CA2111169C - Phenylacetic acid derivatives, process for the preparation thereof and corresponding use - Google Patents
Phenylacetic acid derivatives, process for the preparation thereof and corresponding use Download PDFInfo
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- CA2111169C CA2111169C CA002111169A CA2111169A CA2111169C CA 2111169 C CA2111169 C CA 2111169C CA 002111169 A CA002111169 A CA 002111169A CA 2111169 A CA2111169 A CA 2111169A CA 2111169 C CA2111169 C CA 2111169C
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- phenylacetic acid
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Links
- 238000000034 method Methods 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 150000007513 acids Chemical class 0.000 claims abstract description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 11
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical class OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 7
- MNIPYSSQXLZQLJ-UHFFFAOYSA-N Biofenac Chemical compound OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl MNIPYSSQXLZQLJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002609 medium Substances 0.000 claims abstract description 5
- 239000000730 antalgic agent Substances 0.000 claims abstract description 4
- 229940121363 anti-inflammatory agent Drugs 0.000 claims abstract description 4
- 239000002260 anti-inflammatory agent Substances 0.000 claims abstract description 4
- 229940035676 analgesics Drugs 0.000 claims abstract description 3
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 239000012585 homogenous medium Substances 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 5
- 239000000010 aprotic solvent Substances 0.000 claims description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000011347 resin Substances 0.000 claims description 4
- 229920005989 resin Polymers 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 150000002430 hydrocarbons Chemical class 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 235000013350 formula milk Nutrition 0.000 description 22
- 239000000047 product Substances 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 125000005907 alkyl ester group Chemical group 0.000 description 9
- 230000000202 analgesic effect Effects 0.000 description 8
- -1 benzyl ester Chemical class 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229960001259 diclofenac Drugs 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- MLXDUYUQINCFFV-UHFFFAOYSA-N 2-acetyloxyacetic acid Chemical compound CC(=O)OCC(O)=O MLXDUYUQINCFFV-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- KUYMVWXKHQSIAS-UHFFFAOYSA-N tert-butyl 2-chloroacetate Chemical compound CC(C)(C)OC(=O)CCl KUYMVWXKHQSIAS-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000036647 reaction Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 159000000000 sodium salts Chemical group 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- JFJGNYUOSBSXHF-UHFFFAOYSA-N (1-methylcyclohexyl) 2-chloroacetate Chemical compound ClCC(=O)OC1(C)CCCCC1 JFJGNYUOSBSXHF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XMXAJPQCEPMUMW-UHFFFAOYSA-N 3-methylpentan-3-yl 2-chloroacetate Chemical compound ClCC(=O)OC(CC)(C)CC XMXAJPQCEPMUMW-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- RGPDEAGGEXEMMM-UHFFFAOYSA-N Nefopam Chemical compound C12=CC=CC=C2CN(C)CCOC1C1=CC=CC=C1 RGPDEAGGEXEMMM-UHFFFAOYSA-N 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 208000036366 Sensation of pressure Diseases 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- PASACJUCYZVYOQ-UHFFFAOYSA-N [I].C[SiH](C)C Chemical compound [I].C[SiH](C)C PASACJUCYZVYOQ-UHFFFAOYSA-N 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical class OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- AZFVLHQDIIJLJG-UHFFFAOYSA-N chloromethylsilane Chemical compound [SiH3]CCl AZFVLHQDIIJLJG-UHFFFAOYSA-N 0.000 description 1
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 description 1
- 229960001193 diclofenac sodium Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229940013688 formic acid Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 1
- 229940032007 methylethyl ketone Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000012976 tarts Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/02—Formation of carboxyl groups in compounds containing amino groups, e.g. by oxidation of amino alcohols
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
Abstract
The invention relates to phenylacetic acid derivatives, a process for the preparation thereof and corresponding use. These derivatives are identified by the following formula:
where R1, R2 and R3 are the same or different and are a either methyl, ethyl or propyl radicals; or R2 and R3, which are attached as shown by -(R2....R3)-, jointly form a -(CH2)n- radical where n = 4 or 5, with the exception of the case where R1 = R2 =
R3 = CH3, and also with the exception of the case where R1 = R3 =
CH3 and R2 = ethyl; the process comprises the reaction of a diclofenac salt with the corresponding alkyl haloacetate of formula X-CH2-COO-CR1R2R3, (X = Cl or Br) in an homogenous medium.
They are used for the preparation of [2-(2,6-dichloroanilino)phenyl]acetoxyacetic acid, by treatment with acids in an anhydrous medium. The derivatives have therapeutic activity as analgesics or anti-inflammatories.
where R1, R2 and R3 are the same or different and are a either methyl, ethyl or propyl radicals; or R2 and R3, which are attached as shown by -(R2....R3)-, jointly form a -(CH2)n- radical where n = 4 or 5, with the exception of the case where R1 = R2 =
R3 = CH3, and also with the exception of the case where R1 = R3 =
CH3 and R2 = ethyl; the process comprises the reaction of a diclofenac salt with the corresponding alkyl haloacetate of formula X-CH2-COO-CR1R2R3, (X = Cl or Br) in an homogenous medium.
They are used for the preparation of [2-(2,6-dichloroanilino)phenyl]acetoxyacetic acid, by treatment with acids in an anhydrous medium. The derivatives have therapeutic activity as analgesics or anti-inflammatories.
Description
2~.1~.1C~
PHENYLACETIC ACID DERIVATIVES, PROCESS FOR THE PREPARATION
THEREOF AND CORRESPONDING USE.
D E S C R I P T I O N
This invention relates to phenylacetic acid derivatives, particularly [2-(2,6-dichloroanilino)phenyl]acetic acid, com-monly known as diclofenac, a product known for its analgesic and antiinflammatory properties. The invention also relates to a process for the preparation of said derivatives and to a process for the use thereof in the preparation of [2-(2,6-dichloroanilino)phenyl]acetoxyacetic acid, also known for its analgesic and antiinflammatory properties.
STATE OF THE ART
Diclofenac (formula I) is a product having analgesic and antiinflammatory properties, known since the 60's and which has been extensively used in sodium salt form orally, rectal-ly and parenterally. In view of some of its adverse side effects (gastrointestinal problems, mainly) numerous attempts have been made to prepare diclofenac derivatives which, while maintaining or improving its analgesic and antiinflammatory properties, have weaker adverse side effects, or allow other forms of administration (e. g. topical). One of the diclofenac derivatives used in therapeutics is (2-(2,6-dichloroanilino)-phenyl]acetoxyacetic acid (formula II), described for the first time in 1984 (EP-P-0 119 932). Nevertheless, the design and preparation of agents having good analgesic and antiin flammatory properties, with little or no side effects and good ways of administration, is still a problem of interest in modern therapeutics.
~CH2-COONa CH2-COO-CH2-COON
NH ~ NH
CI. CI C1 C1 ~I) CII) ., ' - 2 -The preparation of [2-(2,6-dichloroanilino)phenyl]acet-oxyacetic acid of formula II suffers from the chemical draw-back of obtaining a free carboxylic group in the presence of a carboxylic acid ester which has not to be modified. Two solutions have been proposed to solve this problem: (a) carry out hydrogenolysis of the formula II benzyl ester (EP-P-0 119 932), and (b) treat certain esters of the. formula II ester with iodine trimethylsilane, prepared in situ from chloro-methylsilane and anhydrous sodium iodide, in an inert at-mosphere, using acetonitrile as solvent (ES-P-2 020 146).
Such esters are prepared, in turn, from diclofenac by reac-tion in a heterogenous medium and phase transfer conditions (ES-P-2 020 145).
With regard to process (a), as mentioned in ES-P-2 020 146, the main drawback of the hydrogenolysis process lies in the need to have special equipment to handle the pressurized gases and the concomitant risk of the industrial use of hydrogen and catalysts. Furthermore, the viability of the method is restricted to the use of the formula II esters susceptible of hydrogenolysis and, more precisely, the benzyl ester.
Process (b) apparently represents a solution to the problems inherent in process (a), although chlorotrimethyl-silane and sodium iodide, both relatively expensive, are used as reactants and acetonitrile, highly toxic, as solvent.
Also, by-products or mixtures of solvents (acetonitrile/-water) are generated, with disposal problems.
It will be gathered from the foregoing that the prepara tion on an industrial scale of [2-(2,6-dichloroanilino)phen yl]acetoxyacetic acid is still a serious technical problem.
DESCRIPTION OF THE INVENTION
The object of the present invention are the tertiary alkyl esters of formula III and their pharmaceutically accep-table solvates, where R~, Rz and R3 are the same or different and are either methyl, ethyl or propyl radicals; or Rz and Rs, which are attached as shown by -(R2....Rs)-, jointly form a -(CHZ)n- radical where n = 4 or 5. Excepted is the case where R~ - RZ -~R3 , = CHs . Particularly preferred are the product wherein R~ is methyl and R2 and R3 are both ethyl and - the product wherein R~ is methyl and Rz and R3 are jointly a -(CHz)s- radical. Also an object of this patent are the above products for use in therapy, particularly for use as anal-gesic or antiinflammatory agents.
Ri NH I -- I
C1 Cl (III>
Also an object of the present invention are the phar-maceutical compositions comprising a therapeutically effec-tive amount of one of the above products and adequate amounts of pharmaceutically acceptable excipients, as well as the use of said products for the manufacture of analgesic or antiinflammatory drugs.
It is also an object of the present invention to provide a process for the preparation of a tertiary alkyl ester of formula III or a pharmaceutically acceptable solvate thereof, where R~ , Rz and R3 are the same or different and are either methyl, ethyl or propyl radicals; or RZ and R3, which are attached as shown by -(Rz . . . .R3 )-, jointly form a -(CHz )n radical v~here n = 4 or 5; comprising the reaction of a diclo-fenac sodium or potassium salt with the corresponding alkyl haloacetate of formula X-CHZ-COO-CR~RzR3, where X is chlorine or bromine; the process being characterized in that the reac-tion is carried out in an homogenous medium, in the presence of a aprotic solvent in which the starting compounds are soluble.
In a preferred embodiment of the above process, the sodium salt of diclofenac of formula I is reacted with a slight excess of the corresponding tertiary alkyl haloacetate (e. g. chloroacetates of tert.-butyl, 1-ethyl-1-methylpropyl or 1-methylcyclohexyl), in the presence of a high polarity j aprotic solvent (e.g. dimethylformamide). The reaction is carried out preferably at a temperature of 50 to 70'C. At the end of the reaction, it is allowed to cool to room tempera-ture and an excess of water is added, whereby the major por-tion of the desired product precipitates out and is there-after separated by filtration. After purification by recrys-tallization in aliphatic hydrocarbon type solvents (e. g.
petroleum ethers), very pure products with a defined melting point are obtained.
Further to their intrinsic therapeutic utility, the formula III tertiary alkyl esters are also useful as syn-thesis intermediates for the preparation of [2-(2,6-dichloro-anilino)phenyl]acetoxyacetic acid of formula II, commercially used as analgesic and antiinflammatory agent. Thus, also an object of this invention is a process for the use of the formula III derivatives for the preparation of the formula IT_ acid from a formula III tertiary alkyl ester or a solvate thereof, where R~, Rz and R3 are methyl, ethyl or propyl radicals; or R2 and R3, which are attached as shown by-(R2 . . . .R3 )-, jointly form a -(CHZ )r,- radical where n = 4 or 5; this process of use being characterized in that the for-mula III tertiary alkyl ester is treated with an acid or mixture of acids in a solvent. In preferred embodiments of this process, the reaction is carried out in an anhydrous medium, the acids used are trifluoroacetic, formic, acetic, sulphuric, hydrochloric, methane sulphonic, p-toluene sul-phonic or sulphonic acids bonded to perfluorinated resins and the solvent is the acid or mixture of acids itself or is of the hydrocarbon type (e. g. toluene), halogenated hydrocarbon (e. g. chloroform or methylene chloride), ketone (e. g, methyl-ethylketone, or methylisobutylketone) or ether (methyltert.-butylether or dioxane). Particularly preferred is the case in which the starting product is R~ - RZ - R3 - CHs.
Under the preferred reaction conditions, the formula III
tertiary alkyl ester is reacted at a temperature ranging from -10°C to the reflux temperature of the solvent; small amounts up to large excesses of acid (e. g. using the acid or mixture of acids itself as solvent) are used. A preferred process for the isolation of the product consists of adding an excess of water at room temperature to dilute the acid used, after hav-ing concentrated, the solvent used, when necessary, to separ-ate the end product by filtration and washing with water or ... 5 an appropriate solvent. If the reaction is carried out with an acid bonded to a resin, in the first place said resin is removed by filtration under solubility conditions of the reaction product. The last stage of the process consists of purifying the product by recrystallization in an appropriate solvent (e. g. a hydrocarbon or an ester).
Unlike the process for the preparation of [2-(2,6-di-chloroanilino)phenyl]acetoxyacetic acid described in ES-P-2 020 146, which uses alkyl (straight or branched chain) or arylalkyl esters as starting products, the process of the invention is specific for tertiary alkyl esters. Thus, unlike the methyl (-COOCHa), primary alkyl (-COOCH2R), secondary alkyl (-COOCHRZ), monoarylalkyl (e. g. -COOCHZAr) and other possible esters, the formula III tertiary alkyl esters in-volved in the process of the invention undergo, in a highly specific way, an elimination reaction by treatment with acid, preferably in an anhydrous medium. In the particular case of the process for the preparation of [2-(2,6-dichloroanilino)-phenyl]acetoxyacetic acid (II), this high specificity is extremely useful, in view of the presence in the molecule of (II) of a primary alkyl ester group which does not have to be modified. Thus, the process of the present invention allows the formula II acid to be prepared with very high yields (over 909K in some cases), with an extraordinary puri-ty. Furthermore, the reactants used are common, low-cost acids and the by-products of the elimination are alkenes, non toxic and easily removable (volatile). Other notable advan-tages afforded by this process are its easy conversion to industrial scale production and the gentleness and safety of its reaction conditions, which are neither dangerous nor involve complex technology.
EXAMPLES
Example 1: Preparation of tert. butyl [2-(2.6-dichloroanili-no)phenYl7acetoxy acetate (Formula III where R~ - Rz - R3 -CH3 ) 10 grams of sodium diclofenac were dissolved in 70 ml of dimethylformamide (DMF) under a nitrogen atmosphere and the temperature was~rai,sed to between 50 to 70°C. Then 5.6 g of tert. butyl chloroacetate were added and the reaction was .. . , .. ,.
_" 21~~.~~9 - continued at the same temperature for 2 hours. The mixture was allowed to cool down to room temperature and an excess of water was added. The product obtained was filtered and dried, to give tert. butyl [2-(2,6-dichloroanilino)phenyl]acetoxy acetate, with an 89% yield. Melting point: 89.5-91.5'C (re-crystallized from petroleum ether).
Example 2: Preparation of 1-ethyl-1-methvloropvl t2-(2.6-dichloroanilino)phenvl7acetoxv acetate (Formula III where R~
- CHa and Rz - R3 - CHZCHa) Operating in a similar way to Example 1, but replacing the tert. butyl chloroacetate with 1-ethyl-1-methylpropyl chloro-acetate (previously prepared according to the synthesis method described in Org. Synth. Coll. Vol. III, p. 142-4), the title product was obtained with m.p. 78.5-80°C.
Example 3: Preparation of 1-methvlcyclohexyl f2-(2,6-di-chloroanilino)phenvl7acetoxy acetate (Formula III where R~ -CHa and -(Rz ,R3 )- - -(CH2 )s-) Operating in a similar way to Example 1, but replacing the tert. butyl chloroacetate with 1-methylcyclohexyl chloroacet-ate (previously prepared according to the synthesis method described in Ors. Synth. Coll. Vol. ITI, p. 142-4), the title product was obtained with m.p. 60-62°C.
Example 4: Preparation of L2-(2,6-dichloroanilino)phenvl]-acetoxyacetic acid (II) 10 g of tert. butyl [2-(2,6-dichloroanilino)phenyl]acetoxy acetate were stirred under nitrogen in 37 g of trifluoro-acetic acid at room temperature. After one hour's stirring, the mixture was concentrated by evaporation at reduced pres-sure and the residue was dispersed in water. After filtra-tion, washing and drying at 40°C, the title product was ob-tained with a 76% yield. Melting point 149.5-151'C (recrys-tallized from toluene).
In a similar test, treating 10 of tart. butyl [2-(2,6-dichlo-. . . . ~ , ..
J-roanilino)phenyl]acetoxy acetate with 34 g of anhydrous for-mic acid at 50'C for 2 hours, the title product was obtained with a 91% yield.
. , ,~.
PHENYLACETIC ACID DERIVATIVES, PROCESS FOR THE PREPARATION
THEREOF AND CORRESPONDING USE.
D E S C R I P T I O N
This invention relates to phenylacetic acid derivatives, particularly [2-(2,6-dichloroanilino)phenyl]acetic acid, com-monly known as diclofenac, a product known for its analgesic and antiinflammatory properties. The invention also relates to a process for the preparation of said derivatives and to a process for the use thereof in the preparation of [2-(2,6-dichloroanilino)phenyl]acetoxyacetic acid, also known for its analgesic and antiinflammatory properties.
STATE OF THE ART
Diclofenac (formula I) is a product having analgesic and antiinflammatory properties, known since the 60's and which has been extensively used in sodium salt form orally, rectal-ly and parenterally. In view of some of its adverse side effects (gastrointestinal problems, mainly) numerous attempts have been made to prepare diclofenac derivatives which, while maintaining or improving its analgesic and antiinflammatory properties, have weaker adverse side effects, or allow other forms of administration (e. g. topical). One of the diclofenac derivatives used in therapeutics is (2-(2,6-dichloroanilino)-phenyl]acetoxyacetic acid (formula II), described for the first time in 1984 (EP-P-0 119 932). Nevertheless, the design and preparation of agents having good analgesic and antiin flammatory properties, with little or no side effects and good ways of administration, is still a problem of interest in modern therapeutics.
~CH2-COONa CH2-COO-CH2-COON
NH ~ NH
CI. CI C1 C1 ~I) CII) ., ' - 2 -The preparation of [2-(2,6-dichloroanilino)phenyl]acet-oxyacetic acid of formula II suffers from the chemical draw-back of obtaining a free carboxylic group in the presence of a carboxylic acid ester which has not to be modified. Two solutions have been proposed to solve this problem: (a) carry out hydrogenolysis of the formula II benzyl ester (EP-P-0 119 932), and (b) treat certain esters of the. formula II ester with iodine trimethylsilane, prepared in situ from chloro-methylsilane and anhydrous sodium iodide, in an inert at-mosphere, using acetonitrile as solvent (ES-P-2 020 146).
Such esters are prepared, in turn, from diclofenac by reac-tion in a heterogenous medium and phase transfer conditions (ES-P-2 020 145).
With regard to process (a), as mentioned in ES-P-2 020 146, the main drawback of the hydrogenolysis process lies in the need to have special equipment to handle the pressurized gases and the concomitant risk of the industrial use of hydrogen and catalysts. Furthermore, the viability of the method is restricted to the use of the formula II esters susceptible of hydrogenolysis and, more precisely, the benzyl ester.
Process (b) apparently represents a solution to the problems inherent in process (a), although chlorotrimethyl-silane and sodium iodide, both relatively expensive, are used as reactants and acetonitrile, highly toxic, as solvent.
Also, by-products or mixtures of solvents (acetonitrile/-water) are generated, with disposal problems.
It will be gathered from the foregoing that the prepara tion on an industrial scale of [2-(2,6-dichloroanilino)phen yl]acetoxyacetic acid is still a serious technical problem.
DESCRIPTION OF THE INVENTION
The object of the present invention are the tertiary alkyl esters of formula III and their pharmaceutically accep-table solvates, where R~, Rz and R3 are the same or different and are either methyl, ethyl or propyl radicals; or Rz and Rs, which are attached as shown by -(R2....Rs)-, jointly form a -(CHZ)n- radical where n = 4 or 5. Excepted is the case where R~ - RZ -~R3 , = CHs . Particularly preferred are the product wherein R~ is methyl and R2 and R3 are both ethyl and - the product wherein R~ is methyl and Rz and R3 are jointly a -(CHz)s- radical. Also an object of this patent are the above products for use in therapy, particularly for use as anal-gesic or antiinflammatory agents.
Ri NH I -- I
C1 Cl (III>
Also an object of the present invention are the phar-maceutical compositions comprising a therapeutically effec-tive amount of one of the above products and adequate amounts of pharmaceutically acceptable excipients, as well as the use of said products for the manufacture of analgesic or antiinflammatory drugs.
It is also an object of the present invention to provide a process for the preparation of a tertiary alkyl ester of formula III or a pharmaceutically acceptable solvate thereof, where R~ , Rz and R3 are the same or different and are either methyl, ethyl or propyl radicals; or RZ and R3, which are attached as shown by -(Rz . . . .R3 )-, jointly form a -(CHz )n radical v~here n = 4 or 5; comprising the reaction of a diclo-fenac sodium or potassium salt with the corresponding alkyl haloacetate of formula X-CHZ-COO-CR~RzR3, where X is chlorine or bromine; the process being characterized in that the reac-tion is carried out in an homogenous medium, in the presence of a aprotic solvent in which the starting compounds are soluble.
In a preferred embodiment of the above process, the sodium salt of diclofenac of formula I is reacted with a slight excess of the corresponding tertiary alkyl haloacetate (e. g. chloroacetates of tert.-butyl, 1-ethyl-1-methylpropyl or 1-methylcyclohexyl), in the presence of a high polarity j aprotic solvent (e.g. dimethylformamide). The reaction is carried out preferably at a temperature of 50 to 70'C. At the end of the reaction, it is allowed to cool to room tempera-ture and an excess of water is added, whereby the major por-tion of the desired product precipitates out and is there-after separated by filtration. After purification by recrys-tallization in aliphatic hydrocarbon type solvents (e. g.
petroleum ethers), very pure products with a defined melting point are obtained.
Further to their intrinsic therapeutic utility, the formula III tertiary alkyl esters are also useful as syn-thesis intermediates for the preparation of [2-(2,6-dichloro-anilino)phenyl]acetoxyacetic acid of formula II, commercially used as analgesic and antiinflammatory agent. Thus, also an object of this invention is a process for the use of the formula III derivatives for the preparation of the formula IT_ acid from a formula III tertiary alkyl ester or a solvate thereof, where R~, Rz and R3 are methyl, ethyl or propyl radicals; or R2 and R3, which are attached as shown by-(R2 . . . .R3 )-, jointly form a -(CHZ )r,- radical where n = 4 or 5; this process of use being characterized in that the for-mula III tertiary alkyl ester is treated with an acid or mixture of acids in a solvent. In preferred embodiments of this process, the reaction is carried out in an anhydrous medium, the acids used are trifluoroacetic, formic, acetic, sulphuric, hydrochloric, methane sulphonic, p-toluene sul-phonic or sulphonic acids bonded to perfluorinated resins and the solvent is the acid or mixture of acids itself or is of the hydrocarbon type (e. g. toluene), halogenated hydrocarbon (e. g. chloroform or methylene chloride), ketone (e. g, methyl-ethylketone, or methylisobutylketone) or ether (methyltert.-butylether or dioxane). Particularly preferred is the case in which the starting product is R~ - RZ - R3 - CHs.
Under the preferred reaction conditions, the formula III
tertiary alkyl ester is reacted at a temperature ranging from -10°C to the reflux temperature of the solvent; small amounts up to large excesses of acid (e. g. using the acid or mixture of acids itself as solvent) are used. A preferred process for the isolation of the product consists of adding an excess of water at room temperature to dilute the acid used, after hav-ing concentrated, the solvent used, when necessary, to separ-ate the end product by filtration and washing with water or ... 5 an appropriate solvent. If the reaction is carried out with an acid bonded to a resin, in the first place said resin is removed by filtration under solubility conditions of the reaction product. The last stage of the process consists of purifying the product by recrystallization in an appropriate solvent (e. g. a hydrocarbon or an ester).
Unlike the process for the preparation of [2-(2,6-di-chloroanilino)phenyl]acetoxyacetic acid described in ES-P-2 020 146, which uses alkyl (straight or branched chain) or arylalkyl esters as starting products, the process of the invention is specific for tertiary alkyl esters. Thus, unlike the methyl (-COOCHa), primary alkyl (-COOCH2R), secondary alkyl (-COOCHRZ), monoarylalkyl (e. g. -COOCHZAr) and other possible esters, the formula III tertiary alkyl esters in-volved in the process of the invention undergo, in a highly specific way, an elimination reaction by treatment with acid, preferably in an anhydrous medium. In the particular case of the process for the preparation of [2-(2,6-dichloroanilino)-phenyl]acetoxyacetic acid (II), this high specificity is extremely useful, in view of the presence in the molecule of (II) of a primary alkyl ester group which does not have to be modified. Thus, the process of the present invention allows the formula II acid to be prepared with very high yields (over 909K in some cases), with an extraordinary puri-ty. Furthermore, the reactants used are common, low-cost acids and the by-products of the elimination are alkenes, non toxic and easily removable (volatile). Other notable advan-tages afforded by this process are its easy conversion to industrial scale production and the gentleness and safety of its reaction conditions, which are neither dangerous nor involve complex technology.
EXAMPLES
Example 1: Preparation of tert. butyl [2-(2.6-dichloroanili-no)phenYl7acetoxy acetate (Formula III where R~ - Rz - R3 -CH3 ) 10 grams of sodium diclofenac were dissolved in 70 ml of dimethylformamide (DMF) under a nitrogen atmosphere and the temperature was~rai,sed to between 50 to 70°C. Then 5.6 g of tert. butyl chloroacetate were added and the reaction was .. . , .. ,.
_" 21~~.~~9 - continued at the same temperature for 2 hours. The mixture was allowed to cool down to room temperature and an excess of water was added. The product obtained was filtered and dried, to give tert. butyl [2-(2,6-dichloroanilino)phenyl]acetoxy acetate, with an 89% yield. Melting point: 89.5-91.5'C (re-crystallized from petroleum ether).
Example 2: Preparation of 1-ethyl-1-methvloropvl t2-(2.6-dichloroanilino)phenvl7acetoxv acetate (Formula III where R~
- CHa and Rz - R3 - CHZCHa) Operating in a similar way to Example 1, but replacing the tert. butyl chloroacetate with 1-ethyl-1-methylpropyl chloro-acetate (previously prepared according to the synthesis method described in Org. Synth. Coll. Vol. III, p. 142-4), the title product was obtained with m.p. 78.5-80°C.
Example 3: Preparation of 1-methvlcyclohexyl f2-(2,6-di-chloroanilino)phenvl7acetoxy acetate (Formula III where R~ -CHa and -(Rz ,R3 )- - -(CH2 )s-) Operating in a similar way to Example 1, but replacing the tert. butyl chloroacetate with 1-methylcyclohexyl chloroacet-ate (previously prepared according to the synthesis method described in Ors. Synth. Coll. Vol. ITI, p. 142-4), the title product was obtained with m.p. 60-62°C.
Example 4: Preparation of L2-(2,6-dichloroanilino)phenvl]-acetoxyacetic acid (II) 10 g of tert. butyl [2-(2,6-dichloroanilino)phenyl]acetoxy acetate were stirred under nitrogen in 37 g of trifluoro-acetic acid at room temperature. After one hour's stirring, the mixture was concentrated by evaporation at reduced pres-sure and the residue was dispersed in water. After filtra-tion, washing and drying at 40°C, the title product was ob-tained with a 76% yield. Melting point 149.5-151'C (recrys-tallized from toluene).
In a similar test, treating 10 of tart. butyl [2-(2,6-dichlo-. . . . ~ , ..
J-roanilino)phenyl]acetoxy acetate with 34 g of anhydrous for-mic acid at 50'C for 2 hours, the title product was obtained with a 91% yield.
. , ,~.
Claims (14)
1. Phenylacetic acid derivatives of formula III
and their pharmaceutically acceptable solvates, where R1, R2 and R3 are the same or different and are either methyl, ethyl or propyl radicals ; or R2 and R3, which are attached as shown by -(R2....R3)-, jointly form a -(CH2)3- radical where n = 4 or 5, with the exception of the case where R1 = R2 = R3 = CH3, and with the exception of the case where R1 = R3 = CH3 and R2 =
ethyl.
and their pharmaceutically acceptable solvates, where R1, R2 and R3 are the same or different and are either methyl, ethyl or propyl radicals ; or R2 and R3, which are attached as shown by -(R2....R3)-, jointly form a -(CH2)3- radical where n = 4 or 5, with the exception of the case where R1 = R2 = R3 = CH3, and with the exception of the case where R1 = R3 = CH3 and R2 =
ethyl.
2. The derivative of claim 1 where R1 is methyl and R2 and R3 are both ethyl.
3. The derivative of claim 1 where R1 is methyl and R2 and R3 are jointly a -(CH2)5- radical.
4. The use of phenylacetic acid derivatives of formula III, where R1, R2 and R3 are defined as in claim 1, for the preparation of pharmaceutical compositions.
5. The use of claim 4, wherein said pharmaceutical compositions are analgesics or antiinflammatories.
6. A pharmaceutical composition comprising (a) a therapeutically effective amount of a phenylacetic acid derivative of formula III
according to any one of claims 1-3, and (b) adequate amounts of pharmaceutically acceptable excipients.
according to any one of claims 1-3, and (b) adequate amounts of pharmaceutically acceptable excipients.
7. A process for the preparation of phenylacetic acid derivatives of formula III
and their pharmaceutically acceptable solvates, where R1, R2 and R3 are the same or different and are either methyl, ethyl or propyl radicals; or R2 and R3, which are attached as shown by -(R2....R3)-, jointly form a -(CH2)n- radical where n = 4 or 5, comprising the reaction of a sodium or potassium salt of [2-(2,6-dichloroanilino)phenyl]acetic acid with the corresponding alkyl haloacetate of formula X-CH2-COO-CR1R2R3, where X is chlorine or bromine; characterized in that the reaction is carried out in an homogenous medium, in the presence of a aprotic solvent in which the starting compounds are soluble.
and their pharmaceutically acceptable solvates, where R1, R2 and R3 are the same or different and are either methyl, ethyl or propyl radicals; or R2 and R3, which are attached as shown by -(R2....R3)-, jointly form a -(CH2)n- radical where n = 4 or 5, comprising the reaction of a sodium or potassium salt of [2-(2,6-dichloroanilino)phenyl]acetic acid with the corresponding alkyl haloacetate of formula X-CH2-COO-CR1R2R3, where X is chlorine or bromine; characterized in that the reaction is carried out in an homogenous medium, in the presence of a aprotic solvent in which the starting compounds are soluble.
8. The process of claim 7, wherein said reaction is carried out with a slight excess of said alkyl haloacetate.
9. The process of claim 7 or claim 8, wherein said aprotic solvent is highly polar.
10. A process for the preparation of [2-(2.6-dichloroanilino)phenyl]acetoxyacetic acid starting from phenylacetic acid derivatives of formula 111 where R1, R2 and R3, are the same or different and are either methyl, ethyl or propyl radicals; or R2 and R3, which are attached as shown by -(R2...R3)-, jointly form a -(CH2)n -radical where n = 4 or 5, characterized in that said formula 111 derivatives are treated with an acid or mixture of acids in a solvent.
11. A process as in claim 10, wherein said treatment is carried out in an anhydrous medium.
12. A process as in claim 10, wherein said acids are trifluoroacetic, formic, acetic, sulphuric, hydrochloric, methane sulphonic, p-toluene sulphonic or sulphonic acids bonded to perfluorinated resins.
13. A process as in claim 10, wherein said solvent is the acid or mixture of acids itself or is of the hydrocarbon, halogenated hydrocarbon, ketone or ether type.
14. A process as in any one of claims 10 to 13, wherein R1 = R2 = R3 = CH3.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES09202523A ES2065242B1 (en) | 1992-12-14 | 1992-12-14 | DERIVATIVES OF PHENYLACETIC ACID, PROCEDURE FOR ITS OBTAINING AND CORRESPONDING USE. |
| ES9202523 | 1992-12-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2111169A1 CA2111169A1 (en) | 1994-06-15 |
| CA2111169C true CA2111169C (en) | 2001-05-01 |
Family
ID=8279093
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002111169A Expired - Fee Related CA2111169C (en) | 1992-12-14 | 1993-12-10 | Phenylacetic acid derivatives, process for the preparation thereof and corresponding use |
Country Status (8)
| Country | Link |
|---|---|
| KR (1) | KR100196240B1 (en) |
| AU (1) | AU670139B2 (en) |
| CA (1) | CA2111169C (en) |
| ES (1) | ES2065242B1 (en) |
| GR (1) | GR1002048B (en) |
| HU (1) | HUT65711A (en) |
| NZ (1) | NZ250409A (en) |
| PL (2) | PL174822B1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE255086T1 (en) * | 1998-04-28 | 2003-12-15 | Russinsky Ltd | METHOD FOR PRODUCING ACECLOFENAC |
| AU4170099A (en) * | 1998-06-03 | 1999-12-20 | Jae Chul Kim | Haloethyl-2-[ (2,6-dichlorophenyl) amino] phenylacetoxyacetate derivatives and their use as an intermediate to synthesize aceclofenac |
| WO2005073163A1 (en) * | 2004-01-30 | 2005-08-11 | J.B.Chemicals & Pharmaceuticals Ltd. | A process for the preparation of [2-(2,6-dichloro anilino) phenyl] acetoxy acetic acid |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3811120A1 (en) * | 1988-03-31 | 1989-10-12 | Merckle Gmbh | NEOPENTYL ESTER DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| ES2020146A6 (en) * | 1990-05-29 | 1991-07-16 | Prodesfarma Sa | Process for obtaining 2-[(2,6-dichlorophenyl)amino]- phenylacetoxyacetic acid |
| ES2020145A6 (en) * | 1990-05-29 | 1991-07-16 | Prodesfarma Sa | Process for obtaining esters of 2-(2,6- dichlorophenyl)amino)phenylacetoxyacetic acid |
-
1992
- 1992-12-14 ES ES09202523A patent/ES2065242B1/en not_active Expired - Fee Related
-
1993
- 1993-12-06 AU AU52177/93A patent/AU670139B2/en not_active Ceased
- 1993-12-08 GR GR930100500A patent/GR1002048B/en not_active IP Right Cessation
- 1993-12-10 NZ NZ250409A patent/NZ250409A/en not_active IP Right Cessation
- 1993-12-10 PL PL93322378A patent/PL174822B1/en not_active IP Right Cessation
- 1993-12-10 PL PL93301415A patent/PL175116B1/en not_active IP Right Cessation
- 1993-12-10 CA CA002111169A patent/CA2111169C/en not_active Expired - Fee Related
- 1993-12-13 HU HU9303551A patent/HUT65711A/en unknown
- 1993-12-14 KR KR1019930027558A patent/KR100196240B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| KR940014301A (en) | 1994-07-18 |
| KR100196240B1 (en) | 1999-06-15 |
| ES2065242B1 (en) | 1995-10-01 |
| AU670139B2 (en) | 1996-07-04 |
| PL175116B1 (en) | 1998-11-30 |
| CA2111169A1 (en) | 1994-06-15 |
| HUT65711A (en) | 1994-07-28 |
| PL301415A1 (en) | 1994-06-27 |
| HU9303551D0 (en) | 1994-04-28 |
| AU5217793A (en) | 1994-06-23 |
| GR1002048B (en) | 1995-11-16 |
| NZ250409A (en) | 1995-07-26 |
| ES2065242A1 (en) | 1995-02-01 |
| GR930100500A (en) | 1994-08-31 |
| PL174822B1 (en) | 1998-09-30 |
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