Azaindoloxoacetica substituted piperazine Derivatives, Crystalline form of 1,2,3 - triazole Derivative, processes for the preparation thereof and Pharmaceutical compositions containing them

摘要

Item 1: the characteristic of the compound is its formula structure (1) a (13),When R18 is h or tar, Hal is halide, R1, R2 and R3 are independent of hydrogen, halide, cyanogen, nitrate, cour56, xr57, C (o) R7, C (o) nr55r56, B, D and E; B is selected from group C (= nr46) (R47),C (o) n40r41, arilo, heteromorphic, heteromorphic, s (o) 2r8, C (o) R7, xr8a, tar 1-6n40r41, tar 1-6coor8b; in these cases, arilo, heteromorphic and heteromorphic substitutes can be replaced by one to three identical or different halogens or one to three identical or different group F substitutes; a. Arilo is a replacement of naftillo or fenilo; heterosexual is a single ring or a double ring; there are 3 to 7 atoms in the ring ring, and up to 12 atoms in a combined double ring system, including 1 to 4 heteroatoms;a. Polymetallic ring is a single periodic ring composed of 3 to 7 members. The ring skeleton may contain 1 to 2 heteroatoms, which can be fused with benzene ring or pyridine. D is selected from C1-6 and alquenilo c2-6 tar groups; C1-6 and alquenilo c2-6 tar in C (o) n55r56, H Xi, cyanogen and xr57 groups can be selectively replaced by 1 to 3 identical or different halogens or 1 to 3 identical or different substitutes; E is selected from 1-6 and alquenilo c2-6 groups;wherein C1-6alkyl and C2-6alkenyl are independently optionally substituted with a member selected from the group consisting of phenyl, heteroaryl, SMe, SPh, -C (O) NR56R57, C (O) R57, SO2C1-6alkyl and SO2Ph; wherein heteroaryl is a monocyclic system which contains from 3 to 7 ring atoms, including from 1 to 4 heteroatoms; F is selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, C1-6 alkoxy, aryloxy, thioalkoxy C1-6, cyano, halogen, nitro, -C (O) R57 , benzyl, -NR42C (O) -C1-6alkyl, -NR42C (O) -C3-6cycloalkyl, -NR42C (O) -aryl, -NR42C (O) -heteroaryl, -NR42C (O) -heteroalicyclic,4. Periodic periodic periodic periodic periodic periodic periodic periodic periodic periodic periodic periodic periodic periodic periodic periodic periodic periodic periodic periodic periodicity 42 r43, OC (o) nr42r43, NHC (o) or54, acquiloc1-6nr42r43, cour54, Among them, C1-6, c3-7 cyclopentadiene, arilo, isobutylene, isopropene, Alcoy C1-6 and ariloxi can be replaced by 1 to 9 or different halogens or 1 to 5 or different substitutes selected from group G; arilo is phenyl;Heteroaryl is a monocyclic system which contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; Heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine; G is selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, C1-6 alkoxy, aryloxy, cyano, halogen, nitro, -C (O) R57, benzyl, -NR48C (O) -C1-6alkyl, -NR48C (O) -C3-6 cycloalkyl, -NR48C (O) -aryl, -NR48C (O) -heteroaryl, -NR48C (O) -heteroalicyclic, a cyclic lactam of 4, 5, or 6 ring members, -NR48S (O) 2-C 1-6 alkyl,-NR48S (O) 2-C3-6 cycloalkyl, -NR48S (O) 2-aryl, -NR48S (O) 2-heteroaryl, -NR48S (O) 2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR48R49, C1-6C-alkyl ( O) NR48R49, C (O) NR48R49, NHC (O) NR48R49, OC (O) NR48R49, NHC (O) OR54 ',1-6nr48r49, cour54, and tar 1-6cour54; arilo is phenyl; heterocyclic is a single ring system, containing 3 to 7 atoms in the ring, including 1 to 4 heterocyclic atoms; heterocyclic atoms are selected from aziridina, azetidina, pirrolidina, piperazina, piperidina, tetrahydrofuran, tetrahydropirano. Azipna and moropolina; R7 are selected from arilo, allomorph and allomorph biota; in arilo, allomorph and allomorph biota, one to three identical or different halogens or one to three identical or different halogens can be selected to replace; in R7, R8, R8a,R8b arilo is phenyl; heterocycle is a single or double cycle system, with 3 to 7 atoms in the ring, at most 10 atoms in the single cycle system, and at most 10 atoms in the single cycle system, including 1 to 4 heteroatoms; heterocycle organisms are selected from aziridina, azetidina, pirrolidina, piperazina, piperidina and other groups. 4. Tetrahydrofuran, tetrahydropyridine, azepine and morphine; R8 was selected from hydrogen, tar 1-6, cyclopropyl compounds c3-7, alquenilo c2-6, cycloacrylonitrile c3-7, acrylonitrile c2-6, arilo, isopropene and isopropene; C1-6, cyclopropyl compounds c3-7, alquenilo c2-6, cyclopropene-c3-7, nile-c6;Non-n-propene and isopropene can be replaced by one to six identical or different halogens or one to five identical or different group F substitutes; R8a is a selected group F member composed of arilo, isopropene and isopropene; In this case, each member may choose to be replaced independently by one to six identical or different halogens or one to five identical or different group F substitutes; r8b is selected from the hydrogen, C1-6 and phenyl groups; R40 and R41 are independently selected from the (a) hydrogen group;(b) Replace No. C1-6 or c3-7 octyl tar with one to three identical or different halogens or one to two identical or different group F substitutes; and O R40 and R41, together with the nitroglycerin attached to them, constitute a member selected from the group, including aziridina, azeidina, pirrolidina, piperazina, 4-ME piperazina, piperidina, azepina and morphine; in this group, arilo is heterogeneous, One to three identical or different halogens, or one to two identical or different group F substitutes can be selected to replace isocyclic propylene;In R40 and R41, the aryl group is a single ring system, and the ring contains 3 to 6 atoms, including 1 to 4 heteroatoms; heterocycles are selected from aziridina, azetidina, pirrolidina, piperazina, piperidina, tetrahydrofuran, tetrahydropirano, azepina and moropolina; however, the conditions are as follows: If B is C (o) n40r41, at least one R40 and R41 are not selected from category (a) or (b);R42 and r43 are selected separately from the groups of hydrogen, C1-6 tar, propylene, propylene, propoxyc1-6, CYCLOPROPYLENE c3-7, arilo, isopropene and isopropene; or R42 and r43 together with the nitrogen attached to them form a member selected from the groups of aziridina, azetidina and pirrolidina, 1. Piperazina, 4-ME piperazina, piperizina, azepina, and morpolina; C1-6, alcoxi C1-6, cycloquilo c3-7, arilo, isopropene and isopropene tar can be replaced by 1-3 same or different halogens or 1-2 same or different group G substitutes; R42 and r43 are called phenyl;Heteromorphism is a single ring system, which contains 3 to 6 atoms, including 1 to 4 heteroatoms. Heteromorphism is a member selected from aziridina, azeidina, pirrolidina, piperazina, piperidina, tetrahydrofuran, tetrahydropirano, azepina and morpolina; R46 was selected from the h, R57 and nr55r56 groups; R47 from the h, amino, halogen, phenyl and C1-6 tar groups; r48 and R49 from the hydrogen, C1-6 and phenyl groups; R54 from the C1-6 and C1-6 hydrocarbons;R56 is selected independently of the hydrogen and hydrocarbon 1-6 groups; R57 is selected from the hydrogen, C1-6 and phenyl groups. Requirement No. 20: crystallization form of 1,2,3-triazole derivatives, generated from formula (14), with structure (15),Or salt, in the form of n-1 free base, which has one or more of the following characteristics: (a) single pronunciation parameters basically equivalent to the following single: a = 39.2481 (14) (angle);B = 5.5577 (2) (angle);C = 21 8072 (1 o) (angle);alfa 3D 90s beta 3D 122 399 (4) s gamma 3D 90s grupo especial C2 2Fc en donde la forma cristalina est a aproximadamente 25sC b) coordenadas atomicas fraccionales sustancialmente como se lista en la tabla 2 c) configuracion de difraccion de rayos X en polvo (e) A thermal scanning thermal imager substantially different from that shown in Fig. 6; (f) substantially in accordance with the thermogravimetric analysis curve shown in Fig. 7; and / or (g) the basic humidity adsorption differential temperature shown in Fig. 8.