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(11) | EP 1 282 084 B9 |
| (12) | CORRECTED EUROPEAN PATENT SPECIFICATION |
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METHOD FOR PREPARING PYRIMIDONE DERIVATIVES WITH ANTIFUNGAL ACTIVITY VERFAHREN ZUR PRÄPARATION VON PYRIMIDONDERIVATEN MIT FUNGIZIDDER AKTIVITÄT PROCEDE DE PREPARATION DE DERIVES DE PYRIMIDONE A ACTIVITE ANTIFONGIQUE |
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| 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). |
Field of the invention
[0001] The present invention relates to a new process for the preparation of pyrimidone derivatives with antifungal activity.
Description of the prior art
[0002] Patent application WO 97/05130 describes a series of pyrimidone derivatives with potent antifungal activity. Amongst the compounds described in this patent, those optically active compounds with a stereochemistry (R,R) are preferred. A particularly preferred compound is (1R,2R)-7-chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy- 1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one, which is known in the literature as UR-9825.
[0003] The process described to date for the preparation of these optically active pyrimidone derivatives suffers from certain disadvantages when considered for industrial scale application. It is therefore necessary to find an alternative process to prepare these optically active pyrimidone derivatives, and specially UR-9825.
Description of the invention
[0004] The present invention thus relates to a new process for the preparation of pyrimidone derivatives of general formula I,
wherein:
Ar represents phenyl or phenyl substituted with one or more halogen and/or trifluoromethyl groups;
R1 is C1-C4 alkyl;
R2 represents hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or cyclopropyl;
A represents a benzene ring or a 5- or 6-membered heterocyclic ring wherein one or more of the ring atoms are selected from the group consisting of N, O and S, which rings can be optionally fused to a benzene ring or to a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, and wherein A can be unsubstituted or have 1, 2, 3 or 4 substituents W in any of the rings;
a group W represents C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, nitro, cyano, hydroxy, benzyloxy, hydroxymethyl, -NR3R4, -CONR3R4, -CH2-OCO-R3, -CO-R3, -COO-R3, -SOzR5, -C(=NR3)NHR6, -C(=NR6)OR3, and additionally one of the groups W can also represent 1-pyrrolyl, 1-imidazolyl,
1H-1,2,4-triazol-1-yl, 5-tetrazolyl (optionally substituted with C1-C4 alkyl), 1-pyrrolidinyl, 4-morpholinyl, 4-morpholinyl-N-oxide, a group -X-R7, or a group of formula (i)-(iv):
R3 represents hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or arylC1-C4 alkyl, wherein aryl represents phenyl or phenyl substituted with one or more C1-C4 alkyl, halogen, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy groups;
R4 represents hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, -COR3 or -COCF3;
R5 represents C1-C4 alkyl;
z represents 0, 1 or 2;
R6 represents hydrogen, -CONH2, -COCH3, -CN, -SO2NHR3, -SO2R3, -OR3, -OCOR3 or -(C1-4 alkyl)-NH2;
X represents a single bond, -O-, -SOz-, -NR3-, or -C(=O)-;
R7 represents a phenyl group optionally substituted with one or more groups R8;
R8 represents C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, nitro, cyano, -NR3R4, -CONR3R4, -CH2-OCO-R3, -CO-R3, -COO-R3, -SOzR5, -C(=NR3)NHR6, -C(=NR6)OR3, a group of formula (iv) or R8 represents a phenyl group (optionally substituted with a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, nitro or cyano group);
R9 represents hydrogen or methyl;
R10 represents hydrogen, isopropyl, cyclopentyl, cyclopropyl, 2-butyl, 3-pentyl, 3-hydroxy-2-butyl, or 2-hydroxy-3-pentyl;
m represents 0 or 1;
R11 represents halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, amino, cyano, or a group of formula (i);
Y represents -CH2- or -C(=O)-; and
Z represents NH or O;
which comprises reacting a compound of formula IIwherein R1 and Ar have the meaning defined above in relation to formula I, with a compound of formula III
wherein A and R2 have the meaning defined above in relation to formula I, in the presence of a base.
[0005] In the above definitions, the term C1-C4 alkyl, as a group or part of a group, means a straight or branched alkyl group having from 1 to 4 carbon atoms. Therefore, it includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
[0006] A C1-C4 haloalkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C1-C4 alkyl group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be the same or different. Examples thereof include trifluoromethyl, trichloromethyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, pentachloroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-chloropropyl, 3,3-dichloropropyl, 3,3,3-trichloropropyl, 2,2,3,3,3-pentachloropropyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-chlorobutyl, 4-fluorobutyl, 4-iodobutyl and 4-bromobutyl.
[0008] A C1-C4 alkoxy group means a group derived from the union of a C1-C4 alkyl group to an oxygen atom of an ether functional group. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
[0009] A C1-C4 haloalkoxy group means a group resulting from the substitution of one or more hydrogen atoms of a C1-C4 alkoxy group with one or more halogen atoms, which can be the same or different. Examples include trifluoromethoxy, fluoromethoxy, 2-chloroethoxy, 2-fluoroethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3-chloropropoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 4-fluorobutoxy, and 4-chlorobutoxy.
[0011] An arylC1-C4 alkyl group means a group resulting from the substitution of a hydrogen atom of a C1-C4 alkyl group with an aryl group, wherein aryl is as defined above.
[0012] In a preferred embodiment, in the preparation process which is the object of the invention R2 represents hydrogen, methyl, trifluoromethyl or cyclopropyl; Ar represents 2-fluorophenyl, 4-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or 4-chlorophenyl; and A represents a benzene ring, which can be optionally fused to a benzene ring or to a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, or A represents a 5- or 6-membered heterocyclic ring wherein one or more of said ring atoms are selected from the group consisting of N, O and S and which can be optionally fused to a benzene ring, wherein A can be unsubstituted or have 1, 2, 3 or 4 substituents W in any of the rings.
[0013] In a more preferred embodiment, R1 represents methyl; R2 represents hydrogen; Ar represents 2-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or 4-chlorophenyl; and A represents a benzene ring or a 5-or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, wherein A can be unsubstituted or have 1, 2, 3 or 4 groups W.
[0014] In a still more preferred embodiment, R1 represents methyl; R2 represents hydrogen; Ar represents 2-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or 4-chlorophenyl; A represents a benzene ring optionally substituted with 1, 2, 3 or 4 groups W; and each W independently represents halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy or cyano.
[0015] In a particularly preferred embodiment, the process of the invention is used to prepare a compound of formula I which is (1R,2R)-7-chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1 -methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one (UR-9825) and it comprises reacting (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1,2,4-triazol-1-yl)methyl]oxirane with 7-chloro-3H-quinazolin-4-one in the presence of a base.
[0016] The process for the preparation of the compounds of formula I which is the object of the invention can be summarized in the following scheme:
[0017] The reaction between an epoxide of formula II and a compound of formula III is carried out in the presence of a base, such as for example sodium hydride, potassium carbonate, butyllithium, sodium hexamethyldisilazane (NaHMDS), lithium hexamethyldisilazane (LiHMDS) or potassium hexamethyldisilazane (KHMDS), in a suitable solvent, such as for example a polar solvent such as a substituted amide (e.g. N-methylpyrrolidone or dimethylformamide) or an ether (e.g. tetrahydrofuran or dioxane), at a temperature preferably comprised between room temperature and that of the boiling point of the solvent.
[0018] The product of formula I thus obtained can be isolated in a conventional manner and can be purified by standard methods well known to those skilled in the art, such as for example by recrystallization from a suitable solvent.
[0019] The starting epoxides of formula II are known compounds and can be prepared using any of the methods already described, for example by following the process described by Tasaka et al. in Chem. Pharm. Bull. 1993, 41(6), 1035-1042.
[0020] The compounds of formula III can be prepared from the compounds of formula IV by reaction with a reactive derivative of an acid R2CO2H, such as its alkyl imidate (for example the methyl or ethyl imidate), its amidine, its acid chloride, its anhydride or its trialkylorthoester, preferably its amidine or trialkylorthoester, at a temperature generally over 50°C, as shown in the following scheme:
[0021] In its turn, the compounds of formula IV are either commercially available or can be prepared by conventional processes, for example from an acid of formula V by treatment with ammonium hydroxide in the presence of a suitable coupling agent, for example dicyclohexylcarbodiimide, alone or associated with 1-hydroxybenzotriazole, in a polar solvent, such as a substituted amide (for example N-methylpyrrolidone or dimethylformamide) or an ether (for example tetrahydrofuran or dioxane), at a temperature preferably comprised between 0°C and 100°C, or from the corresponding nitrile, for example a benzonitrile, by hydrolysis under the standard conditions widely known to those skilled in the art.
[0022] The acids of formula V and of formula R2COOH or derivatives thereof are commercially available, are widely described in the literature or can be prepared by methods analogous to those described in the literature, for example as described in Bartroli et al. J.Med.Chem. 1998, 41, 1855-1868.
[0023] The invention is next illustrated with the following examples, which are not to be understood as limiting the scope of the present invention in any way.
EXAMPLE 1 2-Amino-4-chlorobenzamide
[0025] To a solution of 4-chloroanthranilic acid (70 g, 0.41 mol) in hot (60°C) dimethylformamide (700 mL), dicyclohexylcarbodiimide (93 g, 0.451 mol, 1.1 equiv), hydroxybenzotriazole hydrate (60.9 g, 0.451 mol, 1.1 eq) and 30% aqueous ammonium hydroxide solution (350 mL) were added. The resulting solution was stirred at room temperature for 18 h. The formed urea was filtered off and the filtrate concentrated. The resulting mixture was partitioned between ethyl acetate and 5% K2CO3 solution. The organic phase was separated, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give the desired product as a slightly yellow solid (58.1 g, 83%). mp 179-180 °C; 1H NMR (300 MHz, MeOH-d4) δ (MeOH) 7.46 (d, J=8.5Hz, 1H, arom), 6.74 (d, J=2, 1H, arom), 6.53 (dd, J=2, J=8.5, 1H, arom). Analysis calculated for C7H7ClN2O: C 49.28; H 4.14; N 16.42. Found: C 49.36; H 4.22; N 16.46.
EXAMPLE 2 7-Chloro-3H-quinazolin-4-one
[0027] To a solution of 2-amino-4-chlorobenzamide (58 g, 0.34 mol) in hot (60°C) N-methylpyrrolidone (170 mL), triethylorthoformate (151 g, 1.02 mol, 3 equiv) and a 1,4-dioxane 5N HCI solution (ca. 15 mL) were added. The resulting solution was heated at 110 °C for 18 h. Then, the mixture was cooled to room temperature, was poured over cold water and was brought to pH 7 with saturated NaHCO3 solution. The formed precipitate was filtered, washed with water and dried to give the desired product as a slightly beige solid (58 g, 94%).
mp 253-256 °C; 1H NMR (300 MHz, MeOH-d4) δ (MeOH) 8.19 (d, J=8.6Hz, 1H, arom), 8.10 (s, 1H, N=CH-N), 7.70 (d, J=2, 1H, arom), 7.54 (dd, J=2, J=8.6, 1H, arom). Analysis calculated for C8H5ClN2O: C 53.21; H 2.79; N 15.51. Found: C 53.46; H 2.77; N 15.48.
EXAMPLE 3 (1R,2R)-7-Chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one (UR-9825)
[0029] To a solution of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (2.46 g, 9.8 mmol, obtained as described in Tasaka et al., Chem.Pharm.Bull. 1993, 41, 1035-1042) in N-methylpyrrolidone (10 mL), 7-chloro-3H-quinazolin-4-one (1.77 g, 9.8 mol) and K2CO3 (1.35 g, 9.8 mmol) were added. The resulting solution was heated at 80°C for 3 days. The mixture was cooled to room temperature, water was then added and the pH was adjusted to 7. The mixture was extracted with ethyl acetate (4x). The combined organic extracts were washed with water (4x), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to a reduced volume and was allowed to crystallize at 0°C. The resulting product was filtered, dried and dissolved in hot ethanol (10 mL/g). The insoluble material was filtered off, and the filtrate was then poured over cold water (120 mL/g of UR-9825) under stirring. The resulting precipitate was filtered and dried in vacuo (50 °C) to give the desired product as a white amorphous powder (3.1 g, 75%). mp 93-110 °C (amorphous); IR (KBr) ν 1675, 1601, 1554, 1498 cm-1; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.58 (s, 1H, N=CH-N), 8.26 (d, J=8.6Hz, 1H, arom), 8.11 (d, J=5.7, trace rotamer), 7.76 (s, 2H, triazole), 7.74 (d, J=5.3, 1H, arom), 7.5 (m, 2H, arom), 7.10 (s, trace rotamer), 6.9-6.7 (m, 2H, arom), 5.91 (dq, Jd=2, Jq=7, 1H, MeCH), 5.54 (d, J=2, 1H, OH), 5.15 (d, J=14.2 1H, CH(H)), 4.9-4.7 (m, trace rotamer), 4.30 (d, trace rotamer), 3.99 (d, J=14.2, 1H, CH(H)), 1.46 (d, J=6.9, trace rotamer), 1.29 (d, J=7, 3H, CHMe); GC/MS 224 (Tr-CH2COHAr, C10H8F2N3O), 207 (N-ethylheterocycle group, C10H9ClN2O); [α]D= -8.0° (c 1, CHCl3). Analysis calculated for C20H16ClF2N5O2: C 55.63; H 3.73; N 16.22. Found: C 55.50; H 3.75; N 16.16.
wherein:
Ar represents phenyl or phenyl substituted with one or more halogen and/or trifluoromethyl groups;
R1 is C1-C4 alkyl;
R2 represents hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or cyclopropyl;
A represents a benzene ring or a 5- or 6-membered heterocyclic ring wherein one or more of the ring atoms are selected from the group consisting of N, O and S, which rings can be optionally fused to a benzene ring or to a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, and wherein A can be unsubstituted or have 1, 2, 3 or 4 substituents W in any of the rings;
a group W represents C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, nitro, cyano, hydroxy, benzyloxy, hydroxymethyl, -NR3R4, -CONR3R4, -CH2-OCO-R3, -CO-R3, -COO-R3, -SOzR5, -C(=NR3)NHR6, -C(=NR6)OR3, and additionally one of the groups W can also represent 1-pyrrolyl, 1-imidazolyl,
1H-1,2,4-triazol-1-yl, 5-tetrazolyl (optionally substituted with C1-C4 alkyl), 1-pyrrolidinyl, 4-morpholinyl, 4-morpholinyl-N-oxide, a group -X-R7, or a group of formula (i)-(iv):
R3 represents hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or arylC1-C4 alkyl, wherein aryl represents phenyl or phenyl substituted with one or more C1-C4 alkyl, halogen, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy groups;
R4 represents hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, -COR3 or -COCF3;
R5 represents C1-C4 alkyl;
z represents 0, 1 or 2;
R6 represents hydrogen, -CONH2, -COCH3, -CN, -SO2NHR3, -SO2R3, -OR3, -OCOR3 or -(C1-4 alkyl)-NH2;
X represents a single bond, -O-, -SOz-, -NR3-, or -C(=O)-;
R7 represents a phenyl group optionally substituted with one or more groups R8;
R8 represents C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, nitro, cyano, -NR3R4, -CONR3R4, -CH2-OCO-R3, -CO-R3, -COO-R3, -SOzR5, -C(=NR3)NHR6, -C(=NR6)OR3, a group of formula (iv) or R8 represents a phenyl group (optionally substituted with a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, nitro or cyano group);
R9 represents hydrogen or methyl;
R10 represents hydrogen, isopropyl, cyclopentyl, cyclopropyl, 2-butyl, 3-pentyl, 3-hydroxy-2-butyl, or 2-hydroxy-3-pentyl;
m represents 0 or 1;
R11 represents halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, amino, cyano, or a group of formula (i);
Y represents -CH2- or -C(=O)-; and
Z represents NH or O;
which comprises reacting a compound of formula IIwherein R1 and Ar have the meaning defined above in relation to formula I, with a compound of formula III
wherein A and R2 have the meaning defined above in relation to formula I, in the presence of a base.
worin
Ar Phenyl oder Phenyl, substituiert mit einer oder mehreren Halogen- und/oder Trifluormethylgruppen, bedeutet;
R1 für C1-C4-Alkyl steht;
R2 Wasserstoff, C1-C4-Alkyl, C1-C4-Haloalkyl oder Cyclopropyl bedeutet;
A einen Benzolring oder einen 5- oder 6-gliedrigen heterocyclischen Ring bedeutet,
worin eines oder mehrere der Ringatome ausgewählt sind unter N, O und S, wobei diese
Ringe gegebenenfalls kondensiert sind an einen Benzolring oder an einen 5- oder 6-gliedrigen
heterocyclischen Ring, der ein oder mehrere Heteroatome, ausgewählt unter N, O und
S enthält, und worin A unsubstituiert sein kann oder 1, 2, 3 oder 4 Substituenten
W in jedem der Ringe aufweisen kann; eine Gruppe W C1-C4-Alkyl, C3-C6-Cycloalkyl, C1-C4-Haloalkyl, C1-C4-Alkoxy, C1-C4-Haloalkoxy, Halogen, Nitro, Cyano, Hydroxy, Benzyloxy, Hydroxymethyl, -NR3R4, -CONR3R4, -CH2-OCO-R3, -CO-R3, -COO-R3, -SOzR5, -C(=NR3)NHR6, -C(=NR6)OR3, bedeutet, und zusätzlich eine der Gruppen W auch 1-Pyrrolyl, 1-Imidazolyl, 1H-1,2,4-Triazol-1-yl,
5-Tetrazolyl (gegebenenfalls substituiert mit C1-C4-Alkyl), 1-Pyrrolidinyl, 4-Morpholinyl, 4-Morpholinyl-N-oxid, eine Gruppe -X-R7 oder eine Gruppe der Formeln (i) - (iv) bedeuten kann:
R3 Wasserstoff, C1-C4-Alkyl, C3-C6-Cycloalkyl oder Aryl-C1-C4-alkyl bedeutet, worin Aryl Phenyl oder Phenyl, substituiert mit einer oder mehreren Gruppen C1-C4-Alkyl, Halogen, C1-C4-Haloalkyl, C1-C4-Alkoxy oder C1-C4-Haloalkoxy, bedeutet;
R4 Wasserstoff, C1-C4-Alkyl, C3-C6-Cycloalkyl, -COR3 oder -COCF3 bedeutet;
R5 für C1-C4-Alkyl steht;
z 0, 1 oder 2 bedeutet;
R6 Wasserstoff, -CONH2, -COCH3, -CN, -SO2NHR3, -SO2R3, -OR3, -OCOR3 oder -(C1-4-Alkyl)-NH2 bedeutet;
X für eine Einfachbindung -O-, -SOz-, -NR3-, oder -C(=O)- steht;
R7 eine Phenylgruppe, gegebenenfalls substituiert mit einer oder mehreren Gruppen R8, bedeutet;
R8 C1-C4-Alkyl, C3-C6-Cycloalkyl, C1-C4-Haloalkyl, C1-C4-Alkoxy, C1-C4-Haloalkoxy, Halogen, Nitro, Cyano, -NR3R4, -CONR3R4, -CH2-OCO-R3, -CO-R3, -COO-R3, -SOzR5, -C(=NR3)NHR6, -C(=NR6)OR3, eine Gruppe der Formel (iv) bedeutet, oder R8 eine Phenylgruppe (gegebenenfalls substituiert mit einer Gruppe C1-C4-Alkyl, C1-C4-Haloalkyl, C1-C4-Alkoxy, C1-C4-Haloalkoxy, Halogen, Nitro oder Cyano) bedeutet;
R9 für Wasserstoff oder Methyl steht;
R10 Wasserstoff, Isopropyl, Cyclopentyl, Cyclopropyl, 2-Butyl, 3-Pentyl, 3-Hydroxy-2-butyl oder 2-Hydroxy-3-pentyl bedeutet;
m für 0 oder 1 steht;
R11 Wasserstoff, C1-C4-Haloalkyl, C1-C4-Haloalkoxy, Nitro, Amino, Cyano oder eine Gruppe der Formel (i) bedeutet;
Y für -CH2- oder -C(=O)- steht; und
Z NH oder O bedeutet;
das die Umsetzung einer Verbindung der Formel (II)worin R1 und Ar die vorstehend in Verbindung mit Formel I angegebene Bedeutung besitzen, mit einer Verbindung der Formel III
worin A und R2 die vorstehend in Verbindung mit Formel I angegebene Bedeutung besitzen, in Anwesenheit einer Base umfasst.
où :
Ar représente phényle ou phényle substitué par un ou plusieurs groupes halogènes et/ou trifluorowéthyle ;
R1 est alkyle en C1-C4 ;
R2 représente l'hydrogène, alkyle en C1-C4, halogénoalkyle en C1-C4 ou cyclopropyle ;
A représente un cycle benzénique ou un cycle hétérocyclique à 5 ou 6 chaînons où un
ou plusieurs des atomes du cycle sont choisis dans le groupe consistant en N, O et
S, lesquels cycles peuvent éventuellement être condensés à un cycle benzénique ou
à un cycle hétérocyclique à 5 ou 6 chaînons contenant un ou plusieurs hétéroatomes
choisis parmi N, O et S, et où A peut être non substitué ou avoir 1, 2, 3 ou 4 substituants
W dans l'un quelconque des cycles ; un groupe W représente alkyle en C1-C4, cycloalkyle en C3-C6, halogénoalkyle en C1-C4, alcoxy en C1-C4, halogénoalcoxy en C1-C4, halogène, nitro, cyano, hydroxyle, benzyloxy, hydroxyméthyle/ -NR3R4, -CONR3R4, -CH2-OCO-R3, -CO-R3, -COO-R3, -SOzR5, -C(=NR3)NHR6, -C(=NR6)OR3, et en outre l'un des groupes W peut aussi représenter 1-pyrrolyle, 1-imidazolyle,
1H-1,2,4-triazol-1-yle, 5-tétrazolyle (éventuellement substitué par alkyle en C1-C4), 1-pyrrolidinyle, 4-morpholinyle, 4-morpholinyl-N-oxyde, un groupe -X-R7 ou un groupe de formule (i)-(iv) :
R3 représente l'hydrogène, alkyle en C1-C4, cycloalkyle en C3-C6 ou aryl-alkyle en C1-C4, où aryle représente phényle ou phényle substitué par un ou plusieurs groupes alkyle en C1-C4, halogènes, halogénoalkyle en C1-C4, alcoxy en C1-C4 ou halogénoalcoxy en C1-C4 ;
R4 représente l'hydrogène, alkyle en C1-C4, cycloalkyle en C3-C6, -COR3 ou -COCF3;
R5 représente alkyle en C1-C4 ;
z représente 0, 1 ou 2 ;
R6 représente l'hydrogène, -CONH2, -COCH3, -CN, -SO2NHR3, -SO2R3, -OR3, -OCOR3 ou -(alkyle en C1-C4)-NH2 ;
x représente une simple liaison, -O-, -SOz-, -NR3- ou -C(=O)- ;
R7 représente un groupe phényle éventuellement substitué par un ou plusieurs groupes R8 ;
R8 représente alkyle en C1-C4, cycloalkyle en C3-C6, halogénoalkyle en C1-C4, alcoxy en C1-C4, halogénoalcoxy en C1-C4, halogène, nitro, cyano, -NR3R4, -CONR3R4, -CH2-OCO-R3, -CO-R3, -COO-R3, -SOzR5, -C (=NR3)NHR6, -C(=NR6)OR3, un groupe de formule (iv) ou R8 représente un groupe phényle (éventuellement substitué par. un groupe alkyle en C1-C4, halogénoalkyle en C1-C4, alcoxy en C1-C4, halogénoalcoxy en C1-C4, halogène, nitro ou cyano) ;
R9 représente l'hydrogène ou méthyle ;
R10 représente l'hydrogène, isopropyle, cyclopentyle, cyclopropyle, 2-butyle, 3-pentyle, 3-hydroxy-2-butyle ou 2-hydroxy-3-pentyle;
m représente 0 ou 1 ;
R11 représente halogène, halogénoalkyle en C1-C4, halogénoalcoxy en C1-C4, nitro, amino, cyano, ou un groupe de formule (i) ;
Y représente -CH2- ou -C(=O)- ; et
Z représente NH ou O ;
qui comprend la réaction d'un composé de formule IIoù R1 et Ar ont la signification définie ci-dessus au sujet de la formule I, avec un composé de formule III
où A et R2 ont la signification définie ci-dessus au sujet de la formule I, en présence d'une base.