AR045950A1 - COMPOUNDS DERIVED FROM PIPERAZINE, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND THEIR USE IN THE MANUFACTURE OF MEDICINES. - Google Patents

Abstract

This refers to piperazine-derived compounds, pharmaceutical compositions containing them and their use in the manufacture of medicaments. The compounds are especially suitable as renin inhibitors and also for use in pharmaceutical compositions and medicaments for the treatment or prevention of hypertension, heart failure, glaucoma, myocardial infarction, renal failure and restenosis. Claim 1: Compounds of formula (1) or (2) wherein: R 1 is aryl or heterocyclyl; R2 is phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxopyridinyl, diazinyl, triazolyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl, furyl, tetrazolyl or imidazolyl radicals which may be substituted with 1-3 halogen groups hydroxy, cyano, trifluoromethyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl ,. C 1-6 alkoxy-C 1-6 alkyl, C 1-6 cyanoalkyl, C 1-6 carboxyalkyl, C 1-6 alkanoyloxy, C 1-6 alkoxycarbonyloxy-C 1-6 alkyl, C 1-6 alkoxycarbonyl or C 1-6 alkoxy groups or a C1-6 alkylenedioxy group and / or with a radical L1-T1-L2-T2-L3-T3-L4-T4-L5-U; L1, L2, L3, L4 and L5 are, independently of each other, a bond, C1-8 alkylene, C2-8 alkenylene or C2-8 alkynylene or are absent; T1, T2, T3 and T4 are, independently of each other, (a) a link or are absent, or one of the groups (b) -CH (O) -, (c) -CH (OR6) -, ( d) -CH (NR5R6) -, (e) -CO-, (f) -CR7R8-, (g) -O- or -NR6-, (h) - S (O) 0-2-, (i) -SO2NR6-, (j) -NR6SO2-, (k) -CONR6-, (l) -NR6CO-, (m) -O-CO-, (n) -CO-O-, (o) -O-CO -O-, (p) -O-CO-NR6-, (q) -N (R6) -CO-N (R6) -, (r) -N (R6) -CO-O-, (s) pyrrolidinylene , piperidinylene or piperazinylene, and (t) -C (R11) (R12) -, where the bonds that start from (b) - (t) lead to a saturated or aromatic C atom of the adjacent group, in case the link starts from a heteroatom, and where no more than two groups (b) - (f), three groups (g) - (h) and one group (i) - (t) are absent; R3 is H, C1-6 alkyl, C1-6 alkenyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkoxy-C1-6 alkyl, benzyl, oxo or a group R4-Z1-X1-, wherein R4 is (a) H-, (b) C1-6- alkyl, (c) C1-6 alkenyl, (d) C1-6 hydroxyalkyl, (e) C1-6 polyhydroxyalkyl, (f) C1-6-O-alkyl C1-6- alkyl, (g) aryl, (h) heterocyclyl, (i) arylalkyl, (j) heterocyclylalkyl, (k) aryloxyalkyl, (l) heterocyclyloxyalkyl, (m) (R5, R6) N- (CH2) 1 -3-, (n) (R5, R6) N-, (o) C1-6-S-alkyl (O) 0-2-, (p) aryl-S (O) 0-2, (q) heterocyclyl- S (O) 0-2-, (r) HO-SO3- or its salts, (s) H2N-C (NH) -NH-, and (t) NC-, and the bonds starting from (n) - (t) lead to a C atom of the adjacent group and this C atom is saturated, in case the bond starts from a heteroatom; Z1 is (a) a bond, is absent, or is one of the groups, (b) C1-6 alkylene, (c) C1-6 alkenylene, (d) -O-, -N (R11) -, - S (O) 0-2-, (e) -CO-, (f) -O-CO-, (g) -O-CO-O-, (h) -O-CO-N (R11) -, (i) -N (R11) -CO-O-, (j) -CO-N (R11) -, (k) -N (R11) -CO-, (l) -N (R11) -CO-N - (R11) -, and (m) - CH (OR9) - and the compounds that start from (d) and (f) - (m) lead to a C atom of the adjacent group and this C atom is saturated, in case the link starts from a heteroatom; X1 is a link, is absent or is - (CH2) 1-3-; R5 and R6 are H, C1-6 alkyl, C1-6 alkenyl, C1-6 arylalkyl or acyl or, together with the N atom to which they are attached, they are a 5- or 6-membered heterocyclic ring that may contain an atom of Additional N, O or S or a group -SO- or -SO2-, wherein the additional N atom may be optionally substituted with C1-6 alkyl radicals; R7 and R8 are together with the C atom to which they are attached, a 3-7 membered ring that may contain one or two atoms of -O- or -S- or groups -SO- or -SO2-; R9 is H, C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy-C1-6 alkyl, acyl or arylalkyl; R10 is carboxyalkyl, alkoxycarbonylalkyl, alkyl or H, R11 is H or C1-6 alkyl R12 is H or C1-6 alkyl; U is H, C1-6 alkyl, cycloalkyl, cyano, optionally substituted cycloalkyl, aryl or heterocyclyl; Q is ethylene or is absent (formula 1) or is ethylene or methylene (formula 2); X is a link or group> CH-R11,> CR9R11,> CHOR9,> CO or> C = NOR10; Z is absent or is C1-6 alkylene, C1-6 alkenylene, C1-6 hydroxyalkylidene, -CH-R11-CO-NR9-, -O-, -S-, -NR9, -O-Alk-, -S- Alk-, -NR9-Alk-, -Alk-O-, -Alk-S- or -Alk-NR9-, where Alk is C1-6 alkylene; and where (a) in case Z is -O- or -S-, X is -CR9R11- and R2 contains a substituent L1-T1-L2-T2-L3-T3-L4-T4-L5-U or R3 is a substituent other than H as defined above; (b) in case Z is -O-Alk-, -S-Alk- or -NR9-Alk-, X is -CR9R11-; and (c) in case X is a bond, Z is C1-6 alkenylene, -Alk-O-, -Alk-S- or - Alk-NR9-; and its salts of pharmaceutical utility.