AR004695A1

AR004695A1 - NEUROTROPHIC COMPOUNDS AND COMPOSITIONS THAT HAVE AFFINITY WITH FKBP TYPE IMMUNOFILINS, AND APPLICATIONS OF THOSE.

Info

Publication number: AR004695A1
Application number: ARP960104916A
Authority: AR
Original assignee: Guilford William
Priority date: 1996-05-21
Filing date: 1996-10-25
Publication date: 1999-03-10
Also published as: TWI252226B; ID16707A; TW453992B; ZA968983B; AR030740A2; AR030739A2

Abstract

La presente invención se refiere a compuestos de N-glioxil prolil ester neurotroficos que tienen afinidad con inmunofilinas del tipo FKBP, supreparación y uso como inhibidores de actividad de enzima relacionada con proteinas inmunofilinas,y particularmente inhibidores de actividad de enzimapeptidil-prolil isomerasa o rotamasa. Los compuestos poseen la formula general (I) donde R1 es un grupo de alquilo o alquenilo C1-C9 de cadena recta oramificada opcionalmente sustituido porcicloal quilo C3-C8, cicloalquilo C3 o C5, cicloalquenilo C5-C7, o Ar1 donde los mencionados grupos de alquilo,alquenilo cicloalquilo o cicloalquenilo pueden ser opcionalmente sustituidos por alquilo C1-C4, alquenilo C1-C4, o hidroxi, y dondeAr1 es sel eccionado delgrupo consistente de 1-naftilo, 2-naftilo, 2-indolilo, 3-indolilo, 2-furilo, 3-furilo, 2-tieniloL, 2-,3-, o 4-piridilo, o fenilo, teniendo 1 a 3sustituyentes; X es oxigeno o sulfuro; Y es oxigeno o NR2, donde R2 eshidrogeno o alquilo C1-C6; y Z es alquilo o alquenilo C2-C6 de cadena recta oramificada donde la cadena de alquilo es sustituida en una o mas posiciones por Ar1, segun definido arriba, cicloalquilo C3-C8, cicloalquilo conectado por unacadena dealquilo o alque nilo C1-C6 recta o no ramificada, o Ar2 donde Ar2 es seleccionado del grupo consistente de 2-indolilo, 3-indolilo, 2-furilo,3-furilo 2-tiazolilo, 2-tienilo, 3-tienilo, 2-, 3- o 4- piridilo, o fenilo, teniendo uno a tressustituyentes; Z también puede ser el fragmento (II) dondeR3 es seleccionado del grupo consistente de alquilo recto o ramificado C1-C8 opcionalmente sustituido por cicloalquilo C3-C8, o Ar1, conforme lo definidoarriba; X2 es ONR5,donde R5 esseleccionado del grupo consis tente en hidrogeno, alquilo y alquenilo C1-C6 recto o ramificado; R4 es seleccionado del grupoThe present invention relates to neurotrophic N-glyoxil prolyl ester compounds having affinity for FKBP-type immunophilins, their use and suppression as inhibitors of enzyme activity related to immunophilin proteins, and particularly inhibitors of enzyme activity peptidyl prolyl isomerase or rotamase. The compounds have the general formula (I) where R1 is a branched straight chain C1-C9 alkyl or alkenyl group optionally substituted by C3-C8 cycloalkyl, C3 or C5 cycloalkyl, C5-C7 cycloalkenyl, or Ar1 where said groups of alkyl, alkenyl, cycloalkyl or cycloalkenyl may optionally be substituted by C1-C4 alkyl, C1-C4 alkenyl, or hydroxy, and where Ar1 is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 2- furyl, 3-furyl, 2-thienylL, 2-, 3-, or 4-pyridyl, or phenyl, having 1 to 3 substituents; X is oxygen or sulfide; Y is oxygen or NR2, where R2 is hydrogen or C1-C6 alkyl; and Z is straight-chain oramified C2-C6 alkyl or alkenyl where the alkyl chain is substituted at one or more positions by Ar1, as defined above, C3-C8 cycloalkyl, cycloalkyl connected by a straight chain or C1-C6 alkenyl or unbranched, or Ar2 where Ar2 is selected from the group consisting of 2-indolyl, 3-indolyl, 2-furyl, 3-furyl 2-thiazolyl, 2-thienyl, 3-thienyl, 2-, 3- or 4- pyridyl, or phenyl, having one of three substituents; Z may also be fragment (II) where R3 is selected from the group consisting of C1-C8 straight or branched alkyl optionally substituted by C3-C8 cycloalkyl, or Ar1, as defined above; X2 is ONR5, where R5 is selected from the group consisting of hydrogen, C1-C6 straight or branched alkyl and alkenyl; R4 is selected from the group