AR045381A1 - PROTEASOME INHIBITORS AND METHODS OF THE SAME USE - Google Patents

PROTEASOME INHIBITORS AND METHODS OF THE SAME USE

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Publication number
AR045381A1
AR045381A1 ARP040102935A AR045381A1 AR 045381 A1 AR045381 A1 AR 045381A1 AR P040102935 A ARP040102935 A AR P040102935A AR 045381 A1 AR045381 A1 AR 045381A1
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AR
Argentina
Prior art keywords
alkyl
heterocarbocyclyl
carbocyclyl
optionally substituted
aryl
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Spanish (es)
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Cephalon Inc
Sede Secondaria Della Cell The
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Publication of AR045381A1 publication Critical patent/AR045381A1/en

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Abstract

La presente se refiere a inhibidores de proteasomas. Los compuestos y composiciones se pueden usar en los métodos que inducen la apoptosis y en el tratamiento de enfermedades como el cáncer y otros trastornos asociados en forma directa o indirecta con la actividad de los proteasomas. Reivindicación 1: Un compuesto caracterizado porque es de la fórmula (1) o formas de sal, estereoisoméricas o tautoméricas del mismo farmacéuticamente aceptables: R1 es C1-8 alquilo, C2-8 alquenilo, C2-8 alquinilo, o C3-7 cicloalquilo; R2 es H, -(CH2)aCH2NHC(=NR4)-Y, -(CH2)bCH2CONR5R6, -(CH2)cCH2N(R4)CONH2, -(CH2)dCH(R7)NR9R10, o -(CH2)eCH(R7)ZR8; a, b y c son cada uno, en forma independiente, 0, 1, 2, 3, 4, 5 o 6; d y e son cada uno, en forma independiente, 0, 1, 2, 3 o 4; R4 es H o C1-10 alquilo; R5 y 6 son cada uno, en forma independiente, H, C1-10 alquilo, carbociclilo, heterocarbociclilo, o un grupo protector de amino; como alternativa, R5 y R6 junto con el átomo de N al cual están unidos forman un grupo heterocarbociclilo; R7 es H o C1-10 alquilo; R8 es H, C1-10 alquilo, alquil-S(=O)1-, aril-S(=O)2-, H2NS(=O)2-, -SO3H, o un grupo protector; R9 es H, C1-10 alquilo, carbociclilo, o heterocarbociclilo; R10 es H, C1-10 alquilo, carbociclilo, heterocarbociclilo, C1-10alquil-C(=O)-, C2-10alquenil-C(=O)-, C2-10 alquinil-C(=O)-, carbociclil-C(=O)-, heterocarbociclil-C(=O)-, carbociclilalquil-C(=O)-, heterocarbociclilalquil-C(=O)-, C1-10 alquil-S(=O)2-, carbociclil-S(=O)2-, heterocarbociclil-S(=O)2-, carbociclilalquil-S(=O)2-, heterocarbociclilalquil-S(=O)2-, C1-10alquil-NHC(=O)-, carbociclil-NHC(=O)-, heterocarbociclil-NHC(=O)-, carbociclilalquil-NHC(=O)-, heterocarbociclilalquil-NHC(=O)-, C1-10 alquil-OC(=O)-, carbociclil-OC(=O)-, heterocarbociclil-OC(=O)-, carbociclilalquil-OC(=O)-, heterocarbociclilalquil-OC(=O)-, C1-10 alquil-NH-C(=O)-NHS(=O)2-, carbociclil-NH-C(=O)-NHS(=O)2-, heterocarbociclil-NH-C(=O)-NHS(=O)2-,C1-10 alquil-S(=O)2-NH-C(=O)-, carbociclil-S(=O)2-NH-C(=O)-, heterocarbociclil-S(=O)2-NH-C(=O)-, o un grupo protector de amino; en donde R10 está opcionalmente sustituido con 1, 2 o 3, R23; como alternativa, R9 y R10 junto con el átomo de N al cual están unidos forman un grupo heterocarbociclilo sustituido con 1, 2, o 3 R23; Y es H, -CN, -NO2, -S(=O)2R11, o un grupo protector de guanidino; R11 es C1-6 alquilo, arilo o NR12R13; R12 y R13 son, en forma independiente, H, C1-10 alquilo, carbociclilo, heterocarbociclilo, o un grupo protector de amino; como alternativa, R12 y R13 junto con el átomo de N al cual están unidos forman un grupo heterocarbociclilo; Z es O, S, Se, o Te; Q es -B(OH)2, -B(OR14)2, o un éster borónico cíclico en donde dicho éster borónico cíclico contiene entre 2 y 20 átomos de C, y opcionalmente, un heteroátomo que puede ser N, S o O; R14 es H, C1-4 alquilo, cicloalquilo, cicloalquilalquilo, arilo, o aralquilo; X es RAC(=O)-, RANHC(=O)-, RAS(=O)2-, RAOC(=O)-, RASC(=O)-, o RA; RA es C1-20 alquilo opcionalmente sustituido con R20; C2-20 alquenilo opcionalmente sustituido con R20; C2-20 alquinilo opcionalmente sustituido con R20; carbociclilo opcionalmente sustituido con 1-5R21;m o heterocarbociclilo opcionalmente sustituido con 1-5 R21; R20 se selecciona del grupo formado por: -CN, halo, haloalquil-, C1-4 alquilo, C2-4 alquenilo, C2-4 alquinilo, -CO2H, -C(=O)CO2H, -C(=O)NH2, -C(=O)H, -S(=O)NH2, -S(=O)2NH2, -OH, -SH, -NH2, -NH(alquil), -N(alquil)2, -NHC(=O)NH2, -NHC(=O)R20a, -NHC(=O)OR20a, -OR20a, -SR20a, -S(=O)R20a, -S(=O)R20a, -S(=O)2-NHR20a, -SC(=O)R20a, -C(=O)R20a, -C(=O)NHR20a, -C(=O)O-R20a, -NHS(=O)2R20a, -NHR20b, ftalimido,-(O-alquil)r-OH, -(O-alquil)r-(O-alquil), -OR20c, -SR20c, -O-alquil-R20c, -S-alquil-R20c, -S(=O)-R20c, -S(=O)2-R20c, -S(=O)2-NHR20c, -SC(=O)R20c, -C(=O)R20c, -C(=O)OR20c, -C(=O)NHR20c; carbociclilo opcionalmente sustituido con 1-5 R21; y heterocarbociclilo opcionalmente sustituido con 1-5 R21; R20a es C1-10 alquilo, C2-20 alquenilo, o C2-20 alquinilo, en donde dicho alquilo, alquenilo, o alquinilo está opcionalmente sustituido con uno o más halo, OH, CN, C1-4 alquilo, C1-4 alcoxi, C2-8 alcoxialcoxi, arilo, heteroarilo o -NHR20b; R20b es un grupo protector de amino; R20c es carbociclilo opcionalmente sustituido con 1-5 R22, o heterocarbociclilo opcionalmente sustituido con 1-5 R22; R21 se selecciona del grupo formado por: C1-20 alquilo, C2-20 alquenilo, C2-20 alquinilo, -OR21a, -SR21a, -CN, halo, haloalquilo, -NH2, -NH(alquil), -N(alquil)2, -NHC(=O)O-alquilo, -NHC(=O)alquilo, COOH, -C(=O)O-alquilo, -C(=O)alquilo, -C(O)H, -S(=O)-alquilo, -S(=O)2-alquilo, -S(=O)-arilo, -S(=O)2-arilo, carbociclilo opcionalmente sustituido con 1-5 R22, y heterocarbociclilo opcionalmente sustituido con 1-5 R22; R21a es H, C1-20 alquilo, C2-20 alquenilo, C2-20 alquinilo, carbociclilo o heterocarbociclilo; R22 se selecciona del grupo formado por: C1-10 alquilo, C2-10 alquenilo, C2-10 alquinilo, fenilo, halo, haloalquilo, alcoxi, tialcoxi, amino, alquilamino, dialquilamino, carboxilo, alquil-OC(=O)-, alquil-C(=O)-, aril-OC(=O)-, alquil-OC(=O)NH-, aril-OC(=O)NH-, alquil-C(=O)NH-, alquil-C(=O)O-, (alquil-O)r-alquilo, HO-(alquil-O)r-alquil, -OH, -SH, -CN, -N3, -CNO, -CNS, alquil-S(=O)-, alquil-S(=O)2-, H2NS(=O)-, y H2NS(=O)2-; R23 se selecciona del grupo formado por: C1-6 alquilo, C2-6 alquenilo, C2-6 alquinilo, F, Cl, Br, I, haloalquilo, -NH2, -NHR23a, -N(R23a)2, -N3, -NO2, -CN, -CNO, -CNS, -C(=O)OR23a, -C(=O)R23a, -OC(=O)R23a, -N(R23a)C(=O)R23a, -N(R23a)C(=O)OR23a, -C(=O)N(R23a)2, ureido, -OR23a, -SR23a, -S(=O)-(C1-6 alquil), -S(=O)2-(C1-6 alquil), -S(=O)-arilo, -S(=O)2-arilo, -S(=O)2-N(R23a)2; carbociclilo opcionalmente sustituido con 1-5 R24, y heterocarbociclilo opcionalmente sustituido con 1-5 R24; R23a es H o C1-6 alquilo; como alternativa, dos R23a pueden combinarse, junto con el átomo de N al cual están unidos, para formar un grupo heterocíclico de entre 5 y 7 miembros; y R24 se selecciona del grupo formado por: C1-4 alquilo, C2-4 alquenilo, C2-4 alquinilo, fenilo, halo, haloalquilo, alcoxi, tialcoxi, amino, alquilamino, dialquilamino, carboxilo, alquil-OC(=O)-, alquil-C(=O)-, aril-OC(=O)-, alquil-OC(=O)NH-, aril-OC(=O)NH-, alquil-C(=O)NH-, alquil-C(=O)O-, (alquil-O)r-alquilo, HO-(alquil-O)r-alquil, -OH, -SH, -CN, -N3, -CNO, -CNS, alquil-S(=O)-, alquil-S(=O)2-, H2NS(=O)-, y H2NS(=O)2-; y r es 1, 2, 3, 4, 5, 6, 7, 8, 9 o 10; con la salvedad de que cuando Q es un éster 1,1,2,2-tetrametiletandiolborónico, entonces X no sea aralquiloxicarbonilo; con la salvedad de que cuando Q es un éster 1,1,2,2- tetrametiletandiolborónico, y R1 es cicloalquilo, entonces R2 no sea -CH2CONH2; y con la salvedad de que cuando X es RAC(=O)-, RA es un C4-15 alquilo de cadena lineal sustituido con R20 y R20 es -CN, -CO2H, -C(=O)O-R20a, -NHS(=O)2R20a, -NHC(=O)R20a, -NHR20a, o ftalamido; entonces R2 no sea -(CH2)aCH2NHC(=NR4)NH-Y, en donde Y es H, -CN, -NO2, o un grupo protector de guanidino.This refers to proteasome inhibitors. The compounds and compositions can be used in methods that induce apoptosis and in the treatment of diseases such as cancer and other disorders directly or indirectly associated with the activity of proteasomes. Claim 1: A compound characterized in that it is of the formula (1) or pharmaceutically acceptable salt, stereoisomeric or tautomeric forms thereof: R 1 is C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, or C 3-7 cycloalkyl; R2 is H, - (CH2) aCH2NHC (= NR4) -Y, - (CH2) bCH2CONR5R6, - (CH2) cCH2N (R4) CONH2, - (CH2) dCH (R7) NR9R10, or - (CH2) eCH (R7 ) ZR8; a, b and c are each, independently, 0, 1, 2, 3, 4, 5 or 6; d and e are each, independently, 0, 1, 2, 3 or 4; R4 is H or C1-10 alkyl; R5 and 6 are each, independently, H, C1-10 alkyl, carbocyclyl, heterocarbocyclyl, or an amino protecting group; alternatively, R5 and R6 together with the N atom to which they are attached form a heterocarbocyclyl group; R7 is H or C1-10 alkyl; R8 is H, C1-10 alkyl, alkyl-S (= O) 1-, aryl-S (= O) 2-, H2NS (= O) 2-, -SO3H, or a protecting group; R9 is H, C1-10 alkyl, carbocyclyl, or heterocarbocyclyl; R10 is H, C1-10 alkyl, carbocyclyl, heterocarbocyclyl, C1-10alkyl-C (= O) -, C2-10alkenyl-C (= O) -, C2-10 alkynyl-C (= O) -, carbocyclyl-C (= O) -, heterocarbocyclyl-C (= O) -, carbocyclylalkyl-C (= O) -, heterocarbocyclyl-alkyl-C (= O) -, C1-10 alkyl-S (= O) 2-, carbocyclyl-S ( = O) 2-, heterocarbocyclyl-S (= O) 2-, carbocyclylalkyl-S (= O) 2-, heterocarbocyclylalkyl-S (= O) 2-, C1-10alkyl-NHC (= O) -, carbocyclyl-NHC (= O) -, heterocarbocyclyl-NHC (= O) -, carbocyclylalkyl-NHC (= O) -, heterocarbocyclylalkyl-NHC (= O) -, C1-10 alkyl-OC (= O) -, carbocyclyl-OC (= O) -, heterocarbocyclyl-OC (= O) -, carbocyclylalkyl-OC (= O) -, heterocarbocyclyl-alkyl-OC (= O) -, C1-10 alkyl-NH-C (= O) -NHS (= O) 2 -, carbocyclyl-NH-C (= O) -NHS (= O) 2-, heterocarbocyclyl-NH-C (= O) -NHS (= O) 2-, C1-10 alkyl-S (= O) 2- NH-C (= O) -, carbocyclyl-S (= O) 2-NH-C (= O) -, heterocarbocyclyl-S (= O) 2-NH-C (= O) -, or a protective group of Not me; wherein R10 is optionally substituted with 1, 2 or 3, R23; alternatively, R9 and R10 together with the N atom to which they are attached form a heterocarbocyclyl group substituted with 1, 2, or 3 R23; Y is H, -CN, -NO2, -S (= O) 2R11, or a guanidino protecting group; R11 is C1-6 alkyl, aryl or NR12R13; R12 and R13 are, independently, H, C1-10 alkyl, carbocyclyl, heterocarbocyclyl, or an amino protecting group; alternatively, R12 and R13 together with the N atom to which they are attached form a heterocarbocyclyl group; Z is O, S, Se, or Te; Q is -B (OH) 2, -B (OR14) 2, or a cyclic boronic ester wherein said cyclic boronic ester contains between 2 and 20 C atoms, and optionally, a heteroatom that can be N, S or O; R14 is H, C1-4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; X is RAC (= O) -, RANHC (= O) -, RAS (= O) 2-, RAOC (= O) -, RASC (= O) -, or RA; RA is C1-20 alkyl optionally substituted with R20; C2-20 alkenyl optionally substituted with R20; C2-20 alkynyl optionally substituted with R20; carbocyclyl optionally substituted with 1-5R21; m or heterocarbocyclyl optionally substituted with 1-5 R21; R20 is selected from the group consisting of: -CN, halo, haloalkyl-, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -CO2H, -C (= O) CO2H, -C (= O) NH2, -C (= O) H, -S (= O) NH2, -S (= O) 2NH2, -OH, -SH, -NH2, -NH (alkyl), -N (alkyl) 2, -NHC (= O) NH2, -NHC (= O) R20a, -NHC (= O) OR20a, -OR20a, -SR20a, -S (= O) R20a, -S (= O) R20a, -S (= O) 2- NHR20a, -SC (= O) R20a, -C (= O) R20a, -C (= O) NHR20a, -C (= O) O-R20a, -NHS (= O) 2R20a, -NHR20b, phthalimido, - (O-alkyl) r-OH, - (O-alkyl) r- (O-alkyl), -OR20c, -SR20c, -O-alkyl-R20c, -S-alkyl-R20c, -S (= O) - R20c, -S (= O) 2-R20c, -S (= O) 2-NHR20c, -SC (= O) R20c, -C (= O) R20c, -C (= O) OR20c, -C (= O) NHR20c; carbocyclyl optionally substituted with 1-5 R21; and heterocarbocyclyl optionally substituted with 1-5 R21; R20a is C1-10 alkyl, C2-20 alkenyl, or C2-20 alkynyl, wherein said alkyl, alkenyl, or alkynyl is optionally substituted with one or more halo, OH, CN, C1-4 alkyl, C1-4 alkoxy, C2-8 alkoxyalkoxy, aryl, heteroaryl or -NHR20b; R20b is an amino protecting group; R20c is carbocyclyl optionally substituted with 1-5 R22, or heterocarbocyclyl optionally substituted with 1-5 R22; R21 is selected from the group consisting of: C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, -OR21a, -SR21a, -CN, halo, haloalkyl, -NH2, -NH (alkyl), -N (alkyl) 2, -NHC (= O) O-alkyl, -NHC (= O) alkyl, COOH, -C (= O) O-alkyl, -C (= O) alkyl, -C (O) H, -S ( = O) -alkyl, -S (= O) 2-alkyl, -S (= O) -aryl, -S (= O) 2-aryl, carbocyclyl optionally substituted with 1-5 R22, and heterocarbocyclyl optionally substituted with 1 -5 R22; R21a is H, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, carbocyclyl or heterocarbocyclyl; R22 is selected from the group consisting of: C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, phenyl, halo, haloalkyl, alkoxy, tyalkoxy, amino, alkylamino, dialkylamino, carboxyl, OC-alkyl (= O) -, alkyl-C (= O) -, aryl-OC (= O) -, alkyl-OC (= O) NH-, aryl-OC (= O) NH-, alkyl-C (= O) NH-, alkyl- C (= O) O-, (alkyl-O) r-alkyl, HO- (alkyl-O) r-alkyl, -OH, -SH, -CN, -N3, -CNO, -CNS, alkyl-S ( = O) -, alkyl-S (= O) 2-, H2NS (= O) -, and H2NS (= O) 2-; R23 is selected from the group consisting of: C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, F, Cl, Br, I, haloalkyl, -NH2, -NHR23a, -N (R23a) 2, -N3, - NO2, -CN, -CNO, -CNS, -C (= O) OR23a, -C (= O) R23a, -OC (= O) R23a, -N (R23a) C (= O) R23a, -N ( R23a) C (= O) OR23a, -C (= O) N (R23a) 2, ureido, -OR23a, -SR23a, -S (= O) - (C1-6 alkyl), -S (= O) 2 - (C1-6 alkyl), -S (= O) -aryl, -S (= O) 2-aryl, -S (= O) 2-N (R23a) 2; carbocyclyl optionally substituted with 1-5 R24, and heterocarbocyclyl optionally substituted with 1-5 R24; R23a is H or C1-6 alkyl; alternatively, two R23a can be combined, together with the N atom to which they are attached, to form a 5- to 7-membered heterocyclic group; and R24 is selected from the group consisting of: C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, halo, haloalkyl, alkoxy, tyalkoxy, amino, alkylamino, dialkylamino, carboxyl, OC-alkyl (= O) - , alkyl-C (= O) -, aryl-OC (= O) -, alkyl-OC (= O) NH-, aryl-OC (= O) NH-, alkyl-C (= O) NH-, alkyl -C (= O) O-, (alkyl-O) r-alkyl, HO- (alkyl-O) r-alkyl, -OH, -SH, -CN, -N3, -CNO, -CNS, alkyl-S (= O) -, alkyl-S (= O) 2-, H2NS (= O) -, and H2NS (= O) 2-; and r is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; with the proviso that when Q is a 1,1,2,2-tetramethylenediolboronic ester, then X is not aralkyloxycarbonyl; with the proviso that when Q is a 1,1,2,2-tetramethylenediolboronic ester, and R1 is cycloalkyl, then R2 is not -CH2CONH2; and with the proviso that when X is RAC (= O) -, RA is a C4-15 straight chain alkyl substituted with R20 and R20 is -CN, -CO2H, -C (= O) O-R20a, -NHS (= O) 2R20a, -NHC (= O) R20a, -NHR20a, or phthalamide; then R2 is not - (CH2) aCH2NHC (= NR4) NH-Y, where Y is H, -CN, -NO2, or a guanidino protecting group.

ARP040102935 2003-08-14 2004-08-17 PROTEASOME INHIBITORS AND METHODS OF THE SAME USE AR045381A1 (en)

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CN105837608B (en) * 2007-08-06 2018-06-08 米伦纽姆医药公司 Proteasome inhibitor and combinations thereof and purposes
CN102961387B (en) * 2007-08-06 2016-04-27 米伦纽姆医药公司 Proteasome inhibitor
SI2318419T1 (en) * 2008-06-17 2015-07-31 Millennium Pharmaceuticals, Inc. Boronate ester compounds and pharmaceutical compositions thereof
CN101638414B (en) * 2008-07-30 2014-01-08 江苏先声药物研究有限公司 Peptidyl boronic acid, ester compound thereof, preparation method of peptidyl boronic acid and ester compound thereof, and use of peptidyl boronic acid and ester compound thereof
AR075090A1 (en) * 2008-09-29 2011-03-09 Millennium Pharm Inc ACID DERIVATIVES 1-AMINO-2-CYCLLOBUTILETILBORONICO PROTEOSOMA INHIBITORS, USEFUL AS ANTI-BANKER AGENTS, AND PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND THEM.
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WO2011087822A1 (en) * 2009-12-22 2011-07-21 Cephalon, Inc. Proteasome inhibitors and processes for their preparation, purification and use
RU2012146101A (en) * 2010-03-31 2014-05-10 Милленниум Фармасьютикалз, Инк. 1-AMINO-2-CYCLOPROPYLETHYL BORONIC ACID DERIVATIVES
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CN114437119A (en) * 2020-10-30 2022-05-06 苏州开拓药业股份有限公司 C-Myc protein inhibitor and preparation method and application thereof

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