(19)
(11)EP 3 303 319 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
11.12.2019 Bulletin 2019/50

(21)Application number: 16738889.1

(22)Date of filing:  07.06.2016
(51)International Patent Classification (IPC): 
C07D 401/06(2006.01)
C07D 249/04(2006.01)
(86)International application number:
PCT/PL2016/050026
(87)International publication number:
WO 2016/200283 (15.12.2016 Gazette  2016/50)

(54)

DERIVATIVES OF 1,2,3-TRIAZOLYL CYCLOHEXAN-1-OL AND ITS USE

DERIVATE VON 1,2,3-TRIAZOLYL CYCLOHEXAN-1-OL UND DEREN VERWENDUNG

DÉRIVÉS DE 1,2,3-TRIAZOLYLE CYCLOHEXAN-1-OL ET LEUR UTILISATION


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 08.06.2015 PL 41259415

(43)Date of publication of application:
11.04.2018 Bulletin 2018/15

(73)Proprietor: Uniwersytet Jagiellonski
31-007 Krakow (PL)

(72)Inventors:
  • KASZA, Patryk
    43-100 Tychy (PL)
  • CEGLA, Marek
    30-638 Krakow (PL)

(74)Representative: BRANDPAT Patent and Trademark Attorneys Chlebicka Czyz Galazkiewicz Ziolkowski Professional Partnership 
Hoza 29/31 Apt.31
00-521 Warsaw
00-521 Warsaw (PL)


(56)References cited: : 
WO-A1-2009/038685
WO-A1-2012/021390
  
  • DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 20 December 2013 (2013-12-20), XP002760498, retrieved from STN Database accession no. 1499628-29-3
  • GEORGE ACQUAAH-HARRISON ET AL: "Library of 1,4-Disubstituted 1,2,3-Triazole Analogs of Oxazolidinone RNA-Binding Agents", JOURNAL OF COMBINATORIAL CHEMISTRY., vol. 12, no. 4, 12 July 2010 (2010-07-12), pages 491-496, XP055293238, US ISSN: 1520-4766, DOI: 10.1021/cc100029y
  • ZHOU S ET AL: "Anisotropy studies of tRNA-T box antiterminator RNA complex in the presence of 1,4-disubstituted 1,2,3-triazoles", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 21, no. 23, 22 September 2011 (2011-09-22), pages 7059-7063, XP028334838, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2011.09.095 [retrieved on 2011-09-29]
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description


[0001] The invention concerns novel 1,2,3-triazolylcyclohexan-1-ol derivatives and their use as ligands in copper(I)-catalyzed azide-alkyne cycloaddition (catalyzed variant of the Huisgen reaction) and zinc(II)-catalyzed azide - nitrile cycloaddition.

[0002] Presently, the Huisgen cycloaddition reaction is one of the most widely-known 3+2 cycloaddition reactions. First mentions of this reaction come from the works of Michael at the end of the 19th century[1] and the most important advances in the uncatalyzed variant of this reaction were brought by the work of R. Huisgen in the second half of the 20th century[2,3]. The beginning of the 21st century brought rapid development in the field thanks to the catalytic variants of the reaction using copper(I) (CuAAC) [4-7] and ruthenium(II) (RuAAC) [8,9]. Compared to the uncatalyzed variant, they allow to regioselectively obtain 1,4- and 1,5-disubstituted 1,2,3-triazoles (Scheme 1).



[0003] Thanks to its regioselectivity and high yields, the catalyzed Huisgen cycloaddition variants found a broad range of uses in multiple fields of chemistry and related disciplines.

[0004] The applications of the cycloaddition reaction include the synthesis of novel biologically active compounds or tagging of biomolecules or even whole cells / cell fragments in living systems. A more detailed description of these uses can be found in a number of review articles concerning biological chemistry, pharmacy and drug design [10-14], as well as materials science and polymer research [15,16].

[0005] In 2001, Sharpless[4,6] and Meldal [5,17] independently showed that copper(I) ions catalyze the Huisgen cycloaddition reaction. This discovery together with the "Click chemistry" concept, presented by K. B. Sharpless [4] initiated rapid growth of interest in this reaction in recent years. This allowed to identify a number of problems and limitations of these reactions as well as to develop a number of advanced variants overcoming these limitations [18]. One of these solutions is use of ligands complexing copper(I) ions to increase the efficacy of the reaction.

[0006] The US 7,375,234 patent concerns the copper(I) catalyzed cycloaddition of azides and alkynes (further abbreviated CuAAC). A cycloaddition process was revealed, not including the addition of an amine or a ligand.

[0007] The US 7,763,736 B2 patent discloses a reaction proceeding in an aqueous solution of an alcohol and use of amine or ligand such as e. g. TBTA.

[0008] A number of ligands used for the CuAAC reaction are also known. These ligands can be divided into two categories, depending on the chemical nature of metal-interacting electron pairs. These are the "hard" and "soft" ligands. [19,20] Cu(I) is considered a "marginally weak" Lewis acid.[21]

[0009] The "soft" ligands include phosphines containing a single bond coordinating to the Cu atom. Examples of these are Cu(P(OMe3)3Br,[22] (EtO)3PCuI [22] and Cu(PPh3)3Br.[23,24] The mentioned complexes are most commonly used when the insolubility of Cu(I) species becomes a significant problem. For CuAAC reactions performed in toluene and dichloromethane, bis(phosphine) complexes like Cu(PPh3)2OAc are efficient. [25]

[0010] Information concerning the use of Cu(I) complexes with N-heterocyclic carbene (NHC) ligands in CuAAC have been disclosed. [26,27] The copper concentrations used for these reactions can be reduced to ppm level.[28] The most-often used NHC ligands are [(SiMes)CuBr][29] and [(SiPr)CuCl].[30]

[0011] The "hard" ligands have been dominated by amines and it is the nitrogen atom-based structure that is dominant within the CuAAC ligands. [31] The most important catalytic ligand for CuAAC is TBTA [32] (Scheme 2, below). Due to the poor aqueous solubility of TBTA, water-soluble ligands such as THPTA have been designed, including polar substituents aimed to increase the ligand's solubility in aqueous media.



[0012] Among the "hard" N-donor ligands, tris(triazolyl)methanol derivatives [33,34] should also be mentioned, as well as 4-(2-pyridil)-1,2,3-triazole, proposed by Fukuzawa et all. [35], and the concept of using 2-ethynylpyridine as a reaction-accelerating additive (In situ generated catalytic ligand).

[0013] Further cycloaddition ligands and their uses have been disclosed in patent applications published as WO2012021390 and WO2009038685. The compounds of invention differ in view of the R3, R4, cyclic moiety and in view of the dimethylamino group or piperidinyl group and are alternative ligands which can be used in copper(1)-catalyzed azide-alkyne cycloaddition.

[0014] Publication (registry number: 1499628-29-3) CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 20 December 2013 (2013-12-20) discloses the 1-[(1-cyclopentyl-1H-1,2,3-triazol-4-yl)methyl]-piperazine. However, use of the compound as ligand accelerating the copper (I)-catalyzed azide-alkyne cycloaddition or the zinc(II)-catalyzed azide-nitrile cycloaddition is not disclosed.

[0015] Publication GEORGE ACQUAAH-HARRISON ET AL: "Library of 1,4-Disubstituted 1,2,3-Triazole Analogs of Oxazolidinone RNA-Binding Agents", JOURNAL OF COMBINATORIAL CHEMISTRY., vol. 1 2, no. 4, 12 July 2010 (2010-07-12), pages 491-496, discloses the compound 2{9,4} (p. 494, table 1 ). However, use of the compound as ligand accelerating the copper (I)-catalyzed azide-alkyne cycloaddition or the zinc(II)-catalyzed azide-nitrile cycloaddition is not disclosed.

[0016] Publication ZHOU S ET AL: "Anisotropy studies of tRNA-T box antiterminator RNA complex in the presence of 1 ,4-disubstituted 1 ,2,3-triazoles", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 21, no. 23, 22 September 2011 (2011 -09-22), pages 7059-7063, discloses the compound GHB-62 (p. 7061 , table 1). However, use of the compound as ligand accelerating the copper (I)-catalyzed azide-alkyne cycloaddition or the zinc(II)-catalyzed azide-nitrile cycloaddition is not disclosed.

[0017] Three fundamental types of technical problems with the present 3+2 cycloaddition ligands can be distinguished. The first one is limited efficacy of the known aromatic ligands for aliphatic substrates. Second problem is the difficulty in removing the catalytic ligand from the reaction product.

[0018] The third one is limited number and relative complexity of the known water-soluble CuAAC ligands. Unexpectedly, the abovementioned problems have found solution in the subject invention.

[0019] The subject of the invention is a chemical compound and its use (see Fig. 1) described in the appended patent claims.

[0020] In a particular realization the presented invention concerns a novel chelate ligand, 2-{4-[(dimethylamino)methyl]-1,2,3-triazolyl}cyclohexan-1-ol (further abbreviated AMTC), which allows to obtain higher yields of CuAAC reactions and higher product purities for aliphatic substrates.

[0021] AMTC displays a visible selectivity towards aliphatic substrate sets, in comparison to aromatic substrate sets, for which TBTA is most efficient.

[0022] Aqueous solubility of the presented ligand allows to easily remove it from reaction mixtures through extraction. This allows to obtain higher purity products.

[0023] Thanks to its simple structure and molecular mass lower than that of the known ligands, AMTC is a viable alternative to the known ligands.

[0024] It should be noted that 1-[(1-cyclopentyl-1H-1,2,3-triazol-4-yl)methyl]piperazine and 2-{4-[(morpholin-4-yl)methyl]-1H-1,2,3-triazol-1-yl}cyclohexan-1-ol and 2- {4- [(morpholin-4-yl)methyl] -1H-1,2,3 -triazol-1 - yl}cyclohexan-1-ol in its trans configuration, are not part of the invention.

[0025] The examples presented below describe the structure and synthesis of AMTC and its analogs as well as examples of their use in CuAAC reactions, proving the efficacy of the invention.

[0026] AMTC was obtained in a copper-catalyzed cycloaddition of trans-2-azidocyclohexan-1-01 and N,N-dimethylpropargylamine in water, using the CuSO4 - sodium ascorbate catalytic system applied in various amounts. The reaction product was isolated by extraction with an organic solvent (dichloromethane) from an alkaline aqueous solution and next, it was purified through hydrobromide crystallization if necessary (EXAMPLE 1).

EXAMPLE 1. 2-{4-[(dimethylamino)methyl]-1,2,3-triazolyl}cyclohexan-1-ol



[0027] 0.38g of trans-2-azidocyclohexan-1-ol was suspended in 2mL of water and 1.1mL of DMF was added. Next, the mixture was transferred to a flask containing 0.2g of N,N-dimethylpropargylamine. Next, 60mg (10mol%) of CuSO45H2O was added, dissolved in 2mL of water, followed by 4mL of water. The reaction was initiated by adding 47mg (10mol%) of sodium ascorbate dissolved in 2mL of water. The reaction mixture was stirred overnight at room temperature. After the stirring was finished, 15mL of 10% aqueous NaOH was added and the mixture was extracted with 5x15mL of dichloromethane. The combined organic layers were washed with 2x15mL of 10% aqueous NaOH, dried over MgSO4 and evaporated under reduced pressure. The procedure yielded 0.55g of an oily crude product which was analyzed by 1H NMR.

[0028] 0.545g of the crude product was dissolved in 6mL of ethyl acetate at room temperature and 0.13mL of 48% aqueous HBr was added. An oil precipitated, which crystallized upon cooling overnight at 0°C. The mass of the thus obtained hydrobromide was 389mg.

[0029] The hydrobromide was separated by filtration and dried under reduced pressure, and next it was dissolved in a minimal amount of water followed by alkalization by adding 10mL of 10% aqueous NaOH and extraction with 3x10mL of dichloromethane. The combined organic layers were dried and evaporated under reduced pressure to yield 150mg of the pure product.

EXAMPLE 2. 2-{4-[(dimethylamino)methyl]-1,2,3-triazolyl}cyclohexan-1-ol



[0030] 1.0g of N,N-dimethylpropargylamine and 1.69g of trans-2-azidocyclohexan-1-ol were dissolved in 12mL of 0.05 mol/dm3 CuSO4, and 0.119g of sodium ascorbate was added, dissolved in 3mL of water. The reaction mixture was stirred at room temperature for 1.5h. After the stirring was completed, 30mL of 10% NaOH was added to the mixture, followed by extraction with 4x15mL of dichloromethane. The combined organic layers were washed with 1x10mL of 10% aqueous NaOH with several drops of 0.5% aqueous hydrogen peroxide and 1x15mL of water, dried over anhydrous MgSO4 and evaporated under reduced pressure to yield 1.64 g of the crude product which was further purified.

[0031] 1.64g of the crude product was dissolved in 18mL of ethyl acetate and 0.64mL of 48% aqueous HBr was added. The solution was left for crystallization at 0°C. Thus obtained hydrobromide was washed with a small amount of ethyl acetate, dried and weighed; its mass was 2.23g. Next, the solid was dissolved in a minimal amount of water, followed by adding 50mL of 10% aqueous NaOH and extraction with 3x20mL of dichloromethane. The process yielded 1.039g of the pure product.

EXAMPLE 3. 2-{4-[(dimethylamino)methyl]-1,2,3-triazolyl}cyclohexan-1-ol



[0032] 1.69g of trans-2-azidocyclohexan-1-ol and 1.3mL of N,N-dimethylpropargylamine were added to 7.5mL of water, followed by 2.40mL of 0.05 mol/dm3 aqueous CuSO4 (1mol% Cu). Next, 24mg of sodium ascorbate (0.12mmol, 1mol%), dissolved in 1mL of water, was slowly added during intense stirring. The stirring was continued for 2h at room temperature. After the reaction was finished, 30mL of 40% aqueous NaOH was added and the mixture was extracted with 4x15mL of dichloromethane. The combined organic layers were washed with 2x5mL of 10mg/mL aqueous EDTA solution, 2x5mL of water and dried over anhydrous MgSO4. Evaporation under reduced pressure yielded 2.48g (92%) of a clear oil, which crystallized upon cooling.

[0033] Similar procedures may be used to obtain analogs of AMTC.

EXAMPLE 4. 1-(trans-3-hydroxycyclohexyl)-4-[(dimethylamine)methyl]-1,2,3-triazole



[0034] To 0.4g of N,N-dimethylpropargylamine and 0.67g of trans-3-azidocyclohexanol, 3.6mL of 0.05 mol/dm3 aqueous CuSO4 was added, followed by 6mL of water. After the water was added, 35mg of sodium ascorbate was directly added and the reaction was stirred at room temperature for 1.5h. After the stirring was completed, 15mL of dichloromethane, 10mL of 10% aqueous NaOH and 0.1mL of 0.5% hydrogen peroxide were added and the organic layer was separated. The aqueous layer was extracted with 4x10mL of dichloromethane. The combined organic layers were washed with 1x10mL of 10% aqueous NaOH and 1x5mL of water and dried over anhydrous MgSO4. Evaporation under reduced pressure yielded 0.56g of the crude product.

[0035] The crude product (0.56 g) was dissolved in 15mL of ethyl acetate, 0.25mL of 48% aqueous HBr was added and the mixture was left to crystallize at 0°C. The obtained precipitate was filtered, dried and weighed (m=0.675g), and next, 8mL of 10% aqueous NaOH was added, followed by extraction with 4x10mL of dichloromethane. The combined organic layers were washed with 1x5mL of water and dried over anhydrous MgSO4. Evaporation under reduced pressure yielded 0.352g of the pure product in the form of a white crystalline solid.

EXAMPLE 5. 1-cyclohexyl-4-[(dimethylamine)methyl]-1,2,3-triazole



[0036] N,N-dimethylpropargylamine (0.75g) and azidecyclohexane (1.05g) were dissolved in 0.05 mol/dm3 aqueous CuSO4 (9mL), followed by the addition of water (13mL). Next, sodium ascorbate was added (89mg) and the mixture was stirred at room temperature for 2h. After the stirring was completed, several drops of 5% hydrogen peroxide, 10%aqueous NaOH (10mL) and dichloromethane (15mL) were added, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (4x10mL). The combined organic layers were washed with 10% aqueous NaOH (1x5mL) and water (1x5mL), followed by drying over anhydrous MgSO4. Evaporation under reduced pressure yielded 1.44 of a solid product.

EXAMPLE 6. Structural and analytical data


AMTC



[0037] 1H NMR (D2O, 300MHz): δ = 7.82 (s, 1 H), 4.61 - 4.68 (m, 1 H), 4.07 - 4.24 (m, 1 H), 3.68 - 3.83 (m, 1 H), 3.46 (s, 2 H), 2.03 (s, 6 H), 1.86 - 2.00 (m, 2 H), 1.55 - 1.78 (m, 3 H), 1.13 - 1.38 ppm (m, 3 H)
13C NMR (D2O, 75MHz): δ = 142.7, 124.1, 72.3, 66.6, 52.0, 43.1, 33.7, 31.7, 24.1, 23.6 ppm
IR (ATR/diament), pasma [cm-1] (transmittance): 3153 (86%), 3057(wide,84%), 2935(73%), 2845 (76%), 2782 (78%), 1551 (93%), 1462 (84%), 1080 (82%), 1024 (82%)

LC-MS



[0038] Analytical conditions: C-18 column in reversed-phase mode, water-acetonitrile gradient elution (linear gradient, 0-99% of acetonitrile during 10 min) with 0,1% HCOOH addition

Retention time: 1.66 min

M+1 value: 225.16

ES+ peaks (intensity): 225.09 (100%); 226.02 (∼17%); 227.02 (∼2%)

Elemental analysis. The results are given below (Table 1)

Table 1: Elemental analysis results for AMTC
 ExperimentalCalculated
C 59.24±0.17 58.9%
N 25.28±0.11 24,98%
H 6.774±0.006 8.99%
S 0.1795±0.063 0.0%

1-(trans-3-hydroxycyclohexyl)-4-[(dimethylamine)methyl)-1,2,3-triazole



[0039] 1H NMR (D2O ,300MHz): δ = 7.80 (s, 1 H), 4.56 - 4.72 (m, 1 H), 4.02 - 4.13 (m, 1 H), 3.44 (s, 2 H), 2.01 (s, 6 H), 1.83 - 1.98 (m, 3 H), 1.34 - 1.76 ppm (m, 5 H)
13C NMR (D2O,75MHz): δ = 142.7, 123.2, 66.0, 56.1, 51.9, 43.0, 38.2, 31.8, 30.5, 18.7 ppm

1-cyclohexyl-4-[(dimethylamine)methyl]-1,2,3-triazole



[0040] 1H NMR (D2O,300MHz): δ = 7.81 (s, 1 H), 4.33 (m, 1 H), 3.49 (s, 2 H), 2.05 (s, 6 H), 1.90 - 2.02 (m, 2 H), 1.64 - 1.79 (m, 2 H), 1.58 (m, 3 H), 1.30 (m, 2 H), 1.13 ppm (m, 1 H)
13C NMR (D2O,75MHz): δ = 142.5, 123.1, 60.5, 51.9, 43.0, 32.8, 24.5 ppm

EXAMPLE 7. AMTC efficacy as a CuAAC ligand



[0041] To confirm the efficacy of AMTC as a ligand accelerating the copper catalyzed Huisgen cycloaddition, a set of optimized synthetic procedures was developed, allowing to obtain pure products in high yields, with no need for additional purification. Next, the efficacy and substrate selectivity of AMTC were compared to a commonly used ligand - TBTA. The last part of the tests was a solvent composition study covering the efficacy of AMTC for selected substrate sets in various water-ethanol compositions.

a. Optimal synthetic procedures using AMTC



[0042] To develop efficient cycloaddition procedures using AMTC, a typical synthetic procedure was investigated, using various concentrations of the copper(II)-ascorbate catalytic system, in various solvents. The water-ethanol mixture was selected as the best solvent, which enables to obtain high-purity products in good yields. The reactions in dichloromethane were efficient, but effected in the formation of considerable amounts of impurities difficult to remove, whereas the reactions in tetrahydrofurane gave poor yields and complex byproduct mixtures.

[0043] Optimized synthetic procedures were developed for 10 substrate sets, which are presented below (Table 2). The reactions for aliphatic systems were performed using 1-5mol% of copper and 1-10mol% of AMTC, whereas for aliphatic-aromatic systems, the reactions were performed in 30°C, with 1mol% of copper and AMTC. After the reaction, ethanol was removed under reduced pressure and the residue was diluted with water and extracted with dichloromethane, washed, dried over MgSO4 and evaporated to obtain the product. The reaction times, amounts of copper and AMTC as well as solvent proportions were selected in Table 2. Below, an example optimal procedure for 1-cyclohexyl-4-(1-hydroxycyclohexylo)-1,2,3-triazole is presented.

[0044] It is possible to develop an example using another source of Cu(I) ions - CuBr.

OPTIMAL PROCEDURE



[0045] To 0.05 mol/dm3 aqueous solution of CuSO4 (1.4 ml), AMTC (32 mg) was added, dissolved in water (3.3 ml). Next, cyclohexyl azide (0.304 ml) and 3-butyn-2-ol (0.197 ml) were added, followed by ethanol (2.4 ml). The reaction was initiated by slowly adding sodium ascorbate (14 mg), dissolved in water (0.1 ml). The reaction mixture was stirred vigorously for 1.5 h at room temperature. After that time, ethanol was evaporated under reduced pressure and the residue was diluted by adding water (20 ml), and extracted with dichloromethane (3x15 ml; NaCl was added to break the suspension). The combined organic layers were dried over anhydrous MgSO4 and evaporated under reduced pressure. The desired product was obtained as a clear oil (461 mg, 99%), which crystallized to form a greenish solid upon cooling. Identity and purity of the product were examined using NMR and LC-MS analyses.
Table 2: Optimal synthetic procedures using AMTC for 10 substrate sets
Entry.azidealkyneCatalytic systemTime [h]Isolated yield [%]HPLC purity [%]Water / ethanol
1



10 mol% AMTC, 5 mol% Cu 2.5 82 96.5 2:1
2



2 mol% AMTC, 1 mol% Cu 24 77 97.8 2:1
3



6 mol% AMTC, 3 mol% Cu 1 89 96.7 2:1
4



6 mol% AMTC, 3 mol% Cu 1 82 94.9 2:1
5



3 mol% AMTC, 3 mol% Cu 18 75 100.0 1:2
6



6 mol% AMTC, 3 mol% Cu 1.5 99 97.3 2:1
7



1 mol% AMTC, 1 mol% Cu 24 69 95.7 2:1
8



1 mol% AMTC, 1 mol% Cu 24 82 100.0 2:1
9



1 mol% AMTC, 1 mol% Cu 24 95 95.1 2:1
10



1 mol% AMTC, 1 mol% Cu 24 91 96.4 2:1

b. Analysis of AMTC efficacy and substrate selectivity in comparison to TBTA, THPTA and ligand-free conditions



[0046] To investigate the substrate selectivity of AMTC and to compare its efficacy to the known ligands - TBTA and THPTA as well as ligand-free conditions, a synthetic protocol was selected using 1mol% of copper sulphate and sodium ascorbate in 2:1 water:ethanol mixture. The reactions proceeded for 24h at 30°C, on a 100mg scale. After the reaction was completed, ethanol was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The combined organic layers were washed with 5% aqueous HCl (for efficient ligand removal) and twice with water, dried over anhydrous MgSO4 and evaporated under reduced pressure. Thus obtained product was weighed and analyzed by LC-MS.

[0047] The following procedure was performed for 11 substrate sets: to the 10 substrate sets mentioned above, the reaction of benzyl azide with phenylacetylene (Entry 0 in Table 2), being a "gold standard" for catalytic ligand efficacy testing. The results are collected in Fig. 2, which presents per cent increases in cycloaddition yields relative to a ligand-free procedure.

[0048] For the substrate sets tested, the use of AMTC allowed to increase the reaction yield and product purity compared to ligand-free procedures. The best results were obtained for aliphatic substrate sets, especially those containing α-azidobutyrolactone (entries 3, 4 as well as 7 in the aliphatic-aromatic part), being the most polar of the azides used. The second group of substrate sets, for which high yields and product purities were obtained were the aliphatic-aromatic substrate sets.

[0049] TBTA proved to be more efficient than AMTC only in three cases: for the reaction of benzyl azide with phenylacetylene (Entry 0, the only "purely" aromatic one) ond for reactions using propargyl and 3-methylpropargyl alcohols (entries 5 and 6). However, it should be remarked that for the two latter entries the 2:1 water:ethanol solvent system was not optimal, which was shown by the solvent studies described further (EXAMPLE 7 c.).

[0050] THPTA gave better results than AMTC also in three cases: for entries 1, 5 and 7; for entry 6 the results for those two ligands were comparable. It needs to be noted that THPTA remained efficient for polar or relatively small substrates, and its efficacy considerably deteriorated with increasing alkyl chain length and decreasing polarity of the substrates, whereas AMTC remained efficient for these systems.

c. Solvent composition studies



[0051] Based on the presented results, four substrate sets were selected (entries 1, 2, 5, 6) and for them, cycloaddition reactions were performed in water and water-ethanol mixtures of the following compositions: 2:1, 1:2 and 1:9. The reactions were performed according to the same procedure as the one presented above, using 2mol% of AMTC for entries 1 and 2, and 1mol% of AMTC for entries 5, 6.

[0052] For entries 1 and 2, better results were obtained in water or the 2:1 water:ethanol mixture. It is noteworthy that better product purity was obtained using the ethanol-containing mixture.

[0053] For entries 5 and 6, the differences in yields were considerably larger and the reaction was more efficient in ethanol-rich mixtures (1:2 and 1:9). Higher purity was observed in the 1:2 water:ethanol mixture. A compilation of HPLC yields for the reactions is presented in Fig. 3.

EXAMPLE 8. Spectral data for N-heterocyclic AMTC analogs


2-{4-[(1H-imidazol-1-yl)methyl]-1H-1,2,3-triazol-1-yl}cyclohexan-1-ol (IMTC)



[0054] 1H NMR (300 MHz, DEUTERIUM OXIDE) δ ppm 1.00 - 1.41 (m, 4 H) 1.48 - 1.79 (m, 3 H) 1.80 - 2.06 (m, 3 H) 3.70 - 3.85 (m, 1 H) 4.13 - 4.28 (m, 1 H) 5.24 (s, 2 H) 6.92 (br. s., 1 H) 7.06 (s, 1 H) 7.92 (s, 1 H)

1-cyclohexyl-4-[(1H-imidazol-1-yl)methyl]-1H-1,2,3-triazol (IMTH)



[0055] 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12 - 1.30 (m, 1 H) 1.30 - 1.49 (m, 3 H) 1.56 - 1.76 (m, 3 H) 1.86 (dt, J=13.42, 2.95 Hz, 2 H) 2.06 - 2.19 (m, 2 H) 4.36 (tt, J=11.72, 3.84 Hz, 1 H) 5.20 (s, 2 H) 7.01 (d, J=11.83 Hz, 1 H) 7.37 (s, 1 H) 7.57 (br. s., 1 H)

2-{4-[(piperidin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}cyclohexan-1-ol (PPTC)



[0056] 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07 - 1.60 (m, 6 H) 1.63 - 2.24 (m, 8 H) 2.27 - 2.54 (m, 4 H) 3.58 (s, 2 H) 3.89 - 4.02 (m, 1 H) 4.06 - 4.20 (m, 1 H) 7.55 (s, 1 H)

[0057] (1-[(1-cycloohexyl-1H-1,2,3-triazol-4-yl)methyl]piperidine (PPTH)

[0058] 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18 - 1.81 (m, 12 H) 1.91 (dt, J=13.44, 3.15 Hz, 2 H) 2.13 - 2.26 (m, 2 H) 2.34 - 2.55 (m, 4 H) 2.46 - 2.46 (m, 1 H) 3.58 - 3.65 (m, 2 H) 4.42 (tt, J=11.74, 3.86 Hz, 1 H) 7.47 (s, 1 H)

2-{4-[(piperidin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}cyclopentan-1-ol (PPTP)



[0059] 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.33 - 2.25 (m, 12 H) 2.27 - 2.53 (m, 6 H) 3.62 (s, 1 H) 4.42 - 4.62 (m, 2 H) 7.55 (s, 1 H)

EXAMPLE 9. Comparison of catalytic efficiency of AMTC and its analogs



[0060] To compare the catalytic efficiency of a short series of AMTC analogs,, from the previously investigated substrate sets, one set was chosen, for which the application of a catalytic ligand markedly improved the yield - the reaction between but-1-yn-3-ol and azidocyclohexane (Entry 6 in Fig. 2). This reaction was conducted in small scale for AMTC and its analogs listed in Example 8 as well as THPTA, according to the following procedure:
To 3 mL of ethanol, placed in a test tube thermostated in a water bath at 30°C, 30 µL of azidocyclohexane and 20 µL but-1-yn-3-ol, followed by 50 µL of 0.05 M CuSO4 and 100 µL of 0.05 mol/dm3 solution of the examined ligand in ethanol. After the reagents were added, the reaction mixture was diluted by adding 1.44 mL of water and the reaction was started by adding 50 µL of 10 mg/mL aqueous sodium ascorbate. The reaction was stirred in capped tubes thermostated at 30°C for 18h. After that time it was quenched by adding 50 µL of 3% aqueous hydrogen peroxide and 500 µL sample was taken, diluted 10 times with HPLC-grade acetonitrile and analyzed by HPLC. The reaction yields were estimated by comparing the peak area for the 1,2,3-triazole product obtained in the reaction and the area obtained for a reaction mixture prepared in the way described above, but containing the product in a quantity corresponding to 100% yield instead of the substrates (46 mg).

[0061] The reactions according to this protocol were performed for AMTH, AMTH, IMTH, IMTC, PPTC, PPTH, PPTP, THPTA and a ligand-free system. From the results, the % yield increase was calculated (as in the earlier examples) and plotted in Fig. 4. The highest yield obtained for systems comprising tertiary aliphatic amine. For the rest of systems less significant, however still clear increase of yield of reaction was observed.

Literature references



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Claims

1. The compound of the general formula:

wherein:

substituents in the aliphatic ring are in cis- or trans- relative configuration, and

R1 is one of the following substituents:-H, =O, -OH, -OCH3, -NH2, -N(CH3)2, -NHCH3,

R2 is one of the following substituents:-H, =O, -OH, -OCH3, -NH2, -N(CH3)2, -NHCH3, n is an integer from 0 to 3

R3 is an alkyl chain containing 1 - 3 carbon atoms, especially methyl

R4 is an alkyl chain containing 1 - 3 carbon atoms, especially methyl
or

substituents in the aliphatic ring are in cis- or trans- relative configuration, and

R1 is one of the following substituents:-H, =O, -OH, -OCH3, -NH2, -N(CH3)2, -NHCH3, R2 is one of the following substituents:-H, =O, -OH, -OCH3, -NH2, -N(CH3)2, -NHCH3, n is an integer from 0 to 3 and R3 and R4 together with the nitrogen atom form one of the systems presented below:



wherein R is the remaining part of the molecule described above except the compounds below:

1-[(1-cyclopentyl-1H-1,2,3-triazol-4-yl)methyl]piperazine

and

2-{4-[(morpholin-4-yl)methyl]-1H-1,2,3-triazol-1-yl}cyclohexan-1-ol and 2-{4-[(morpholin-4-yl)methyl]-1H-1,2,3-triazol-1-yl}cyclohexan-1-ol in its trans configuration.


 
2. The compound according to claim 1, wherein the structure is characterized by the following formula:

wherein R1 is hydrogen and R2 is a hydroxyl group in trans- position or R2 is hydrogen and R1 - a hydroxyl group in any relative configuration, or R1 and R2 are hydrogen atoms.
 
3. The compound according to claim 1, wherein the structure is characterized by the following formula:

wherein R1 is hydrogen and R2 is a hydroxyl group in trans- position or R2 is hydrogen and R1 - a hydroxyl group in any relative configuration, or R1 and R2 are hydrogen atoms.
 
4. The compound according to claim 1, characterized by being 2-{4-[(dimethylamine)methyl]-1,2,3-triazolyl}cyclohexan-1-ol.
 
5. Use of the compound as described in claims 1 - 4 as a ligand accelerating the copper(I)-catalyzed azide - alkyne cycloaddition.
 
6. Use of the compound as described in claims 1 - 4 as a ligand accelerating the zinc(II)-catalyzed azide - nitrile cycloaddition.
 


Ansprüche

1. Verbindung der allgemeinen Formel:

worin:

Substituenten im aliphatischen Ring cis- oder trans-relative Konfiguration haben, und

R1 für einen der folgenden Substituenten steht: -H, =O, -OH, -OCH3, -NH2, -N(CH3)2, -NHCH3,

R2 für einen der folgenden Substituenten steht: -H, =O, -OH, -OCH3, -NH2, -N(CH3)2, -NHCH3,

n eine ganze Zahl von 0 bis 3 ist

R3 eine Alkylkette darstellt, welche 1-3 Kohlenstoffatome enthält, insbesondere Methyl

R4 eine Alkylkette darstellt, welche 1-3 Kohlenstoffatome enthält, insbesondere Methyl
oder

Substituenten im aliphatischen Ring cis- oder -trans-relative Konfiguration haben und

R1 einen der folgenden Substituenten darstellt: -H, =O, -OH, -OCH3, -NH2, -N(CH3)2, -NHCH3,

R2 einen der folgenden Substituenten darstellt: -H, =O, -OH, -OCH3, -NH2, -N(CH3)2, -NHCH3,

n eine ganze Zahl von 0 bis 3 ist und R3 und R4 zusammen mit dem Stickstoffatom eines der unten gezeigten Systeme bilden:



worin R den verbleibenden Teil des oben beschriebenen Moleküls darstellt, mit Ausnahme der Verbindungen unten:

1-[(1-Cyclopentyl-1H-1,2,3-triazol-4-yl)methyl]piperazin

und

2-{4-[(Morpholin-4-yl)methyl]-1H-1,2,3-triazol-1-yl}cyclohexan-1-ol und 2-{4-[(Morpholin-4-yl)methyl]-1H-1,2,3-triazol-1-yl}-cyclohexan-1-ol in ihrer trans-Konfiguration.


 
2. Verbindung gemäß Anspruch 1, worin die Struktur durch die folgende Formel gekennzeichnet ist:

worin R1 für Wasserstoff steht und R2 eine Hydroxylgruppe in trans-Position darstellt, oder R2 für Wasserstoff steht und R1 - eine Hydroxylgruppe in irgendeiner relativen Konfiguration darstellt, oder R1 und R2 Wasserstoffatome darstellen.
 
3. Verbindung gemäß Anspruch 1, worin die Struktur durch die folgende Formel gekennzeichnet ist:

worin R1 Wasserstoff darstellt und R2 für eine Hydroxylgruppe in trans-Position steht, oder R2 Wasserstoff darstellt und R1 - für eine Hydroxylgruppe in irgendeiner relativen Konfiguration steht, oder R1 und R2 Wasserstoffatome darstellen.
 
4. Verbindung gemäß Anspruch 1, dadurch gekennzeichnet, dass sie 2-{4-[(Dimethylamin)methyl]-1,2,3-triazolyl}cyclohexan-1-ol ist.
 
5. Verwendung der Verbindung wie in Ansprüchen 1-4 beschrieben als Ligand, welcher die Kupfer(I)-katalysierte Azid-Alkin-Cycloaddition beschleunigt.
 
6. Verwendung der Verbindung wie in Ansprüchen 1-4 beschrieben als Ligand, welcher die Zink(II)-katalysierte Azid-Nitril-Cycloaddition beschleunigt.
 


Revendications

1. Composé de la formule générale :

dans laquelle:

les substituants du cycle aliphatique sont en configuration relative cis ou trans; et

R1 est l'un des substituants suivants: -H, =O, -OH, -OCH3, -NH2, -N(CH3)2, -NHCH3;

R2 est l'un des substituants suivants: -H, =O, -OH, -OCH3, -NH2, -N(CH3)2, -NHCH3, n est un entier de 0 à 3;

R3 est une chaîne alkyle contenant 1 à 3 atomes de carbone, notamment méthyle:

R4 est une chaîne alkyle contenant 1 à 3 atomes de carbone, notamment méthyle
ou

les substituants du cycle aliphatique sont en configuration relative cis ou trans, et

R1 est l'un des substituants suivants : -H, =O, -OH, -OCH3,

-NH2, -N(CH3)2, -NHCH3, R2 est l'un des substituants suivants: -H, =O, -OH, -OCH3, -NH2, -N(CH3)2, -NHCH3, n est un entier de 0 à 3

et R3 et R4 conjointement avec l'atome d'azote forment l'un des systèmes présentés ci-après:



dans lesquels R est la partie restante de la molécule décrite ci-dessus excepté les composés ci-après:

1-[(1-cyclopentyl-1H-1,2,3-triazol-4-yl)méthyl]pipérazine

et

2-{4-[(morpholin-4-yl)méthyl]-1H-1,2,3-triazol-1-yl}cyclohexan-1-ol et 2-{4-[(morpholin-4-yl)méthyl]-1H-1,2,3-triazol-1-yl}cyclohexan-1-ol dans sa configuration trans.


 
2. Composé selon la revendication 1, dans lequel la structure est caractérisée par la formule suivante:

dans laquelle R1 est hydrogène et R2 est un groupe hydroxyle en position trans ou R2 est hydrogène, et Ri, un groupe hydroxyle dans n'importe quelle configuration relative, ou R1 et R2 sont des atomes d'hydrogène.
 
3. Composé selon la revendication 1, dans lequel la structure est caractérisée par la formule suivante :

dans laquelle R1 est hydrogène et R2 est un groupe hydroxyle en position trans ou R2 est hydrogène, et Ri, un groupe hydroxyle dans n'importe quelle configuration relative, ou R1 et R2 sont des atomes d'hydrogène.
 
4. Composé selon la revendication 1, caractérisé comme étant le 2-{4-[(diméthylamine)méthyl]-1,2,3-triazolyl}cyclohexan-1-ol.
 
5. Utilisation du composé tel que décrit dans les revendications 1 à 4 en tant que ligand accélérant la cycloaddition azide-alcyne catalysée par le cuivre (I).
 
6. Utilisation du composé tel que décrit dans les revendications 1 à 4 en tant que ligand accélérant la cycloaddition azide-nitrile catalysée par le zinc (II).
 




Drawing











Cited references

REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description




Non-patent literature cited in the description