AR033859A1 - Inhibidores de la metaloproteinasa de la matriz - Google Patents

Inhibidores de la metaloproteinasa de la matriz

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Publication number
AR033859A1
AR033859A1 ARP020100472A ARP020100472A AR033859A1 AR 033859 A1 AR033859 A1 AR 033859A1 AR P020100472 A ARP020100472 A AR P020100472A AR P020100472 A ARP020100472 A AR P020100472A AR 033859 A1 AR033859 A1 AR 033859A1
Authority
AR
Argentina
Prior art keywords
hydrogen bond
hydrophobic group
bond acceptors
mmp
angstrom
Prior art date
Application number
ARP020100472A
Other languages
English (en)
Inventor
Daniel Fred Ortwine
Alexander Gregory Pavlovsky
William Howard Roark
Charles Andrianjara
Original Assignee
Warner Lambert Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner Lambert Co filed Critical Warner Lambert Co
Publication of AR033859A1 publication Critical patent/AR033859A1/es

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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
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    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
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    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms
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    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
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    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
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    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
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    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
    • C07D285/26—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals
    • C07D285/32—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals 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 in position 3
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    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • C07D513/04—Ortho-condensed systems

Abstract

Un compuesto que se une alostéricamente con una MMP-13 y que comprende un primer y un segundo grupos hidrofóbicos; y un primer y un segundo aceptores de enlace de hidrógeno, que comprende: (a) las posiciones relativas de los centroides con las características anteriores se definen por las siguientes coordenadas cartesianas en Angstrom: (i) primer aceptor de enlace de hidrógeno, 0,00, 0,00, 0,00; (ii) segundo aceptor de enlace de hidrógeno, 5,08, 2,23, 0,00; (iii) primer grupo hidrofóbico, -1,52,-3,06, -0,23, (iv) segundo grupo hidrofóbico, 9,07, 0,00, 0,00; y (b) las tolerancias en las posiciones de los grupos hidrofóbicos y los aceptores de enlace de hidrógeno son +/- 1,0 Angstrom y +/- 1,5 Angstrom respectivamente. Un ligando que se une alostéricamente con la MMP-13 y que comprende un andamiaje, un primer y un segundo aceptores de enlace de hidrógeno y un primer y un segundo grupos hidrofóbicos conectados por cadenas laterales al andamiaje; una estructura cíclica que forma parte del andamiaje está situada entre el primer y el segundo aceptores de enlace de hidrógeno, y los aceptores de enlace de hidrógeno y los grupos hidrofóbicos estas dispuestos de manera tal que cuando el ligando se une a la MMP-13: el primer y el segundo aceptores de enlace de hidrógeno se enlazan respectivamente, con Thr245, Thr247; el primer grupo hidrofóbico se ubica dentro del canal S1'; y el segundo grupo hidrofóbico está relativamente abierto al solvente. Composición farmacéutica que comprende dicho compuesto y un excipiente farmacéuticamente aceptable. Uso de dicho compuesto para la preparación de un medicamento destinado al tratamiento de una enfermedad, mediante la inhibición de la MMP-13 y que es para el tratamiento de la artritis, artritis reumatoidea, osteoartritis, osteoporosis, etc, degeneración macular relacionada con la edad o cáncer. El medicamento es de aplicación en un método para el tratamiento de dichas enfermedades.
ARP020100472A 2001-02-14 2002-02-13 Inhibidores de la metaloproteinasa de la matriz AR033859A1 (es)

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MXPA03007250A (es) 2005-07-25
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AU2002228302A1 (en) 2002-08-28
EP1361873A4 (en) 2005-10-26
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US20030078276A1 (en) 2003-04-24
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BR0207864A (pt) 2004-03-09
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