HETEROCYCLES

Note | Regular issue | Vol. 78, No. 9, 2009, pp. 2343-2352
Received, 20th March, 2009, Accepted, 28th May, 2009, Published online, 28th May, 2009.
DOI: 10.3987/COM-09-11711

■ Transformations of Ethyl 2-Amino-4-(2-ethoxy-2-oxoethyl)thioazole-5-carboxylate into 5-Substituted 2-Amino-4-oxo-4,5-dihydrothiazolo[5,4-c]pyridine-7-carboxylates

Alen Albreht, Uroš Uršič, Jurij Svete, and Branko Stanovnik*

Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, 1000 Ljubljana, Slovenia

Abstract

Ethyl 4-[1-(dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl]-2-[(dime- thylamino)methylideneamino]thiazole-5-carboxylate (2), prepared from ethyl 2-amino-4-(2-ethoxy-2-oxoethyl)thiazole-5-carboxylate (1) according to a known procedure, was transformed with aromatic amines 3a-d into 5-aryl substituted 2-aminothiazolo[5,4-c]pyridine-7-carboxylates 5a-d, while treatment of 2 with monosubstituted hydrazines 6a-h produced 5-N-amino substituted thiazolo[5,4-c]pyridine-7-carboxylates 8a-h.

In connection with our interest in enaminones and related compounds, as building blocks for the preparation of various heterocyclic systems,1 including also some natural products,2,3 dialkyl acetone-1,3-dicarboxylates have been recently employed for the synthesis of heteroaryl substituted pyrimidines,4 dialkyl 1-substituted 4-oxo-1,4-dihydropyridine-3,5-dicarboxylates,5 pyrazolo[4,3-d]- pyridine-7-carboxylates,6 pyrazolyl substituted pyridopyrimidines, pyranopyranediones, chromene- diones,7 and pyrazolo[4,3-d][1,2]diazepines.8,9 Recently, we reported in this connection also the synthesis of substituted 2-amino-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylates,10 and (4-oxo-4H-pyri- do[1,2-a]pyrimidin-3-yl)thiazole-5-carboxylates.11
In this paper we describe the synthesis of 2-amino-4-oxo-4,5-dihydrothiazolo[5,4-c]pyridine-7-carbo- xylates from diethyl acetone-1,3-dicarboxylate. Derivatives of thiazolo[5,4-c]pyridine system have been previously prepared by cyclization of 2-aminobenzothiol with carboxylic anhydrides,12 by cyclization of S-(2-aminoheteroaryl)dithiocarbamates in the presence of a base,13 by cyclization of substituted 4-(2-isocyanatovinyl)thiazole,14 and by cyclization of o-disubstituted aminopyridines with diethoxymethyl acetate.15 A review on the methods for preparation of benzothiazoles and related thiazolazines has been published.16 They show various biological activities.17 Among others they have been reported to be potent inhibitors of factor Xa(fXa) blood coagulation cascade.18,19

2-Amino-4-(2-ethoxy-2-oxoethyl)thiazole-5-carboxylate (1), prepared from diethyl acetone-1,3-dicarbo- xylate according to the procedure described in the literature,20 was transformed with excess N,N-dimethylformamide dimethyl acetal (DMFDMA) into ethyl 4-[1-(dimethylamino)-3-ethoxy-3-oxo- prop-1-en-2-yl]-2-[(dimethylamino)methylideneamino]thiazole-5-carboxylate (2). Compound 2 was treated with an excess of amines 3a-d in ethanol in the presence of catalytic amounts of hydrochloric acid under reflux for several hours. The initial substitution of the N,N-dimethylaminomethylene group from the amino group of the side chain is followed by cyclization taking place to the ester group at position 5 and elimination of the N,N-dimethylaminomethylene group from the N,N-dimethylaminomethyleneamino group at position 2 of the thiazole ring to give the corresponding 6-substituted 2-aminothiazolo[5,4-c] pyridine-4-carboxylates (5a-d). In the reaction of 2 with hydrazines 6a-h in ethanol in the presence of hydrochloric acid the corresponding 6-aminosubstituted 2-aminothiazolo[5,4-c]pyridine-4-carboxylates (8a-h) were isolated.

The structure of the products were determined on the basis of elemental analysis for C, H, and N, and IR, 1H, 13C NMR, MS, and HRMS spectra. While in the reaction of compound 2 with primary amines 3a-d only one type of products could be formed, i.e. thiazolo[5,4-c]pyridines 5a-d, in the reaction of 2 with hydrazine and its derivatives 6a-h three types of products could be formed: thiazolo[5,4-c]pyridine derivatives 8a-h, thiazolo[5,4-d][1,2]diazepine derivatives 9a-h, and pyrazolylthiazole derivatives 10a-h. In order to differentiate among these three structures the comparison of 1H NMR spectral characteristics were taken into account. Namely, protons attached at position 6 in condensed pyridine ring appear at δ = 8.06 - 8.10 ppm for those derived from 2 and 3a-d, and at δ = 8.2 - 8.31 ppm for those derived from 2 and 6a-h. This observation is consistent with the structures 5a-d and 8a-h, since the chemical shifts for the protons in analogous environments in 5-oxo-5,6-dihydro-pyrido[4,3-d]pyrimidine-8-carboxylates are of the same order.21 This conclusion is also supported by 1H NMR spectrum of compound derived from hydrazine 6a. In the product 8a the CH2 group of the CH2CF3 group appears as a quartet of a doublet with JNHCH2 = 4.5 Hz and JCH2CF3 =9 Hz. This means that this group is coupled to NH group on one and to CF3 group on the other side. This is consistent only with the structure 8a and not with the structures 9 and 10.

EXPERIMENTAL
Melting points were taken on a Kofler micro hot stage. The 1H NMR spectra were obtained on a Bruker Avance DPX 300 (300 MHz) spectrometer in DMSO-d6 or CDCl3 with TMS as the internal standard, MS spectra on an AutoSpecQ spectrometer, IR spectra on a Perkin-Elmer 1310 infrared spectrophotometer and elemental analyses for C, H and N on a Perkin-Elmer CHN Analyser 2400.

Ethyl 4-(1-(dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl)-2-((dimethylamino)methyleneamino)- thiazole-5-carboxylate (2)
A mixture of ethyl 2-amino-4-(2-ethoxy-2-oxoethyl)thiazole-5-carboxylate (1; 2.58 g, 10 mmol) and DMFDMA (8.5 mL, 100 mmol) was refluxed for 15 h. Volatile components were evaporated in vacuo and water (20-30 mL) was added to the residue. Precipitated product was separated by filtration and washed with water. Yield: 2.83 g (77%) of yellow orange crystals; mp 119–121 °C (from toluene and heptanes). 1H NMR (CDCl3): δ 1.16 (3H, t, J = 7.1 Hz, CH2CH3), 1.28 (3H, t, J = 7.1 Hz, CH2CH3), 2.79 (6H, s, N-(CH3)2), 3.09 (3H, s, N-CH3), 3.11 (3H, s, N-CH3), 4.00–4.17 (2H, m, CH2CH3), 4.23 (2H, q, J = 7.1 Hz, CH2CH3), 7.56 (1H, s, CH), 8.39 (1H, s, CH). Anal.Calcd for C16H24N4O4S: C, 52.16; H, 6.57; N, 15.21. Found: C, 52.20; H, 6.59; N, 15.19. IR (KBr) ν (cm-1): 3546, 3474, 3414, 1704, 1677, 1621, 1594, 1460, 1374, 1298, 1248, 1218, 1085.

General Procedure for the Synthesis of 5a-d.
A mixture of ethyl 4-(1-(dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl)-2-((dimethylamino)methylene- amino)thiazole-5-carboxylate (2) and aromatic amine or its hydrochloride (3a-d) and conc. aq. HCl in EtOH was refluxed. The reaction mixture was cooled overnight at 4 °C. The precipitated product was separated by filtration, washed with EtOH, and recrystallized from an appropriate solvent.

Ethyl 2-amino-4-oxo-5-phenyl-4,5-dihydrothiazolo[5,4-c]pyridine-7-carboxylate (5a)
This compound was prepared from (2; 0.368 g, 1 mmol), aniline (3a; 0.191 mL, 2.1 mmol) and conc. aq. HCl (6 drops) in EtOH (4 mL), 6 h. Yield: 0.062 g (20%) of white solid; mp 247–251 °C (from EtOH). 1H NMR (DMSO-d6): δ 1.26 (3H, t, J = 7.1 Hz, CH2CH3), 4.24 (2H, q, J = 7.1 Hz, CH2CH3), 7.45–7.56 (5H, m, 5H of Ph), 8.09 (1H, s, CH), 8.29 (2H, br s, NH2). Anal. Calcd for C15H13N3O3S: C, 57.13; H, 4.16; N, 13.33. Found: C, 57.22; H, 3.81; N, 13.38. IR (KBr) ν (cm-1): 3440, 3137, 1724, 1667, 1645, 1541, 1488, 1402, 1295, 1269, 1124.

Ethyl 2-amino-5-(4-fluorophenyl)-4-oxo-4,5-dihydrothiazolo[5,4-c]pyridine-7-carboxylate (5b)
This compound was prepared from (2; 0.368 g, 1 mmol), 4-fluoroaniline (3b; 0.201 mL, 2.1 mmol) and conc. aq. HCl (6 drops) in EtOH (4 mL), 6 h. Yield: 0.106 g (32%) of white solid; mp 272–275 °C (from EtOH). EI-MS: m/z = 333 (M+). 1H NMR (DMSO-d6): δ 1.26 (3H, t, J = 7.1 Hz, CH2CH3), 4.24 (2H, q, J = 7.1 Hz, CH2CH3), 7.32–7.41 (2H, m, 2H of Ph), 7.52–7.60 (2H, m, 2H of Ph), 8.10 (1H, s, CH), 8.29 (2H, br s, NH2). Anal. Calcd for C15H12FN3O3S: C, 54.05; H, 3.63; N, 12.61. Found: C, 53.89; H, 3.89; N, 12.53. ESI-HRMS: m/z = 334.0651 (MH+); C15H13FN3O3S requires: m/z = 334.0662. IR (KBr) . ν (cm-1): 3473, 3315, 3125, 1726, 1659, 1636, 1541, 1508, 1488, 1414, 1269, 1214, 1116, 846, 781.

Ethyl 2-amino-4-oxo-5-p-tolyl-4,5-dihydrothiazolo[5,4-c]pyridine-7-carboxylate (5c)
This compound was prepared from (2; 0.368 g, 1 mmol) and p-toluidine hydrochloride (3c; 0.201 mL, 2.1 mmol) in EtOH (2 mL), 4.5 h. Yield: 0.191 g (58%) of white solid; mp 248–254 °C (from EtOH). 1H NMR (DMSO-d6): δ 1.26 (3H, t, J = 7.1 Hz, CH2CH3), 2.38 (3H, s, CH3), 4.23 (2H, q, J = 7.1 Hz, CH2CH3), 7.30–7.38 (4H, m, 4H of Ph), 8.06 (1H, s, CH), 8.27 (2H, br s, NH2). Anal. Calcd for C16H15N3O3S: C, 58.34; H, 4.59; N, 12.76. Found: C, 58.31; H, 4.50; N, 12.77. IR (KBr) ν (cm-1): 3481, 3392, 3274, 3114, 1716, 1662, 1640, 1543, 1514, 1487, 1423, 1334, 1294, 1265, 1125, 823, 775.

Ethyl 2-amino-5-(4-methoxyphenyl)-4-oxo-4,5-dihydrothiazolo[5,4-c]pyridine-7-carboxylate (5d)
This compound was prepared from (2; 0.368 g, 1 mmol), 4-methoxyaniline (3d) (0.258 mL, 2.1 mmol) and conc. aq. HCl (6 drops) in EtOH (4 mL), 5 h. Yield: 0.084 g (24%) of white solid; mp 267–270 °C (from EtOH). 1H NMR (DMSO-d6): δ 1.26 (3H, t, J = 7.1 Hz, CH2CH3), 3.82 (3H, s, OCH3) 4.23 (2H, q, J = 7.1 Hz, CH2CH3), 7.03–7.09 (2H, m, 2H of Ph), 7.37–7.43 (2H, m, 2H of Ph), 8.06 (1H, s, CH), 8.26 (2H, br s, NH2). Anal. Calcd for C16H15N3O4S: C, 55.64; H, 4.38; N, 12.17. Found: C, 55.61; H, 4.29; N, 12.25. IR (KBr) ν (cm-1): 3480, 3428, 3250, 3120, 2989, 1727, 1673, 1627, 1515, 1494, 1426, 1402, 1264, 1121, 834, 772.

General Procedure for the Synthesis of 8a-h
A mixture of ethyl 4-(1-(dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl)-2-((dimethylamino)methylene amino)thiazole-5-carboxylate (2) and hydrazine or substituted hydrazine or its hydrochloride (6) and conc. aq. HCl in EtOH was refluxed. The reaction mixture was cooled over night at 4 °C. The precipitated product was filtrated under reduced pressure and washed with EtOH.

Ethyl 2-amino-4-oxo-5-(2,2,2-trifluoroethylamino)-4,5-dihydrothiazolo[5,4-c]pyridine-7-carboxy- late (8a)
This compound was prepared from (2; 0.184 g, 0.5 mmol), (2,2,2-trifluoroethyl)hydrazine (6a; 0.174 mL, 1.2 mmol) and conc. aq. HCl (3 drops) in EtOH (2 mL), 2 h. Yield: 0.138 g (82%) of white solid; mp 239–243 °C (from toluene and EtOH). EI-MS: m/z = 336 (M+). 1H NMR (DMSO-d6): δ 1.28 (3H, t, J = 7.1 Hz, CH2CH3), 3.82 (2H, dq, J = 9.9, 4.5 Hz, CH2CF3), 4.25 (2H, q, J = 7.1 Hz, CH2CH3), 7.44 (1H, t, J = 4.5 Hz, NH), 8.12 (1H, s, CH), 8.28 (2H, br s, NH2). Anal. Calcd for C11H11F3N4O3S: C, 39.29; H, 3.30; N, 16.66. Found: C, 39.42; H, 3.34; N, 16.75. IR (KBr) ν (cm-1): 3491, 3259, 3111, 1731, 1664, 1618, 1532, 1483, 1410, 1278, 1192, 1151, 1107.

Ethyl 2-amino-4-oxo-5-(phenylamino)-4,5-dihydrothiazolo[5,4-c]pyridine-7-carboxylate (8b)
This compound was prepared from (2; 0.736 g, 2 mmol) and phenylhydrazine hydrochloride (6b; 0.592 g, 4.1 mmol) in EtOH (7 mL), 2 h. Yield: 0.240 g (37%) of orange solid; mp 240–244 °C (from DMF and Et2O). EI-MS: m/z = 330 (M+). 1H NMR (DMSO-d6): δ 1.28 (3H, t, J = 7.1 Hz, CH2CH3), 4.25 (2H, q, J = 7.1 Hz, CH2CH3), 6.57–6.62 (2H, m, 2H of Ph), 6.82–6.89 (1H, m, 1H of Ph), 7.17–7.24 (2H, m, 2H of Ph), 8.22 (1H, s, CH), 8.31 (2H, br s, NH2), 9,39 (1H, s, NH). Anal. Calcd for C15H14N4O3S: C, 54.53; H, 4.27; N, 16.96. Found: C, 54.27; H, 4.47; N, 16.78. EI-HRMS: m/z = 330.0795 (M+); C15H14N4O3S requires: m/z = 330.0787 IR (KBr) ν (cm-1): 3458, 3237, 3128, 2977, 1733, 1651, 1625, 1574, 1546, 1525, 1484, 1406, 1269, 1108.

Ethyl 2-amino-5-(3-chlorophenylamino)-4-oxo-4,5-dihydrothiazolo[5,4-c]pyridine-7-carboxylate (8c)
This compound was prepared from (2; 0.184 g, 0.5 mmol) and (3-chlorophenyl)hydrazine hydrochloride (6c; 0.216 g, 1.2 mmol) in EtOH (2 mL), 2 h. Yield: 0.055 g (30%) of pale yellow solid; mp 272–276 °C (from DMF and diethyl ether). EI-MS: m/z = 364 (M+). 1H NMR (DMSO-d6): δ 1.29 (3H, t, J = 7.1 Hz, CH2CH3), 4.25 (2H, q, J = 7.1 Hz, CH2CH3), 6.53–6.58 (1H, m, 1H of Ph), 6.63 (1H, t, J = 2.0 Hz, 1H of Ph), 6.87–6.93 (1H, m, 1H of Ph), 7.22 (1H, t, J = 8.1 Hz, 1H of Ph), 8.23 (1H, s, CH), 8.34 (2H, br s, NH2), 9.62 (1H, s, NH). Anal. Calcd for C15H13ClN4O3S: C, 49.39; H, 3.59; N, 15.36. Found: C, 49.36; H, 3.83; N, 15.53. EI-HRMS: m/z = 364.0407 (M+); C15H13ClN4O3S requires: m/z = 364.0396. IR (KBr) ν (cm-1): 3471, 3416, 1738, 1649, 1620, 1479, 1404, 1273, 1115.

Ethyl 2-amino-4-oxo-5-(p-tolylamino)-4,5-dihydrothiazolo[5,4-c]pyridine-7-carboxylate (8d)
This compound was prepared from (2; 0.736 g, 2 mmol) and 4-tolylhydrazine hydrochloride (6d; 0.666 g, 4.2 mmol) in EtOH (4 mL), 2 h.. Yield: 0.290 g (42%) of pale yellow solid; mp 194–198 °C (from toluene, DMF and MeOH). EI-MS: m/z = 344 (M+). 1H NMR (DMSO-d6): δ 1.28 (3H, t, J = 7.1 Hz, CH2CH3), 2.19 (3H, s, CH3Ph), 4.25 (2H, q, J = 7.1 Hz, CH2CH3), 6.48–6.54 (2H, m, 2H of Ph), 6.98–7.04 (2H, m, 2H of Ph), 8,21 (1H, s, CH), 8,30 (2H, br s, NH2), 9,23 (1H, s, NH). 13C NMR (DMSO-d6): δ 14.1, 20.0, 60.3, 104.6, 113.1, 115.9, 129.4, 129.5, 144.4, 145.2, 155.3, 156.2, 162.5, 173.2. Anal. Calcd for C16H16N4O3S: C, 55.80; H, 4.68; N, 16.17. Found: C, 55.95; H, 4.93; N, 16.27. EI-HRMS: m/z = 344.0951 (M+); C16H16N4O3S requires: m/z = 344,0943. IR (KBr) ν (cm-1): 3420, 3268, 3124, 1708, 1667, 1663, 1531, 1483, 1409, 1272, 1105.

Ethyl 2-amino-5-(4-nitrophenylamino)-4-oxo-4,5-dihydrothiazolo[5,4-c]pyridine-7-carboxylate (8e)
This compound was prepared from (2; 0.736 g, 2 mmol), (4-nitrophenyl)hydrazine (6e; 0.627 g, 4.1 mmol) and conc. aq. HCl (12 drops) in EtOH (4 mL), 3 h. Yield: 0.627 g (83%) of brown solid; mp 257–261 °C (from toluene, DMF and EtOH). EI-MS: m/z = 375 (M+). 1H NMR (DMSO-d6): δ 1.28 (3H, t, J = 7.1 Hz, CH2CH3), 4.25 (2H, q, J = 7.1 Hz, CH2CH3), 6.71–6.78 (2H, m, 2H of Ph), 8.08–8.15 (2H, m, 2H of Ph), 8.27 (1H, s, CH), 8.38 (2H, br s, NH2), 10.38 (1H, s, NH). 13C NMR (DMSO-d6): δ 14.1, 60.4, 105.6, 112.0, 115.6, 125.7, 140.1, 143.9, 153.3, 154.8, 156.4, 162.4, 173.3. Anal. Calcd for C15H13N5O5S: C, 48.00; H, 3.49; N, 18.66. Found: C, 47.72; H, 3.63; N, 18.74. EI-HRMS: m/z = 375.0645 (M+); C15H13N5O5S requires: m/z = 375.0637. IR (KBr) ν (cm-1): 3428, 3260, 3125, 1720, 1663, 1628, 1596, 1410, 1337, 1273, 1110, 845.

Ethyl 2-amino-5-(6-chloropyridazin-3-ylamino)-4-oxo-4,5-dihydrothiazolo[5,4-c]pyridine-7-carbo- xylate (8f)
This compound was prepared from (2; 0.184 g, 0.5 mmol), 3-chloro-6-hydrazinylpyridazine (6f; 0.173 g, 1.2 mmol) and conc. aq. HCl (3 drops) in EtOH (2 mL), 1 h. Yield: 0.148 g (81%) of pale brown solid; mp 246–250 °C (from toluene, DMF and MeOH). 1H NMR (DMSO-d6): δ 1.28 (3H, t, J = 7.1 Hz, CH2CH3), 4.25 (2H, q, J = 7.1 Hz, CH2CH3), 7.27 (1H, d, J = 9.3 Hz, 4'-H), 7.70 (1H, d, J = 9.3 Hz, 5'-H), 8.27 (1H, s, 6-H), 8.34 (2H, br s, NH2), 10.56 (1H, br s, NH). Anal. Calcd for C13H11ClN6O3S: C, 42.57; H, 3.02; N, 22.91. Found: C, 42.48; H, 3.11; N, 22.65. IR (KBr) ν (cm-1): 3416, 3265, 3127, 2989, 1718, 1662, 1627, 1533, 1486, 1427, 1370, 1274, 1113, 778.

Ethyl 2-amino-4-oxo-5-(pyrimidin-2-ylamino)-4,5-dihydrothiazolo[5,4-c]pyridine-7-carboxylate (8g)
This compound was prepared from (2; 0.184 g, 0.5 mmol), 2-hydrazinylpyrimidine (6g; 0.133 g, 1.2 mmol) and conc. aq. HCl (3 drops) in EtOH (2 mL), 4 h. Yield: 0.122 g (73%) of white solid; mp 283–287 °C (from DMF and Et2O). 1H NMR (DMSO-d6): δ 1.28 (3H, t, J = 7.1 Hz, CH2CH3), 4.24 (2H, q, J = 7.1 Hz, CH2CH3), 6.97 (1H, t, J = 4.8 Hz, 5'-H), 8.21 (1H, s, 6-H), 8.30 (2H, br s, NH2), 8.46 (2H, d, J = 4.8 Hz, 4'-H and 6'-H), 10.39 (1H, s, NH). Anal. Calcd for C13H12N6O3S: C, 46.98; H, 3.64; N, 25.29. Found: C, 46.91; H, 3.70; N, 25.12. IR (KBr) ν (cm-1): 3487, 3256, 3106, 2983, 1723, 1677, 1645, 1621, 1598, 1487, 1447, 1417, 1286, 1263, 1108, 772.

Ethyl 2-amino-4-oxo-5-(6-phenylpyridazin-3-ylamino)-4,5-dihydrothiazolo[5,4-c]pyridine-7-carboxylate (8h)
This compound was prepared from (2; 0.368 g, 1 mmol), 3-hydrazinyl-6-phenylpyridazine (6h; 0.409 g, 2.2 mmol) conc. aq. HCl (6 drops) in EtOH (4 mL), 1 h. Yield: 0.224 g (55%) of pale yellow solid; mp 259–261 °C (from toluene, DMF and MeOH). 1H NMR (DMSO-d6): δ 1.29 (3H, t, J = 7.1 Hz, CH2CH3), 4.26 (2H, q, J = 7.1 Hz, CH2CH3), 7.26 (1H, d, J = 9.3 Hz, 4'-H), 7.41–7.52 (3H, m, 3H of Ph), 7.98–8.04 (2H, m, 2H of Ph), 8.09 (1H, d, J = 9.3 Hz, 5'-H), 8.31 (1H, s, 6-H), 8.33 (2H, br s, NH2), 10.45 (1H, s, NH). Anal. Calcd for C19H16N6O3S: C, 55.78; H, 3.95; N, 20.58). Found: C, 55.62; H, 3.89; N, 20.39. IR (KBr) ν (cm-1): 3469, 3256, 3120, 2924, 1724, 1661, 1621, 1488, 1449, 1435, 1408, 1275, 1112.

ACKNOWLEDGEMENTS
The financial support from the Slovenian Research Agency, Slovenia through grants P0-0502-0103, P1-0179, and J1-6689-0103-04 is gratefully acknowledged. Financial support by the pharmaceutical companies LEK-SANDOZ, Ljubljana, and KRKA, Novo mesto, is fully appreciated.

References

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