AR035547A1 - AULMATIC AULMATIC HYDROXAMIC ACIDS INHIBITORS OF METALOPROTEASAS - Google Patents

AULMATIC AULMATIC HYDROXAMIC ACIDS INHIBITORS OF METALOPROTEASAS

Info

Publication number
AR035547A1
AR035547A1 ARP000102342A AR035547A1 AR 035547 A1 AR035547 A1 AR 035547A1 AR P000102342 A ARP000102342 A AR P000102342A AR 035547 A1 AR035547 A1 AR 035547A1
Authority
AR
Argentina
Prior art keywords
group
heteroaryl
alkylthio
aryl
mmp
Prior art date
Application number
Other languages
Spanish (es)
Inventor
Jeffrey N Carroll
Stephen A Kolodziej
Deborah A Mischke
Tollefson
William F Vernier
Terry L Boehm
Joseph G Rico
Louis J Bedell
Yvette M Fobian
Susan C Howard
Nathan W Stehle
Gary A Decrescenzo
Madeleine Hui Li
Susan L Hockerman
Joseph J Mcdonald
Thomas E Barta
Robert Becker
John N Freskos
Daniel P Getman
Clara Villamil
Original Assignee
Searle & 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 Searle & Co filed Critical Searle & Co
Publication of AR035547A1 publication Critical patent/AR035547A1/en

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Un proceso de tratamiento que comprende la administración, a un huésped que presenta una afección asociada con actividad patológica de metaloproteasas de matriz, de una cantidad eficaz de un ácido sulfon-hidroxámico aromático que presenta una excelente actividad inhibitoria de una o más de las enzimas metaloproteasa matriz (MMP), tales como MMP-2, MMP-9 y MMP-13, mientras que presenta una actividad inhibidora sustancialmente menor al menos contra la MMP-1. Compuestos inhibidores metaloproteasas que presentan esas actividades selectivas, procesos para la elaboración de dichos compuestos y composiciones farmacéuticas que utilizan un inhibidor. Reivindicación 1: Un proceso para el tratamiento de un mamífero huésped que presenta una condición asociada con actividad patológica de la metaloproteasa matriz (MMP), el cual comprende la administración de un compuesto inhibidor de la metaloproteasa o una sal farmacéuticamente aceptable de dicho compuesto, en una cantidad efectiva a un mamífero huésped que presenta dicha condición; el mencionado inhibidor de la metaloproteasa inhibe la actividad de una o más de las enzimas MMP-2, MMP-9 y MMP-13, mientras presenta una actividad inhibitoria sustancialmente menor contra la MMP-1; la estructura de dicho compuesto corresponde a la fórmula (1) en la cual: tanto R1 como R2 son hídridos, o R1 y R2 junto con los átomos a los cuales están unidos forman un anillo de 5-8 ramificaciones que contiene uno, dos o tres heteroátomo que son oxígeno, azufre o nitrógeno; R3 es un radical arilo o heteroarilo opcionalmente sustituido, y cuando dicho radical arilo o heteroarilo es sustituido, el sustituyentes es (a) seleccionado del grupo consistente en un radical opcionalmente sustituido cicloalquilo, heterocicloalquilo, arilo, heteroarilo, aralquilo, heteroaralquilo, aralcoxi, heteroaralcoxi, aralcoxialquilo, ariloxialquilo, aralcanoilalquilo, arilcarbonilalquilo, aralquilarilo, ariloxialquilarilo, aralcoxiarilo, arilazoarilo, arilhidrazinoarilo, alquiltioarilo, ariltioalquilo, alquiltioaralquilo, aralquiltioalquilo, y aralquiltioarilo, el sulfóxido o sulfono de cualesquiera de los sustituyentes tio, y una estructura fundida de anillo que comprende dos o más anillos de 5 o 6 ramificaciones, seleccionados del grupo consistente en arilo, heteroarilo, cicloalquilo y heterocicloalquilo; y (b) es opcionalmente sustituido con uno o dos sustituyentes independientemente seleccionados del grupo consistente en ciano, perfluoroalquilo, trifluorometoxi, trifluorometiltio, haloalquilo, trifluormetilalquilo, aralcoxicarbonilo, ariloxicarbonilo, hidroxi, halo, alquilo, alcoxi, nitro, tiol, hidroxicarbonilo, ariloxi, ariltio, aralquilo, arilo, arilcarbonilamino, heteroariloxi, heteroariltio, heteroaralquilo, cicloalquilo, heterocicloxi, heterociclotio, heterocicloamino, cicloalquiloxi, cicloalquiltio, heteroaralcoxi, heteroaralquiltio, aralcoxi, aralquiltio, aralquilamino, heterociclo, heteroarilo, arilazo, hidrocarbonilalcoxi, alcoxicarbonilalcoxi, alcanoílo, arilcarbonilo, aralcanoílo, alcanoiloxi, aralcanoiloxi, hidroxialquilo, hidroxialcoxi, alquiltio, alcoxialquiltio, alcoxicarbonilo, ariloxialcoxiarilo, ariltioalquiltioarilo, ariloxialquiltioarilo, ariltioalcoxiarilo, hidroxicarbonilalcoxi, hidroxicarbonilalquiltio, alcoxicarbonilalcoxi, alcoxicarbonilalquiltio, amino en el cual en nitrógeno amino es (i) mantenido, o (ii) sustituido con uno o dos sustituyentes que son independientemente seleccionados del grupo consistente en alquilo, arilo, heteroarilo, aralquilo, cicloalquilo, aralcoxicarbonilo, alcoxicarbonilo, arilcarbonilo, aralcanoílo, heteroarilcarbonilo, heteroaralcanoílo, y un grupo alcanoílo, o (iii) en el cual el nitrógeno de amino y dos sustituyentes unidos al mismo forman un anillo heterociclo o heteroarilo de 5-8 ramificaciones que contiene de 0 a 2 heteroátomos adicionales que son nitrógeno, oxígeno o azufre, y dicho anillo es (a) mantenido, o (b) sustituido con uno o dos grupos independientemente seleccionados del grupo consistente en un arilo, alquilo, heteroarilo, aralquilo, heteroaralquilo, hidroxi, alcoxi, alcanoílo, cicloalquilo, heterocicloalquilo, alcoxicarbonilo, hidroxialquilo, trifluorometilo, heterocicloalquilo benzo-fundido, hidroxialcoxialquilo, aralcoxicarbonilo, hidroxicarbonilo, ariloxicarbonilo, heterocicloalcoxi benzo-fundido, cicloalquilcarbonilo benzo-fundido, heterociclo-alquilcarbonilo, y un grupo cicloalquilcarbonilo, carbonilamino, en el cual el nitrógeno carbonilamino es (i) mantenido, o (ii) es la amina reactiva de un aminoácido, o (iii) sustituido con uno o dos radicales seleccionados de un grupo consistente en un alquilo, hidroxialquilo, hidroxiheteroaralquilo, cicloalquilo, aralquilo, trifluormetilalquilo, heterocicloalquilo, heterocicloalquilo benzo-fundido, cicloalquilo benzo-fundido, y un grupo N,N-dialquil sustituido alquilamino-alquilo, o (iv) el nitrógeno carboxamido y dos sustituyentes unidos al mismos forman un anillo heterociclo, heteroarilo o heterocicloalquilo benzo-fundido de 5-8 ramificaciones, que puede o no ser sustituido con uno o dos radicales independientemente seleccionados del grupo consistente en un alquilo, alcoxicarbonilo, nitro, heterocicloalquilo, hidroxi, hidroxicarbonilo, arilo, aralquilo, heteroaralquilo y un grupo amino, en el cual el nitrógeno amino es (i) mantenido, o (ii) sustituido con uno o dos sustituyentes que son seleccionados independientemente del grupo consistente en alquilo, arilo, y heteroarilo, o (iii) en el cual el nitrógeno amino y dos sustituyentes unidos al mismo forman un anillo heterociclo o heteroarilo de 5-8 ramificaciones, y un grupo aminoalquilo, en el cual el nitrógeno aminoalquilo es (i) mantenido, o (ii) sustituido con uno o dos sustituyentes seleccionados independientemente del grupo consistente en un alquilo, arilo, aralquilo, cicloalquilo, aralcoxicarbonilo, alcoxicarbonilo, y un grupo alcanoílo, o (iii) en el cual el nitrógeno aminoalquilo y dos sustituyentes unidos al mismo forman un anillo heterociclo o heteroarilo de 5-8 ramificaciones.A treatment process comprising the administration, to a host presenting a condition associated with pathological activity of matrix metalloproteases, of an effective amount of an aromatic sulfon-hydroxamic acid that exhibits excellent inhibitory activity of one or more of the metalloprotease enzymes matrix (MMP), such as MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibitory activity against MMP-1. Metalloprotease inhibitor compounds that exhibit these selective activities, processes for the elaboration of said compounds and pharmaceutical compositions that use an inhibitor. Claim 1: A process for the treatment of a host mammal presenting a condition associated with pathological activity of the matrix metalloprotease (MMP), which comprises the administration of a metalloprotease inhibitor compound or a pharmaceutically acceptable salt of said compound, in an effective amount to a host mammal presenting said condition; said metalloprotease inhibitor inhibits the activity of one or more of the MMP-2, MMP-9 and MMP-13 enzymes, while exhibiting substantially less inhibitory activity against MMP-1; the structure of said compound corresponds to the formula (1) in which: both R1 and R2 are hydrides, or R1 and R2 together with the atoms to which they are attached form a 5-8 branching ring containing one, two or three heteroatoms that are oxygen, sulfur or nitrogen; R3 is an optionally substituted aryl or heteroaryl radical, and when said aryl or heteroaryl radical is substituted, the substituents is (a) selected from the group consisting of an optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxy radical , aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, alkylthioarylalkyl, aralkyl, and a thio-alkylthio, which substitutes for the two-ring-alkyl of which the alkylthio-alkylthio of which sulfide is the alkylthio of which sulfide of which sulfide, which is the alkylthio of which sulfide, which is the alkylthio of which sulfide, which is the alkylthio of which sulfide, which is the alkylthio of which sulfide, which is the alkylthio of which sulfide, which is substituted by the sulfide or more rings of 5 or 6 branches, selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocycloalkyl; and (b) is optionally substituted with one or two substituents independently selected from the group consisting of cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluormethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hidrocarbonilalcoxi, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, ariloxialcoxiarilo, ariltioalquiltioarilo, ariloxialquiltioarilo, ariltioalcoxiarilo, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alcoxicarbonilalquiltio, amino which in amino nitrogen is (i) maintained, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl , and an alkanoyl group, or (iii) in which the amino nitrogen and two substituents attached thereto form a 5-8 branched heterocycle or heteroaryl ring containing from 0 to 2 additional heteroatoms that are nitrogen, oxygen or sulfur, and said ring is (a) maintained, or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzo-molten heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, heterocycloalcox i benzo-molten, cycloalkylcarbonyl benzo-molten, heterocycloalkylcarbonyl, and a cycloalkylcarbonyl group, carbonylamino, in which the nitrogen carbonylamino is (i) maintained, or (ii) is the reactive amine of an amino acid, or (iii) substituted with one or two radicals selected from a group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluormethylalkyl, heterocycloalkyl, benzo-molten heterocycloalkyl, benzo-molten cycloalkyl, and an N, N-dialkyl substituted alkylamino-alkyl group, or (iv) the carboxamide nitrogen and two substituents attached thereto form a 5-8 branched heterocyclic, heteroaryl or heterocycloalkyl ring, which may or may not be substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl , nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group, in which nitrogen ami it is not (i) maintained, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) in which the amino nitrogen and two substituents attached thereto form a 5-8 branched heterocycle or heteroaryl ring, and an aminoalkyl group, in which the aminoalkyl nitrogen is (i) maintained, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) in which the aminoalkyl nitrogen and two substituents attached thereto form a 5-8 branched heterocycle or heteroaryl ring.

ARP000102342 1999-05-14 2000-05-15 AULMATIC AULMATIC HYDROXAMIC ACIDS INHIBITORS OF METALOPROTEASAS AR035547A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US31183799A 1999-05-14 1999-05-14

Publications (1)

Publication Number Publication Date
AR035547A1 true AR035547A1 (en) 2004-06-16

Family

ID=27757522

Family Applications (1)

Application Number Title Priority Date Filing Date
ARP000102342 AR035547A1 (en) 1999-05-14 2000-05-15 AULMATIC AULMATIC HYDROXAMIC ACIDS INHIBITORS OF METALOPROTEASAS

Country Status (5)

Country Link
AR (1) AR035547A1 (en)
CO (1) CO5251417A1 (en)
PE (1) PE20010202A1 (en)
UY (1) UY26145A1 (en)
ZA (1) ZA200109006B (en)

Also Published As

Publication number Publication date
ZA200109006B (en) 2002-12-02
PE20010202A1 (en) 2001-02-19
CO5251417A1 (en) 2003-02-28
UY26145A1 (en) 2000-12-29

Similar Documents

Publication Publication Date Title
US5025001A (en) S-nitroso derivatives of ACE inhibitors and the use thereof
ES2229790T3 (en) DERIVATIVES OF LIPOIC ACID AND ITS USE FOR THE TREATMENT OF DISEASES.
BR9814643A (en) Aromatic hydroxamic acid sulfone metalloprotease inhibitor
EA199800541A1 (en) METALLOPROTEINASE INHIBITORS, PHARMACEUTICAL COMPOUNDS, THEIR CONTAINING THEM, AND THEIR PHARMACEUTICAL APPLICATIONS, AND WAYS AND INTERMEDIATE CONNECTIONS, SUITABLE FOR THEM
CO4920240A1 (en) DIHETERO-CYCLIC METALOPROTEASE INHIBITOR COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND METHODS FOR ITS USE
CO4920241A1 (en) HETERO-CYCLIC METALOPROTEASE INHIBITOR COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND METHODS FOR ITS USE
CO4900035A1 (en) METALOPROTEASE INHIBITING COMPOUNDS 1,3-DIHETEROCICLICOS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND METHODS FOR USE
SE8303824D0 (en) N-IMIDAZOLYL DERIVATIVES OF BICYCLIC COMPOUNDS AND PROCESS FOR THEIR PREPARATION
UY28674A1 (en) 11-BETA-HYDROXIESTEROID DEHYDROGENASE TYPE 1 INHIBITORS AMINO
AR033989A1 (en) A COMPOUND DERIVED FROM 3-INDOLIL-4-FENIL-1H-PIRROL-2,5-DIONA, A METHOD TO PREPARE IT, AND A MEDICINAL PRODUCT CONTAINING IT
AR036598A1 (en) DERIVATIVES OF 4,5-DIHIDRO-1H-PIRAZOL THAT HAVE POWERFUL CB1 ANTAGONIST ACTIVITY
UY28132A1 (en) PIRROLOPIRIMIDINE DERIVATIVES
DE69332860D1 (en) BICYCLIC FIBRINOGEN ANTAGONISTE
CO5090848A1 (en) SUBSTITUTED BENZENE COMPOUNDS, PREPARATION PROCEDURES, AND HERBICIDE AND FOLIANT COMPOSITIONS CONTAINING THEM
NO20045403L (en) New thiophenamidines, their compositions and methods for the treatment of complement-mediated diseases and conditions
CO4900045A1 (en) SPYROCYCLIC METALOPROTEASE INHIBITING COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND METHODS FOR ITS USE
EA201170607A1 (en) ACRYLAMID DERIVATIVES APPLICABLE AS INHIBITORS
CA2655828A1 (en) Compositions and methods of treating cns disorders
AU6972098A (en) Peptidyl-2-amino-1-hydroxyalkanesulfonic acid cysteine protease inhibitors
PT96030A (en) PROCESS FOR THE PREPARATION OF FINOESTIGMINE RELATED AMINOCARBONILCARBAMATES AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM
ES2291722T3 (en) AMINOALCOXYINDOLS AS LIGANDS 5-HT6-RECEPTORS FOR THE TREATMENT OF CNS DISORDERS.
UY25888A1 (en) DERIVATIVES OF 4-BIARILBUTIRICO AND 5-BIARILPENTANOICO ACID SUBSTITUTES USEFUL AS MATRIX METALPROTEASE INHIBITORS FOR THE TREATMENT OF RESPIRATORY DISEASES
CS255891B2 (en) Process for preparing new derivatives of amidine
AR035547A1 (en) AULMATIC AULMATIC HYDROXAMIC ACIDS INHIBITORS OF METALOPROTEASAS
AR029001A1 (en) DERIVATIVES OF BENCIL-3,4-METHYLENDIOXYCHINAMIC AND THE USE OF THEM FOR THE MANUFACTURE OF A MEDICINAL PRODUCT

Legal Events

Date Code Title Description
FC Refusal
FB Suspension of granting procedure