New 6-aminoalkyl-dihydropyrimidine-5-carboxylate ester derivatives, useful as antiviral agents having strong activity against hepatitis B virus and low cytotoxicity

• Main Authors: NIEWOEHNER, ULRICH, SCHLEMMER, KARL-HEINZ DR, PAESSENS, ARNOLD DR, DERES, KARL DR, STOLTELFUS, JUERGEN, WEBER, OLAF DR, KELDENICH, JOERG DR, GOLDMANN, SIEGFRIED DR, GRAEF, ERWIN DR
• Format: Patent
• Language: English; German
• Published: 20.09.2001
• Edition: 7
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

4-(Aryl or heteroaryl)-2-(heteroaryl)-6-aminoalkyl-1,4-dihydropyrimid ine-5-carboxylate ester derivatives (I) and corresponding 3,4-dihydropyrimidine isomers (I') are new. Also new are 5-bromomethyl-pyrimidine derivative intermediates (IX). Dihydropyrimidine derivatives of formula (I) or (I') and their salts are new. [Image] R1pyridyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl (all optionally substituted (os) by 1-3 of halo and/or alkyl); R2aryl or heteroaryl (both os by 1-3 of alkyl, alkoxycarbonyl, halo, NO2 or 1-4C polyfluoroalkyl); R31-14C alkyl (optionally having 1 or 2C replaced by O or S; and os by 1-3 of OH, CN, NR6R7, alkoxycarbonyl or aryl or heteroaryl (both os by 1-3 of OH, alkyl, alkoxy, alkoxycarbonyl, halo or haloalkyl); R6, R7H or alkoxycarbonyl; or linear, branched or cyclic, saturated or unsaturated 1-10C hydrocarbyl (os by dialkylamino); or NR6R73-8 membered ring (os by 1-3 alkyl and optionally containing a further O, S or N heteroatom); R41-10C alkyl (os by halo, OH, NH2, aryl and/or heteroaryl and optionally interrupted by O, S, SO2 and/or N(alkyl)); or aryl, heteroaryl or 5-10 membered heterocyclyl (all os by halo, alkoxy and/or alkyl); and R5H; 1-10C alkyl (os by halo, OH or Ph and optionally interrupted by O, S, SO2 and/or N(alkyl)); or aryl or heteroaryl (both os by halo, alkyl and/or alkoxy); or NR4R5saturated or partially unsaturated, mono- or bicyclic ring system of up to 10C, where (i) 1-3 ring C may be replaced by O, N(R8) or S, (ii) monocyclic systems are os on C or N by one or more of OH, CN, NO2, COOH, NH2, =O, 1-10C alkyl, 1-10C alkoxy, 3-6C cycloalkyl, hydroxyalkyl, mono- or dialkylaminoalkyl or alkoxycarbonylamino; 6-10C aralkyl or aryl (both os by halo, CN, NO2, COOH, NH2, alkoxy and/or alkyl); or -CO-Ry; (iii) monocyclic systems are os on S by 1 or 2 O; (iv) bicyclic systems are linked by the same C (spiro), two adjacent C (fused) or two non-adjacent C (overbridged); and (v) bicyclic systems are os by 1-3 substituents as defined above; Ry1-10C alkyl, 1-10C haloalkyl or 1-10C alkoxy; aryl, or aryloxy (both os by 1-10C alkoxy); 6-10C aralkoxy; aryloxy-(1-10C) alkoxy (os by halo); or 5-10 membered heterocycle (os by halo, alkoxy and/or alkyl); R81-10C alkyl or 3-10C cycloalkyl (both os by OH and/or Ph); 1-6C acyl; benzoyl; or aryl or heteroaryl (both os by halo, alkoxy and/or alkyl); and X : 1-3C alkylene (optionally interrupted by O and os by alkyl). Provided that: (1) R4 and R5 are not both unsubstituted alkyl; and (2) X is other than CH2-Y-(CH2)z (where Y = O, S, NH or N-alkyl and z = 2-4). Unless specified otherwise alkyl moieties have 1-6C, aryl moieties have 6-10C and heteroaryl moieties are 5-10 membered. Independent claims are included for: (1) the preparation of (I)/(I'); (2) new bromomethyl-pyrimidine intermediates of formula (IX); (3) the use of (I)/(I') (without provisos (a) and (b)) for the treatment or prophylaxis of viral diseases; and (4) combinations of (A) at least one compound (I)/(I') (without provisos (a) and (b)), (B) at least one other anti-hepatitis B virus (HBV) agent and optionally (C) at least one immunomodulator. [Image] - ACTIVITY : Virucide; hepatotropic; antiinflammatory. In tests in HepG2.2.15 cells, methyl 4-(2-chloro-4-fluorophenyl)-6-((3-oxo-1-piperazinyl)-me thyl)-2-(3,5-difluoro-2-pyridinyl)-1,4-dihydropyrimidine-5-carboxylate (Ia) had IC50 0.04 MicroM against hepatitis B virus and cytotoxicity CC50 34 MicroM. - MECHANISM OF ACTION : None given. 4-(Aryl or heteroaryl)-2-(heteroaryl)-6-aminoalkyl-1,4-dihydropyrimidine-5-carbox ylate ester derivatives (I) and corresponding 3,4-dihydropyrimidine isomers (I') are new. Also new are 5-bromomethyl-pyrimidine derivative intermediates (IX). Dihydropyrimidine derivatives of formula (I) or (I') and their salts are new. R1 = pyridyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl (all optionally substituted (os) by 1-3 of halo and/or alkyl); R2 = aryl or heteroaryl (both os by 1-3 of alkyl, alkoxycarbonyl, halo, NO2 or 1-4C polyfluoroalkyl); R3 = 1-14C alkyl (optionally having 1 or 2C replaced by O or S; and os by 1-3 of OH, CN, NR6R7, alkoxycarbonyl or aryl or heteroaryl (both os by 1-3 of OH, alkyl, alkoxy, alkoxycarbonyl, halo or haloalkyl); R6, R7 = H or alkoxycarbonyl; or linear, branched or cyclic, saturated or unsaturated 1-10C hydrocarbyl (os by dialkylamino); or NR6R7 = 3-8 membered ring (os by 1-3 alkyl and optionally containing a further O, S or N heteroatom); R4 = 1-10C alkyl (os by halo, OH, NH2, aryl and/or heteroaryl and optionally interrupted by O, S, SO2 and/or N(alkyl)); or aryl, heteroaryl or 5-10 membered heterocyclyl (all os by halo, alkoxy and/or alkyl); and R5 = H; 1-10C alkyl (os by halo, OH or Ph and optionally interrupted by O, S, SO2 and/or N(alkyl)); or aryl or heteroaryl (both os by halo, alkyl and/or alkoxy); or NR4R5 = saturated or partially unsaturated, mono- or bicyclic ring system of up to 10C, where (i) 1-3 ring C may be replaced by O, N(R8) or S, (ii) monocyclic systems are os on C or N by one or more of OH, CN, NO2, COOH, NH2, =O, 1-10C alkyl, 1-10C alkoxy, 3-6C cycloalkyl, hydroxyalkyl, mono- or dialkylaminoalkyl or alkoxycarbonylamino; 6-10C aralkyl or aryl (both os by halo, CN, NO2, COOH, NH2, alkoxy and/or alkyl); or -CO-Ry; (iii) monocyclic systems are os on S by 1 or 2 O; (iv) bicyclic systems are linked by the same C (spiro), two adjacent C (fused) or two non-adjacent C (overbridged); and (v) bicyclic systems are os by 1-3 substituents as defined above; Ry = 1-10C alkyl, 1-10C haloalkyl or 1-10C alkoxy; aryl, or aryloxy (both os by 1-10C alkoxy); 6-10C aralkoxy; aryloxy-(1-10C) alkoxy (os by halo); or 5-10 membered heterocycle (os by halo, alkoxy and/or alkyl); R8 = 1-10C alkyl or 3-10C cycloalkyl (both os by OH and/or Ph); 1-6C acyl; benzoyl; or aryl or heteroaryl (both os by halo, alkoxy and/or alkyl); and X = 1-3C alkylene (optionally interrupted by O and os by alkyl). Provided that: (1) R4 and R5 are not both unsubstituted alkyl; and (2) X is other than CH2-Y-(CH2)z (where Y = O, S, NH or N-alkyl and z = 2-4). Unless specified otherwise alkyl moieties have 1-6C, aryl moieties have 6-10C and heteroaryl moieties are 5-10 membered. Independent claims are included for: (1) the preparation of (I)/(I'); (2) new bromomethyl-pyrimidine intermediates of formula (IX); (3) the use of (I)/(I') (without provisos (a) and (b)) for the treatment or prophylaxis of viral diseases; and (4) combinations of (A) at least one compound (I)/(I') (without provisos (a) and (b)), (B) at least one other anti-hepatitis B virus (HBV) agent and optionally (C) at least one immunomodulator. Neue Dihydropyrimidine und ihre Kombinationen mit anderen antiviralen Mitteln eignen sich zur Bekämpfung von HBV-Infektionen.