,6-dimethylbenzoate are initially charged in 50 ml of chlorobenzene admixed at room temperature with 8.2 g of sulfuryl chloride and 40 mg of AIBN. The mixture is stirred at 60-908C for 2 h. Afterwards, the mixture is admixed with 80 ml of saturated NaHCC>3 solution. After the 15 phase separation, the organic phase is washed with 100 ml of 10% Na2S03 solution, the organic phase is dried over magnesium sulfate and the chlorobenzene is distilled off in vacuo. 15.5 g of colorless liquid are obtained. The product is distilled under high vacuum (0.1 mbar, 66-77°C). Yield: 10.2g (71% of theory; 95.2 area%).
Example 2:
Synthesis of isopropyl 2-chloromethyl-6-methylbenzoate
19.2 g of isopropyl 2,6-dimethylbenzoate are initially charged in 100 ml of 25 carbon tetrachloride admixed at room temperature with 13.3 g of N-chlorosuccinimide and 200 mg of AIBN. The mixture is heated to reflux for 3 h. After the mixture has been cooled, it is filtered with suction and the succinimide is washed with 20 ml of carbon tetrachloride. The filtrates are combined and carbon tetrachloride is distilled off in vacuo. 21.8 g of color-30 less liquid are obtained. The product is distilled under high vacuum (0.05 mbar, 94-97°C). Yield: 13.9 g (61 % of theory; 93.6 area%).
Example 3:
Synthesis of 2-methoxyethyl 2-chloromethyl-6-methylbenzoate
.4 g of 2-methoxyethyl 2,6-dimethylbenzoate are admixed at room temperature with 5.4 g of sulfuryl chloride and 40 mg of AIBN. The mixture is stirred at 60-90°C for 1-2 h. Afterwards, the mixture is admixed with 20 ml of water, the phases are separated and the organic phase is dried
Claims (14)
1. A compound of the formula (I) CI intellectual property OFFICE OF N.z. C02R (0 31 OCT 2007 where received R is H, Ci-ci2-alkylt c3-c8-cycloalkyl, C6-Ci2-aryl. c1-c4-alkyl-C6-Ci2-ary' or C5-Cio-heteroaryl, and, in alkyl and cycloalkyl, one or more CH2 groups may be replaced by -0-, and alkyl, cycloalkyl and aryl may be substituted by halogen.
2. A compound of the formula (I) as claimed in claim 1 in which R is C1-C8 alkyl, c3-c6-cycloalkyl or C1 -C4-aIkyl-c6-C 12-aryl, each of which may optionally be substituted by halogen and in which one or two CH2 groups may be replaced by -O-.
3. A compound of the formula (I) as claimed in claim 1 or 2 in which R is C1-C6 alkyl or Ci-c4-alkyl-c6-ci2-aryl, each of which may optionally be substituted by halogen and in which one CH2 group may be replaced by -0-.
4. A compound of the formula (I) as claimed in any one of claims 1 to 3 in R is methyl, ethyl, propyl, i-propyl, t-butyl, phenyl, 2-methoxyethyl or benzyl.
5. A process for preparing the compounds of the formula (I) as claimed in any one of claims 1 to 4, which comprises reacting dimethylbenzoic esters of the formula (II) which 10 co2r (II) where R is as defined above with a chlorinating reagent in an inert solvent or without solvents above 40°C and subsequently optionally purifying.
A process for preparing the compounds of the formula (C) c02r (C) in which R is H, Ci-C-i2-alkyl, c3-c8-cycloalkyl, C6-Ci2-aryl, c1-c4-alkyl-c6-ci2-aryl or Cs-C-fQ-heteroaryl and, in alkyl and cycloalkyl, one or more CH2 groups may be replaced by -O-and alkyl, cycloakyl and aryl may be substituted by halogen, Y is -(CH2)3-, 1,3-phenylene, 1,3-cyclohexanediyl, R' is H, F, Br, cf3, (C-|-c6)-alkyl, 0-(C-|-C6)-alkyl, phenyl; R" is H, (Ci-c6)-alkyl, (Ci-c3)-alkylphenyl, (c5-c6)-cycloalkyl, phenyl, cf3; which comprises reacting compounds of the formula (C1) 11 HO Y (CI) where Y, R' and R" are each as defined above with compounds of the formula (I) CI co2r (I) where R is as defined above in toluene, NMP or other aprotic solvents, in the presence of a suitable base, at -78 to +50°C, and subsequently working up extractively and optionally crystallizing the end product.
The process for preparing the compounds of the formula (C) as claimed in claim 6, wherein the phenyl ring is substituted by R* in the m- or p-position.
The use of the compounds of the formula (I) as claimed in any one of claims 1 to 4 for preparing PPAR agonists of the general formula (C). INTELLECTUAL PROPERTY OFFICE OF hfcZ- 3 t OCT 2007 received 12
9. A compound according to claim 1, substantially as herein described or exemplified.
10. A process according to claim 5, substantially as herein described or exemplified.
11. A process according to claim 6, substantially as herein described or exemplified.
12. A use according to claim 8, substantially as herein described or exemplified.
13. A compound of the formula (I) as defined in any one of claims 1 to 4, when prepared by a process of claim 5.
14. A compound of the formula (C), when prepared by a process of claim 6 or 7.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10313228A DE10313228A1 (en) | 2003-03-25 | 2003-03-25 | Synthesis of 2-chloromethyl-6-methylbenzoic acid esters |
PCT/EP2004/002579 WO2004085377A1 (en) | 2003-03-25 | 2004-03-12 | Synthesis of 2-chloromethyl-6-methylbenzoic acid esters |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ542603A true NZ542603A (en) | 2007-12-21 |
Family
ID=33015963
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ542603A NZ542603A (en) | 2003-03-25 | 2004-03-12 | Synthesis of 2-chloromethyl-6-methylbenzoic acid esters |
Country Status (25)
Country | Link |
---|---|
EP (1) | EP1611083B1 (en) |
JP (1) | JP4510805B2 (en) |
KR (1) | KR20050116388A (en) |
CN (1) | CN100378065C (en) |
AR (1) | AR043752A1 (en) |
AT (1) | ATE374742T1 (en) |
AU (1) | AU2004224177B2 (en) |
BR (1) | BRPI0408653A (en) |
CA (1) | CA2519715A1 (en) |
CO (1) | CO5690546A2 (en) |
CY (1) | CY1107029T1 (en) |
DE (2) | DE10313228A1 (en) |
DK (1) | DK1611083T3 (en) |
ES (1) | ES2293237T3 (en) |
HK (1) | HK1087098A1 (en) |
IL (1) | IL171031A (en) |
MX (1) | MXPA05010001A (en) |
NO (1) | NO20054875L (en) |
NZ (1) | NZ542603A (en) |
PL (1) | PL1611083T3 (en) |
PT (1) | PT1611083E (en) |
RU (1) | RU2345982C2 (en) |
TW (1) | TW200502213A (en) |
WO (1) | WO2004085377A1 (en) |
ZA (1) | ZA200506499B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102005029382B3 (en) | 2005-06-24 | 2006-12-21 | Sanofi-Aventis Deutschland Gmbh | New alkoxymethylyl substituted benzoic acid derivatives are peroxisome proliferation activated receptor agonists used for treating and/or preventing e.g. diabetes mellitus, dyslipidemia and disturbances in fatty acid metabolism |
CN114805120A (en) * | 2022-05-23 | 2022-07-29 | 江苏瑞达环保科技有限公司 | Synthesis process of m-cyanomethyl benzoate |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4689425A (en) * | 1986-11-06 | 1987-08-25 | Stauffer Chemical Company | Photochlorination of aromatic compounds in the side chain |
SK15522001A3 (en) * | 1999-04-28 | 2002-06-04 | Aventis Pharma Deutschland Gmbh | Tri-aryl acid derivatives as ppar receptor ligands |
ES2287016T3 (en) * | 1999-04-28 | 2007-12-16 | Sanofi-Aventis Deutschland Gmbh | DERIVATIVES OF DIARIL-ACID AS LIGANDS OF THE PPAR RECEIVER. |
UA76773C2 (en) * | 2001-08-31 | 2006-09-15 | Санофі-Авентіс Дойчланд Гмбх | Diaryl cycloalkyl derivatives, method for the preparation thereof and use thereof as ppar-activators |
-
2003
- 2003-03-25 DE DE10313228A patent/DE10313228A1/en not_active Withdrawn
-
2004
- 2004-03-12 RU RU2005132827/04A patent/RU2345982C2/en not_active IP Right Cessation
- 2004-03-12 PL PL04719953T patent/PL1611083T3/en unknown
- 2004-03-12 AU AU2004224177A patent/AU2004224177B2/en not_active Ceased
- 2004-03-12 CN CNB2004800062464A patent/CN100378065C/en not_active Expired - Fee Related
- 2004-03-12 WO PCT/EP2004/002579 patent/WO2004085377A1/en active IP Right Grant
- 2004-03-12 KR KR1020057017893A patent/KR20050116388A/en not_active Application Discontinuation
- 2004-03-12 AT AT04719953T patent/ATE374742T1/en not_active IP Right Cessation
- 2004-03-12 DE DE502004005137T patent/DE502004005137D1/en not_active Expired - Lifetime
- 2004-03-12 JP JP2006504662A patent/JP4510805B2/en not_active Expired - Fee Related
- 2004-03-12 BR BRPI0408653-8A patent/BRPI0408653A/en not_active IP Right Cessation
- 2004-03-12 PT PT04719953T patent/PT1611083E/en unknown
- 2004-03-12 MX MXPA05010001A patent/MXPA05010001A/en active IP Right Grant
- 2004-03-12 EP EP04719953A patent/EP1611083B1/en not_active Expired - Lifetime
- 2004-03-12 ES ES04719953T patent/ES2293237T3/en not_active Expired - Lifetime
- 2004-03-12 NZ NZ542603A patent/NZ542603A/en unknown
- 2004-03-12 DK DK04719953T patent/DK1611083T3/en active
- 2004-03-12 CA CA002519715A patent/CA2519715A1/en not_active Abandoned
- 2004-03-23 AR ARP040100955A patent/AR043752A1/en not_active Application Discontinuation
- 2004-03-23 TW TW093107693A patent/TW200502213A/en unknown
-
2005
- 2005-08-15 ZA ZA200506499A patent/ZA200506499B/en unknown
- 2005-09-21 IL IL171031A patent/IL171031A/en not_active IP Right Cessation
- 2005-09-23 CO CO05096625A patent/CO5690546A2/en active IP Right Grant
- 2005-10-21 NO NO20054875A patent/NO20054875L/en not_active Application Discontinuation
-
2006
- 2006-06-28 HK HK06107312A patent/HK1087098A1/en not_active IP Right Cessation
-
2007
- 2007-12-04 CY CY20071101544T patent/CY1107029T1/en unknown
Also Published As
Publication number | Publication date |
---|---|
RU2345982C2 (en) | 2009-02-10 |
DK1611083T3 (en) | 2008-01-21 |
NO20054875L (en) | 2005-12-27 |
HK1087098A1 (en) | 2006-10-06 |
IL171031A (en) | 2010-11-30 |
ZA200506499B (en) | 2006-07-26 |
ES2293237T3 (en) | 2008-03-16 |
ATE374742T1 (en) | 2007-10-15 |
PT1611083E (en) | 2007-11-26 |
AU2004224177A1 (en) | 2004-10-07 |
CA2519715A1 (en) | 2004-10-07 |
AR043752A1 (en) | 2005-08-10 |
JP2006521307A (en) | 2006-09-21 |
PL1611083T3 (en) | 2008-01-31 |
EP1611083A1 (en) | 2006-01-04 |
WO2004085377A1 (en) | 2004-10-07 |
CO5690546A2 (en) | 2006-10-31 |
CY1107029T1 (en) | 2012-09-26 |
MXPA05010001A (en) | 2005-11-17 |
AU2004224177B2 (en) | 2010-01-21 |
BRPI0408653A (en) | 2006-03-07 |
TW200502213A (en) | 2005-01-16 |
JP4510805B2 (en) | 2010-07-28 |
DE502004005137D1 (en) | 2007-11-15 |
DE10313228A1 (en) | 2004-10-21 |
NO20054875D0 (en) | 2005-10-21 |
KR20050116388A (en) | 2005-12-12 |
EP1611083B1 (en) | 2007-10-03 |
CN1759092A (en) | 2006-04-12 |
CN100378065C (en) | 2008-04-02 |
RU2005132827A (en) | 2006-02-10 |
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