Patent Grant
8912218
The invention relates to alkylthiazole carbamate derivatives, their preparation and their application in therapy.
There is still a need to find and to develop products which are inhibitors of the enzyme FAAH. The compounds of the invention meet this objective.
The compounds of the invention are of the general formula (I):
in which
R2 represents a hydrogen or fluorine atom, a hydroxyl, cyano, trifluoromethyl, C1-6 alkyl or C1-6 alkoxy group or a group NR8R9;
n represents an integer 1, 2 or 3 and m represents an integer 1 or 2;
A represents a covalent bond or a C1-8 alkylene group;
R1 represents A group R5 which is optionally substituted by one or more groups R6 and/or R7;
The following compounds, described in document EP1780210, are excluded from the general formula (I):
Among the compounds of general formula (I) a first subgroup of compounds is composed of the compounds for which R2 represents a hydrogen atom.
Among the compounds of general formula (I) a second subgroup of compounds is composed of the compounds for which n represents an integer 1 or 2 and m represents an integer 2.
Among the compounds of general formula (I) a third subgroup of compounds is composed of the compounds for which A represents a C1-8 alkylene group, more particularly a methylene or ethylene group.
Among the compounds of general formula (I), a fourth subgroup of compounds is composed of the compounds for which R1 represents group R5 which is optionally substituted by one or more groups R6 and/or R7;
Among the compounds of general formula (I) a fifth subgroup of compounds is composed of the compounds for which R3 represents a hydrogen atom, a C1-6 alkyl group, more particularly methyl, or a trifluoromethyl group.
Among the compounds of general formula (I) a sixth subgroup of compounds is composed of the compounds for which R4 represents a thiazole which is optionally substituted by one or more substituents selected from a halogen atom, more particularly chlorine, a C1-6 alkyl group, more particularly methyl, a C1-6 haloalkyl group, more particularly trifluoromethyl, a pyridinyl group or a group CONR8R9;
R8 and R9 represent independently of one another a hydrogen atom or a C1-6 alkyl group, more particularly a methyl.
Among the compounds of general formula (I) a seventh subgroup of compounds is composed of the compounds of general formula (I) in which at one and the same time R1 and/or R2 and/or R3 and/or R4 and/or n and/or m and/or A are as defined in the groups above.
The compounds of general formula (I) include the following compounds (IUPAC nomenclature generated by the AutoNom software):
The compounds of general formula (I) may include one or more asymmetric carbons. They may exist in the form of enantiomers or diastereoisomers. The compounds of general formula (I) may also exist in the form of cis [Z] or trans [E] stereoisomers. These stereoisomers, enantiomers and diastereoisomers, and also mixtures thereof, including the racemic mixtures, form part of the invention.
The compounds of formula (I) may exist in the form of bases or of addition salts with acids. Addition salts of this kind form part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids, although the salts of other acids useful, for example, for purifying or isolating the compounds of formula (I) likewise form part of the invention,
In the context of the invention, the terms are understood as follows:
The compounds of the invention may be prepared by various methods, these methods being illustrated by the schemes below.
Thus a first method (scheme 1) comprises reacting an amine of general formula (II) in which A, R1, R2, m and n are as defined in the general formula (I) defined above with a carbonate of general formula (III) in which Z represents a hydrogen atom or a nitro group and R3 and R4 are as defined in the general formula (I) defined above, in the presence of a base such as triethylamine, pyridine, N,N-dimethylaminopyridine or diisopropylethylamine, in a solvent such as toluene or dichloroethane, at a temperature between the ambient temperature and the reflux temperature of the solvent.
One variant way of obtaining compounds of general formula (I) (scheme 1) comprises reacting an amine of general formula (II) as defined above with phenyl or 4-nitrophenyl chloroformate in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane or tetrahydrofuran, at a temperature between 0° C. and the ambient temperature, to give the carbamate derivative of general formula (IV) in which A, R1, R2, m and n are as defined in the general formula (I) defined above, and Z represents a hydrogen atom or a nitro group. The carbamate derivative of general formula (IV) thus obtained is then converted into a compound of general formula (I) by the action of an alcohol of general formula HOCHR3R4 (IIIa), in which R3 and R4 are as defined in the general formula (I) defined above, in the presence of a base such as triethylamine, pyridine, N,N-dimethylaminopyridine or diisopropylethylamine, in a solvent such as toluene or dichloroethane, at a temperature between the ambient temperature and the reflux temperature of the solvent.
A second method (scheme 2) comprises reacting, in a first stage, an amine of general formula (IIa) in which A, R2, m and n are as defined in the general formula (I) defined above, and PG represents a protecting group such as a Boc (tert-butyloxycarbonyl), a Cbz (benzyloxycarbonyl), a benzyl or a benzhydryl, with a carbonate of general formula (III) as defined above, under the conditions described above for the reaction of the amine of general formula (II) with the carbonate of general formula (III), followed by a deprotecting reaction, for example in the presence of a solution of hydrochloric acid (5N) in isopropanol or dioxane, to give the intermediate of general formula (Ia) in which A, R2, R3, R4, m and n are as defined in the general formula (I).
One variant way of obtaining intermediates of general formula (Ia) (scheme 2) comprises reacting an amine of general formula (IIa) as defined above with phenyl or 4-nitrophenyl chloroformate in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane or tetrahydrofuran, at a temperature between 0° C. and the ambient temperature, to give the carbamate derivative of general formula (IVa) in which A. R2, m and n are as defined in the general formula (I) defined above. PG is as defined above and Z represents a hydrogen atom or a nitro group. The carbamate derivative of general formula (IVa) thus obtained is subsequently converted into a compound of general formula (Ia) by the action of an alcohol of general formula HOCHR3R4 (IIIa) as defined above, in the presence of a base such as triethylamine, pyridine, N,N-dimethylaminopyridine or diisopropylethylamine, in a solvent such as toluene or dichloroethane, at a temperature between the ambient temperature and the reflux temperature of the solvent, followed by a deprotecting reaction, for example in the presence of a solution of hydrochloric acid (5N) in isopropanol or dioxane.
The compound of general formula (I) is then obtained by reacting the compound of general formula (Ia) with a derivative of general formula (V) in which R1 is as defined in the general formula (I) and U1 represents a halogen atom or an O-triflate group, utilizing the conditions of aromatic or heteroaromatic nucleophilic substitution reactions, by means for example of a base such as triethylamine, diisopropylamine, pyridine or N,N-dimethylaminopyridine in a solvent such as dichloromethane, dichloroethane, acetonitrile. N,N-dimethylformamide, dioxane or tetrahydrofuran, at a temperature between 0° C. and the reflux temperature of the solvent. This conversion may also be performed using the Buchwald N-arylation or N-heteroarylation conditions, for example by means of a palladium or copper catalyst.
According to scheme 2 the compounds of general formula (I) in which R1 represents a group R5 which is substituted in particular by a group R6 of C1-6 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl-C1-3 alkylene type, or by a group R7 as defined in the general formula (I) defined above, may also be prepared by a coupling reaction, catalysed by means of a transition metal, for example palladium(0), performed on the compound of general formula (Ib) in which A, R2, R3, R4, R5, m and n are as defined in the general formula (I) and U2 represents a chlorine, bromine or iodine atom or a triflate group. U2 being in the position in which it is desired to introduce the group R6 or R7 (scheme 2):
alternatively by a Suzuki reaction, for example by means of an alkyl-, cycloalkyl-, aryl- or heteroaryl-boronic acid,
or by a Stille reaction, for example using an aryl or heteroaryl trialkyltin derivative
or by a Negishi reaction, for example using an alkyl, cycloalkyl, aryl or heteroaryl halide zincate derivative.
The intermediate of general formula (Ib) as defined above is obtained beforehand by reacting an amine of general formula (Ia) as defined above with a derivative of general formula (Va) in which R5, U1 and U2 are as defined above, utilizing aromatic or heteroaromatic nucleophilic substitution reactions or Buchwald N-arylation or N-heteroarylation reactions, for example by means of a palladium or copper catalyst.
One variant way of obtaining intermediates of general formula (Ib) (scheme 2) comprises reacting, in a first stage, an amine of general formula (IIb) in which A, R5, R2, m and n are as defined in the general formula (I) defined above, and U2 is as defined above, with a carbonate of general formula (III) as defined above, under the conditions described above for the reaction of the amine of general formula (II) with the carbonate of general formula (III), to give the intermediate of general formula (Ib) in which A. R5, R2, R3, R4, m and n are as defined in the general formula (I), and U2 is as defined above.
The compounds of general formulae (II), (IIa), (IIb), (III), (IIIa), (V) and (Va) and also the other reactants are available commercially or are described in the literature, or else may be prepared by methods which are described therein or which are known to a person skilled in the art.
In particular the carbonate of general formula (III) may be prepared by any method described in the literature, for example by reaction of an alcohol of general formula HOCHR3R4 (IIIa), in which R3 and R4 are as defined in the general formula (I) as defined above, with phenyl or 4-nitrophenyl chloroformate, in the presence of a base such as triethylamine. N-methyl-morpholine or diisopropylethylamine, in a solvent such as dichloromethane or tetrahydrofuran, at a temperature between 0° C. and the ambient temperature.
The examples which follow illustrate the preparation of a number of compounds of the invention. These examples are not limiting and serve merely to illustrate the invention. The microanalyses, the IR and NMR spectra and/or the LC-MS (liquid chromatography coupled to mass spectroscopy) confirm the structures and the purities of the compounds obtained.
m.p. (° C.) represents the melting point in degrees Celsius,
The numbers between brackets in the titles of the examples correspond to those in the 1st column of the subsequent table.
IUPAC (International Union of Pure and Applied Chemistry) nomenclature has been used for the naming of the compounds in the examples below.
An autoclave is charged with 11 g (46.43 mmol) of 2,5-dibromopyridine, 6 g (46.43 mmol) of piperidin-4-ylethanol and 6.74 g (48.76 mmol) of potassium carbonate in 8 ml of DMSO. This charge is subsequently heated at 160° C. for 20 hours.
Following return to ambient temperature, the reaction mixture is taken up in ethyl acetate and water. The aqueous phase is separated off and extracted twice with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate, and the filtrate is concentrated under reduced pressure.
This gives 11 g of product in the form of an oil, which is used as it is in the following step.
Under an inert atmosphere, 3.6 g (12.62 mmol) of 2-(5′-bromo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)ethanol, prepared in step 1.1., 3.53 g (25.25 mmol) of 4-fluorophenylboronic acid, 5.23 g (37.87 mmol) of potassium carbonate and 4.88 g (15.15 mmol) of tetrabutylammonium bromide in suspension in 20 ml of water are introduced. Subsequently, 0.142 g (0.63 mmol) of Pd(OAc)2 is added. The reaction mixture is subsequently heated at reflux for 24 hours.
Following return to ambient temperature, the salts are separated by filtration on Celite, and than the filtrate is taken up in ethyl acetate; the aqueous phase is separated off and extracted twice with ethyl acetate, and the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate. Following evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 50/50 mixture of ethyl acetate and cyclohexane.
This gives 1.6 g of product in the form of a white powder.
m.p. (° C.)=118-120° C.
A solution of 2 g (6.66 mmol) of 2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethanol, prepared in step 1.2., 2.096 g (7.99 mmol) of triphenylphosphine and 1.077 g (7.32 mmol) of phthalimide in 40 ml of tetrahydrofuran, cooled to approximately −2° C., is admixed dropwise under an inert atmosphere with a solution of 1.61 g (7.99 mmol) of diisopropyl azodicarboxylate (DIAD) in 4 ml of tetrahydrofuran, the temperature of the reaction mixture being maintained at between −2° C. and 0° C. Stirring is continued at 0° C. for 1 hour, and then at ambient temperature for 12 hours. The reaction mixture is concentrated under reduced pressure the residue is taken up in dichloromethane and water. The aqueous phase is separated off and then extracted twice with dichloromethane. The organic phases are combined and washed in succession with aqueous hydrochloric acid (1N), then with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and the filtrate is concentrated under reduced pressure. The resulting residue is purified by chromatography on silica gel, eluting with a 20/80 mixture of ethyl acetate and cyclohexane.
This gives 2.1 g of the expected product in the form of a white powder.
m.p. (° C.)=180-182° C.
A solution of 1.3 g (3.03 mmol) of 2-{2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethyl}isoindole-1,3-dione, prepared in step 1.3., in 30 ml of ethanol is admixed slowly at ambient temperature with 0.485 g (15.13 mmol) of hydrazine monohydrate. The reaction mixture is subsequently heated at reflux for three hours.
Following return to ambient temperature, the insoluble material is separated off by filtration and the filtrate is concentrated under reduced pressure. The residue is taken up in 20 ml of ether and is left with stirring at ambient temperature for an hour. The insoluble material is separated off again and the filtrate is concentrated under reduced pressure.
This gives 0.70 g of the expected product in the form of a white powder.
m.p. (° C.)=88-94° C.
1H NMR (CDCl3) δ (ppm): 8.3 (d, 1H); 7.55 (dd, 1H); 7.35 (m, 2H); 7.05 (d, 1H); 7.1 (d, 1H); 6.65 (d, 1H); 4.25 (broad d, 2H); 3.0-2.8 (m, 4H); 1.8 (m, 2H); 1.6-1.1 (m, 5H).
A solution of 0.3 g (1.07 mmol) of 2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethylamine, prepared in step 1.4., 0.35 g (1.18 mmol) of thiazol-4-ylmethyl (4-nitrophenyl)carbonate (WO2008/013834) and 0.21 g (1.61 mmol) of N,N-diisopropylethylamine in 5 ml of 1,2-dichloroethane is heated at 70° C. for 12 hours.
Following return to ambient temperature, the insoluble material is separated off by filtration and the filtrate is concentrated under reduced pressure. The residue is taken up in dichloromethane and water, the aqueous phase is separated off and extracted three times with dichloromethane, and the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate. Following evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol.
This gives 0.3 g of pure product in the form of a white powder.
LC-MS: M+H=441
m.p. (° C.): 130-132° C.
1H NMR (DMSO) δ (ppm): 9.1 (s, 1H); 8.45 (s, 1H); 7.85 (d, 1H); 7.7 (m, 4H); 7.3 (m, 2H); 6.95 (d, 1H); 5.15 (s, 2H); 4.30 (broad d, 2H); 3.1 (m, 2H); 2.8 (m, 2H); 1.8 (m, 2H); 1.6 (m, 1H); 1.4 (m, 2H); 1.1 (m, 2H).
The procedure described in Example 1 (step 1.4.) is followed. Starting from 0.3 g (1.07 mmol) of 2-[5-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-yl]ethylamine, described in Example 1 (step 1.3.) and 0.35 g (1.18 mmol) of thiazol-2-ylmethyl (4-nitrophenyl)carbonate (EP486948A2), and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, gives 0.25 g of pure product in the form of a white powder.
LC-MS: M+H=441
m.p. (° C.): 131-133° C.
1H NMR (DMSO) δ (ppm): 8.45 (s, 1H); 7.80 (m, 3H); 7.65 (dd, 2H); 7.45 (m, 1H); 7.25 (dd, 2H); 6.9 (d, 1H); 5.30 (s, 2H); 4.30 (broad d, 2H); 31 (m, 2H); 2.8 (m, 2H); 1.75 (m, 2H); 1.6 (m, 1H); 1.4 (m, 2H); 1.1 (m, 2H).
The procedure described in Example 1 (step 1.4.) is followed. Starting from 0.16 g (0.53 mmol) of 2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethylamine, described in Example 1 (step 1.3.) and 0.22 g (0.8 mmol) of thiazol-5-ylmethyl (4-nitrophenyl)carbonate, and after chromatography on silica gel, eluting with a 40/60 mixture of ethyl acetate and cyclohexane, gives 0.180 g of pure product in the form of a white powder.
LC-MS: M+H=441
m.p. (° C.): 100-102° C.
1H NMR (DMSO) δ (ppm): 9.1 (s, 1H); 8.4 (broad s, 1H); 7.9 (s, 1H); 7.8 (dd, 1H); 7.60 (dd, 2H); 7.20 (m, 3H); 6.90 (d, 1H); 5.2 (s, 2H); 4.30 (broad d, 2H); 3 (m, 2H); 2.75 (m, 2H); 1.8-1.1 (m, 7H).
Under an inert atmosphere, 3.6 g (12.62 mmol) of 2-(6′-bromo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)ethanol (WO2004/099176), 3.53 g (25.25 mmol) of 4-fluorophenylboronic acid, 5.23 g (37.87 mmol) of potassium carbonate and 4.88 g (15.15 mmol) of tetrabutylammonium bromide in suspension in 20 ml of water are introduced. Subsequently 0.142 g (0.63 mmol) of Pd(OAc)2 is added. The reaction mixture is subsequently heated at reflux for 24 hours.
Following return to ambient temperature, the salts are separated off by filtration on Celite, and then the filtrate is taken up in ethyl acetate; the aqueous phase is separated off and extracted twice with ethyl acetate, and the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate. Following evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 99/1 mixture of dichloromethane and methanol.
This gives 3.6 g of product in the form of a white powder.
m.p. (° C.)=96-100° C.
The procedure described in Example 1 (step 1.2.) is followed, Starting from g (6.66 mmol) of 2-[6′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethanol, prepared in step 4.1., 2.096 g (7.99 mmol) of triphenylphosphine, 1.077 g (7.32 mmol) of phthalimide and 1.61 g (7.99 mmol) of diisopropyl azodicarboxylate (DIAD), and after chromatography on silica gel, eluting with a 15/85 mixture of ethyl acetate and cyclohexane, gives 1.4 g of pure product in the form of a white powder.
m.p. (° C.)=112-114° C.
The procedure described in Example 1 (step 1.3.) is followed. Starting from 1.3 g (3.03 mmol) of 2-{2-[6′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethyl}isoindole-1,3-dione, prepared in step 4.2., and 0.485 g (15.13 mmol) of hydrazine monohydrate gives 0.8 g of product in the form of a colourless liquid, which is used as it is in the following step.
1H NMR (CDCl3) δ (ppm): 8.2 (d, 1H); 8.15 (d, 1H); 775 (dd, 1H); 7.35 (broad t, 2H); 7.2 (d, 1H); 6.75 (d, 1H); 4.75 (broad d, 2H); 3.2-3.0 (m, 4H); 2.15 (m, 2H); 1.8-1.3 (m, 5H).
A solution of 5 g (16.7 mmol) of 2-[6′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethylamine, prepared in step 4.3., 4.32 g (33.40 mmol) of N,N-diisopropylethylamine and 0.10 g (0.84 mmol) of N,N-dimethylaminopyridine in 80 ml of dichloromethane, cooled to approximately 0° C., is admixed in small portions with 3.7 g (18.37 mmol) of 4-nitrophenyl chloroformate. Stirring is continued at 0° C. for 1 hour and then at ambient temperature for 2 hours.
Water is added to the reaction mixture, the aqueous phase is separated off and extracted a number of times with dichloromethane, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate, and the filtrate is concentrated under reduced pressure.
Chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, gives 4.6 g of pure product in the form of a white powder.
m.p. (° C.): 138-142° C.
A solution of 2 g (17.68 mmol) of thiazole-2-carboxaldehyde and 0.88 ml (0.88 mmol) of a 1M solution of tetrabutylammonium fluoride in THF, in 88 ml of THF, is admixed slowly at approximately 0° (ice bath) with 2.7 g (19.44 mmol) of trifluoromethyltrimethylsilane (TMS-CF3). Stirring is continued at ambient temperature for 2 hours. The reaction mixture is admixed with 25 ml of 1N aqueous hydrochloric acid and ethyl acetate. The aqueous phase is separated off and extracted twice with ethyl acetate, and the combined organic phases are washed successively with saturated aqueous sodium bicarbonate solution and than with saturated aqueous sodium chloride solution and are dried over sodium sulphate. Following evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol.
This gives 2.33 g of product in the form of a beige solid.
m.p. (° C.): 90-92° C.
A solution of 0.465 g (1 mmol) of 4-nitrophenyl 2-[6′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-yl]ethylcarbamate, prepared in step 4.4., 0.19 g (1.5 mmol) of N,N-diisopropylethylamine, 0.006 g (0.05 mmol) of N,N-dimethylaminopyridine and 0.20 g (1.1 mmol) of 2,2,2-trifluoro-1-thiazol-2-ylethanol, obtained in step 4.5., in 5 ml of 1,2-dichloroethane is heated at 80° C. for 12 hours.
Following return to ambient temperature, the insoluble material is separated off by filtration and the filtrate is concentrated under reduced pressure. The residue is taken up in dichloromethane and water, the aqueous phase is separated off and extracted twice with dichloromethane, the combined organic phases are washed successively with 1N aqueous sodium hydroxide and then with saturated aqueous sodium chloride solution and are dried over sodium sulphate. Following evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol.
This gives 0.28 g of pure product in the form of a white powder.
LC-MS: M+H=509
m.p. (° C.): 121-123° C.
1H NMR (DMSO) δ (ppm): 8.1 (m, 3H); 7.95 (m, 2H); 7.6 (t, 1H); 7.3 (t, 2H); 7.20 (d, 1H); 6.80 (d, 1H); 6.60 (m, 1H); 4.40 (broad d, 2H); 3.1 (m, 2H); 2.8 (m, 2H); 1.75 (broad d, 2H); 1.55 (m, 1H); 1.4 (m, 2H); 1.1 (m, 2H).
The method described in Example 4 (step 4.5.) is followed. Starting from 1 g (8.84 mmol) of thiazole-4-carboxaldehyde, 0.10 ml (0.10 mmol) of a 1M solution of tetrabutylammonium fluoride in THF and 1.38 g (9.72 mmol) of trifluoromethyltrimethylsilane (TMS-CF3), and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, gives 0.54 g of pure product in the form of a colourless oil.
The procedure described in Example 4 (step 4.6.) is followed. Starting from 0.183 g (1 mmol) of 4-nitrophenyl 2-[6′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethylcarbamate, described in Example 4 (step 4.4.), 0.19 g (1.5 mmol) of N,N-diisopropylethylamine, 0.006 g (0.05 mmol) of N,N-dimethylaminopyridine and 0.51 g (1.1 mmol) of 2,2,2-trifluoro-1-thiazol-4-ylethanol, obtained in step 5.1., and after chromatography on silica gel, eluting with a 40/60 mixture of ethyl acetate and cyclohexane, followed by recrystallization from a mixture of diethyl ether and hexane, gives 0.240 g of pure product in the form of a white powder.
LC-MS: M+H=509
m.p. (° C.): 79-83° C.
1H NMR (DMSO) δ (ppm): 9.2 (s, 1H); 8.1 (dd, 2H); 8 (s, 1H); 7.85 (broad t, 1H); 7.6 (dd, 1H); 7.35 (t, 2H); 7.15 (d, 1H); 6.80 (d, 1H); 6.45 (m, 1H); 4.40 (broad d, 2H); 3.15 (m, 2H); 2.8 (m, 2H); 1.75 (broad d, 2H); 1.55 (m, 1H); 1.4 (m, 2H); 1.1 (m, 2H).
The method described in Example 4 (step 4.5.) is followed. Starting from 2 g (17.68 mmol) of thiazole-5-carboxaldehyde, 0.88 ml (0.88 mmol) of a 1M solution of tetrabutylammonium fluoride in THF and 2.765 g (19.44 mmol) of trifluoromethyltrimethylsilane (TMS-CF3), and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, gives 2.23 g of pure product in the form of a colourless oil.
The procedure described in Example 4 (step 4,6.) is followed. Starting from 0.464 g (1 mmol) of 4-nitrophenyl 2-[6′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[0,2′]bipyridinyl-4-yl]ethylcarbamate, described in Example 4 (step 4.4.), 0.19 g (1.5 mmol) of N,N-diisopropylethylamine, 0.006 g (0.05 mmol) of N,N-dimethylaminopyridine and 0.201 g (1.1 mmol) of 2,2,2-trifluoro-1-thiazol-5-ylethanol, obtained in step 6.1., and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, gives 0.240 g of pure product in the form of a gum.
LC-MS: M+H=509
1H NMR (DMSO) δ (ppm): 9.3 (5, 1H); 8.2 (5, 1H); 8.1 (dd, 2H); 7.85 (broad t, 1H); 7.6 (dd, 1H); 7.25 (dd, 2H); 7.15 (d, 1H); 6.90 (m, 1H); 6.80 (d, 1H); 4.40 (broad d, 2H); 3.15 (m, 2H); 2.8 (m, 2H); 1.75 (broad d, 2H); 1.55 (m, 1H); 1.4 (m, 2H); 1.1 (m, 2H).
A solution of 4 g (13.76 mmol) of 2-[1-(6-chloroquinolin-2-yl)piperidin-4-yl]ethanol (WO2004/099176), 3.55 g (27.51 mmol) of diisopropylethylamine and 0.84 g (6.88 mmol) of N,N-dimethylaminopyridine in 30 ml of dichloromethane, cooled to approximately 0° C., is admixed dropwise under an inert atmosphere with a solution of 2.36 g (20.63 mmol) of mesyl chloride in 3 ml of dichloromethane. Stirring is continued at 0° C. for two hours and then at ambient temperature for one hour.
Water is added to the reaction mixture, the aqueous phase is separated off and extracted a number of times with dichloromethane, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate, and the filtrate is concentrated under reduced pressure.
This gives 5.1 g of product in the form of an oil, which is used as it is in the following step.
A solution of 5 g (13.55 mmol) of 2-[1-(6-chloroquinolin-2-yl)piperidin-4-yl]ethyl methanesulphonate, prepared in step 7.1., and 1.76 g (27.11 mmol) of sodium azide in 30 ml of N,N-dimethylformamide is heated at reflux for 4 hours under an inert atmosphere.
Following return to ambient temperature, the reaction mixture is concentrated under reduced pressure. The residue is taken up in dichloromethane and water and the aqueous phase is separated off and extracted twice with dichloromethane, the combined organic phases are washed with saturated aqueous sodium chloride solution, and dried over sodium sulphate. Evaporation of the solvent gives 3.8 g of product in the form of an oil, which is used as it is in the following step.
A solution of 3.5 g (11.08 mmol) of 2-[4-(2-azidoethyl)piperidin-1-yl]-6-chloroquinoline, obtained in step 7.2., in 100 ml of THF/water (1/1), is admixed in small portions at ambient temperature with 4.36 g (16.62 mmol) of triphenylphosphine. Stirring is continued at ambient temperature for ten hours.
The reaction mixture is concentrated under reduced pressure. Ethyl acetate is added, the aqueous phase is separated off and extracted three times with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate, and the filtrate is concentrated under reduced pressure. Chromatography on silica gel, eluting with a 90/10/1 mixture of dichloromethane, methanol and 28% aqueous ammonia, gives 1.77 g of pure product in the form of an oil which crystallizes at ambient temperature.
m.p. (° C.): 68-70° C.
1H NMR (CDCl3) δ (ppm): 7.7 (d, 1H); 7.5 (m, 2H); 7.35 (m, 1H); 6.95 (d, 1H); 4.45 (broad d, 2H); 2.9 (broad td, 2H); 2.7 (t, 2H); 1.7 (m, 2H); 1.6-1.1 (m, 5H).
The method described in Example 4 (step 4.4.) is followed. Starting from 5 g (17.25 mmol) of 2-[1-(6-chloroquinolin-2-yl)piperidin-4-yl]ethylamine, prepared in step 7.3., 3.825 g (18.98 mmol) of 4-nitrophenyl chloroformate, 4.46 g (34.51 mmol) of N,N-diisopropylethylamine and 0.105 g (0.86 mmol) of N,N-dimethylaminopyridine, and after trituration in a mixture of diisopropyl ether and hexane, gives 7.8 g of pure product in the form of a white powder.
m.p. (° C.): 80-84° C.
The procedure described in Example 4 (step 4.6.) is followed. Starting from 0.455 g (1 mmol) of 4-nitrophenyl 2-[1-(6-chloroquinolin-2-yl)piperidin-4-yl]ethyl}carbamate obtained in step 7.4., 0.19 g (1.5 mmol) of N,N-diisopropylethylamine, 0.006 g (0.05 mmol) of N,N-dimethylaminopyridine and 0.201 g (1.1 mmol) of 2,2,2-trifluoro-1-thiazol-2-ylethanol, described in Example 5 (step 5.5.), and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, followed by recrystallization from a mixture of diethyl ether and hexane, gives 0.3 g of pure product in the form of a white powder.
LC-MS: M+H=499
m.p. (° C.): 114-116° C.
1H NMR (DMSO) δ (ppm); 8.1 (t, 1H); 8 (m, 2H); 7.8 (s, 1H); 7.5 (m, 3H); 7.30 (d, 1H); 6.60 (m, 1H); 4.55 (broad d, 2H); 3.15 (m, 2H); 2.9 (m, 2H); 1.8 (broad d, 2H); 1.55 (m, 1H); 1.4 (m, 2H); 1.1 (m, 2H).
An autoclave is charged with 10.37 g (43.80 mmol) of 2,5-dibromopyridine, 10 g (43.80 mmol) of tert-butyl 2-piperidin-4-ylethylcarbamate and 6.05 g (43.8 mmol) of potassium carbonate. This initial charge is subsequently heated at 130° C. for 12 hours.
Following return to ambient temperature, the reaction mixture is taken up in chloroform and saturated aqueous sodium hydrogencarbonate solution. The aqueous phase is separated off and extracted twice with chloroform, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate, and the filtrate is concentrated under reduced pressure.
Chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol, gives 6.9 g of pure product in the form of a white powder.
m.p. (° C.): 108-110° C.
A solution of 6.9 g (17.95 mmol) of tert-butyl 2-(5′-bromo-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-yl)ethylcarbamate obtained in step 8.1., in 100 ml of dichloromethane, cooled by an ice/water bath, is admixed slowly with 20.47 g (179.54 mmol) of trifluoroacetic acid. Stirring is continued at ambient temperature for 2 hours. The reaction mixture is poured into a mixture of ice-water and 28% aqueous ammonia. The mixture is decanted, the aqueous phase is extracted twice with dichloromethane, and the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure.
This gives 4.9 g of product in the form of an oil, which is used as it is in the following step.
The procedure described in Example 1 (step 1.4.) is followed. Starting from 4.3 g (15.13 mmol) of 2-(5′-bromo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)ethylamine, obtained in step 8.2., 4.66 g (16.64 mmol) of thiazol-2-ylmethyl (4-nitrophenyl)carbonate (EP486948A2), 2.93 g (2270 mmol) of N,N-diisopropylethylamine and 0.09 g (076 mmol) of N,N-dimethylamino-pyridine, and after chromatography on silica gel, eluting with a 20/80 mixture of ethyl acetate and cyclohexane, gives 2.6 g of pure product in the form of a white powder.
Under an inert atmosphere, 0.425 g (1 mmol) of thiazol-2-ylmethyl 2-(5′-bromo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)ethylcarbamate, obtained in step 8.3., 0.2 g (1.2 mmol) of 4-ethoxyphenylboronic acid and 0.977 g (3 mmol) of caesium carbonate in suspension in 5 ml of a 9/1 mixture of tetrahydrofuran and water are introduced. Subsequently 0.082 g (0.1 mmol) of PdCl2dppf.CH2Cl2 is added. The mixture is subsequently heated at approximately 75° C. for 12 hours.
Following return to ambient temperature, the salts are separated off by filtration on Celite, and then the filtrate is taken up in ethyl acetate and water; the aqueous phase is separated off and extracted twice with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate. Following evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. The solid obtained is subsequently recrystallized from isopropanol.
This gives 0.39 g of product in the form of a white powder.
LC-MS: M+H=467
m.p. (° C.): 157-159° C.
1H NMR (DMSO) δ (ppm): 8.40 (s, 1H); 7.85 (d, 1H); 7.75 (m, 2H); 7.55 (d, 2H); 7.45 (t, 1H); 7 (d, 2H); 6.9 (d, 1H); 5.30 (s, 2H); 4.30 (broad d, 2H); 4.1 (q, 2H); 3.1 (m, 2H); 2.8 (t, 2H); 1.8 (d, 2H); 1.7 (m, 1H); 1.4 (m, 2H); 1.3 (t, 3H); 1.1 (m, 2H).
The procedure described in Example 1 (step 1.4.) is followed. Starting from 5 g (21.90 mmol) of tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate, 4.63 g (23 mmol) of 4-nitrophenyl chloroformate, 5.66 g (43.80 mmol) of diisopropylethylamine and 0.134 g (1.09 mmol) of N,N-dimethylaminopyridine gives 8.6 g of product in the form of an oil which is used as it is in the following step.
The procedure described in Example 4 (step 4,6.) is followed. Starting from 8.6 g (21.86 mmol) of tert-butyl 4-[2-(4-nitrophenoxycarbonylamino)ethyl]-piperidine-1-carboxylate, obtained in step 9.1., 2.77 g (24.04 mmol) of thiazol-2-ylmethanol, 5.65 g (43.72 mmol) of N,N-diisopropylethylamine and 0.134 g (1.09 mmol) of N,N-dimethylaminopyridine gives 3.6 g of product in the form of an oil, which is used as it is in the following step.
A solution of 3.6 g (9.74 mmol) of tert-butyl 4-[2-(thiazol-5-ylmethoxycarbonylamino)ethyl]piperidine-1-carboxylate, obtained in step 9.2., in 97 ml of diethyl ether, cooled by an ice/water bath, is admixed slowly with 40 ml (160 mmol) of a 4N solution of hydrochloric acid in dioxane. Stirring is continued at ambient temperature for 12 hours.
Evaporation under reduced pressure gives 2.4 g of product in the form of the hydrochloride, which is used as it is in the following step.
A sealed tube is charged with 0.09 g (0.39 mmol) of 2-bromo-6-fluoroquinoline, 0.1 g (0.33 mmol) of thiazol-5-ylmethyl 2-piperidin-4-ylethylcarbamate hydrochloride, obtained in step 9.3., and 0.2 ml (1.14 mol) of N,N-diisopropylethylamine. The system is subsequently heated at 100° C. for 12 hours.
Following return to ambient temperature, the reaction mixture is taken up in dichloromethane and saturated aqueous ammonium chloride solution. The aqueous phase is separated off and extracted twice with dichloromethane, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate, and the filtrate is concentrated under reduced pressure.
Chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol, gives 0.039 g of pure product in the form of a white powder.
LC-MS: M+H=415
m.p. (° C.): 100-102° C.
1H NMR (DMSO) δ (ppm): 9.1 (s, 1H); 8 (d, 1H); 7.9 (s, 1H); 7.7 (m, 1H); 7.60 (dd, 1H); 7.5 (m, 1H); 7.30 (m, 2H); 5.3 (s, 2H); 4.50 (broad d, 2H); 3.10 (m, 2H); 2.85 (t, 2H); 1.9 (broad d, 2H); 1.60 (m, 1H); 1.4 (m, 2H); 1.1 (m, 2H).
Table 1 below illustrates the chemical structures and the physical properties of a number of compounds according to the invention. In this table:
LC-MS methods (M+H):
Acetonitrile+0.5% trifluoroacetic acid/H2O+0.05% trifluoroacetic acid
Columns: Waters Xbridge C18 4 or YMC Jsphere 33*2
Flow rate: 1 ml/min
The compounds of the invention were subjected to pharmacological tests allowing determination of their inhibitory effect on the enzyme FAAH (Fatty Acid Amide Hydrolase).
The inhibitory activity was demonstrated in a radioenzymatic assay based on measuring the product of hydrolysis of anandamide [1-3H ethanolamine] by FAAH (Life Sciences (1995), 56, 1999-2005 and Journal of Biochemical and Biophysical Methods (2004), 60(2), 171-177). Accordingly, mouse brains (minus the cerebellum) are removed and stored at −80° C. Membrane homogenates are prepared at the time of use by homogenizing the tissues using a Precellys® apparatus in the reaction buffer (10 mM Tris-HCl pH=8, 150 mM NaCl and 1 mM ethylenediaminetetraacetic acid (EDTA)). The enzymatic reaction is conducted in 96-well Multiscreen filter plates, in a final volume of 70 μl. Reaction buffer supplemented with bovine serum albumin without fatty acids (BSA, 1 mg/ml) is used for the enzymatic reaction, the dilution of the compounds and of anandamide [1-3H ethanolamine]. Added in succession to the wells are the reaction buffer containing the BSA (43 μl/well), the diluted test compounds at different concentrations (7 μl/well containing 1% DMSO) and the membrane preparation (10 μl/well or 200 of tissue per assay). After the compounds have been pre-incubated with the enzyme at 25° C. for 20 minutes, the reaction is initiated by the addition of anandamide [1-3H ethanolamine] (specific activity of 15-20 Ci/mmol) diluted with cold anandamide (10 μl/well, final concentration of 10 μM, 0.01 per assay). After 20 minutes of incubation at 25° C., the enzymatic reaction is halted by addition of a 5M active carbon solution prepared in a 1.5M NaCl and 0.5M HCl buffer (50 μl/well). The mixture is stirred for 10 minutes and then the aqueous phase containing the ethanolamine [1-3H] is recovered by filtration under vacuum and counted by liquid scintillation.
Under these conditions the most active compounds of the invention exhibit IC50 values (concentration inhibiting by 50% the control enzymatic activity of FAAH) of between 0.001 and 1 μM; for example compounds 28 and 30 have IC50 values of 0.003 and 0.007 μM respectively.
It is therefore apparent that the compounds according to the invention have an inhibitory activity on FAAH enzyme.
The in vivo activity of the compounds of the invention was evaluated in an analgesia test.
Accordingly, intraperitoneal (i.p.) administration of PBQ (phenylbenzoquinone, 2 mg/kg in a 0.9% sodium chloride solution containing 5% of ethanol) to male OF 1 mice weighing 25 to 30 g causes abdominal stretches, on average 30 twists or contractions during the period from 5 to 15 minutes after injection. The test compounds are administered orally (p.o.) or intraperitoneally (i.p.) in suspension in Tween 80 at 0.5%, 60 minutes or 120 minutes before the administration of PBQ. Under these conditions the most potent compounds of the invention reduce by 35% to 80% the number of stretches induced by PBQ, within a dose range of between 1 and 30 mg/kg.
For example, compounds 28 and 30 of the table reduce by 33% and 80%, respectively, the number of stretches induced by PBQ, at a dose of 30 mg/kg p.o. at 120 minutes.
The enzyme FAAH (Chemistry and Physics of Lipids, (2000), 108, 107-121) catalyses the hydrolysis of endogenous derivatives of amides and of esters of various fatty acids such as N-arachidonoylethanolamine (anandamide), N-palmitoylethanolamine, N-oleoylethanolamine, oleamide or 2-arachidonoylglycerol. These derivatives exert various pharmacological activities by interacting, inter alia, with cannabinoid and vanilloid receptors. The compounds of the invention block this degradation pathway and increase the tissue level of these endogenous substances. They can be used in this respect in the prevention and treatment of pathologies involving endogenous cannabinoids and/or any other substrates metabolized by the FAAH enzyme. Mention may be made, for example, of the following diseases and conditions:
pain, especially acute or chronic pain of neurogenic type: migraine, neuropathic pain, including forms associated with the herpes virus and with diabetes and with chemotherapy, acute or chronic pain associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis. Crohn's disease, irritable bowel syndrome, acute or chronic peripheral pain, dizziness, vomiting, nausea, especially subsequent to chemotherapy, eating disorders, especially anorexia and cachexia of various kinds, neurological and psychiatric pathologies: shaking, dyskinesia, dystonia, spasticity, obsessive-compulsive behaviours, Tourette's syndrome, all forms of depression and anxiety of any kind and cause, mood disorders, psychoses, acute and chronic neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, lesions associated with cerebral ischaemia and with cranial and medullary trauma, epilepsy, sleep disorders, including sleep apnoea, cardiovascular diseases, especially hypertension, cardiac arrhythmias, arteriosclerosis, heart attack, cardiac ischaemia, renal ischaemia, cancers: benign skin tumours, papillomas and brain tumours, prostate tumours, brain tumours (glioblastomas, medulloepitheliomas, medulloblastomas, neuroblastomas, tumours of embryonic origin, astrocytomas, astroblastomas, ependyomas, oligodendrogliomas, plexus tumour, neuroepitheliomas, epiphysial tumour, ependymoblastomas, malignant meningiomas, sarcomatoses, malignant melanomas, schwannomas), disorders of the immune system, especially autoimmune diseases: psoriasis, lupus erythematosis, diseases of the connective tissue or collagen diseases. Sjögren's syndrome, ankylosing spondylarthritis, undifferentiated spondylarthritis. Behcet's disease, haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloses, transplant rejection, diseases affecting the plasmocytic line, allergic diseases: immediate or delayed-onset hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis, infectious parasitic, viral or bacterial diseases: AIDS, meningitis, inflammatory diseases, especially diseases of the joints: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis. Crohn's disease, irritable bowel syndrome, osteoporosis, ocular conditions: ocular hypertension, glaucoma, pulmonary conditions: diseases of the respiratory tract, bronchospasms, coughing, asthma, chronic bronchitis, chronic obstruction of the respiratory tract, emphysema, gastrointestinal diseases: irritable bowel syndrome, intestinal inflammatory disorders, ulcers, diarrhoea, urinary incontinence and bladder inflammation.
The use of the compounds according to the invention, in the form of the base, an addition salt with an acid, a hydrate or pharmaceutically acceptable solvate, for preparing a medicinal product intended for treating the abovementioned pathologies forms an integral part of the invention.
The invention also provides medicinal products which comprise a compound of formula (I), or an addition salt with an acid, or else a hydrate or a pharmaceutically acceptable solvate of the compound of formula (I). These medicinal products are employed in therapy, especially in the treatment of the abovementioned pathologies.
According to another of its aspects the present invention provides pharmaceutical compositions comprising as active principle at least one compound according to the invention. These pharmaceutical compositions include an effective dose of a compound according to the invention, or an addition salt with an acid, or a hydrate, or a pharmaceutically acceptable solvate of said compound, and, optionally, one or more pharmaceutically acceptable excipients.
The said excipients are selected, according to the pharmaceutical form and the desired mode of administration, from the customary excipients which are known to a person skilled in the art.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intrathecal, intranasal, transdermal, pulmonary, ocular or rectal administration, the active principle of formula (I) above, or its addition salt with an acid, solvate or hydrate, where appropriate, may be administered in a unit-dose administration form, in a mixture with conventional pharmaceutical excipients, to animals and to humans for the prophylaxis or treatment of the above disorders or diseases.
The unit-dose administration forms which are appropriate include oral forms such as tablets, soft or hard gelatin capsules, powders, granules, chewing gums and oral solutions or suspensions, forms for sublingual, buccal, intratracheal, intraocular and intranasal administration, and for administration by inhalation, forms for subcutaneous, intramuscular or intravenous administration, and forms for rectal or vaginal administration. For topical application the compounds according to the invention may be used in creams, ointments or lotions.
By way of example, a unit-dose administration form of a compound according to the invention in tablet form may comprise the following components:
The said unit-dose forms contain a dose permitting daily administration of 0.01 to 20 mg of active principle per kg of body weight, depending on the pharmaceutical form.
There may be particular cases in which higher or lower doses are appropriate; such doses also belong to the invention. In accordance with customary practice, the dosage appropriate for each patient is determined by the doctor according to the mode of administration, the weight and the response of the said patient.
According to another of its aspects the invention likewise provides a method of treating the pathologies indicated above, which comprises administering an effective dose of a compound according to the invention, one of its addition salts with a pharmaceutically acceptable acid, a solvate or a hydrate of the said compound.
| Number | Date | Country | Kind |
|---|---|---|---|
| 08 04179 | Jul 2008 | FR | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/FR2009/051457 | 7/21/2009 | WO | 00 | 5/19/2011 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2010/010288 | 1/28/2010 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 7691841 | Legrand | Apr 2010 | B2 |
| 7902367 | Nomura et al. | Mar 2011 | B2 |
| 8293752 | Chen et al. | Oct 2012 | B2 |
| 20120015950 | Abouabdellah et al. | Jan 2012 | A1 |
| Number | Date | Country |
|---|---|---|
| 1 780 210 | May 2007 | EP |
| 2 854 633 | Nov 2004 | FR |
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| Improper Marlush p. 1, 64-67 (2011). |
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| Number | Date | Country | |
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| 20110212963 A1 | Sep 2011 | US |
