Patent DE-10012549-A1 (DE)
Title: New heterocyclic-substituted dihydropyrimidine derivatives useful for treatment of viral infections, especially hepatitis B infections
Inventor: NIEWOEHNER ULRICH
IPC: C07D413/14
Filed: 2000-03-15
Abstract: Heterocyclic-substituted dihydropyrimidine derivatives are new. Heterocyclic-substituted dihydropyrimidine derivatives of formula (I), their isomers of formula (Ia) and salts are new. [Image] R1>-R3>H, halo, CN, 1-6C alkyl, 1-6C alkoxy or NO2; R4>aliphatic hydrocarbyl with up to 8C optionally containing 1 or 2 O, S and/or NR7> and optionally substituted with 1 or 2 OH, 1-6C alkoxy, imidazolyl, tetrazolyl and/or NR8>R9>; R7>H or 1-6C alkyl; R8>, R9>H, or 1-4C alkoxy or 1-6C alkyl (each optionally substituted with OH, CF3 or phenyl); or NR8>R9>mono- or bicyclic ring containing 2-10C (the hydrocarbyl chain is optionally interrupted with 1 or more O, NR1>0>, CO, S, SO or SO2 and optionally substituted with 1 or more OH, 1-6C alkyl, 1-6C hydroxyalkyl and/or halo); R1>0>H, or 1-6C alkyl or 3-8C cycloalkyl (each optionally substituted with OH or phenyl), 1-6C acyl, 1-6C alkoxycarbonyl, or 6-10C aryl or 5 or 6 membered heteroaryl (both optionally substituted with halo, 1-6C alkyl or 1-6C alkoxy); R5>pyridyl, thiazolyl, oxazolyl, furyl or thienyl (each optionally substituted with 1-3 halo, OH, CN, CF3, 1-6C alkoxy, 1-6C alkyl, 1-6C alkylthio, 1-6C acyloxy, NH2, NO2, HN(1-6C alkyl) and/or N(1-6C alkyl)2; R6>5-7 membered, aromatic or partly unsaturated heterocycle containing up to 4 N, O and/or S optionally carrying a fused benzene ring on 2 adjacent C atoms and optionally substituted with 1 or 2 NH2 and/or 1-6C alkyl. Independent claims are also included for: (1) preparation of compounds (I) and (Ia) by; (a) cyclization of a dihydropyrimidine carboxamide of formula (X) with a dehydrating agent; (b) reaction of an optionally substituted benzaldehyde of formula (II) with a beta -ketoester of formula (III), reaction of the resulting substituted beta -ketoester of formula (IV) with an amidine of formula R5>C(=NH)NH2 (V) or its salt, de-esterifying the dihydropyrimidine carboxylic acid ester obtained with a base or F ions, reacting the resulting dihydropyrimidine carboxylic acid of formula (VII) with N,N-carbonyldiimidazole, reacting the dihydropyrimidinyl imidazolyl ketone of formula (VIII) with an amine of formula Z-A-NH2 (IX) and cyclizing the dihydropyrimidine carboxamide (X) with a dehydrating agent; or (c) reaction of a heterocyclic-substituted methyl-dihydropyrimidine derivative of formula (XIII) with a brominating agent and reaction of the resulting heterocyclic-substituted bromomethyl-dihydropyrimidine derivative with an amine of formula HNR8>R9>. (2) heterocyclic-substituted bromomethyl-dihydropyridine derivatives of formula (XIV); and (3) combinations containing: (i) compound(s) (I) and/or (Ia); (ii) hepatitis B virus (HBV) antiviral agent(s) other than compounds (I) and (Ia); and (iii) immunomodulator(s). [Image] [Image] [Image] Z : OH or -C(L)-R1>1>; R1>1>H, NH2 or 1- 6C alkyl; L : O, S or NH; A : -NH-, -CH2CH2- or -CH2CH2-O-; and X : CN or (CH3)3Si. - ACTIVITY : Virucide. The activity of compounds (I) and (Ia) against hepatitis B virus was determined by the methods described in Proc. Natl. Acad. Sci. 84, 1005-1009 (1987) and Antiviral Research 19, 55-70 (1992). 4-(2-Chloro-4-fluorophenyl)-6-morpholino-5-(1,3,4-oxadiazol-2-yl)-2-( 1,3-thiazol-2-yl)-1,4-dihydropyrimidine (I) displayed an IC50 value of 100 nM. - MECHANISM OF ACTION : None given.