N-(hydroxyethyl)butanediamide derivatives as renin inhibitors

Details N-(hydroxyethyl)butanediamide derivatives as renin inhibitors N-(hydroxyethyl)butanediamide derivatives as renin inhibitors

C - Chemistry, Metallurgy

07

C

C07C 233/17 (2006.01) A61K 31/16 (2006.01) A61K 31/40 (2006.01) A61K 31/41 (2006.01) A61K 31/44 (2006.01) C07C 233/18 (2006.01) C07C 233/19 (2006.01) C07D 207/27 (2006.01) C07D 213/40 (2006.01) C07D 213/56 (2006.01) C07D 233/54 (2006.01) C07D 233/64 (2006.01) C07D 263/32 (2006.01) C07D 277/20 (2006.01) C07D 277/30 (2006.01) C07D 277/40 (2006.01) C07D 317/58 (2006.01) C07D 317/60 (2006.01) C07D 417/12 (2006.01)

Patent

CA 2143301

Disclosed herein are compounds of the formula: A-N(R1)C(O)CH2CHR2C(O)-B, wherein A is an oxygen-bearing radical selected from the group consisting of: (a) HO-CH(R3)CH2 wherein R3 is, for example, hydrogen, lower alkyl, lower cycloalkyl, phenyl or an unsubstituted five- or six-membered heterocyclic ring containing one or two hereroatoms selected from the group of N, O or S; (b) HO-CH2CH(R4) wherein R4 is, for example, lower alkyl or phenyl(lower)alkyl; and (c) HO-CR5(R6)CH2 wherein each of R5 and R6 is lower alkyl; or R5 and R6 together with the carbon atom to which they are attached form a 1,1-(lower cycloalkanediyl), 1,1-(4-hydroxycyclohexanediyl) or 1,1-(4-oxocyclohexanediyl); (d) (lower alkoxy)CR5A(R6A)CH2 wherein each of R5A and R6A is lower alkyl; or R5A and R6A together with the carbon atom to which they are attached form a 1,1-(lower cycloalkanediyl); and (e) (lower alkyl)C(O)CH2; R1 is, for example, benzyl, alkyl, a substituted alkyl such as cyclohexylmethyl, or R7R8NC(O)CH2 wherein R7 and R8 are alkyl such as methyl or ethyl; R2 is, for example, alkyl, cycloalkylmethyl, 1H-imidazol-4-ylmethyl, 4-thiazolylmethyl or (2-amino-4-thiazolyl)methyl; and B is a renin substrate transition state mimic, for example, [1(S)-(cyclohexyhlmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino. The compounds inhibit renin activity and are indicated for the treatment of hypertension and congestive heart failure.

Composés de formule A-N(R1)C(O)CH2CHR2C(O)-B, où A est un radical oxygéné, choisi dans le groupe constitué de : a) HO-CH(R3)CH2 où R3 est, par exemple, un hydrogène, un alkyle inf., un cycloalkyle inf., un phényle ou un hétérocycle à cinq ou six chaînons, sans substitution, contenant un ou deux hétéroatomes choisis parmi N, O ou S; b) HO-CH2CH(R4) où R4 est, par exemple, un alkyle inf. ou un phénylalkyle (inf.); c) HO-CR5(R6)CH2 où R5 et R6 sont chacun un alkyle inf.; ou R5 et R6 forment ensemble, avec le carbone auquel ils sont liés, un 1,1-(cycloalcanediyle inf.), un 1,1-(4-hydroxycyclohexanediyle) ou un 1,1-(4-oxocyclohexanediyle); d) (alcoxy inf.)CR5A(R6A)CH2 où R5A et R6A sont chacun un alkyle inf.; ou R5A et R6A forment ensemble, avec le carbone auquel ils sont liés, un 1,1-(cycloalcanediyle inf.); e) (alkyle inf.)C(O)CH2; R1 est, par exemple, un benzyle, un alkyle, un alkyle avec substitution, comme le cyclohexylméthyle, ou R7R3NC(O)CH2, R7 et R8 étant un alkyle, comme un méthyle ou un éthyle; R2 est, par exemple, un alkyle, un cycloalkylméthyle, un 1H-imidazol-4-ylméthyle, un 4-thiazolylméthyle ou un (2-amino-4-thiazolyl)méthyle; B est un analogue à l'état de transition d'un substrat de la rénine, comme un [1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-metthylhexyl]amino. Ces composés sont des inhibiteurs de l'activité de la rénine et ils sont utiles pour le traitement de l'hypertension et de l'insuffisance cardiaque globale.

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