WO2011058161A2 - Process for preparing (11beta, 16alpha)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione - Google Patents
Process for preparing (11beta, 16alpha)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione Download PDFInfo
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- WO2011058161A2 WO2011058161A2 PCT/EP2010/067443 EP2010067443W WO2011058161A2 WO 2011058161 A2 WO2011058161 A2 WO 2011058161A2 EP 2010067443 W EP2010067443 W EP 2010067443W WO 2011058161 A2 WO2011058161 A2 WO 2011058161A2
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- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 title claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 10
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- 238000001556 precipitation Methods 0.000 claims abstract description 5
- 229960002117 triamcinolone acetonide Drugs 0.000 claims abstract description 5
- 238000002425 crystallisation Methods 0.000 claims abstract description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 239000012296 anti-solvent Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 6
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 6
- 229940011051 isopropyl acetate Drugs 0.000 claims description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- NXYIECYJINSHGC-UHFFFAOYSA-N 4-(nitrooxymethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(CO[N+]([O-])=O)C=C1 NXYIECYJINSHGC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 230000020477 pH reduction Effects 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 230000003472 neutralizing effect Effects 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 230000008030 elimination Effects 0.000 claims description 2
- 238000003379 elimination reaction Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 229940113088 dimethylacetamide Drugs 0.000 claims 3
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims 3
- 229940093499 ethyl acetate Drugs 0.000 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 235000017550 sodium carbonate Nutrition 0.000 claims 1
- -1 nitrooxymethyl Chemical group 0.000 abstract description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 abstract 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000002245 particle Substances 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000004292 cyclic ethers Chemical class 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 2
- 229910000071 diazene Inorganic materials 0.000 description 2
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 150000003738 xylenes Chemical class 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WSQFGHCDTDUKGX-NIJRNGOMSA-N CC(C)(O[C@]([C@H]1C2)([C@@](C)(C[C@@H]([C@@](C3CC4)([C@@](C)(C=C5)C4=CC5=O)[F]#C)O)[C@@]23[N]#C)C(CO)=O)[O]1=C Chemical compound CC(C)(O[C@]([C@H]1C2)([C@@](C)(C[C@@H]([C@@](C3CC4)([C@@](C)(C=C5)C4=CC5=O)[F]#C)O)[C@@]23[N]#C)C(CO)=O)[O]1=C WSQFGHCDTDUKGX-NIJRNGOMSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
- C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/08—Antiseborrheics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Definitions
- This invention relates to a new process for the preparation of the compound (1 1 ⁇ , 16a)-9-fluoro-1 1 -hydroxy-16,17-[1 -methyl- ethyl idenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1 ,4-dien- 3,20-dione, used as a topic anti-inflammatory drug.
- Compound (1 1 ⁇ , 16a)-9-fluoro-1 1 -hydroxy-16,17-[1 -methyl- ethylidenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1 ,4-dien- 3,20-dione with formula (I) is a corticosteroid previously described in application WO2007025632 (Example 1 ). This compound is especially useful in the treatment of certain inflammatory diseases such as corticosteroid- sensitive dermatosis, atopic dermatitis, contact dermatitis, psoriasis and seborrhoeic dermatitis.
- Said compound is applied topically, preferably using creams, ointments, lotions and gels and similar formulations.
- the compound of formula (I) is obtained in example 1 of application WO2007025632 by the reaction of triamcinolone acetonide (II) with 4- (nitrooxymethyl)benzoic acid (III) in the presence of 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (IV) and 4-dimethylaminopyridine (V) according to Diagram 1 .
- the invention provides a new industrial process for preparing (1 1 ⁇ , 16a)-9-fluoro-1 1 -hydroxy-16,17-[1 -methyl-ethyl idenebis(oxy)]- 21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1 ,4-dien-3,20-dione (I) with a good yield, starting from cost effective products and providing an end product with suitable purity and particle size.
- the solvent of step (i) is chosen from the group consisting of halogenated hydrocarbons such as dichloromethane, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, nitriles such as acetonitrile, sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures thereof.
- the solvent is preferably dichloromethane.
- the acidification is performed with an acid chosen from the group consisting of mineral acids such as hydrochloric acid, sulphuric acid, phosphoric acid and hydrobromic acid, carboxylic acids such as acetic acid, trifluoroacetic acid and formic acid, sulphonic acids such as methane sulphonic acid, trifluoromethane sulphonic acid and p-toluene sulphonic acid and other similar acids and mixtures thereof.
- the acid is preferably hydrochloric acid.
- the neutralisation is performed with a base chosen from the group consisting of alkaline bicarbonates such as sodium bicarbonate and potassium bicarbonate and alkaline carbonate such as sodium carbonate and potassium carbonate.
- the base is preferably sodium bicarbonate.
- the anti-solvent of step (i) is chosen from the group consisting of Ci-C 4 alkanols such as ethanol, methanol and isopropanol, aromatic hydrocarbons such as toluene and xylenes, as well as water and other similar anti-solvents and mixtures thereof.
- the anti-solvent is preferably ethanol.
- the solvent of step (ii) is chosen from the group consisting of halogenated hydrocarbons such as dichloromethane, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, nitriles such as acetonitrile, sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures thereof.
- the solvent is preferably dichloromethane.
- the anti-solvent of step (ii) is chosen from the group consisting of Ci-C 4 alkanols such as ethanol, methanol and isopropanol, aromatic hydrocarbons such as toluene and xylenes, as well as water and other similar anti-solvents and mixtures thereof.
- the anti-solvent is preferably ethanol.
- the solvent of step (iii) is chosen from the group consisting of esters such as ethyl acetate and isopropyl acetate, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone, nitriles such as acetonitrile, halogenated hydrocarbons such as dichloromethane and sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures thereof.
- the solvent is preferably ethyl acetate.
- the anti-solvent of step (iii) is chosen from a group consisting of C6-C9 aliphatic hydrocarbons such as heptane, aliphatic ethers such as isopropyl ether and ethyl ether, the group consisting of Ci-C 4 alkanols such as ethanol, methanol and isopropanol, and similar anti- solvents and mixtures thereof.
- the anti-solvent is preferably heptane. Examples Example 1
- the dichloromethane extracts were placed together and 203 I of 0.5 N HCI were added.
- 203 I of 0.5 N HCI were added to the organic phase, followed by 129 I of 0.25 N NaHCO3. It was washed with water until the pH of the aqueous phase was similar to that of the water added.
- the wet solid was dried under vacuum.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
This invention relates to a new process for preparing (11 β, 16α)-9-fluoro-11 - hydroxy-16,17-[1 -methyl -ethyl idenebis(oxy)]-21 -[1 -oxo-[4- (nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione, comprising the steps of (i) reaction of triamcinolone acetonide with 4-(nitrooxymethyl)benzoic, 4- dimethylaminopyridine and N-N'-diisopropylcarbodiimide, (ii) crystallisation, and (iii) controlled precipitation.
Description
Process for preparing (11 β, 16a)-9-fluoro-11 -hydroxy-16,17-[1 -methyl- ethylidenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1 ,4- dien-3,20-dione Field of the invention
This invention relates to a new process for the preparation of the compound (1 1 β, 16a)-9-fluoro-1 1 -hydroxy-16,17-[1 -methyl- ethyl idenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1 ,4-dien- 3,20-dione, used as a topic anti-inflammatory drug.
Background art
Compound (1 1 β, 16a)-9-fluoro-1 1 -hydroxy-16,17-[1 -methyl- ethylidenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1 ,4-dien- 3,20-dione with formula (I) is a corticosteroid previously described in application WO2007025632 (Example 1 ). This compound is especially useful in the treatment of certain inflammatory diseases such as corticosteroid- sensitive dermatosis, atopic dermatitis, contact dermatitis, psoriasis and seborrhoeic dermatitis.
Said compound is applied topically, preferably using creams, ointments, lotions and gels and similar formulations.
The compound of formula (I) is obtained in example 1 of application WO2007025632 by the reaction of triamcinolone acetonide (II) with 4- (nitrooxymethyl)benzoic acid (III) in the presence of 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (IV) and 4-dimethylaminopyridine (V) according to Diagram 1 .
Diagram 1
The yield of this reaction is of 34.4%, which makes it industrially unviable. Also, the price of the diimide used (IV) is also a drawback for use in industrial processes.
It is therefore necessary to find a different process for the industrial production of compound (I) with a high yield and using cheaper starting products.
The authors of the present invention have achieved a new industrial process to obtain (I) that produces the product with a much higher yield and also replaces diimide (IV) with Ν,Ν'-diisopropylcarbodiimide (VI), which is cheaper. On the other hand, we have found that the resulting product is of very high purity. Moreover, the new process also comprises a final step of controlled precipitation, which provides the end product with a suitable particle size for the preparation of topical formulations. Summary of the invention
In a single aspect, the invention provides a new industrial process for preparing (1 1 β, 16a)-9-fluoro-1 1 -hydroxy-16,17-[1 -methyl-ethyl idenebis(oxy)]- 21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1 ,4-dien-3,20-dione (I) with a good yield, starting from cost effective products and providing an end product with suitable purity and particle size.
Detailed description of the invention The process for preparing 1 1 β, 16a)-9-fluoro-1 1 -hydroxy-16,17-[1 - methyl-ethylidenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1 ,4- dien-3,20-dione (I), which is the single aspect of the invention, comprises the following steps:
(i) reaction of triamcinolone acetonide (II)
(iii) precipitation of the compound (I) crystallised in step (ii) in a mixture of a solvent and an anti-solvent.
In a preferred embodiment, the solvent of step (i) is chosen from the group consisting of halogenated hydrocarbons such as dichloromethane, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, nitriles such as acetonitrile, sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures thereof. The solvent is preferably dichloromethane.
In another preferred embodiment, the acidification is performed with an acid chosen from the group consisting of mineral acids such as hydrochloric acid, sulphuric acid, phosphoric acid and hydrobromic acid, carboxylic acids such as acetic acid, trifluoroacetic acid and formic acid, sulphonic acids such as methane sulphonic acid, trifluoromethane sulphonic acid and p-toluene sulphonic acid and other similar acids and mixtures thereof. The acid is preferably hydrochloric acid.
In another preferred embodiment, the neutralisation is performed with a base chosen from the group consisting of alkaline bicarbonates such as sodium bicarbonate and potassium bicarbonate and alkaline carbonate such as sodium carbonate and potassium carbonate. The base is preferably sodium bicarbonate.
In another embodiment preferred, the anti-solvent of step (i) is chosen from the group consisting of Ci-C4 alkanols such as ethanol, methanol and isopropanol, aromatic hydrocarbons such as toluene and xylenes, as well as water and other similar anti-solvents and mixtures thereof. The anti-solvent is preferably ethanol.
In another preferred embodiment, the solvent of step (ii) is chosen from the group consisting of halogenated hydrocarbons such as dichloromethane, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone,
esters such as ethyl acetate and isopropyl acetate, nitriles such as acetonitrile, sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures thereof. The solvent is preferably dichloromethane. In another preferred embodiment, the anti-solvent of step (ii) is chosen from the group consisting of Ci-C4 alkanols such as ethanol, methanol and isopropanol, aromatic hydrocarbons such as toluene and xylenes, as well as water and other similar anti-solvents and mixtures thereof. The anti-solvent is preferably ethanol.
In another preferred embodiment, the solvent of step (iii) is chosen from the group consisting of esters such as ethyl acetate and isopropyl acetate, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone, nitriles such as acetonitrile, halogenated hydrocarbons such as dichloromethane and sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures thereof. The solvent is preferably ethyl acetate.
In another preferred embodiment, the anti-solvent of step (iii) is chosen from a group consisting of C6-C9 aliphatic hydrocarbons such as heptane, aliphatic ethers such as isopropyl ether and ethyl ether, the group consisting of Ci-C4 alkanols such as ethanol, methanol and isopropanol, and similar anti- solvents and mixtures thereof. The anti-solvent is preferably heptane. Examples Example 1
Synthesis of (1 13, 16a)-9-fluoro-1 1 -hvdroxy-16.17-ri-methyl- ethyl idenebis(oxy)1-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy1lpregna-1 ,4-dien-
3,20-dione (I)
Diagram 2
(i) Reaction
12.92 Kg of triamcinolone acetonide (II), 6.50 Kg of 4-(nitrooxymethyl)benzoic acid (III), 401 g of 4-dimethylaminopyridine (V) and 5.8 I of Ν,Ν'- diisopropylcarbodiimide (VI) were added to 284 I of dichloromethane. The solution was placed at ambient temperature and maintained with stirring until the reaction was completed. 13 I of dichloromethane were added. The solid formed (Ν,Ν'-diisopropylurea) was removed by filtration and the filter was washed with dichloromethane.
The dichloromethane extracts were placed together and 203 I of 0.5 N HCI were added. 203 I of 0.5 N HCI were added to the organic phase, followed by
129 I of 0.25 N NaHCO3. It was washed with water until the pH of the aqueous phase was similar to that of the water added.
465 I of absolute ethanol were added to the organic phase and it was distilled at atmospheric pressure to a final volume of between 465 I and 504 I, and it was left to reach room temperature.
The suspension was filtered and the wet solid was washed with ethanol. The wet solid was dried under vacuum, producing 15.59 Kg of compound (I). Yield = 85.5%. HPLC Purity = 98.41 %.
(ii) Crystallisation 15.56 Kg of the solid obtained in the previous step were added to 467 I of dichloromethane. This was heated to reflux and distilled at atmospheric pressure to a final volume of 47 I. It was left to reach ambient temperature and 560 I of ethanol were added. The suspension was filtered and the wet solid was washed with ethanol.
The wet solid was dried under vacuum.
(iii) Precipitation
1 1 .21 Kg of the solid obtained in the previous step were added to 516 I of ethyl acetate. It was heated to reflux and stirred until solution. It was cooled to 40-50°C. 538 I of heptane were added and it was taken to ambient temperature. The solution was filtered through a 0.2 μιτι filter. It was washed with ethyl acetate and stirred at least for 3 hours at ambient temperature.
The suspension was filtered and the wet solid was washed with heptane.
The wet solid was dried under vacuum. Example 2
Particle size distribution for (I)
The particle size distribution of the product obtained in the final step of Example 1 showed a Gaussian distribution characterised by values d(0.9) = 10.79 pm; d(0.5) = 5.26 pm; and d(0.1 ) = 2.34 μητι.
Claims
1 . A process for preparing (1 1 β, 16a)-9-fluoro-1 1 -hydroxy-16,17-[1 -methyl- ethyl idenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1 ,4-dien- 3,20-dione (I)
(i) reaction of triamcinolone acetonide (II)
(ii) crystallisation of compound (I) formed in step (i) in a mixture of a solvent and an anti-solvent; and
(iii) precipitation of the compound (I) crystallised in step (ii) in a mixture of a solvent and an anti-solvent.
2. The process according to claim 1 , wherein the solvent of step (i) is chosen from the group consisting of dichloromethane, dimethylformamide, tetrahydrofurane, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, dimethylacetamide and dimethyl sulphoxide.
3. The process according to claim 2, wherein the solvent is dichloromethane.
4. The process according to claim 1 , wherein the acidification is performed with an acid chosen from the group consisting of hydrochloric acid, sulphuric acid, acetic acid, trifluoroacetic acid, hydrobromic acid, formic acid, methane sulphonic acid, trifluoromethane sulphonic acid and p- toluene sulphonic acid.
5. The process according to claim 4, wherein the acid is hidrochloric acid.
6. The process according to claim 1 , wherein the neutralising is performed with a base chosen from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.
7. The process according to claim 6, wherein the base is sodium bicarbonate.
8. The process according to claim 1 , wherein the anti-solvent of step (i) is chosen from the group consisting of ethanol, methanol, isopropanol, toluene and water.
9. The process according to claim 8, wherein the anti-solvent is ethanol.
10. The process according to claim 1 , wherein the solvent of step (ii) is chosen from the group consisting of dichloromethane, dimethylformamide, tetrahydrofurane, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, dimethylacetamide and dimethyl sulphoxide.
1 1 . The process according to claim 10, wherein the solvent is dichloromethane.
12. The process according to claim 1 , wherein the anti-solvent of step (ii) is chosen from the group consisting of ethanol, methanol, isopropanol, toluene and water.
13. The process according to claim 12, wherein the anti-solvent is ethanol.
14. The process according to claim 1 , wherein the solvent of step (iii) is chosen from the group consisting of ethyl acetate, dimethylformamide, tetrahydrofurane, acetone, acetonitrile, dichloromethane, isopropyl acetate, methyl isobutyl ketone, dimethylacetamide and dimethyl sulphoxide.
15. The process according to claim 14, wherein the solvent is ethyl acetate.
16. The process according to claim 1 , wherein the anti-solvent of step (iii) is chosen from the group consisting of heptane, isopropyl ether and isopropanol.
17. The process according to claim 16, wherein the anti-solvent is heptane.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2012538352A JP2013510826A (en) | 2009-11-16 | 2010-11-15 | (11β, 16α) -9-Fluoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)]-21- [1-oxo- [4- (nitrooxymethyl) benzoxy]] pregna- Process for preparing 1,4-diene-3,20-dione |
| CA2780139A CA2780139A1 (en) | 2009-11-16 | 2010-11-15 | Process for preparing (11.beta., 16.alpha.)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione |
| RU2012124815/04A RU2012124815A (en) | 2009-11-16 | 2010-11-15 | METHOD FOR PRODUCING (11β, 16α) -9-FLUOR-11 - HYDROXY-16, 17- [1-METHYL-ETHYLIDENBIS- (OXY)] - 21- [1-OXO- [4-NITROXYMETHYL) BENZOXY]] PREGNA-1 , 4-DIEN-3,20-DIONA |
| EP10776364A EP2501710A2 (en) | 2009-11-16 | 2010-11-15 | Process for preparing (11beta, 16alpha)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione |
| CN2010800517342A CN102612522A (en) | 2009-11-16 | 2010-11-15 | Process for preparing (11beta, 16alpha)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione. |
| MX2012005616A MX2012005616A (en) | 2009-11-16 | 2010-11-15 | Process for preparing (11beta, 16alpha)-9-fluoro-11-hydroxy-16,17 -[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benz oxy]]pregna-1,4-dien-3,20-dione. |
| BR112012011552A BR112012011552A2 (en) | 2009-11-16 | 2010-11-15 | process for preparing (11beta, 16alpha) -9-fluoro-11-hydroxy-16,17- [1-methyl-ethylidene-bis (oxy)] -21- [1-oxo- [4- (nitro-oxy-methyl ) benzoxyl] 17pregna-1,4-diene-3,20-dione |
| AU2010317895A AU2010317895A1 (en) | 2009-11-16 | 2010-11-15 | Process for preparing (11beta, 16alpha)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl) benzoxy]]pregna-1,4-dien-3,20-dione |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES200930999A ES2359708B1 (en) | 2009-11-16 | 2009-11-16 | PREPARATION PROCEDURE OF THE (11BETA, 16ALFA) -9-FLUORO-11-HIDROXI-16,17- [1-METHYL-ETHYLENEBIS (OXI)] - 21- [1-OXO- [4- (NITROOXIMETILE) BENZOXI]] PREÑA-1,4-DIEN-3,20-DIONA. |
| ESP200930999 | 2009-11-16 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2011058161A2 true WO2011058161A2 (en) | 2011-05-19 |
| WO2011058161A3 WO2011058161A3 (en) | 2011-07-07 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2010/067443 WO2011058161A2 (en) | 2009-11-16 | 2010-11-15 | Process for preparing (11beta, 16alpha)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP2501710A2 (en) |
| JP (1) | JP2013510826A (en) |
| KR (1) | KR20120084788A (en) |
| CN (1) | CN102612522A (en) |
| AR (1) | AR078909A1 (en) |
| AU (1) | AU2010317895A1 (en) |
| BR (1) | BR112012011552A2 (en) |
| CA (1) | CA2780139A1 (en) |
| ES (1) | ES2359708B1 (en) |
| MX (1) | MX2012005616A (en) |
| PE (1) | PE20121315A1 (en) |
| RU (1) | RU2012124815A (en) |
| TW (1) | TW201130861A (en) |
| UY (1) | UY33032A (en) |
| WO (1) | WO2011058161A2 (en) |
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| CN106632562B (en) * | 2015-10-30 | 2020-02-18 | 天津法莫西医药科技有限公司 | Fluorometholone refining process |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007025632A2 (en) | 2005-09-02 | 2007-03-08 | Nicox S.A. | Nitrooxy derivatives op glucocorticoids |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1238912B (en) * | 1964-01-31 | 1967-04-20 | Thomae Gmbh Dr K | Process for the preparation of new esters of triamcinolone-16alpha, 17alpha-acetonide |
| US4323512A (en) * | 1981-05-13 | 1982-04-06 | Schering Corporation | Process for the preparation of steroidal 17α-arylcarboxylates |
| GB9919693D0 (en) * | 1999-08-19 | 1999-10-20 | Rhone Poulenc Rorer Ltd | Process |
| US6696592B2 (en) * | 2001-05-22 | 2004-02-24 | Nicox-S.A. | Methods of making 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivatives and intermediates useful in the synthesis thereof |
| EP1336602A1 (en) * | 2002-02-13 | 2003-08-20 | Giovanni Scaramuzzino | Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases |
| EP1964550A1 (en) * | 2007-03-01 | 2008-09-03 | NicOx S.A. | Glucocorticoid-nitrooxyderivative compositions |
| ES2324007A1 (en) * | 2007-10-25 | 2009-07-28 | Ferrer Internacional, S.A. | Amorphous form of (11beta,16alpha)-9-fluoro-11-hydroxy-16,17-[(1-methylethyliden)bis(oxy)]-21-[[4- [(nitrooxy)methyl]benzoyl]oxy]-pregna-1,4-dien-3,20-dione |
-
2009
- 2009-11-16 ES ES200930999A patent/ES2359708B1/en not_active Expired - Fee Related
-
2010
- 2010-10-19 TW TW099135537A patent/TW201130861A/en unknown
- 2010-11-04 AR ARP100104079A patent/AR078909A1/en unknown
- 2010-11-15 KR KR1020127015331A patent/KR20120084788A/en not_active Application Discontinuation
- 2010-11-15 JP JP2012538352A patent/JP2013510826A/en active Pending
- 2010-11-15 BR BR112012011552A patent/BR112012011552A2/en not_active IP Right Cessation
- 2010-11-15 CA CA2780139A patent/CA2780139A1/en not_active Abandoned
- 2010-11-15 UY UY0001033032A patent/UY33032A/en unknown
- 2010-11-15 RU RU2012124815/04A patent/RU2012124815A/en unknown
- 2010-11-15 EP EP10776364A patent/EP2501710A2/en not_active Withdrawn
- 2010-11-15 PE PE2012000618A patent/PE20121315A1/en not_active Application Discontinuation
- 2010-11-15 MX MX2012005616A patent/MX2012005616A/en not_active Application Discontinuation
- 2010-11-15 AU AU2010317895A patent/AU2010317895A1/en not_active Abandoned
- 2010-11-15 WO PCT/EP2010/067443 patent/WO2011058161A2/en active Application Filing
- 2010-11-15 CN CN2010800517342A patent/CN102612522A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007025632A2 (en) | 2005-09-02 | 2007-03-08 | Nicox S.A. | Nitrooxy derivatives op glucocorticoids |
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| Publication number | Publication date |
|---|---|
| JP2013510826A (en) | 2013-03-28 |
| KR20120084788A (en) | 2012-07-30 |
| PE20121315A1 (en) | 2012-10-06 |
| WO2011058161A3 (en) | 2011-07-07 |
| TW201130861A (en) | 2011-09-16 |
| CN102612522A (en) | 2012-07-25 |
| UY33032A (en) | 2011-05-31 |
| ES2359708B1 (en) | 2012-03-30 |
| AR078909A1 (en) | 2011-12-14 |
| EP2501710A2 (en) | 2012-09-26 |
| AU2010317895A1 (en) | 2012-05-24 |
| ES2359708A1 (en) | 2011-05-26 |
| BR112012011552A2 (en) | 2015-10-06 |
| MX2012005616A (en) | 2012-10-15 |
| CA2780139A1 (en) | 2011-05-19 |
| RU2012124815A (en) | 2013-12-27 |
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