Patent CO-5011122-A1 (CO)
Title: Inhibidores de las neuraminidasas
Inventor: MARING J CLARENE
IPC: C07D403/06
Filed: 1999-04-21
Abstract: Un compuesto de la fórmula:ó una sal, éster o precursor de droga farmacéuticamente aceptable de éste,en donde:R1 se selecciona del grupo conformado por:(a) -CO2 H, (b) -CH2 CO2 H, (c) -SO3 H, (d) -CH2 SO3 H, (e) -SO2 H, (f) -CH2 SO2 H, (g) -PO3 H2 , (h) -CH2 PO3 H2 , (i) -PO2 H, (j) -CH2 PO2 H, (k) tetrazolil, (l) -CH2 -tetrazolil, (m) -C(=O)-NH-S(O)2 -R11 ,(n) -CH2 C(=O)-NH- S(O)2 -R11 (o) -SO2 N(T-R11 )R12 y (p) -CH2 SO2 N(T-R11 )R12 en donde T se selecciona del grupo conformado por(i) un enlace, (ii) -C(=O)-, (iii) -C(=O)O-, (iv) -C(=O)S-, y (v) -C(=O)NR36 -, (vi) -C(=S)O-, (vii) -C(=S)S-, y (viii) -C(=S)NR36 -,R11 se selecciona del grupo conformado por(i) alquil C1 -C12 , (ii) alquenil C2 -C12 , (iii) cicloalquil, (iv) (cicloalquil)alquil, (v) (cicloalquil)alquenil, (vi) cicloalquenil, (vii) (cicloalquenil)alquil, (viii) (cicloalquenil)alquenil, (ix) aril, (x) (aril)alquil, (xi) (aril)alquenil, (xii) heterocíclico, (xiii) (heterocíclico)alquil y (xiv) (heterocíclico)alquenil; yR12 y R36 se seleccionan independientemente del grupo conformado por(i) hidrógeno, (ii) alquil C1 -C12 , (iii) alquenil C2 -C12 , (iv) cicloalquil, (v) (cicloalquil)alquil,(vi) (cicloalquil)alquenil, (vii) cicloalquenil,(viii) (cicloalquenil)alquil, - 2 -(ix) (cicloalquenil)alquenil, (x) aril, (xi) (aril)alquil, (xii) (aril)alquenil,(xiii) heterocíclico, (xiv) (heterocíclico)alquil y(xv) (heterocíclico)alquenil;X se selecciona del grupo conformado por(a) C(=O)-N(R* )-, (b) N(R* )-C(=O)-, (c) C(=S)-N(R* )-, (d) N(R* )-C(=S)-, (e) N(R* )-SO2 -, y (f) SO2 -N(R* )- en donde R* es hidrógeno, alquil de cadena corta C1 -C3 ó ciclopropil;R2 se selecciona del grupo conformado por(a) hidrógeno, (b) alquil C1 -C6 , (c) alquenil C2 -C6 , (d) cicloalquil C3 -C6 , (e) cicloalquenil C5 -C6 , (f) haloalquil C1 -C6 y (g) haloalquenil C2 -C6 ; ó R2 -X- esen donde Y1 es -CH2 -, -O-, -S- ó -NH- y Y2 es -C(=O)- ó -C(Raa )(Rbb ) en donde Raa y Rbb son independientemente seleccionados del grupo conformado por hidrógeno, alquil de cadena corta C1 -C3 , hidroximetil, 1-hidroxietil, 2-hidroxietil, aminometil, 1-aminoetil, 2-aminoetil, tiolmetil, 1-tioletil, 2-tioletil, metoximetil, N-metilaminometil y metiltiometil;R3 y R4 son independientemente seleccionados del grupo conformado por(a) hidrógeno, (b) cicloalquil, (c) cicloalquenil (d) heterocíclico, (e) aril y (f) AND#8209;ZAND#8209;R14en donde Z es (i) -C(R37a )(R37b )AND#8209; (ii) AND#8209;C(R47 )=C(R48 )AND#8209;, (iii) AND#8209;CºCAND#8209;, (iv) AND#8209;C(=O)AND#8209;, (v) AND#8209;C(=S)AND#8209;, (vi) AND#8209;C(=NR15 )AND#8209;, (vii) -C(R37a )(OR37c )-, (viii) -C(R37a )(SR37c )AND#8209;, (ix) AND#8209;C(R37a )(N(R37b )(R37c )), (x) AND#8209;C(R37a )(R37b )-O-, (xi) AND#8209;C(R37a )(R37b )-N(R37c )-, (xii) -C(R37a )(R37b )AND#8209;N(O)(R37c )AND#8209;,(xiii) AND#8209;C(R37a )(R37b )AND#8209;N(OH)AND#8209;, (xiv) AND#8209;C(R37a )(R37b )AND#8209;SAND#8209;, (xv) AND#8209;C(R37a )(R37b )AND#8209;S(O)AND#8209;, (xvi) AND#8209;C(R37a )(R37b )AND#8209;S(O)2 AND#8209;,(xvii) -C(R37a )(R37b )AND#8209;C(=O)AND#8209;, (xviii) AND#8209;C(R37a )(R37b )AND#8209;C(=S)-, (xix) AND#8209;C(R37a )(R37b )AND#8209;C(=NR15 )AND#8209;,(xx) AND#8209;C(R37a )(OR37c )AND#8209;C(=O)AND#8209;,(xxi) AND#8209;C(R37a )(SR37c )AND#8209;C(=O),(xxii) AND#8209;C(R37a )(OR37c )C(=S)AND#8209;,(xxiii) C(R37a )(SR37c )AND#8209;C(=S)AND#8209;,(xxiv) AND#8209;C(=O)AND#8209;C(R37a )(OR37c )-,(xxv) -C(=O)AND#8209;C(R37a )(SR37c )-,(xxvi) AND#8209;C(=S)AND#8209;C(R37a )(OR37c )-,(xxvii) AND#8209;C(=S)AND#8209;C(R37a )(SR37c )AND#8209;(xxviii) -C(R37a )(OR37c )AND#8209;C(R37a )(OR37c )-,(xxix) -C(37a )(SR37c )-C(R37a )(OR37c )-,(xxx) -C(R37a )(OR37c )-C(R37a )(SR37c )-,(xxxi) -C(R37a )(SR37c )-C(R37a )(SR37c )-,(xxxii) AND#8209;C(=O)AND#8209;C(=O)AND#8209;, (xxxiii)AND#8209;C(=S)AND#8209;C(=S)AND#8209;,(xxxiv) AND#8209;C(=O)AND#8209;OAND#8209;, (xxxv) AND#8209;C(=O)AND#8209;SAND#8209;,(xxxvi) AND#8209;C(=S)AND#8209;OAND#8209;, (xxxvii) AND#8209;C(=S)AND#8209;SAND#8209;,(xxxviii) AND#8209;C(=O)AND#8209;N(R37a )AND#8209;, (xxxix) AND#8209;C(=S)AND#8209;N(R37a )-,(xl) AND#8209;C(R37a )(R37b )AND#8209;C(=O)AND#8209;N(R37a )-,(xli) AND#8209;C(R37a )(R37b )AND#8209;C(=S)AND#8209;N(R37a )-,(xlii) AND#8209;C(R37a )(R37b )AND#8209;C(=O)-O-,(xliii) AND#8209;C(R37a )(R37b )AND#8209;C(=O)-S-,(xliv) AND#8209;C(R37a )(R37b )AND#8209;C(=S)-O-,(xlv) AND#8209;C(R37a )(R37b )AND#8209;C(=S)AND#8209;SAND#8209;,(xlvi ) AND#8209;C(R37a )(R37b )-N(R37b )-C(=O)-,(xlvii) C(R37a )(R37b )-N(R37b )-C(=S)-,(xlviii) AND#8209;C(R37a )(R37b )-O-C(=O)-,(xlix) AND#8209;C(R37a )(R37b )-S-C(=O)-,(l) -C(R37a )(R37b )-O-C(=S)AND#8209;,(li) -C(R37a )(R37b )-S-C(=S)AND#8209;,(lii) -C(R37a )(R37b )AND#8209;N(R37b )AND#8209;C(=O)AND#8209;N(R37a )-,(liii) C(R37a )(R37b )-N(R37a )-C(=S)AND#8209;N(R37a )-,(liv) AND#8209;C(R37a )(R37b )AND#8209;N(R37b )AND#8209;C(=O)AND#8209;OAND#8209;,(lv) AND#8209;C(R37a )(R37b )AND#8209;N(R37b )AND#8209;C(=O)AND#8209;SAND#8209;,(Ivi) AND#8209;C(R37a )(R37b )AND#8209;N(R37b )AND#8209;C(=S)AND#8209;OAND#8209;,(lvii) AND#8209;C(R37a )(R37b )N(R37b )-C(=S)-S-,(lviii) AND#8209;C(R37a )(R37b )AND#8209;OAND#8209;C(=O)AND#8209;N(R37a )-,(lix) AND#8209;C(R37a )(R37b )AND#8209;SAND#8209;C(=O)AND#8209;N(R37a )-,(lx) AND#8209;C(R37a )(R37b )-O-C(=S)AND#8209;N(R37a )-,(lxi) -C(R37a )(R37b )AND#8209;SAND#8209;C(=S)AND#8209;N(R37a )-,(lxii) AND#8209;C(R37a )(R37b )AND#8209;OAND#8209;C(=O)-O-,(lxiii) AND#8209;C(R37a )(R37b )AND#8209;SAND#8209;C(=O)-O-,(lxiv) -C(R37a )(R37b )AND#8209;OAND#8209;C(=O)-S-,(lxv) -C(R37a )(R37b )AND#8209;SAND#8209;C(=O)AND#8209;SAND#8209;,(lxvi) AND#8209;C(R37a )(R37b )AND#8209;OAND#8209;C(=S)AND#8209;OAND#8209;, (lxvii) AND#8209;C(R37a )(R37b )AND#8209;SAND#8209;C(=S)AND#8209;OAND#8209;,(lxviii) AND#8209;C(R37a )(R37b )AND#8209;OAND#8209;C(=S)AND#8209;OAND#8209;,(lxix) -C(R37a )(R37b )AND#8209;SAND#8209;C(=S)AND#8209;SAND#8209; ó(lxx) -C(R37a )(R37b )AND#8209;C(R37a )(OR37c )AND#8209;; y en dondeR14 es(i) hidrógeno, (ii) alquil C1 AND#8209;C12 , (iii) haloalquil, (iv) hidroxialquil, (v) alquil sustituido con tiol, (vi) alquil sustituidocon AND#8209;R37 CO, (vii) alquil sustituido con AND#8209;R37 CS, (viii) aminoalquil, (ix) alquil sustituido con AND#8209;(R37c )AND#8209;NH, (x) alquil sustituido con AND#8209;(R37a )(R37c )N, (xi) alquil sustituido conAND#8209;R37a OAND#8209;(O=)C, (xii) alquil sustituido con AND#8209;R37a SAND#8209;(O=)C, (xiii) alquil sustituido con AND#8209;R37a OAND#8209;(S=)C, (xiv) alquil sustituido con AND#8209;R37a SAND#8209;(S=)C, (xv) alquil sustituido con AND#8209;(R37a O)2 AND#8209;P(=O), (xvi) cianoalquil, (xvii) alquenil C2 AND#8209;C12 , (xviii) haloalquenil, (xix) alquinil C2 AND#8209;C12 ,(xx) cicloalquil, (xxi) (cicloalquil)alquil, (xxii) (cicloalquil)alquenil, (xxiii) (cicloalquil)alquinil, (xxiv) cicloalquenil,(xxv) (cicloalquenil)alquil, (xxvi) (cicloalquenil)alquenil,(xxvii) (cicloalquenil)alquinil, (xxviii) aril,(xxix) (aril)alquil, (xxx) (aril)alquenil, (xxxi) (aril)alquinil, (xxxii) heterocíclico, (xxxiii) (heterocíclico)alquil, (xxxiv) (heterocíclico)alquenil ó (xxxv) (heterocíclico)alquinil,con la condición de que R14 sea diferente a hidrógeno cuando Z sea AND#8209;C(R37a )(R37b )AND#8209;N(R37b )-C(=O)-O-,-C(R37a )R37b )-N(R37b )-C(=S)-O-,-(CR37a )(R37b )-N(R37b )-C(=O)-S-,-C(R37a )(R37b )-N(R37b )-C(=S)-S-, -C(R37a )(R37b )AND#8209;O-C(=O)-O-, -C(R37a )(R37b )-O-C(=S)-O-, -C(R37a )(R37b )AND#8209;SAND#8209;C(=O)AND#8209;O, AND#8209;C(R37a )(R37b )-S-C(=S)-O-,-C(R37a )(R37b )-O-C(=O)-SAND#8209;, AND#8209;C(R37a )(R37b )AND#8209;OAND#8209;C(=S)AND#8209;SAND#8209;,AND#8209;C(R37a )(R37b )AND#8209;SAND#8209;C(=O)AND#8209;SAND#8209;, ó AND#8209;C(R37a )(R37b )AND#8209;S-C(=S)-S-;R37a , R37b , R47 , y R48 en cada ocurrencia se seleccionan independientemente del grupo conformado por:(i) hidrógeno, (ii) alquil C1 AND#8209;C12 , (iii) haloalquil, (iv) hidroxialquil, (v) alcoxialquil, (vi) alquenil C2 AND#8209;C12 ,(vii) haloalquenil, (viii) alquinil C2 AND#8209;C12 , (ix) cicloalquil, (x) (cicloalquil)alquil, (xi) (cicloalquil)alquenil,(xii) (cicloalquil)alquinil, (xiii) cicloalquenil,(xiv) (cicloalquenil)alquil, (xv) (cicloalquenil)alquenil,(xvi) (cicloalquenil)alquinil, (xvii) aril, (xviii) (aril)alquil, (xix) (aril)alquenil, (xx) (aril)alquinil, (xxi) heterocíclico,(xxii) (heterocíclico)alquil, (xxiii) (heterocíclico)alquenil y(xxiv) (heterocíclico)alquinil;R37c en cada ocurrencia se selecciona independientemente del grupo conformado por:(i) hidrógeno, (ii) alquil C1 AND#8209;C12 , (iii) haloalquil, (iv) alquenil C2 AND#8209;C12 , (v) haloalquenil, (vi) alquinil C2 AND#8209;C12 ,(vii) cicloalquil, (viii) (cicloalquil)alquil,(ix) (cicloalquil)alquenil, (x) (cicloalquil)alquinil,(xi) cicloalquenil, (xii) (cicloalquenil)alquil,(xiii) (cicloalquenil)alquenil,(xiv) (cicloalquenil)alquinil, (xv) aril, (xvi) (aril)alquil, (xvii) (aril)alquenil,(xviii) (aril)alquinil, (xix) heterocíclico,(xx) (heterocíclico)alquil, (xxi) (heterocíclico)alquenil,(xxii) (heterocíclico)alquinil, (xxiii) AND#8209;C(=O)AND#8209;R14 ,(xxiv) AND#8209;C(=S)AND#8209;R14 , (xxv) AND#8209;S(O)2 AND#8209;R14 y (xxvi) hidroxialquil; óen caso de que Z sea AND#8209;C(R37a )(R37b )AND#8209;N(R37c ), entonces N(R37c ) y R14 tomados en conjunto forman un grupo azido;óen caso de que Z sea AND#8209;(R37a )(R37b )AND#8209;N(O)(R37c )AND#8209;, entonces N(O)(R37c ) y R14 tomados en conjunto forman un anillo heterocíclico NAND#8209;oxidado de 3 AND#8209; 7 miembros que tiene por lo menos un átomo de nitrógeno en el anillo NAND#8209;oxidadoóen caso de que Z sea AND#8209;C(R37a )(OR37c ), AND#8209;C(R37a )(SR37c ) ó C(R37a )(N(R37b )(R37c ))AND#8209;, entonces R37a , R14 y el átomo de carbono alcual van ligados, tomados en conjunto forman un anillo ciclopentil, ciclopentenil, ciclohexil ó ciclohexenil;R15 se selecciona del grupo conformado por:(i) hidrógeno, (ii) hidroxi, (iii) amino, (iv) alquil C1 AND#8209;C12 , (v) haloalquil, (vi) alquenil C