Derivatives of 4 - (1 - alkyl - 2 - oxo - 4 - 3 - pyridyl) - piperidinacarboxamida, Crystalline Form I of hydrochloride (3S, 4R) - N - ({3 - bromo - 4 - methyl - 5 - 3 - (metiloxi) propyl} - N - phenyl methyl cyclopropyl) - 4 - (1 - methyl - 2 - oxo - 1, 2 - dihydro - 4 - piridinil) - 3 - piperidinacarboxamida, Process for preparing Said derivatives and Mencius

摘要

Renin inhibitors Compounds, and their use in the treatment of cardiovascular diseases and renal failure.Claim 1: a compound with the formula (1) or a pharmaceutically acceptable Salt thereof, which has the formula (1) wherein R1 is selected from the group consisting of C1 - 6 alkyl, cycloalkyl alquenilo C2 - C3 - 6, 6, 6 alquinilo cicloalquenilo C2 and C2 - 6Where each previous is optionally substituted by Halogen 1 - 3 - 5 C1 and / or alkoxy; R2 and R3 are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl C1 - C5 - 5, 8, alquenilo C2 - C3 - cicloalquenilo 5, 8, alquinilo C2 - 5, ciano alkoxy, C1 - 5 Aryl and heteroaryl heteroaryl, which contains 1 to 3 heteroatoms,Independently selected among the group consisting of N, o and S N, where each is optionally in the form of an oxide and each s is optionally in the form of an oxide selected from the group consisting of S (= o) and S (= o) 2, where these aryl and heteroaryl are optionally replacing Go for 1 - 4 Halogen; where such alkyl, cycloalkyl, alquenilo, cicloalquenilo,Alquinilo and are optionally substituted by alkoxy substituents 1 - 3, which are each independently selected from the group consisting of: Halogen, alkyl of C1 - C2 - 5, 5 alquenilo, ciano and alkoxy c1-5, where each of the alkyl and alkoxy substituents, alquenilo Previous Is optionally substituted by Halogen W is 1 - 3; ciclopropilo, without replacing or mono -, di -, Tri -,Tetra - or Penta substituted by Fluorine; X is selected from the group consisting of: (alquileno or4, R4 - C1 - (5) - (OR) 0 - 1 - aryl - and (alquileno C1 - (5) - (heteroaryl) 0 - 1 -, where r is selected from the Group It consists of hydrogen, alkyl, cycloalkyl C1 - C3 - 5, 8, alquenilo cicloalquenilo C2 - C3 - 8 5 Alquinilo C2 - 5 - (cyano, alquileno c1-5) - or - (R5, alquileno c1-5) - N (R5) - C (= o) - (c1-5 alkyl)- (alquileno c1-5) - C (= o) - (-) - (alkyl) - 5 - (C1), alquileno c1-5) - N (R5) - C (= o) - O - (alkyl) - 5 - (C1), alquileno c1-5) - or - C (= o) - N - (alkyl (R5) - 5 - (C1), alquileno C1 - 5 (R5) - N - (alkyl) - 5 - (C1), alquileno C1 - 5 - S - (alkyl) - 5 - (C1), alquileno C1 - 5 (= o) - O - (alkyl) - 5 - (C1) and alquileno c1-5) - S (= o) - 2 - (alkyl C1 5), except where R4 is Hydrogen, optionally substituted by 1 - 3 substituents.Regardless of the selected Group is Halogen, C (= o) Oh, alquenilo c1-5 alkyl, alkoxy C1 and C2 - 5 - 5, where each of the alkyl and alkoxy substituents, alquenilo is optionally substituted by Halogen 1 - 3 - (heteroaryl; where the alquileno c1-5) - (o) 0 - 1 - heteroar ILO contains 1-3 hetero Atoms selected from the group consisting of independently,Or N and S, where each is optionally in the form of an oxide and each s is optionally in the form of an oxide selected from the group consisting of S (= o) and S (= o) 2, where aryl and heteroaryl - (alquileno C1 - (5) - (0) - 1 - aryl - (alquileno C1 - and (OR) 5 - 0 - 1 - heteroaryl, respectively, is 1 - 4 n optionally substituted by HalogenAnd where R5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl C1 - C3 - 6, 6, 6 alquenilo C2, C3 and C2 alquinilo cicloalquenilo - 6 - 6, where each of the substituents alquenilo alkyl, cycloalkyl, Optionally, cicloalquenilo and previous alquinilo is replaced by 1 - 3 Halogen alquileno c1-2; Z is optionally substituted by 1 - 2 SubstituentRegardless of the selected Group is Halogen, alkyl and cycloalkyl 2 C1 - C3 - 6, where the substituents are optionally substituted alkyl and cycloalkyl previous 3-1 Halogen; N1 is 0 OR 1; and (i) is a monocyclic Heterocyclic ring, or carbocu00edclico,Saturated or unsaturated five or six members ("ring monocu00edclicou00f6) or (ii) a Heterocyclic Ring or carbocu00edclico, saturated or unsaturated, five or six members which is Condensed with a Heterocyclic Ring or carbocu00edclico, saturated or unsaturated, five or six members (u00f4anillo count Nsadou00f6), where the Ring or Heterocyclic Rings In (i) or (ii) 1 - 3 contain heteroatoms.Selected regardless of N, o and S N, where each is optionally in the form of an oxide and each s is optionally in the form of an oxide selected from the group consisting of: S (= o) and S (= o) 2, where the Ring or Heterocyclic Rings or (i) or (carbocu00edclicos (ii) option Nally mono -, di -, Tri -, tetra -, penta - and hexa -, substitutedEach Substituent which is selected independently from the group consisting of: Halogen, - Oh, - NH (r6), Oxo, - C (= o) - R6, OC (= o) - R6 c1-5 alkyl, optionally substituted by Halogen 1 - 3 - 8, optionally substituted cycloalkyl C3 1 - 3 - 5 alquenilo Halogen, optionally a C2 Stituido 3-1 halogens, cicloalquenilo C3 - 1 - 3 8 optionally substituted by HalogenAlquinilo C2 - 5, 1 - 3 optionally substituted by Halogen, alkoxy optionally substituted C1 - 5, 1 - 3 Halogen, cyano, ciano c1-5 optionally substituted by Halogen ocf3 1 - 3, -, - C (R7) 3 - (alquileno c1-5) - 1 - 3 0R8 optionally substituted by Halogen (r6) - N - (alquileno c1-5) - opcionalment 0R8 Replaced by 1 - and 3 - (alquileno Halogen or - C1 - (5) - 1 - 3 0R8 optionally substituted by Halogen- S - (alquileno c1-5) - 0R8 optionally replaced by halogen - 1 - 3, S (= o) - (alquileno c1-5) - 0R8 optionally substituted by halogen - 1 - 3, S (= o) 2 - (alquileno c1-5) - 0R8 optionally replaced by 1 - 3 halogen - (alquileno c1-5) - N (r6) - C (= o) - (alquileno C1 - 5} - R8 optionally replaced by Hal 1 - 3 Ogenos, - (alquileno c1-5) - N (r6) - C (= o) - 1 - 3 0R8 optionally substituted by Halogen- (alquileno c1-5) - N (r6) (R8) optionally substituted by Halogen or - 1, - 3, - (alquileno c1-5) - C (r6) 2 - (c = o) 0R8 optionally substituted by halogen - (1 - 3, 5 - alquileno C1 (r6) - C 2) - C (= o) 0R8 optionally substituted by Halogen or - 1, - 3, - (alquileno c1-5) - Morpholine optionally replaced by 1 - 3 haloge We, OC (= o) - Morpholine - sr8, - S, - R8 (= o) - S (= o) 2 - R8 (r6), - N (R8),- (alquileno c1-5) - C (r6) 2 - (R8) optionally substituted by Halogen 1 - 3 - 0 - 1r10 (R9), alquenil C2 - 5 - 1 - 3 0R8 optionally substituted by Halogen, alquinil C2 - 5 - 1 - 3 0R8 optionally substituted by halogen - (alquileno C1 - (5) - C (= o) - (alquileno c1-5) - R8 optionally substituted by Halogen 1 - 3, - (alquileno c1-5) - or - C (= o) - (alquileno c1-5) - R8 optionally substituted by Halogen 1 - 3,- (alquileno c1-5) - C (= o) - N (r6) (R8) optionally substituted by halogen - (1 - 3, alquileno c1-5) - or - C (= o) - N (r6) (R8) optionally substituted by halogen - (1 - 3, alquileno C1 - (5) - sr8 optionally substituted by halogen - (1 - 3, alquileno c1-5) - S (= o) - R8 optionally replaced by 1 - and 3 - (Halogen Alquileno c1-5) - S (= OR) 1 - 3 2r8 optionally substituted by HalogenWhere R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl C3 C1 - 8, - 8, - 6 cicloalquenilo alquenilo C2, C3 and C2 - 6 - 8 alquinilo, where each of the substituents alquenilo alkyl, cycloalkyl, Optionally, cicloalquenilo and previous alquinilo is replaced by 1 - 3 Where is Halogen Halogen, R7, R8 is selected from the group consisting of hydrogen,C1 C3 cycloalkyl alkyl - 6, - 8, - 6 cicloalquenilo alquenilo C2, C3 and C2 - 6 - 8 alquinilo, where each of the substituents alquenilo alkyl, cycloalkyl, Optionally, cicloalquenilo and previous alquinilo is replaced by 1 - 3 Halogen, where R0 is selected from the group consisting of (H) - C (OH) (= o) - - - -, OC (= o) -, - C (= o) - O -, o -, OC (= o) - O - alquileno C1, C2 alquenileno - 5, - 5, - N - (r6),- S - S - (= o) - O - (= o) 2 -, - N (r6) - C (= o) -, - C (= o) - N - (r6), OC (= o) - N - (r6), N (r6) - C (= o) - O - (r6), N - S (= o) - 2, S 2 (= o) - N - (r6), where each of the previous alquenileno alquileno substituents and are optionally substituted by Halogen 1 - 3, and R6 are as defined above, and where is an R10 Heterocyclic or carbocu00edclico Illo, saturated or unsaturated,Five or six members which is optionally mono -, di -, Tri -, tetra - or Penta substituted, where each Substituent selected from the group consisting of independently Halogen, - Oh, - SR6, - N (r6) (R8) alkyl, cycloalkyl C3 C1 - 5, - 6, alquenilo C2 - C3 - cicloalquenilo 6, 6, 5 alquinilo C2 C1, 5 alkoxy -, cyano and cyano c1-5, where said Heterocyclic Ring contains 1 to 3 heteroatoms,Selected regardless of N, o and S N, where each is optionally in the form of an oxide and each s is optionally in the form of an oxide selected from the group consisting of: S (= o) or s (= o) 2 and R6, R8 and are defined above.Claim: a 28 hydrochloride Crystal Form I of (3S, 4R) - N - ({3 - bromo - 4 - methyl - 5 - [3 - (metiloxi) propyl] phenyl} - N - Cyclopropyl methyl) - 4 - (1 - methyl - 2 - oxo - 1.2 - dihydro - 4 - piridinil) - 3 - piperidinacarboxamida or a pharmaceutically acceptable hydrate of the same.Claim 1: The Crystal Form I of claim 28 which is characterized by the following ssrmn 13C Chemical shifts are expressed in parts per million; 120.1; 17.1 43.5 41.6 31.2;;;; 29.4 28.7 71.4 (;;;; 42.5; Truth; and Company.Claim 1: The Crystal Form I of claim 28 which was characterized by x-ray Powder diffraction has the following Reflections corresponding to Displacement interplanares 10.59; D: 7.04; 4:24; diesel; 3.88; 3.58; 3.51, 3.31 and 3.08.