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ES2602902T3 - Derivados aminopropiónicos sustituidos como inhibidores de neprilisina - Google Patents

Derivados aminopropiónicos sustituidos como inhibidores de neprilisina Download PDF

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Publication number
ES2602902T3
ES2602902T3 ES13151795.5T ES13151795T ES2602902T3 ES 2602902 T3 ES2602902 T3 ES 2602902T3 ES 13151795 T ES13151795 T ES 13151795T ES 2602902 T3 ES2602902 T3 ES 2602902T3
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Spain
Prior art keywords
7alkyl
condition
intermediary
acid
room temperature
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ES13151795.5T
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Inventor
Gary Mark Coppola
Yuki Iwaki
Rajeshri Ganesh Karki
Toshio Kawanami
Gary Michael Ksander
Muneto Mogi
Robert Sun
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Novartis AG
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Novartis AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D317/34—Oxygen atoms
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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Abstract

Un compuesto de Fórmula I':**Fórmula** o una sal farmacéuticamente aceptable del mismo, en donde: R1 es H, C1-7alquilo, hidroxi, C1-7alcoxi, halógeno,-SH,-S-C1-7alquilo o NRaRb; R2 para cada ocurrencia, es independientemente C1-7alquilo, halo, NO2, CN, C1-7alcanoilamino, C3-7cicloalquilo, hidroxi, C1-7alcoxi, haloC1-7alquilo,-NRaRb, C6-10arilo, heteroarilo o heterociclilo; en donde Ra y Rb para cada ocurrencia son independientemente H o C1-7alquilo; R3 es A1-C(O)X1; R5 10 es H, halo, hidroxi, C1-7alcoxi, halo, C1-7alquilo o halo-C1-7alquilo; y X y X1 son independientemente OH,-O-C1-7alquilo,-NRaRb,-NHS(O)2-C1-7alquilo,-NHS(O)2-bencilo o-O-C6-10arilo; en donde alquilo está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente del grupo que consiste de C6-10arilo, heteroarilo, heterociclilo, C(O)NH2, C(O)NH- C1-6alquilo, y C(O)N(C1-6alquilo)2; B1 es-C(O)NH- o-NHC(O)-; A1 es un C1-7alquileno lineal o ramificado; el cual está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente del grupo que consiste de halo, C3-7cicloalquilo, C1-7alcoxi, hidroxi, O-Acetato; en donde dos alquilo germinales pueden opcionalmente combinarse para formar un C3-7cicloalquilo; o A1 es un C1-7alquenileno lineal o ramifiado; o A1 es un C1-4alquileno lineal en donde uno o más átomos de carbono están reemplazados por un heteroátomo seleccionado de O, NRc; y A1 está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente del grupo que consistente de halo y C1-7alquilo; en donde Rc para cada aparición, es independientemente H, C1-7alquilo,-C(O)-O-C1-7alquilo, o-CH2C(O)OH; y n es 0, 1, 2, 3, 4 o 5; en donde cada heteroarilo es un anillo aromático monocíclico o bicíclico que comprende de 5-10 átomos de anillo seleccionados de átomos de carbono y 1 a 5 heteroátomos, y cada heterociclilo es una unidad estructural monocíclica saturada o parcialmente saturada, pero no aromática que comprende 4-7 átomos de anillo seleccionados de átomos de carbono y 1-5 heteroátomos, en donde cada heteroátomo de un heteroarilo o un heterociclilo es seleccionado independientemente de O, N y S.

Description

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forma de un derivado, por ejemplo, en una forma protegida o en la forma de una sal, o un compuesto obtenible por el proceso de acuerdo con la invención se produce bajo las condiciones de proceso y se procesa adicionalmente in situ.
Todos los materiales de partida, bloques de la construcción, reactivos, ácidos, bases, agentes deshidratantes,
5 solventes y catalizadores utilizados para sintetizar los compuestos de la presente invención están, bien sea, disponibles comercialmente o pueden ser producidos por métodos de síntesis orgánica conocidos para una persona de experiencia normal en la técnica (Houben-Weil 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volumen 21).
Los compuestos de la invención de acuerdo con cualquiera de las Fórmulas I’ y I a IIIC se pueden preparar por el 10 procedimiento descrito en las siguientes secciones.
Abreviaturas:
ATP: 5’-trifosfato de adenosina
AS: Aldosterona Sintasa
Alloc: aliloxicarbonilo
BOC: carboxi butilo terciario
BOP: hexafluorofosfato de benzotriazol1iloxi)tris(dimetilamino) fosfonio
BINAP: 2,2’-bis(difenil fosfino)-1,1’-binaftil racémico
br: ancho
bs: singlete ancho
Ac: Acetilo
Atm: atmósfera
Aq: acuoso
calcd: calculado
Bn: bencilo
Cbz: benciloxicarbonilo
Bu, i-bu y t-Bu: butilo, isobutilo y t-butilo
Pr e i-Pr: propilo e isopropilo
CDI: 1, 1’-carbonildiimidazol
COD: 1,5-ciclooctadieno
DBU: 1,8-diazabiciclo[5.4.0]undec-7-eno
DCC: 1,3-diciclohexilcarbodiimida
DIAD: azodicarboxilato de diisopropilo
DAST: trifluoruro de (dietilamino)azufre
d: doblete dd: doblete de dobletes
DCM: diclorometano
DIEA: dietilisopropilamina
DME: 1,4-dimetoxietano
DMF: N,N-dimetilformamida
DMSO: dimetilsulfóxido
DIPEA: N,N-diisopropiletilamina
DMAP: N,N-dimetilaminopiridina
Dppb: 1,2-bis(difenilfosfino)butano
Dppe: 1,2-bis(difenilfosfino) etano
DAD: detector de conjunto de diodos
DTT: ditiotreitol
DPPA: difenilfosforilazida
EDCI, EDIC: Clorhidrato de N-Etil-N’-(3dimetilaminopropil)carbodiimida
EDTA: ácido de etilendiamino tetraacético
ESI: ionización por electroaspersión
Et y EtOAc: etilo y acetato de etilo
EDC: Clorhidrato de N-Etil-N’-(3dimetilaminopropil)carbodiimida
HATU: O-(7-azobenzotriazol-1-il)-1,1,3,3tetrametiluroniohexafluorofosfato
HOBt: 1-hidroxi-7-azabenzotriazol
HPLC: cromatografía líquida de alta presión
LC y LCMS: cromatografía líquida y cromatografía líquida y espectrometría de masas
H: Hora(s)
HOAt: 1-hidroxi-7-azabezotriazole
IR: infrarrojo
LDA: diisopropilamida de litio
KHMDS: bis(trimetilsilil)amida de potasio
LHMDS: bis(trimetilsilil)amida de litio
18
(continuación)
LTA: tetraacetato de plomo
NHMDS: bis(trimetilsilil)amida de sodio
MeOD: metanol-d4
MeOH: metanol
MS: espectrometría de masas
m: multiplete
min: minutos
m/z: relación de masa a carga
Ms: mesilo
Me: metilo
M y mM: Molar y milimolar
Mg: miligramo
n.d.: no determinado
RMN: resonancia magnética nuclear
ppm: partes por millón
Pr e iPr: propilo e isopropilo
Ph: Fenilo
Pd/C: Paladio sobre carbono
PyBOP:benzotriazol-1-iloxi Tripirrolidinofosfoniohexafluorofosfato
RT: temperatura ambiente
PIDA: bis(trifluoroacetato) de yodobenceno
PIFA: diacetato de yodobenceno
PS: soportado por polímero
RP: fase reversa
s: singlete y t: triplete
Ts: tosilo
TFA: ácido trifluoroacético
THF: tetrahidrofurano
Tf: triflato
tBu: terc-butilo
TLC: cromatografía de capa fina
Tris·HCl: clorhidrato de aminotris(hidroximetil) metano
mL, mL y L: microlitro, mililitro y litro
TMS: Trimetilsililo
WSC: carbodiimida soluble en agua (N-Etil-N’-(3dimetilaminopropil)carbodiimida)
UV: ultravioleta
Los compuestos de la invención de la fórmula II se pueden preparar por hidrólisis de los intermedios A a C en donde X, X1, A1, R1, R2 y n tienen la definición de la Fórmula I o I', supra; y P1 y P2 son grupos protectores apropiado seleccionado de, pero no limitado a, metilo, etilo, isopropilo, terc-butilo, metoxibencilo o bencilo.
imagen17
Intermediario A Intermediario B
19
imagen18
imagen19
imagen20
imagen21
imagen22
imagen23
imagen24
imagen25
imagen26
imagen27
imagen28
imagen29
imagen30
imagen31
imagen32
imagen33
imagen34
imagen35
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-3
Ácido (R)-5-(1-(3’-clorobifenil-4-il)-4-etoxi-4-oxobutan-2-ilamino)-5oxopentanoico imagen36 DIPEA, DCM, Temperatura ambiente 1.57 min. (A) 432.1
Ejemplo 1-4
Ácido (R)-5-(4-etoxi-1-(5’-fluoro-2’-metoxibifenil-4-il)-4-oxobutan-2ilamino)-5-oxopentanoico imagen37 DIPEA, DCM, Temperatura ambiente 0,93 min. (B) 446.3
Ejemplo 1-5
Ácido (R)-5-(1-(5’-cloro-2’-metoxibifenil-4-il)-4-etoxi-4-oxobutan-2-ilamino)5-oxopentanoico imagen38 DIPEA, DCM, Temperatura ambiente 1.14 min. (B) 462.5
(continuación) (continuación)
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-6
Ácido (R)-4-(1-(2’-cloro-5’-fluorobifenil-4-il)-4-etoxi-4-oxobutan-2-ilamino)4-oxobutanoico imagen39 DIPEA, DCM, Temperatura ambiente 0,97 min. (B) 436.2
Ejemplo 1-7
Ácido (R)-4-(4-etoxi-1-(3’-fluorobifenil-4-il)-4-oxobutan-2-ilamino)-4oxobutanoico imagen40 DIPEA, DCM, Temperatura ambiente 1.23 min. (B) 402.0
Ejemplo 1-8
Ácido (R)-4-(4-(benciloxi)-1-(3’-clorobifenil-4-il)-4-oxobutan-2-ilamino)-4oxobutanoico imagen41 DIPEA, DCM, Temperatura ambiente 1.37 min. (B) 480,2
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-9
imagen42 imagen43 Piridina, Temperatura ambiente 1.32 min. (C) 490,2
Ejemplo 1-10
imagen44 imagen45 DIPEA, DCM, Temperatura ambiente 1.52 min. (B) 506.4
=
=
=
imagen46
imagen47
= =
imagen48
imagen49
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-18
Metil éster del ácido (2S,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4il)-2-hidroxi-butírico Metil éster del ácido (2R,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4il)-2-hidroxi-butírico Intermediario 50 Et3N, DCM 1.29 min. (A) 420,0
(continuación) (continuación) (continuación) (continuación)
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-19
Metil éster del ácido (2S,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4il)-2-metoxi-butírico Metil éster del ácido (2R,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4il)-2-metoxi-butírico Intermediario 51 DIPEA, DCM 1.21 min. (A) 434.2
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-20
Etil éster del ácido (2S,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4-il)2-metoxi-butírico Intermediario 52 DIPEA, DCM 1.57 min. (A) 448.3
Etil éster del ácido (2R,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4-il)2-metoxi-butírico
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-21
Metil éster del ácido (2S,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4il)-2-fluoro-butírico Metil éster del ácido (2R,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4il)-2-fluoro-butírico Intermediario 53 Et3N, DCM 0,83 min. (B) 422.1
Ejemplo 1-22
Etil éster del ácido (R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4-il)-2metil-butírico Nuevo intermediario 54 Et3N, DCM 0,98 min. (B) 432
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-23
Etil éster del ácido (R)-3-(2-Carboximetoxi-acetilamino)-4-(3’-cloro-bifenil-4-il)butírico imagen50 Et3N, DCM 0,75 min. (B) 434
==
imagen51
imagen52
imagen53
imagen54
= =
imagen55
= =
imagen56
imagen57
Ejemplo #
Producto Material de partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 3-2
6-(1-(3’-clorobifenil-4-il)-4-etoxi-4-oxobutan2-ilamino)-6-oxohexanoato de (R)-metilo imagen58 EDCI, HOAt, DIPEA, DMF, temperatura ambiente 1,40 min (B) 460,5
Ejemplo 3-3
4-(3’-clorobifenil-4-il)-3-(4-etoxi-4oxobutanamido) butanoato de (R)-bencilo imagen59 EDCI, HOAt, DIPEA, DMF, temperatura ambiente 1,56 min (B) 508,3
Ejemplo 3-4
5-(4-(benciloxi)-1-(3’-clorobifenil-4-il)-4oxobutan-2-ilamino)-5-oxopentanoato de (R)etilo imagen60 EDCI, HOAt, DIPEA, DMF, temperatura ambiente 1,57 min (B) 522,4
(continuación)
Ejemplo #
Producto Material de partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 3-5
4-(1-(3’-cloro-3-fluorobifenil-4-il)-4-etoxi-4oxobutan-2-ilamino)-4-oxobutanoato de tercbutilo imagen61 EDCI, HOAt, DMF, temperatura ambiente 1,46 min (B) 492,5
imagen62
==
imagen63
imagen64
=
=
imagen65
== =
imagen66
==
=
imagen67
Ejemplo #
Producto Material de partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 4-4
Ácido (R)-2-(tert-butoxicarbonil(2-(1-(3’-cloro bifenil-4-il)-4-etoxi-4-oxobutan-2-ilamino)-2oxoetil)amino)acético imagen68 EDCI, HOAt, DIPEA, DMF, temperatura ambiente 1,53 min (A) 533.2
Ejemplo 4-5
Ácido 4-(3’-clorobifenil-4-il)-3-(4-etoxi-4oxobutanamido) butanoato de (R)-butanoico imagen69 EDCI, HOAt, DIPEA, DMF, temperatura ambiente 1,00 min (B) 416,1
imagen70
(continuación)
imagen71
imagen72
(continuación)
Ejemplo
Producto Material de partida Condición HPLC-RT MS
de hidrólisis
(condición) (M+1)
NaOH
Ejemplo 5-16
acuoso, THF, MeOH, temperatura ambiente 1.44 min. (H) 386.2
Ácido (R)-4-(1-carboxi-3-(3’metoxibifenil-4-il)propan-2ilamino)-4-oxobutanoico
Ejemplo 2-14
NaOH
Ejemplo 5-17
acuoso, THF, MeOH, temperatura ambiente 0.49 min. (B) 381.1
Ácido (R)-4-(1-carboxi-3-(3’cianobifenil-4-il)propan-2-ilamino)4-oxobutanoico
Ejemplo 2-15
NaOH
Ejemplo 5-18
acuoso, THF, MeOH, temperatura ambiente 1.02 min. (B) 408.1
Ácido (R)-4-(1-carboxi-3-(3’-cloro5’-fluorobifenil-4-il)propan-2ilamino)-4-oxobutanoico
Ejemplo 2-16
NaOH
Ejemplo 5-19
acuoso, THF, MeOH, temperatura ambiente 0.53 min. (B) 424.0
Ácido (R)-4-(1-carboxi-3-(2’(trifluorometil)bifenil-4-il)propan-2ilamino)-4-oxobutanoico
Ejemplo 2-17
NaOH
Ejemplo 5-20
Ácido (R)-4-(1-carboxi-3-(2’cianobifenil-4-il)propan-2-ilamino)4-oxobutanoico Ejemplo 2-18 acuoso, THF, MeOH, temperatura ambiente 1.11 min. (A) 381.1
imagen73
imagen74
=
=
=
=
imagen75
imagen76
Condición de hidrólisis
LCMS-RT (condición) MS (M+1)
NaOH acuoso, MeOH, temperatura ambiente
1.52 min. (D) 420.1
NaOH acuoso, MeOH, temperatura ambiente
1.42 min. (D) 390.2
NaOH acuoso, MeOH, temperatura ambiente
1.53 min. (D) 420.2
NaOH acuoso, MeOH, temperatura ambiente
1.26 min. (A) 389.3
imagen77
(continuación) (continuación)
Ejemplo #
Producto Material de partida Condición de hidrólisis LCMS-RT (condición) MS (M+1)
Ejemplo 5-29
ÁcidoR-4-(1-carboxi-3-(3’-trifluorometoxi)bifenil-4-il)propan-2ilamino)-4-oxobutanoico imagen78 NaOH acuoso, MeOH, temperatura ambiente 1.57 min. (D) 440.1
Ejemplo 5-30
ÁcidoR-4-(1-carboxi-3-(2’-trifluorometoxi)bifenil-4-il)propan-2ilamino)-4-oxobutanoico imagen79 NaOH acuoso, MeOH, temperatura ambiente 1.41 min. (D) 440.0
Ejemplo 5-31
ÁcidoR-4-(1-carboxi-3-(2’-hidroxibifenil-4-il)propan-2ilamino)-4-oxobutanoico imagen80 NaOH acuoso, MeOH, temperatura ambiente 1.16 min (D) 373.2
Ejemplo 5-32
ÁcidoR-4-(1-carboxi-3-(2’,3’-difluoro-6’-metoxibifenil-4il)propan-4-ilamino)-4-oxobutanoico imagen81 NaOH acuoso, MeOH, temperatura ambiente 1.34 min. (D) 422.2
Ejemplo #
Producto Material de partida Condición de hidrólisis LCMS-RT (condición) MS (M+1)
Ejemplo 5-33
ÁcidoR-4-(1-carboxi-3-(3-fluoro-metoxibifenil-4-il)propan-2ilamino)-4-oxobutanoico imagen82 NaOH acuoso, MeOH, temperatura ambiente 1.29 min (D) 404.1
Ejemplo 5-34
ÁcidoR-4-(1-carboxi-3-(4-piridina-2’-il)fenil)propan-2-ilamino)4-oxobutanoico imagen83 NaOH acuoso, MeOH, temperatura ambiente 1.43 min. (D) 356.2
Ejemplo 5-35
ÁcidoR-4-(1-carboxi-3-(3’,5’-difluoro-2’-metoxibifenil-4il)propan-2-ilamino)-4-oxobutanoico imagen84 NaOH acuoso, MeOH, temperatura ambiente 1.42 min (D) 422.0
-
imagen85
=
imagen86
7.62 (m, 2H), 7.71 (m, 1 H), 12.07 (s, 1 H). Ejemplo 9-1: Síntesis del ácido (R)-4-(1-carboxi-3-(3'-clorobifenil-4-il)propan-2-ilamino)-4-oxobutanoico
imagen87
A una solución del ácido (R)-4-(1-(bifenil-4-il)-4-etoxi-4-oxobutan-2-ilamino)-4-oxobutanoico (110 mg, 0,263 Mmol) en THF (2 ml) y metanol (0,2 ml), se le añade solución acuosa 1 M de NaOH (1,053 ml, 1,053 mmol) a temperatura ambiente. Después de agitar durante 1 hora, la reacción se detiene con HCl acuoso 0,1 M, y la solución se diluye 10 con DCM (15 ml) y se deja agitar durante 1,5 horas. El sólido precipitado se recoge en un embudo, se lava con agua, DCM, heptano y luego DCM en ese orden, y se seca a presión reducida para producir el ácido (R)-4-(1carboxi-3-(3'-clorobifenil-4-Il)propan-2-ilamino)-4-oxobutanoico (66 mg). Tiempo de retención de HPLC = 0,87 minutos (condición B); MS (m + 1) = 390,0; 1H NMR (400 MHz, CD3OD) δ ppm 2.39 -2.55 (m, 6 H) 2.86 (A de ABX, Jab = 13.6 Hz, Jax = 7.6 Hz, 1 H) 2.92 (B de ABX, Jab = 13.6 Hz, Jbx = 6.2 Hz, 1 H) 4.42 -4.49 (m, 1 H) 7.30 -7.34 (m, 3
15 H) 7.40 (t, J = 7.4Hz, 1 H) 7.51 -7.56 (m, 3 H) 7.60 (t, J = 1.8 Hz, 1 H).
Los siguientes compuestos se preparan usando un procedimiento similar al descrito en el ejemplo 9-1:
Ejemplo
Producto Material de partida Condición de HPLC-RT MS
#
hidrólisis (condición) (M+1)
Ejemplo 9-2
NaOH acuoso, THF, MeOH, 0,79 min (B) 404.1
temperatura ambiente
Ácido (R)-5-(1-carboxi-3-(3’-clorobifenil -4-il)propan-2-ilamino)-5-oxopentanoico
Ejemplo 9-3
imagen88 imagen89 NaOH acuoso, THF, MeOH, temperatura ambiente 0,65 min (B) 418.2
Ácido (R)-5-(1-carboxi-3-(5’-fluoro-2’metoxibifenil-4-il)propan-2-ilamino)-5oxopentanoico
Ejemplo 9-4
imagen90 imagen91 NaOH acuoso, THF, MeOH, temperatura ambiente 0,63 min (B) 434.3
Ácido (R)-5-(1-carboxi-3-(5’-cloro-2’metoxibifenil-4-il)propan-2-ilamino)-5oxopentanoico
imagen92
imagen93
(continuación)
Ejemplo
Producto Material de partida Condición de HPLC-RT MS
#
hidrólisis (condición) (M+1)
Ejemplo 9-15
imagen94 imagen95 NaOH acuoso, MeOH, temperatura ambiente 0,96 min (A) 420.1
(producto principal) Ácido (R)-3-(3Carboxipropionilamino)-4-(3’clorobifenil-4-il)-2-metoxi-butírico
imagen96
Ejemplo 9-16
imagen97 NaOH acuoso, MeOH, temperatura ambiente 1,07 min (A) 408.1
Ácido (R)-3-(3-Carboxipropionilamino)4-(3’-clorobifenil-4-il)-2-fluoro-butírico
imagen98
Ejemplo 9-17
imagen99 imagen100 NaOH acuoso, MeOH, temperatura ambiente 0,53 min (B) 404
Ácido (R)-3-(3-Carboxipropionilamino)4-(3’-clorobifenil-4-il)-2-metil-butírico
Ejemplo 9-18
imagen101 imagen102 NaOH acuoso, MeOH, temperatura ambiente 0,37 min (B) 406
Ácido (R)-3-(2-carboximetoxiacetilamino)-4-(3’-clorobifenil-4-il)-butírico
Ejemplo 9-2: 1H RMN (400 MHz, CD3OD) δ ppm 1.76 -1.83 (m, 2 H) 2.15 -2.21 (m, 4 H) 2.49 (A de ABX, Jab = 15.7 Hz, Jax = 7.3 Hz, 1 H) 2.53 (B de ABX, Jab = 15.7 Hz, Jbx = 6.1 Hz, 1 H) 2.83 (A de ABX, Jab = 13.6 Hz, Jax = 8.3 Hz, 1 H) 2.93 (B de ABX, Jab = 13.6 Hz, Jbx = 5.8 Hz, 1 H) 4.46 -4.53 (m, 1 H) 7.30 -7.33 (m, 3 H) 7.39 (t" J = 7.8 Hz, 1 H)
7.51 -7.55 (m, 3 H) 7.59 -7.60 (m, 1 H). Ejemplo 9-3: 1H RMN (400 MHz, CD3OD) δ ppm 1.77 -1.84 (m, 2 H) 2.16 -2.23 (m ,4 H) 2.39 -2.42 (m, 2 H) 2.49
81
imagen103
imagen104
imagen105
Ejemplo #
Producto Material de partida HPLC-RT (condición) MS (M+1)
Ejemplo 12-2
Ácido N-[(R)-1-(3’-cloro-bifenil-4-ilmetil)-3-oxo-3(propano-1-sulfonilamino)-propil]-succinámico imagen106 1,26 min (condición A) 495
Ejemplo 12-3
Ácido N-[(R)-1-(3’-cloro-bifenil-4-ilmetil)-3-oxo-3fenilmetanosulfonil aminopropil]-succinámico imagen107 1,34 min (condición A) 543
Ejemplo 12-4
Ácido N-[(R)-2-carbamoil-1-(3’-cloro-bifenil-4ilmetil)-etil]-succinámico imagen108 1,33 min (condición A) 389
imagen109
imagen110
(continuación)
Intermediario #
Producto Condición HPLC-RT (condición) MS (ES+; 100%)
Intermediario 2-3
3-(tert-butoxicarbonilamino)-4-(5’cloro-2’-metoxibifenil-4-il)butanoato de (R)-etilo Complejo de PdCl2(dppf).CH2Cl2, ácido 5cloro-2-metoxifenilborónico, Na2CO3 2M acuoso, tolueno, 95°C 1.58 min. (B) 348.1 (m-BOC+2)
Intermediario 2-4
3-(tert-butoxicarbonilamino)-4-(5’fluoro-2’-metoxibifenil-4-il)butanoato de (R)-etilo Complejo de PdCl2(dppf).CH2Cl2, ácido 5fluoro-2-metoxifenilborónico, Na2CO3 2M acuoso, tolueno, 95°C 1.42 min. (B) 332.2 (m-BOC+2)
Intermediario 2-5
3-(tert-butoxicarbonilamino)-4-(2’cloro-5’-fluorobifenil-4-il)butanoato (R)-etilo Pd(PPh3)4, ácido 2-cloro-5fluorofenilborónico, Na2CO3 2M acuoso, tolueno, 95 °C 1.49 min. (B) 336.1 (m-BOC+2)
Intermediario 2-6
3-(tert-butoxicarbonilamino)-4-(5’cloro-2’-fluorobifenil-4-il)butanoato de (R)-etilo Pd(PPh3)4, ácido 5-cloro-2fluorofenilborónico, Na2CO3 2M acuoso, DME, 95 °C 1.47 min. (B) 336.1 (m-BOC+2)
88
imagen111
CLOROFORMO-d) δ ppm 1.41 (s, 9 H) 1.47 (s, 9 H) 2.36 (A de ABX, Jab = 15.6 Hz, Jax = 6.2 Hz, 1 H) 2.44 (B de ABX, Jab = 15.5 Hz, Jbx = 5.45 Hz) 2.82-2.97 (m, 2 H) 4.15 (br s) 5.09 (br d) 7.6-7.35 (m, 3H) 7.41-7.45 (m, 2 H) 7.51-7.56 (m, 4 H).
Intermediario 5: 4-(4-bromofenil)-3-(tert-butoxicarbonilamino)butanoato de (R)-etilo
imagen112
5
A una suspensión de ácido (R)-4-(4-bromofenil)-3-(tert-butoxicarbonilamino)butanoico (9.98 g, 27.9 mmol) y NaHCO3
(4.68 g, 55.7 mmol) en DMF (45 mL) se agrega yoduro de etilo (6.75 mL, 84 mmol) a temperatura ambiente bajo nitrógeno. Después de agitar durante 71 horas, la mezcla de reacción es detenida con H2O (300 mL), y luego el sólido precipitado se recolecta y se lava con H2O (500 mL) para producir 4-(4-bromofenil)-3-(tert
10 butoxicarbonilamino)butanoato de (R)-etilo (10,25 g, 94%). Tiempo de retención de HPLC = 1.48 minutos (condición B); MS (ES+) = 329.9 (m-tBu+2); 286.0 (m-Boc+2; 100%); 1 H RMN (400 MHz, CLOROFORMO-d) δ ppm 1.27 (t, J =
7.2 Hz, 3 H) 1.40 (s, 9 H), 2.43 (A de ABX, Jab = 15.8 Hz, Jax = 5.7 Hz, 1 H) 2.50 (B de ABX, Jab = 15.8 Hz, Jbx = 5.4 Hz, 1 H) 2.74-2.90 (m, 2 H) 4.11 (br s) 4.15 (q, J = 7.1 Hz, 2 H) 5.04 (br d) 7.07 (d, J = 8.3 Hz, 2 H) 7.40-7.43 (m, 2 H).
15 Los siguientes intermediarios se preparan usando el procedimiento similar al descrito en el intermediario 5:
Intermediario #
Producto Condición HPLC-RT (condición) MS (ES+; 100%)
Intermediario 5-2
4-(4-bromofenil)-3-(tertbutoxicarbonilamino)butanoato de (R)-bencilo BnBr, NaHCO3, DMF, Temperatura ambiente 1.56 min. (B) 348 (m-BOC+2)
Intermediario 5-3
Propil éster del ácido (R)-4-(4-Bromo-fenil)-3tert-Butoxicarbonilamino-butírico yoduro de npropilo, NaHCO3, DMF, Temperatura ambiente 1.47 min. (B) 400 (m+1)
Intermediario 5-4
Butil éster del ácido (R)-4-(4-Bromo-fenil)-3-tertButoxicarbonilamino-butírico Yoduro de nbutilo, NaHCO3, DMF, Temperatura ambiente 1.55 min. (B) 414 (m+1)
90
(continuación)
Intermediario #
Producto Condición HPLC-RT (condición) MS (ES+; 100%)
Intermediario 5-5
5-metil-2-oxo-[1,3]dioxol-4-ilmetil éster del ácido (R)-4-(4-Bromo-fenil)-3-tert-butoxicarbonilaminobutírico K2CO3, DMF, Temperatura ambiente 1.28 min. (B) 470 (m+1)
Intermediario 5-6
Dimetilcarbamoil metil éster del ácido (R)-4-(4Bromo-fenil)-3-tert-butoxicarbonilamino-butírico K2CO3, DMF, Temperatura ambiente 1.65 min. (B) 444 (m+1)
Intermediario 5-7
2-morfolin-4-il-etil éster del ácido (R)-4-(4Bromo-fenil)-3-tert-butoxicarbonilamino-butírico K2CO3, DMF, Temperatura ambiente 1.19 min. (B) 471 (m+1)
Intermediario 5-2: 4-(4-bromofenil)-3-(tert-butoxicarbonilamino)butanoato de (R)-bencilo
imagen113
5 A una suspensión de ácido (R)-4-(4-bromofenil)-3-(tert-butoxicarbonilamino)butanoico (5.02 g, 14.01 mmol) y NaHCO3 (3.53 g, 42.0 mmol) en DMF (20 mL) se agrega Bromuro de bencilo (5.10 mL, 42 mmol) a temperatura ambiente bajo nitrógeno. Después de agitar durante 46 horas, la reacción se diluye con H2O (200 mL), y luego el sólido precipitado se recolecta y se lava con H2O (500 mL) y luego con heptano (200 ml) para producir 4-(4bromofenil)-3-(tert-butoxicarbonilamino)butanoato de (R)-bencilo (5.61 g, 89%). Tiempo de retención de HPLC = 1.56
10 minutos (condición B); MS (ES+) = 392.1 (m-tBu+2); 348.1 (m-Boc+2; 100%); 1 H RMN (400 MHz, CLOROFORMOd) δ ppm 1.39 (s, 9 H) 2.48 (A de ABX, Jab = 15.9 Hz, Jax = 5.6 Hz, 1 H) 2.54 (B de ABX, Jab = 15.9 Hz, Jbx = 5.3 Hz, 1 H) 2.72-2.88 (m, 2 H) 4.11 (br s, 1 H) 5.02 (br s, 1 H) 5.10 (A de AB, J = 12.1 Hz, 1 H) 5.16 (A de AB, J = 12.1 Hz, 1 H) 7.00 (d, J = 8.1 Hz, 2 H) 7.34-7.39 (m, 7 H).
Intermediario 6: Ácido (R)-3-(bifenil-4-ilmetil)-4-(3-metoxi-3-oxopropilamino)-4-oxobutanoico
91
imagen114
imagen115
imagen116
imagen117
imagen118
imagen119
Intermediario #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Intermediario 16-2
Clorhidrato de 3-amino-4-(bifenil-4-il)butanoato de (R)-etilo Intermediario 2 HCl 4M/1,4-dioxano 0,89 min. (B) 284.1
Intermediario 16-3
Clorhidrato de 3-amino-4-(3’-fluorobifenil-4-il)butanoato de (R)-etilo Intermediario 2-2 HCl 4M/1,4-dioxano 0,94 min. (B) 302.1
Intermediario 16-4
Clorhidrato de 3-amino-4-(5’-cloro-2’-metoxibifenil-4-il)butanoato de (R)-etilo Intermediario 2-3 HCl 4M/1,4-dioxano 0,94 min. (B) 348.2
Intermediario 16-5
Clorhidrato de 3-amino-4-(5’-fluoro-2’-metoxibifenil-4-il)butanoato de (R)-etilo Intermediario 2-4 HCl 4M/1,4-dioxano 1.38 min. (A) 332.2
(continuación)
Intermediario #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Intermediario 16-6
Clorhidrato de 3-amino-4-(2’-cloro-5’-fluorobifenil-4-il)butanoato de (R)-etilo Intermediario 2-5 HCl 4M/1,4-dioxano 0,93 min. (B) 336.1
Intermediario 16-7
3-amino-4-(3’-clorobifenil-4-il)butanoato de (R)-bencilo Intermediario 17-2 HCl 4M/1,4-dioxano 1.20 min. (B) 380,2
Intermediario 16-8
3-amino-4-(5’-cloro-2’-fluorobifenil-4-il)butanoato de (R)-etilo Intermediario 2-6 HCl 4M/1,4-dioxano 0,88 min. (B) 336.1
imagen120
Intermediario #
Producto Condición HPLC-RT (condición) MS (ES+; 100%)
Intermediario 17-2
3-(tert-butoxicarbonilamino)-4-(3’clorobifenil-4-il)butanoato de (R)bencilo Pd(PPh3)4, ácido 3clorofenilborónico, Na2CO3 2M acuoso, tolueno, 95 °C 1.74 min. (B) 380,2 (m-BOC+2)
Intermediario 17-3
Propil éster del ácido (R)-3-tertButoxicarbonilamino-4-(3’clorobifenil-4-il)-butírico Pd(PPh3)4, ácido 3clorofenilborónico, Na2CO3 2M acuoso, tolueno, 95 °C 1.66 min. (B) 432 (m+1)
Intermediario 17-4
Butil éster del ácido (R)-3-tertButoxicarbonilamino-4-(3’-clorobifenil-4-il)-butírico Pd(PPh3)4, ácido 3clorofenilborónico, Na2CO3 2M acuoso, tolueno, 95 °C 1.73 min. (B) 446 (m+1)
Intermediario 17-5
5-metil-2-oxo-[1,3]dioxol-4-ilmetil éster del ácido (R)-3-tertButoxicarbonilamino-4-(3’clorobifenil-4-il)-butírico Pd(OAc)2, diciclohexil-(2’,6’dimetoxi-bifenil-2-il)-fosfano, ácido 3-clorofenilborónico, K3PO4, tolueno, 95 °C 1.53 min. (B) 502 (m+1)
Intermediario 17-6
dimetilcarbamoil metil éster del ácido (R)-3-tertButoxicarbonilamino-4-(3’clorobifenil-4-il)-butírico Pd(PPh3)4, ácido 3clorofenilborónico, K3PO4, DMF, 95 °C 1.51 min. (B) 475 (m+1)
101
imagen121
imagen122
imagen123
imagen124
imagen125
imagen126
imagen127
imagen128
imagen129
imagen130
imagen131
imagen132
imagen133
mezcla de reacción se acidifica con HCl 1 M y se extrae con EtOAc. La capa orgánica se lava con salmuera, se seca sobre Na2SO4 y se concentra in vacuo. A una solución de este residuo en DMF (2 mL) se agregan metilsulfonamida (85 mg, 0,897 mmol), EDC (172 mg, 0,897 mmol), HOAt (98 mg, 0,718 mmol), y Et3N (0,125 mL, 0,897 mmol). Después de ser agitada a temperatura ambiente durante la noche, la mezcla de reacción se diluye con EtOAc, se 5 lava con HCl 1 M y salmuera. La capa orgánica se seca sobre Na2SO4 y se concentra. El residuo se purifica por cromatografía de columna instantánea (sílica gel, eluyente: DCM/MeOH al 10% en DCM = 100:0 a 0:100) para producir tert-butil éster del ácido [(R)-1-(3’-cloro-bifenil-4-ilmetil)-3-metanosulfonilamino-3-oxo-propil]-carbámico (244 mg). Tiempo de retención de HPLC = 1.30 minutos (condición B); MS (m+1) = 467; 1 H RMN (400 Mz, DMSO-d6) δ ppm 1.30 (s, 9 H), 2.41-2.48 (m, 2 H), 2.70-2.78 (m, 2 H), 3.18 (s, 3 H), 3.99-4.11 (m, 1 H), 7.28 (d, 2 H, J = 8.34 Hz),
10 7.38-7.44 (m, 1 H), 7.48 (t, 1 H, J =7.83 Hz), 7.59-7.66 (m, 3 H), 7.69 (s, 1 H).
Los siguientes compuestos se preparan usando un procedimiento similar al descrito en el ejemplo 53-1:
Ejemplo
Producto Reactivo HPLC-RT (condición) MS (M+1)
Ejemplo 53-2
imagen134 imagen135 1.22 min. (condición B) 496
Ejemplo 53-3
imagen136 imagen137 1.33 min. (condición B) 544
Ejemplo 53-4
imagen138 NH4Cl 1.17 min. (condición B) 389
Intermediario 54-1: etil éster del ácido (R)-3-[2-(tert-butoxicarbonil-etoxicarbonilmetil-amino)-propionilamino]-4-(3’clorobifenil-4-il)-butírico
imagen139
A una suspensión de sal de TFA del ácido 2-(tert-butoxicarbonil-etoxicarbonilmetil-amino)-propiónico (197 mg, 0,714 mmol) en THF (10 ml) a temperatura, ambiente se agrega EDCI (219 mg, 1.142 mmol) y HOBT (164 mg, 1.071 mmol). La mezcla se agita a temperatura ambiente durante 10 minutos y luego se agrega una solución de etil éster del ácido (R)-3-amino-4-(3’-cloro-bifenil-4-il)-butírico (202 mg, 0,571 mmol) en THF y TEA (0,199 ml, 1.428 mmol). La
20 mezcla se agita a temperatura ambiente. HPLC en fase reversa [30 a 90% de ACN-H2O (TFA al 0,1%) durante 10 minutos mediante columna de fenilo de X-Bridge] da el compuesto del título (290 mg, rendimiento del 71%). LCMS (condición B): 575 (M+1): tiempo de retención = 1.52 minutos.
115
imagen140

Claims (1)

  1. imagen1
    imagen2
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Families Citing this family (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ME01923B (me) 2009-05-28 2015-05-20 Novartis Ag Supstituisani derivati aminopropionske kiseline kao inhibitori neprilizina
UY32660A (es) 2009-05-28 2010-12-31 Novartis Ag Derivados aminobutricos sustituidos como inhibidores de neprilisina
JO2967B1 (en) * 2009-11-20 2016-03-15 نوفارتس ايه جي Acetic acid derivatives of carbamoyl methyl amino are substituted as new NEP inhibitors
AR079967A1 (es) 2010-01-26 2012-02-29 Sanofi Aventis Derivados de acido 3-heteroaroilamino-propionico sustituidos con oxigeno y su uso como productos farmaceuticos
WO2011092284A1 (en) * 2010-01-29 2011-08-04 Euroscreen S.A. Novel amino acid derivatives and their use as gpr43 receptor modulators
US8877815B2 (en) * 2010-11-16 2014-11-04 Novartis Ag Substituted carbamoylcycloalkyl acetic acid derivatives as NEP
US8673974B2 (en) * 2010-11-16 2014-03-18 Novartis Ag Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors
US8993631B2 (en) * 2010-11-16 2015-03-31 Novartis Ag Method of treating contrast-induced nephropathy
CA2817368C (en) 2010-12-15 2019-12-31 Theravance, Inc. Neprilysin inhibitors
CA2819153A1 (en) * 2010-12-15 2012-06-21 Theravance, Inc. Neprilysin inhibitors
UY33874A (es) * 2011-01-26 2012-08-31 Sanofi Aventis Derivados de ácido 3-heteroaroilamino-propiónico sustituidos y su uso como sustancias farmacéuticas
WO2012154249A1 (en) 2011-02-17 2012-11-15 Theravance, Inc. Substituted aminobutyric derivatives as neprilysin inhibitors
WO2012112742A1 (en) 2011-02-17 2012-08-23 Theravance, Inc. Substituted aminobutyric derivatives as neprilysin inhibitors
WO2012166390A1 (en) 2011-05-31 2012-12-06 Theravance, Inc. Neprilysin inhibitors
ES2642883T3 (es) 2011-05-31 2017-11-20 Theravance Biopharma R&D Ip, Llc Inhibidores de neprilisina
ES2653215T3 (es) 2011-05-31 2018-02-06 Theravance Biopharma R&D Ip, Llc Inhibidores de neprilisina
WO2013010679A1 (en) * 2011-07-15 2013-01-24 Novartis Ag Salts of aza-bicyclic di-aryl ethers and methods to make them or their precursors
MY169319A (en) 2011-07-26 2019-03-21 Sanofi Sa 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals
MX339433B (es) * 2011-07-26 2016-05-26 Sanofi Sa Derivados de acido 3 - tiazoloamino - propionico sustituidos y su uso como sustancias farmaceuticas.
MX2014004503A (es) 2011-10-17 2015-01-16 Biotheryx Inc Biaril alquil amidas sustituidas.
TWI560172B (en) 2011-11-02 2016-12-01 Theravance Biopharma R&D Ip Llc Neprilysin inhibitors
WO2013113773A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013113720A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
AU2013214353A1 (en) 2012-02-03 2014-08-21 Basf Se Fungicidal pyrimidine compounds
EA201491472A1 (ru) 2012-02-03 2015-01-30 Басф Се Фунгицидные соединения пиримидина
WO2013113716A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013113791A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
WO2013113776A1 (en) 2012-02-03 2013-08-08 Basf Se Fungicidal pyrimidine compounds
TWI562986B (en) * 2012-02-15 2016-12-21 Theravance Biopharma R&D Ip Llc Process for preparing 4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid compounds
AR089954A1 (es) * 2012-02-15 2014-10-01 Theravance Inc Forma cristalina del ester 5-metil-2-oxo-[1,3]dioxol-4-ilmetilico del acido (2s,4r)-5-bifenil-4-il-2-hidroximetil-2-metil-4-[(1h-[1,2,3]triazol-4-carbonil)amino]pentanoico
ES2609810T3 (es) * 2012-05-31 2017-04-24 Theravance Biopharma R&D Ip, Llc Inhibidores de neprilisina donadores de óxido nítrico
US8871792B2 (en) 2012-06-08 2014-10-28 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
PL2864292T3 (pl) 2012-06-08 2017-10-31 Theravance Biopharma R&D Ip Llc Inhibitory neprylizyny
AR092073A1 (es) * 2012-08-08 2015-03-18 Theravance Inc Inhibidores de neprilisina
WO2014053533A1 (en) * 2012-10-05 2014-04-10 Sanofi Use of substituted 3-heteroaroylamino-propionic acid derivatives as pharmaceuticals for prevention/treatment of atrial fibrillation
UY35144A (es) 2012-11-20 2014-06-30 Novartis Ag Miméticos lineales sintéticos de apelina para el tratamiento de insuficiencia cardiaca
CA2900226A1 (en) * 2013-02-14 2014-08-21 Novartis Ag Substituted bisphenyl butanoic acid derivatives as nep inhibitors with improved in vivo efficacy
LT2956464T (lt) 2013-02-14 2018-07-10 Novartis Ag Pakeisti bisfenilbutanoinės fosfonrūgšties dariniai, kaip nep (neutralios endopeptidazės) inhibitoriai
RS56300B1 (sr) 2013-03-05 2017-12-29 Theravance Biopharma R&D Ip Llc Inhibitori neprilizina
AP2016009019A0 (en) 2013-07-25 2016-02-29 Novartis Ag Bioconjugates of synthetic apelin polypeptides
JP6501775B2 (ja) 2013-07-25 2019-04-17 ノバルティス アーゲー 心不全治療用の環状ポリペプチド
CN105683153B (zh) * 2013-09-17 2018-07-13 维克图斯生物系统有限公司 用于治疗高血压和/或纤维化的组合物
EP3087060B1 (en) 2013-12-23 2020-05-13 Merck Sharp & Dohme Corp. Pyrimidone carboxamide compounds as pde2 inhibitors
MX2016009759A (es) 2014-01-30 2016-11-17 Theravance Biopharma R&D Ip Llc Inhibidores de neprilisina.
SG11201605965UA (en) * 2014-01-30 2016-08-30 Theravance Biopharma R&D Ip Llc Neprilysin inhibitors
WO2015189862A1 (en) * 2014-06-10 2015-12-17 Council Of Scientific & Industrial Research Chiral amines, a process for preparation and use thereof
CN107074744B (zh) * 2014-12-03 2019-06-18 上海翰森生物医药科技有限公司 Nep抑制剂结晶型游离酸、钙盐多晶型及其制备方法和应用
PE20171328A1 (es) 2015-01-23 2017-09-12 Novartis Ag Conjugados de acidos grasos y apelina sintetica con mayor vida media
CN104557600B (zh) * 2015-01-26 2016-05-04 苏州明锐医药科技有限公司 沙库比曲的制备方法
MX372773B (es) 2015-02-11 2020-06-29 Theravance Biopharma R&D Ip Llc Ácido (2s, 4r)-5-(5'-cloro-2'-fluorobifenil-4-il)-4-(etoxioxalilamino)-2-hidroximetil-2-metilpentanoico.
TW201632493A (zh) * 2015-02-13 2016-09-16 諾華公司 新穎方法
MX370065B (es) * 2015-02-19 2019-11-29 Theravance Biopharma R&D Ip Llc Acido (2r,4r)-5-(5'-cloro-2'-fluorobifenil-4-il)-2-hidroxi-4-[(5-m etiloxazol-2-carbonil)amino]pentanoico.
CN107847462B (zh) * 2015-03-13 2021-08-10 美国印第安纳大学研究和技术公司 靶向cGMP相关的磷酸二酯酶以减少囊性肾病的囊肿形成和相关的材料与方法
WO2016145614A1 (en) 2015-03-17 2016-09-22 Merck Sharp & Dohme Corp. Triazolyl pyrimidinone compounds as pde2 inhibitors
EP3285581B1 (en) 2015-03-26 2021-08-11 Merck Sharp & Dohme Corp. Pyrazolyl pyrimidinone compounds as pde2 inhibitors
WO2016179059A1 (en) 2015-05-05 2016-11-10 Merck Sharp & Dohme Corp. Heteroaryl-pyrimidinone compounds as pde2 inhibitors
WO2016183741A1 (en) 2015-05-15 2016-11-24 Merck Sharp & Dohme Corp. Pyrimidinone amide compounds as pde2 inhibitors
WO2016191935A1 (en) 2015-05-29 2016-12-08 Merck Sharp & Dohme Corp. 6-alkyl dihydropyrazolopyrimidinone compounds as pde2 inhibitors
WO2016192083A1 (en) 2015-06-04 2016-12-08 Merck Sharp & Dohme Corp. Dihydropyrazolopyrimidinone compounds as pde2 inhibitors
US10647727B2 (en) 2015-06-25 2020-05-12 Merck Sharp & Dohme Corp. Substituted pyrazolo/imidazolo bicyclic compounds as PDE2 inhibitors
WO2017000277A1 (en) 2015-07-01 2017-01-05 Merck Sharp & Dohme Corp. Substituted triazolo bicycliccompounds as pde2 inhibitors
WO2017000276A1 (en) 2015-07-01 2017-01-05 Merck Sharp & Dohme Corp. Bicyclic heterocyclic compounds as pde2 inhibitors
AR107165A1 (es) 2015-12-23 2018-03-28 Chiesi Farm Spa Inhibidores de quinasa
MX377177B (es) 2016-03-08 2025-03-07 Theravance Biopharma R&D Ip Llc Acido (2s,4r)-5-(5'-cloro-2'-fluoro-[1,1'-bifenil]-4-il)-2-(etoximetil)-4-(3-hidroxiisoxazol-5-carboxamido)-2-metilpentanoico cristalino, y sus usos.
CN106831473B (zh) * 2017-02-22 2019-07-16 江西瑞雅药业有限公司 3-酰胺基-4-(2’-烷氧基-4-联苯基)丁酸衍生物及其制备方法、药物组合物
FR3072379B1 (fr) * 2017-10-18 2020-08-07 Pharmasynthese Nouveaux derives de la strombine et leur utilisation en cosmetique
WO2019154665A1 (en) * 2018-02-07 2019-08-15 Basf Se New pyridine carboxamides
UY38072A (es) * 2018-02-07 2019-10-01 Novartis Ag Compuestos derivados de éster butanoico sustituido con bisfenilo como inhibidores de nep, composiciones y combinaciones de los mismos
EP3887388A1 (en) 2018-11-27 2021-10-06 Novartis AG Cyclic peptides as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorders
US20230089867A1 (en) 2018-11-27 2023-03-23 Novartis Ag Cyclic pentamer compounds as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorder
UY38485A (es) 2018-11-27 2020-06-30 Novartis Ag Compuestos tetrámeros cíclicos como inhibidores de proproteína convertasa subtilisina/kexina tipo 9 (pcsk9), método de tratamiento, uso y su preparación
TW202333563A (zh) 2021-11-12 2023-09-01 瑞士商諾華公司 用於治療疾病或障礙之二胺基環戊基吡啶衍生物
CN115806501B (zh) * 2022-12-13 2025-01-07 中国药科大学 N-草酰-d-苯丙氨酸类化合物及其酯类前药、制法、药物组合物和应用

Family Cites Families (140)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2090595B (en) * 1978-11-25 1983-05-11 Nippon Kayaku Kk Threo-3-amino-2-hydroxybutanoylacetice acid derivatives
DE2951135A1 (de) 1979-12-19 1981-06-25 Hoechst Ag, 6230 Frankfurt Sulfonylharnstoffe, verfahren zu ihrer herstellung, pharmazeutische praeparate auf basis dieser verbindungen und ihre verwendung
DE3162404D1 (en) 1980-04-11 1984-04-05 Wellcome Found Pharmaceutical amides, and preparation, formulations and use thereof
PT72878B (en) 1980-04-24 1983-03-29 Merck & Co Inc Process for preparing mannich-base hydroxamic acid pro-drugs for the improved delivery of non-steroidal anti-inflammatory agents
US4610816A (en) * 1980-12-18 1986-09-09 Schering Corporation Substituted dipeptides as inhibitors of enkephalinases
US4721726A (en) * 1980-12-18 1988-01-26 Schering Corporation Substituted dipeptides as inhibitors of enkephalinases
JPS5865260A (ja) 1981-10-13 1983-04-18 Microbial Chem Res Found ３−アミノ−２−ヒドロキシ−４−フエニル酪酸誘導体および医薬組成物
FR2518088B1 (fr) * 1981-12-16 1987-11-27 Roques Bernard Nouveaux derives d'aminoacides, et leur application therapeutique
EP0103077B1 (en) 1982-06-17 1988-05-18 Schering Corporation Substituted dipeptides, methods for their production, pharmaceutical compositions containing them, method for making such pharmaceutical compositions
US4889861A (en) 1982-12-21 1989-12-26 Ciba-Geigy Corp. Substituted imidazo[1,5-a]pyridine derivatives and other substituted bicyclic derivatives and their use as aromatase inhibitors
US4617307A (en) 1984-06-20 1986-10-14 Ciba-Geigy Corporation Substituted imidazo[1,5-A]pyridine derivatives as aromatase inhibitors
GR81744B (es) 1983-01-28 1984-12-12 Schering Corp
US4559332A (en) 1983-04-13 1985-12-17 Ciba Geigy Corporation 20-Spiroxanes and analogues having an open ring E, processes for their manufacture, and pharmaceutical preparations thereof
CN1008092B (zh) * 1983-10-03 1990-05-23 E·R·斯奎布父子公司 脑啡肽酶抑制剂的制备方法
EP0136883B1 (en) 1983-10-03 1987-11-25 E.R. Squibb & Sons, Inc. Enkephalinase inhibitors
DE3347565A1 (de) 1983-12-30 1985-07-11 Thomae Gmbh Dr K Neue phenylessigsaeurederivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung
JPS60248659A (ja) * 1984-05-25 1985-12-09 Microbial Chem Res Found ３−〔ｎ−（メルカプトアシル）〕アミノ−４−アリ−ル酪酸誘導体及びそれを有効成分とする鎮痛剤
JPS6354321A (ja) 1985-03-27 1988-03-08 Ajinomoto Co Inc 血糖降下剤
US4743587A (en) 1985-09-10 1988-05-10 G. D. Searle & Co. Hydroxamic acid based collagenase inhibitors
FR2597865B1 (fr) 1986-04-29 1990-11-09 Roussel Uclaf Nouveaux derives d'un acide benzyl alkyl carboxylique substitue par un radical 4-pyridinyl aminocarbonyle, leur procede de preparation, les nouveaux intermediaires obtenus, leur application a titre de medicaments et les compositions pharmaceutiques les renfermant
US5120712A (en) 1986-05-05 1992-06-09 The General Hospital Corporation Insulinotropic hormone
US5118666A (en) 1986-05-05 1992-06-02 The General Hospital Corporation Insulinotropic hormone
FR2605004B1 (fr) 1986-09-25 1989-01-13 Centre Nat Rech Scient Nouveaux derives d'amino-acides, leur procede de preparation et composition pharmaceutiques les contenant
KR880007441A (ko) * 1986-12-11 1988-08-27 알렌 제이.스피겔 스피로-치환된 글루타르아미드 이뇨제
FR2609289B1 (fr) 1987-01-06 1991-03-29 Bellon Labor Sa Roger Nouveaux composes a activite d'inhibiteurs de collagenase, procede pour les preparer et compositions pharmaceutiques contenant ces composes
CA1337400C (en) 1987-06-08 1995-10-24 Norma G. Delaney Inhibitors of neutral endopeptidase
WO1990001940A1 (en) 1988-08-18 1990-03-08 California Biotechnology Inc. Atrial natriuretic peptide clearance inhibitors
FR2651229B1 (fr) 1989-08-24 1991-12-13 Inst Nat Sante Rech Med Nouveaux derives d'amino-acides, leur procede de preparation et leur application therapeutique.
AU7168091A (en) 1989-12-22 1991-07-24 Schering Corporation Mercaptocycloacyl aminoacid endopeptidase inhibitors
JP3262329B2 (ja) 1990-01-24 2002-03-04 アイ． バックレイ，ダグラス 糖尿病治療に有用なｇｌｐ―１アナログ
US5449682A (en) * 1990-02-13 1995-09-12 Merck & Co., Inc. Angiotensin II antagonists incorporating a substituted benzyl element
US5223516A (en) * 1990-03-22 1993-06-29 E. R. Squibb & Sons, Inc. 3,3,3-trifluoro-2-mercaptomethyl-N-tetrazolyl substituted propanamides and method of using same
US5200426A (en) * 1990-08-14 1993-04-06 Board Of Regents, The University Of Texas Inhibitors of neutral endopeptidase/CALLA as chemotherapeutic agents
JPH04149166A (ja) * 1990-10-12 1992-05-22 Nippon Kayaku Co Ltd 新規ケト酸アミド誘導体
CA2058797A1 (en) * 1991-02-01 1992-08-02 Michael John Broadhurst Amino acid derivatives
AU654331B2 (en) 1991-03-30 1994-11-03 Kissei Pharmaceutical Co. Ltd. Succinic acid compounds
US5294632A (en) * 1991-05-01 1994-03-15 Ciba-Geigy Corporation Phosphono/biaryl substituted dipetide derivatives
RU2086544C1 (ru) 1991-06-13 1997-08-10 Хоффманн-Ля Рош АГ Бензолсульфонамидные производные пиримидина или их соли, фармацевтическая композиция для лечения заболеваний, связанных с активностью эндотелина
PL170210B1 (pl) 1991-06-21 1996-11-29 Thomae Gmbh Dr K Sposób wytwarzania nowego kwasu (S)(+)-2-etoksy-4-/N-/1-(2-piperydynofenylo)-3-metylo- 1-butyloaminokarbonylometylo/-benzoesowego i jego soli PL
GB9114006D0 (en) 1991-06-28 1991-08-14 Fujisawa Pharmaceutical Co New propionamide derivatives,processes for the preparation thereof and pharmaceutical composition comprising the same
ATE149483T1 (de) 1991-07-30 1997-03-15 Ajinomoto Kk Kristalle von n-(trans-4- isopropylcyclohexylcarbonyl)-d-phenylalanin und verfahren zu ihrer herstellung
EP0533130A1 (de) 1991-09-19 1993-03-24 Hoechst Aktiengesellschaft 2-Hydroxymethylpyridine, die entsprechenden Pyridin-N-oxide und ihre Derivate, Verfahren zu ihrer Herstellung sowie deren Verwendung
ZA927211B (en) 1991-09-27 1993-03-24 Merrell Dow Pharma Novel carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE.
US5273990A (en) * 1992-09-03 1993-12-28 Ciba-Geigy Corporation Phosphono substituted tetrazole derivatives
US5250522A (en) * 1992-10-09 1993-10-05 Ciba-Geigy Corporation Phosphono/biaryl substituted amino acid derivatives
WO1993011782A1 (en) 1991-12-19 1993-06-24 Southwest Foundation For Biomedical Research Cetp inhibitor polypeptide, antibodies against the synthetic polypeptide and prophylactic and therapeutic anti-atherosclerosis treatments
US5217996A (en) * 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
JPH06234630A (ja) 1992-12-17 1994-08-23 Tanabe Seiyaku Co Ltd 中性メタロエンドペプチダーゼ阻害剤
WO1994020457A1 (en) 1993-03-02 1994-09-15 G.D. Searle & Co. N-acyl beta amino acid derivatives useful as platelet aggregation inhibitors
IL111785A0 (en) 1993-12-03 1995-01-24 Ferring Bv Dp-iv inhibitors and pharmaceutical compositions containing them
JP3576193B2 (ja) 1993-12-03 2004-10-13 第一製薬株式会社 ビフェニルメチル置換バレリルアミド誘導体
US5705483A (en) 1993-12-09 1998-01-06 Eli Lilly And Company Glucagon-like insulinotropic peptides, compositions and methods
US5517996A (en) * 1994-04-21 1996-05-21 Hitachi Medical Corporation Ultrasonic diagnostic apparatus
IT1270261B (it) 1994-06-21 1997-04-29 Zambon Spa Derivati peptidici ad attivita' inibitrice delle metallopeptidasi
US5512549A (en) 1994-10-18 1996-04-30 Eli Lilly And Company Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
US5891912A (en) * 1994-11-04 1999-04-06 Santen Pharmaceutical Co., Ltd. 1,3-dialkylurea derivatives having a hydroxyl group
WO1996018606A1 (en) * 1994-12-14 1996-06-20 Santen Pharmaceutical Co., Ltd. Novel 1,3-dialkylurea derivatives
TW313568B (es) 1994-12-20 1997-08-21 Hoffmann La Roche
FR2729668A1 (fr) * 1995-01-23 1996-07-26 Adir Nouveaux derives de mercaptoalcanoyldipeptides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US5550119A (en) * 1995-03-02 1996-08-27 Ciba-Geigy Corporation Phosphono substituted tetrazole derivatives as ECE inhibitors
US5710171A (en) * 1995-05-24 1998-01-20 Merck & Co., Inc. Bisphenyl inhibitors of farnesyl-protein transferase
DE122010000020I1 (de) 1996-04-25 2010-07-08 Prosidion Ltd Verfahren zur Senkung des Blutglukosespiegels in Säugern
GB9609794D0 (en) * 1996-05-10 1996-07-17 Smithkline Beecham Plc Novel compounds
IL118657A0 (en) 1996-06-14 1996-10-16 Arad Dorit Inhibitors for picornavirus proteases
EP0927156A1 (en) 1996-09-04 1999-07-07 Warner-Lambert Company Biphenyl butyric acids and their derivatives as inhibitors of matrix metalloproteinases
FR2755135B1 (fr) 1996-10-25 2002-12-27 Inst Nat Sante Rech Med Nouveaux derives d'(alpha-aminophosphino)peptides, leur procede de preparation et les compositions qui les contiennent
TW492957B (en) 1996-11-07 2002-07-01 Novartis Ag N-substituted 2-cyanopyrrolidnes
DE69833654T2 (de) 1997-05-29 2006-12-14 Merck & Co., Inc. (A New Jersey Corp.) Biarylalkansäuren in der verwendung als zelladhäsionsinhibitoren
US6576664B1 (en) * 1997-08-18 2003-06-10 Bristol-Myers Squibb Pharma Company Inhibitors of aggrecanase and matrix metalloproteinases for the treatment of arthritis
WO1999026923A1 (en) 1997-11-20 1999-06-03 Merck & Co., Inc. Para-aminomethylaryl carboxamide derivatives
AU1463499A (en) 1997-11-21 1999-06-15 Merck & Co., Inc. Substituted pyrrole derivatives as cell adhesion inhibitors
JP2001524465A (ja) * 1997-11-24 2001-12-04 メルク エンド カムパニー インコーポレーテッド 細胞接着阻害剤としての置換β−アラニン誘導体
MY153569A (en) 1998-01-20 2015-02-27 Mitsubishi Tanabe Pharma Corp Inhibitors of ?4 mediated cell adhesion
US6169103B1 (en) * 1998-03-03 2001-01-02 Warner-Lambert Fluorine-substituted biphenyl butyric acids and their derivatives as inhibitors of matrix metalloproteinases
GT199900147A (es) 1998-09-17 1999-09-06 1, 2, 3, 4- tetrahidroquinolinas 2-sustituidas 4-amino sustituidas.
US6197786B1 (en) 1998-09-17 2001-03-06 Pfizer Inc 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines
CO5150173A1 (es) 1998-12-10 2002-04-29 Novartis Ag Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv
JP4070357B2 (ja) 1999-06-03 2008-04-02 花王株式会社 皮膚外用剤
GB2354440A (en) 1999-07-20 2001-03-28 Merck & Co Inc Aryl amides as cell adhesion inhibitors
US6683113B2 (en) 1999-09-23 2004-01-27 Pharmacia Corporation (R)-chiral halogenated substituted N,N-Bis-benzyl aminioalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity
US6509330B2 (en) * 2000-02-17 2003-01-21 Bristol-Myers Squibb Company Hydroxamic acid containing compounds useful as ACE inhibitors and/or NEP inhibotors
AR032316A1 (es) 2000-04-12 2003-11-05 Novartis Ag Uso de una composicion farmaceutica para la fabricacion de medicamentos y una composicion farmaceutica
ATE310719T1 (de) 2000-09-29 2005-12-15 Topotarget Uk Ltd Carbaminsäurederivate enthaltend eine amidgruppe als hdac-inhibitoren
JP4149166B2 (ja) 2002-01-08 2008-09-10 東京エレクトロン株式会社 処理システム及び処理方法
WO2003059345A1 (en) 2002-01-17 2003-07-24 Novartis Ag Pharmaceutical compositions comprising valsartan and nep inhibitors
JP4233353B2 (ja) 2002-02-27 2009-03-04 田辺三菱製薬株式会社 医薬組成物
US20040063761A1 (en) * 2002-08-06 2004-04-01 Kuduk Scott D. 2-(biarylalkyl)amino-3-(fluoroalkanoylamino)pyridine derivatives
AU2003253387A1 (en) 2002-08-07 2004-02-25 Novartis Ag Organic compounds as agents for the treatment of aldosterone mediated conditions
CA2505752A1 (en) 2002-11-18 2004-06-03 Novartis Ag Imidazo[1,5a]pyridine derivatives and methods for treating aldosterone mediated diseases
US20040142379A1 (en) 2003-01-16 2004-07-22 Carlsberg Research Laboratory Affinity fishing for ligands and proteins receptors
EP1631260A2 (en) 2003-02-28 2006-03-08 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
WO2004099171A2 (en) 2003-04-30 2004-11-18 The Institutes For Pharmaceutical Discovery, Llc Substituted amino carboxylic acids as inhibitors of protein tyrosine phosphatase-1b
CN1566065A (zh) * 2003-06-27 2005-01-19 中国医学科学院药物研究所 α位杂原子取代的γ芳基丁本酮酸衍生物及其制法和其药物组合物与用途
US20070197541A1 (en) 2003-07-29 2007-08-23 Oyelere Adegboyega K Biaryl heterocyclic amines,amides, and sulfur-containing compounds and methods of making and using the same
US7501538B2 (en) 2003-08-08 2009-03-10 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions and methods of use
WO2005097806A1 (en) 2004-03-26 2005-10-20 Eli Lilly And Company Compounds and methods for treating dyslipidemia
UA90269C2 (ru) 2004-04-02 2010-04-26 Мицубиси Танабе Фарма Корпорейшн Тетрагидрохинолиновые производные и способ их получения
TW200616623A (en) 2004-05-28 2006-06-01 Speedel Experimenta Ag Organic compounds
CN1956987A (zh) 2004-05-28 2007-05-02 斯皮德尔实验股份公司 杂环化合物及其作为醛固酮合酶抑制剂的应用
EP1748986B1 (en) 2004-05-28 2010-12-01 Novartis AG Heterocyclic compounds and their use as aldosterone synthase inhibitors
WO2006005726A2 (en) 2004-07-09 2006-01-19 Speedel Experimenta Ag Heterocyclic compounds
EP1778214A4 (en) 2004-07-27 2010-04-14 Glaxosmithkline Llc NEW BIPHENYL COMPOUNDS AND THEIR USE
EP1814869A2 (en) 2004-11-18 2007-08-08 The Institutes for Pharmaceutical Discovery, LLC Substituted amino acids as protein tyrosine phosphatase inhibitors
WO2006069096A1 (en) 2004-12-20 2006-06-29 Pharmacyclics, Inc. Silanol derivatives as inhibitors of histone deacetylase
MY146830A (en) * 2005-02-11 2012-09-28 Novartis Ag Combination of organic compounds
ES2400287T3 (es) * 2005-03-14 2013-04-08 High Point Pharmaceuticals, Llc Derivados de benzazol, composiciones y procedimientos de uso como inhibidores de beta-secretasa
TW200716634A (en) 2005-05-31 2007-05-01 Speedel Experimenta Ag Heterocyclic spiro-compounds
TW200716636A (en) 2005-05-31 2007-05-01 Speedel Experimenta Ag Heterocyclic spiro-compounds
TW200716105A (en) 2005-05-31 2007-05-01 Speedel Experimenta Ag Imidazole compounds
GT200600381A (es) 2005-08-25 2007-03-28 Compuestos organicos
WO2007045663A2 (en) 2005-10-19 2007-04-26 Novartis Ag Combination of an ati receptor antagonist and a np inhibitor fro treating ia hypertension and heartfailure
CN101300030A (zh) 2005-11-08 2008-11-05 诺瓦提斯公司 血管紧张素ⅱ受体阻滞剂、钙通道阻滞剂和另一活性物质的组合产品
AR057882A1 (es) 2005-11-09 2007-12-26 Novartis Ag Compuestos de accion doble de bloqueadores del receptor de angiotensina e inhibidores de endopeptidasa neutra
AR056888A1 (es) 2005-12-09 2007-10-31 Speedel Experimenta Ag Derivados de heterociclil imidazol
WO2007116908A1 (ja) 2006-04-04 2007-10-18 Taiyo Nippon Sanso Corporation メタン分離方法、メタン分離装置及びメタン利用システム
TW200808813A (en) 2006-04-12 2008-02-16 Speedel Experimenta Ag Imidazo compounds
TW200808812A (en) 2006-04-12 2008-02-16 Speedel Experimenta Ag Imidazo compounds
EP2018166A2 (en) 2006-05-15 2009-01-28 Irm Llc Terephthalamate compounds and compositions, and their use as hiv integrase inhibitors
EP1886695A1 (en) 2006-06-27 2008-02-13 Speedel Experimenta AG Pharmaceutical combination of an aldosterone synthase inhibitor and a glucocorticoid receptor antagonist or a cortisol synthesis inhibitor or a corticotropin releasing factor antagonist
RU2009110442A (ru) 2006-08-25 2010-09-27 Новартис АГ (CH) Конденсированные производные имидазола для лечения нарушений, опосредованных альдостеронсинтазой, и/или 11-бета-гидроксилазой, и/или ароматазой
EP1903027A1 (en) 2006-09-13 2008-03-26 Novartis AG Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors
AU2007333902A1 (en) 2006-12-18 2008-06-26 Novartis Ag 4-imidazolyl-1,2,3,4-tetrahydroquinoline derivatives and their use as aldosterone/11-beta-hydroxylase inhibitors
BRPI0721284A2 (pt) 2006-12-18 2014-04-08 Novartis Ag Compostos orgânicos
BRPI0721290A2 (pt) 2006-12-18 2014-03-25 Novartis Ag Compostos orgânicos
MY151993A (en) 2007-01-12 2014-07-31 Novartis Ag Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid
TW200838501A (en) * 2007-02-02 2008-10-01 Theravance Inc Dual-acting antihypertensive agents
CN101711252A (zh) 2007-03-29 2010-05-19 诺瓦蒂斯有限公司 杂环螺环化合物
TWI448284B (zh) * 2007-04-24 2014-08-11 Theravance Inc 雙效抗高血壓劑
US8980833B2 (en) 2007-05-10 2015-03-17 R&D-Biopharmaceuticals Gmbh Tubulysine derivatives
TWI406850B (zh) 2007-06-05 2013-09-01 Theravance Inc 雙效苯并咪唑抗高血壓劑
JP2010538071A (ja) * 2007-09-07 2010-12-09 セラヴァンス， インコーポレーテッド 二重作用性降圧剤
FI3067043T3 (fi) 2007-11-06 2023-03-18 Novartis Ag Angiotensiinireseptoriantagonistin/-salpaajan (arb) ja neutraalin endopeptidaasin (nep) estäjän superrakenteisiin perustuvia farmaseuttisia koostumuksia
CA2705921A1 (en) 2007-12-11 2009-06-18 Theravance, Inc. Dual-acting benzoimidazole derivatives and their use as antihypertensive agents
EP2070928A1 (en) 2007-12-12 2009-06-17 NERVIANO MEDICAL SCIENCES S.r.l. 7-azaindol-3-ylacrylamides active as kinase inhibitors
AR070176A1 (es) 2008-01-17 2010-03-17 Novartis Ag Procesos de sintesis de inhibidores de nep, compuestos intermediarios y uso de los mismos en la sintesis
WO2010011821A2 (en) 2008-07-24 2010-01-28 Theravance, Inc. Dual-acting antihypertensive agents
WO2011035569A1 (en) 2009-09-23 2011-03-31 Zhejiang Jiuzhou Pharmaceutical Co., Ltd. Process for manufacture of n-acylbphenyl alanine
ME01923B (me) 2009-05-28 2015-05-20 Novartis Ag Supstituisani derivati aminopropionske kiseline kao inhibitori neprilizina
UY32660A (es) 2009-05-28 2010-12-31 Novartis Ag Derivados aminobutricos sustituidos como inhibidores de neprilisina
JO2967B1 (en) * 2009-11-20 2016-03-15 نوفارتس ايه جي Acetic acid derivatives of carbamoyl methyl amino are substituted as new NEP inhibitors

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