ES2513291T3 - Derivados alquinilo útiles como inhibidores de la DPP-1 - Google Patents

Derivados alquinilo útiles como inhibidores de la DPP-1 Download PDF

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ES2513291T3
ES2513291T3 ES10774098.7T ES10774098T ES2513291T3 ES 2513291 T3 ES2513291 T3 ES 2513291T3 ES 10774098 T ES10774098 T ES 10774098T ES 2513291 T3 ES2513291 T3 ES 2513291T3
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phenyl
4alkyl
ethyl
oxy
piperidin
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Michael H. Parker
Dennis J. Hlasta
Yifang Huang
Allen B. Reitz
Edward C. Lawson
Carsten Schubert
Eric Strobel
Brett Tounge
Kimberly White
Michael P. Winters
Shyamali Ghosh
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Janssen Pharmaceutica NV
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    • C07C237/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and unsaturated
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Abstract

Compuesto de fórmula (I)**Fórmula** en el que R1 está seleccionado del grupo que consiste en hidrógeno, cicloalquilo C3-8, fenilo, benciloxi- y piperidinil-oxi-; es una estructura de anillo seleccionada del grupo que consiste en fenilo, naftilo, fluorenilo, isoquinolinilo, benzofurilo, benzotiofenilo, benzo[1,3]dioxolilo y 2,3-dihidro-benzo[1,4]dioxinilo; en el que la estructura de anillo está opcionalmente sustituida con uno o más sustituyentes seleccionados independientemente del grupo que consiste en halógeno, hidroxi, alquilo C1-4, alquilo C1-4 halogenado, alcoxi C1-4, alcoxi C1-4 halogenado, (alcoxi C1-4)-(alquilo C1-4)-, (alquilo C1-4)-SO2- y (alquilo C1-4)-C(O)-NH-; n es un número entero seleccionado de entre 0 y 1; R2 está seleccionado del grupo que consiste en alquilo C1-4, alquenilo C2-4, alquinilo C2-4, alquilo C1-4 sustituido con hidroxi, NRARB-(alquilo C1-2)-, ciclopropil-metil-, bencil- y heteroaril-(CH2)1-2; en el que RA y RB están seleccionados cada uno independientemente de entre hidrógeno o alquilo C1-4; a condición de que R2 sea distinto de t-butilo; o una sal farmacéuticamente aceptable del mismo.

Description

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Derivados alquinilo útiles como inhibidores de la DPP-1
Descripción
CAMPO DE LA INVENCIÓN
La presente invención se refiere a nuevos derivados alquinilo, a composiciones farmacéuticas que los contienen y a nuevos derivados alquinilo para su uso en el tratamiento de trastornos y afecciones modulados por DPP-1.
ANTECEDENTES DE LA INVENCIÓN
La enfermedad pulmonar obstructiva crónica (EPOC) se caracteriza por el desarrollo progresivo de una limitación irreversible del flujo respiratorio. La EPOC consiste en bronquitis obstructiva crónica, con obstrucción de las vías respiratorias pequeñas, y enfisema, con dilatación de las cavidades aéreas y destrucción del parénquima pulmonar, pérdida de elasticidad pulmonar y cierre de las vías aéreas pequeñas. En los pacientes con EPOC, hay un aumento del número de neutrófilos, linfocitos T citotóxicos y macrófagos en el lavado broncoalveolar (BAL) de las vías respiratorias y el parénquima pulmonar. La presencia de estas células inflamatorias se correlaciona bien con la gravedad de la obstrucción de las vías respiratorias y la destrucción de la pared alveolar. Se ha demostrado que la elastasa de neutrófilos, la catepsina G y la proteinasa 3 pueden producir enfisema e hipersecreción de moco en animales de laboratorio. Las granzimas A y B son las serina proteasas neutras que se expresan exclusivamente en los gránulos de los linfocitos T citotóxicos activados. En la EPOC el equilibrio proteasa-antiproteasa parece inclinarse a favor del aumento de la proteólisis debido al aumento de proteasas derivadas de neutrófilos polimorfonucleares (PMN), catepsinas y metaloproteasas de la matriz (MMP). Por lo tanto, se espera que un fármaco que inhiba la totalidad o la mayor parte de las proteasas pertinentes anteriormente mencionadas sea eficaz en el tratamiento de la EPOC.
La dipeptidil peptidasa-1 (DPP-1, catepsina C) es un miembro de la familia de cisteína proteasas de tipo papaína lisosomiales, que también incluye catepsina B, K, H, L, O y S. La DPP-1 (MW 200 kD) está compuesta por un dímero de cadenas pesada y ligera unidas por enlaces disulfuro, ambas de un único precursor de la proteína. El ARNm de DPP-1 se expresa abundantemente en tejidos tales como pulmón, bazo, riñón e hígado; en células inflamatorias tales como PMN, linfocitos T citotóxicos, macrófagos alveolares y mastocitos. La función biológica de la DPP-1 es convertir las proenzimas inactivas en la enzima activa eliminando un dipéptido del extremo N-terminal. Las proenzimas que son activadas por la DPP-1 son las proteasas derivadas de los PMN, las granzimas A y B, la quimasa y la triptasa. Dado que estas enzimas juegan un papel patológico importante en la EPOC, la inhibición de la DDP-1 por moléculas pequeñas sería una intervención terapéutica lógica para la EPOC. Las indicaciones terapéuticas adicionales para un inhibidor de la DPP-1 son el asma, la rinitis y la artritis reumatoide.
Sigue existiendo la necesidad de inhibidores de la DPP-1 para el tratamiento de las afecciones y los trastornos mediados por DPP-1, incluidas, pero no limitadas a, la artritis reumatoide, el asma, la enfermedad pulmonar obstructiva crónica, la sepsis, el síndrome del intestino irritable, la fibrosis quística y el aneurisma aórtico abdominal.
En el documento US 2007/155803 A1 se describen compuestos de monoacil semicarbazida para su uso como inhibidores de la catepsina C.
Greenspan P.D. et al. "Identification of Dipeptidyl Nitriles as Potent and Selective Inhibitors of Cathepsin B through Structure-Based Drug Design" J. Med. Chem., 2001, 44 (26), pág. 4524-4534 describen dipeptidil nitrilos para su uso como inhibidores de la catepsina B.
RESUMEN DE LA INVENCIÓN
La presente invención se refiere a compuestos de fórmula (I)
imagen2
en los que
2
imagen3
imagen4
imagen5
E10774098
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Tabla 1: Compuestos representativos de Fórmula (I)
5
15
25
35
45
55
ID No
R1 imagen6 n * R2
1
3-(piperidin-4-il-oxi) fenilo 1 S bencilo
3
3-(piperidin-4-il-oxi) fenilo 1 S propin-2-ilo
6
3-(piperidin-4-il-oxi) fenilo 0 S propin-2-ilo
7
3-(piperidin-4-il-oxi) 5-metoxi-fenilo 1 S propin-2-ilo
8
3-(piperidin-4-il-oxi) fenilo 1 S n-buten-3-ilo
9
3-(piperidin-4-il-oxi) fenilo 1 S etilo
11
3-(piperidin-4-il-oxi) fenilo 1 S ciclopropil-metil
12
3-(piperidin-4-il-oxi) fenilo 1 S n-butilo
13
3-(piperidin-4-il-oxi) fenilo 1 S amino-n-propil
15
3-(piperidin-4-il-oxi) fenilo 1 S hidroxi-etil
16
3-(piperidin-4-il-oxi) fenilo 1 S isopropilo
18
3-(piperidin-4-il-oxi) fenilo 1 S n-propilo
19
3-(piperidin-4-il-oxi) fenilo 1 S pirazol-1-il-metil
20
3-(piperidin-4-il-oxi) fenilo 1 S midazol-4-ilmetil
24
3-(fenil) fenilo 1 S propin-2-il
25
3-(piperidin-4-il-oxi) fenilo 1 S hidroxi-metil
31
3-(piperidin-4-il-oxi) fenilo 1 S isobutilo
33
3-(piperidin-4-il-oxi) fenilo 1 S pirid-3-il-metil
6
E10774098
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15
25
35
45
55
35
H 3-metoxi-fenilo 1 S etilo
39
H 3,4-difluoro-fenilo 1 S etilo
40
H 4-metoxi-fenilo 1 S etilo
41
H naft-1-ilo 1 S etilo
49
H 2,6-dimetil-fenilo 1 S etilo
51
H benzo[1,3]-dioxol-5-ilo 1 S etilo
55
H 2,4,6-trimetil-fenilo 1 S etilo
56
H 4-metil-sulfonil-fenilo 1 S etilo
57
H 3,4-dimetoxi-fenilo 1 S etilo
58
H 4-trifluoro-metilfenilo 1 S etilo
59
H 3,5-dimetoxi-fenilo 1 S etilo
60
H benzo-tiofen-5-ilo 1 S etilo
61
2-(fenil) fenilo 1 S etilo
63
3-(piperidin-4-il-oxi) fenilo 1 S tien-2-il-metil
71
3-(piperidin-4-il-oxi) fenilo 1 R etilo
72
H 3-trifluoro-metilfenilo 1 S etilo
73
H naft-2-ilo 1 S etilo
74
H 2-trifluoro-metilfenilo 1 S etilo
75
2-(ciclohexil) fenilo 1 S etilo
76
H 2,3,5,6-tetra-metilfenilo 1 S etilo
77
H 3,6-dimetil-fenilo 1 S etilo
78
3-(piperidin-3R-il-oxi) fenilo 1 S etilo
79
3-(piperidin-3R-il-oxi) fenilo 1 S propin-2-ilo
80
3-(piperidin-3S-il-oxi) fenilo 1 S etilo
81
4-(fenil) fenilo 1 S etilo
82
H isoquinolin-5-ilo 1 S etilo
83
H 4-metil-naft-1-ilo 1 S etilo
84
H 4-fluoro-naft-1-ilo 1 S etilo
85
3-(piperidin-3S-il-oxi) fenilo 1 S propin-2-ilo
86
4-(bencil-oxi) fenilo 1 S etilo
87
H 2-metoxi-naft-1-ilo 1 S etilo
88
H 2-(metoxi-metil-naft-1-ilo) 1 S etilo
89
H isoquinolin-4-ilo 1 S etilo
90
3-(piperidin-4-il-oxi) fenilo 1 S pirid-2-il-metil
91
H benzofur-5-ilo 1 S etilo
92
H 3-metoxi-fenilo 1 R etilo
95
H 4-isopropil-fenilo 1 S etilo
96
H 3,5-dimetil-fenilo 1 S etilo
97
H 2,3-dihidro-benzo[1,4]-dioxin-6-ilo 1 S etilo
98
H fenilo 1 S etilo
99
H 2-metoxi-fenilo 1 S etilo
7
imagen7
imagen8
imagen9
imagen10
imagen11
imagen12
imagen13
imagen14
imagen15
imagen16
imagen17
imagen18
imagen19
imagen20
imagen21
imagen22
imagen23
imagen24
imagen25
imagen26
imagen27
imagen28
imagen29

Claims (1)

  1. imagen1
    imagen2
    imagen3
ES10774098.7T 2009-10-29 2010-10-28 Derivados alquinilo útiles como inhibidores de la DPP-1 Active ES2513291T3 (es)

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WO2012119941A1 (en) 2011-03-04 2012-09-13 Prozymex A/S Peptidyl nitrilcompounds as peptidase inhibitors
EA201491667A1 (ru) 2012-03-13 2015-03-31 Басф Се Фунгицидные соединения пиримидина
AR091858A1 (es) * 2012-07-25 2015-03-04 Sova Pharmaceuticals Inc INHIBIDORES DE CISTATIONIN-g-LIASA (CSE)
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Family Cites Families (20)

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Publication number Priority date Publication date Assignee Title
US548021A (en) * 1895-10-15 Wiiitfield potter toomee
US4847241A (en) * 1985-08-14 1989-07-11 G. D. Searle & Co. Fluorenyl substituted tyrosyl dipeptide amides which are useful in treating pain
EP0574545B1 (en) 1991-03-06 1994-11-30 G.D. Searle & Co. Phenyl amidines derivatives useful as platelet aggregation inhibitors
US5424334A (en) 1991-12-19 1995-06-13 G. D. Searle & Co. Peptide mimetic compounds useful as platelet aggregation inhibitors
DE4321502A1 (de) 1993-06-29 1995-01-12 Bayer Ag Alkinol-substituierte Peptide, Verfahren zu ihrer Herstellung und ihre Verwendung als antiretrovirale Mittel
EP0827495A4 (en) 1995-07-14 1998-11-04 Smithkline Beecham Corp SUBSTITUTED PENT-4-IN ACIDS
IL123164A (en) 1995-08-30 2001-03-19 Searle & Co Meta-guanidine urea thiourea or azacyclic amino benzoic acid derivatives and pharmaceutical compositions containing them
JP2002145897A (ja) 2000-11-10 2002-05-22 Kyorin Pharmaceut Co Ltd アミノ酸誘導体及びその製造法
AU2003222738B2 (en) * 2002-05-07 2009-09-17 Neurosearch A/S Novel azacyclic ethynyl derivatives
ATE396969T1 (de) * 2002-07-31 2008-06-15 Ranbaxy Lab Ltd 3,6-disubstituierte azabicyclo (3.1.0)hexanderivate, die sich als muscarinrezeptorantagonisten eignen
US20040186151A1 (en) * 2003-02-12 2004-09-23 Mjalli Adnan M.M. Substituted azole derivatives as therapeutic agents
US20040192743A1 (en) * 2003-02-12 2004-09-30 Mjalli Adnan M.M. Substituted azole derivatives as therapeutic agents
EP1975153A3 (en) * 2003-05-30 2010-03-31 Prozymex A/S Protease inhibitors
US7638513B2 (en) * 2004-06-02 2009-12-29 Schering Corporation Compounds for the treatment of inflammatory disorders
DE102005009784B4 (de) * 2005-03-03 2009-06-18 Technische Universität Darmstadt Peptid-Mimetika, Verfahren zur deren Herstellung, diese enthaltende pharmazeutische Zusammensetzung und deren Verwendung als Inhibitoren von Proteasomen und zur Induktion von Apoptose
NZ561939A (en) * 2005-03-30 2011-03-31 Conforma Therapeutics Corp Alkynyl pyrrolopyrimidines and related analogs as HSP90-inhibitors
MX2008012053A (es) 2006-03-21 2008-12-17 Joyant Pharmaceuticals Inc Promotores de apoptosis de molecula pequeña.
US7678894B2 (en) 2007-05-18 2010-03-16 Helicos Biosciences Corporation Nucleotide analogs
TW200922556A (en) 2007-08-20 2009-06-01 Glaxo Group Ltd Novel cathepsin C inhibitors and their use
EA201000958A1 (ru) 2007-12-12 2010-12-30 Астразенека Аб Пептидилнитрилы и их применение в качестве ингибиторов дипептидилпептидазы i

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