CO5190701A1 - TREATMENT OF COMBINATION WITH II-1RA AND COMPOUNDS THAT INHIBIT THE PROCESSING AND RELEASE OF II-1 - Google Patents

TREATMENT OF COMBINATION WITH II-1RA AND COMPOUNDS THAT INHIBIT THE PROCESSING AND RELEASE OF II-1

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Publication number
CO5190701A1
CO5190701A1 CO00066883A CO00066883A CO5190701A1 CO 5190701 A1 CO5190701 A1 CO 5190701A1 CO 00066883 A CO00066883 A CO 00066883A CO 00066883 A CO00066883 A CO 00066883A CO 5190701 A1 CO5190701 A1 CO 5190701A1
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Colombia
Prior art keywords
alkyl
aryl
heteroaryl
piperidyl
amino
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CO00066883A
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Spanish (es)
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Bruce Henry Littman
Louise Goodwin Woodwort Thasia
Mark Anthony Dombroski
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Pfizer Prod Inc
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Publication of CO5190701A1 publication Critical patent/CO5190701A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Un método para tratar o prevenir estados morbosos mediados por IL-1, que comprende administrar conjuntamente, a un animal mamífero que necesite dicho tratamiento, cantidades eficaces de un polipéptido IL-1ra o de una variante del mismo, y de un agente no esteroide que inhibe el procesamiento y la liberación de IL-1.Un método de acuerdo con la reivindicación 1, en el que el inhibidor del procesamiento y la liberación de IL-1 es una diarilsulfonilurea de fórmula I<EMI FILE="00066883_1" ID="1" IMF=JPEG >o una sal farmacéuticamente aceptable de la misma, fórmula en la que cada uno de R1 y R2 es independientemente un grupo de fórmula II<EMI FILE="00066883_2" ID="2" IMF=JPEG >En la que las líneas discontinuas ( --- ) representan dobles enlaces opcionales; n es 0, 1, 2 ó 3; y cada uno de A, B, D, E y G es independientemente oxígeno, azufre, nitrógeno o CR5R6 en el que cada uno de R5 y R6 es independientemente seleccionado entre (1) hidrógeno; (2) alquilo (C1-C6) opcionalmente sustituido con uno o dos grupos seleccionados entre alquil (C1-C6)amino, alquil (C1-C6)tio,alcoxilo(C1-C6), hidroxilo, ciano, perfluoroalquilo(C1-C6), arilo(C6-C10), heteroarilo(C5-C9), aril(C6-C10)amino, aril-(C6-C10)tio, aril(C6-C10)oxilo en que el grupo arilo está opcionalmente sustituido con alcoxilo(C1-C6), acilo(C1-C6), carboxilo, hidroxilo o halógeno; heteroaril(C5-C9)amino, heteroaril(C5-C9)tio, heteroaril(C5-C9)oxilo, aril(C6-C10)-arilo(C6-C10), cicloalquilo(C3-C6), hidroxilo, piperazinilo, aril(C6-C10)alcoxilo(C1-C6), heteroaril(C5-C9)alcoxilo(C1-C6),acil (C1-C6) amino, acil (C1-C6) tio, acil (C1-C6) oxilo, alquil-(C1-C6)sulfinilo, aril(C6-C10)sulfinilo, alquil (C1-C6)sulfonilo, aril(C6-C10) sulfonilo, amino, alquil(C1-C6)amino y [alquil (C1-C6)]2amino; (3) halógeno; (4) ciano; (5) amino; (6) hidroxilo; (7) perfluoroalquilo (C1-C6); (8) perfluoroalcoxilo(C1-C6); (9) alquenilo(C2-C6); (10) carboxi-alquenilo-(C2-C6); (11) alquinilo(C2-C6); (12) alquil(C1-C6)amino; (13) [alquil(C1-C6)]2amino; (14) alquil(C1-C6) sulfonilamido; (15) alquil(C1-C6)sulfinilo; (16) alquil(C1-C6)sulfonilo; (17) aminosulfonilo; (18) alquil (C1-C6) aminosulfinilo; (19) [alquil(C1-C6)]2aminosulfonilo; (20) alquil (C1-C6)tio; (21) alcoxilo(C1-C6); (22) perfluoroalquilo- 2 -(C1-C6); (23) arilo -(C6-C10); (24) heteroarilo(C5-C9); (25) aril (C6-C10) amino; (26) aril (C6-C10) tio; (27) aril(C6-C10) alcoxilo(C1-C6); (28) heteroaril(C5-C9)amino; (29) heteroaril(C5-C9) tio; (30) heteroaril(C5-C9)oxilo; (31) cicloalquilo(C3-C6); (32) alquil-(C1-C6)hidroximetileno; (33) piperidil=; (34) piridinilo; (35) tienilo; (36) furanilo; (37) alquil(C1-C6)piperidilo; (38) acil(C1-C6)amino; (39)acil(C1-C6)tio; 40) acil(C1-C6)-oxilo; (41) R7 alquilo(C1-C6) en que R7 es acil(C1-C6)piperazino, aril(C6-C10)piperazino, heteroaril(C5-C9)piperazino, alquil (C1-C6) piperazino, aril (C6-C10) alquil (C1-C6) piperazino, heteroaril(C5-C9)alquil(C1-C6)piperazino, morfolino, tiomorfolino, piperidino, pirrolidinilo, piperidilo, alquil (C1-C6)-piperidilo, aril(C6-C10)piperidilo, heteroaril(C5-C9)piperidilo, alquil(C1-C6)piperidil-alquilo(C1-C6), aril (C6-C10) piperidil-alquilo(C1-C6), heteroaril(C5-C9)piperidil-alquilo-(C1-C6) o acil(C1-C6)piperidilo;(42) un grupo de fórmula III<EMI FILE="00066883_3" ID="3" IMF=JPEG >en la ques es de 0 a 6;t es 0 ó 1;X es oxígeno o NR8 en que R8 es hidrógeno, alquilo(C1-C6 ) o cicloalquil(C3-C7)alquilo(C1-C6); eY es hidrógeno, hidroxilo, alquilo(C1-C6) opcionalmente sustituido con halógeno, hidroxilo o ciano; alcoxilo (C1-C6),ciano, alquinilo(C2-C6), arilo(C6-C10) en el que el grupo arilo está opcionalmente sustituido con halógeno, hidroxilo, carboxilo, alquilo(C1-C6), alcoxilo(C1-C6), perfluoroalquilo (C1-C6), alcoxi (C1-C6) alquilo (C1-C6) o NR9R10 en el que cada uno de R9 y R10 es independientemente seleccionado del grupo que consiste en hidrógeno y alquilo (C1-C6) opcionalmente sustituido con alquil(C1-C6)piperidilo, aril(C6-C10)piperidilo, heteroaril(C5-C9)piperidilo, arilo(C6-C10), heteroarilo(C5-C9) o cicloalquilo(C3-C6); piperidilo, alquil(C1-C6)piperidilo, aril(C6-C10)piperidilo, heteroaril(C5-C9)piperidilo, acil(C1-C6)piperidilo, arilo(C6-C10), heteroarilo(C5-C9), cicloalquilo (C3-C6), R11 alquilo (C2-C6), alquil (C1-C5) - (CHR11) -alquilo(C1-C6) en que R11 es hidroxilo, acil(C1-C6), oxilo, alcoxilo(C1-C6), piperazino, acil (C1-C6)amino, aIquiI (C1-C6)-tio, aril(C6-10)tio, alquil(C1-C6)sulfinilo, aril(C6-C10)-sulfinilo, alquil(C1-C6)sulfoxilo, aril(C6-10)sulfoxilo, amino, alquil (C1-C6) amino, [alquil(C1-C6)]2amino, acil (C1-C6)-piperazino, alquil (C1-C6) piperazino, aril(C6-C10)alquil(C1-C6)piperazino, heteroaril(C5-C9)alquil (C1-C6) piperazino, morfolino, tiomorfolino, piperidino o pirroIidino; R12 alquilo(C1-C6), alquil(C1-C5)-(CHR12)alquilo(C1-C6) en que R12 es piperidilo o alquil(C1-C6)piperidilo; y CH(R13)COR14 en que R14 es como se define más adelante y R13 es hidrógeno, alquilo(C1-C6), aril(C6-C10) alquilo (C1-C6), heteroaril (C5-C9) alquilo(C1-C6), alquil(C1-C6)tioalquilo(C1-C6), aril(C6-C10)tio-alquilo(C1-C6), alquil(C1-C6)sulfinil-alquilo(C1-C6), aril(C6-C10)sulfinil-alquilo(C1-C6), alquil(C1-C6)sulfonil-alquilo(C1-C6), aril(C6-C10)sulfonil-alquilo(C1-C6), hidroxialquilo(C1-C6), aminoalquilo(C1-C6), alquil(C1-C6)aminoalquilo-(C1-C6), [alquil(C1-C6)amino]2alquilo(C1-C6), R15R16NCOalquilo(C1-C6) o R15 OCOalquilo(C1-C6), en los que cada uno de R15 y R16 es independientemente seleccionado del grupo que consiste en hidrógeno, alquilo(C1-C6), aril(C6-C10) alquilo(C1-C6) y heteroaril(C5-C9) alquilo(C1-C6); y R14 es R17O o R17R18N, en los que cada uno de R17 y R18 es independientemente seleccionado del grupo que consiste en hidrógeno, alquilo(C1-C6), aril(C6-C10)alquilo(C1-C6) y heteroaril(C5-C9)alquilo(C1-C6);(43) un grupo de fórmula IV<EMI FILE="00066883_4" ID="4" IMF=JPEG >en la queu es 0, 1 ó 2;R19 es hidrógeno, alquilo(C1-C6) o perfluoroalquilo(C1-C6); yR20 es hidrógeno, alquilo(C1-C6), carboxiaquilo(C1-C6) o aril(C6-C10)alquilo(C1-C6); y(44) un grupo de fórmula V<EMI FILE="00066883_5" ID="5" IMF=JPEG >en la quea es 0, 1 ó 2;b es 0 ó 1;c es 1, 2 ó 3;d es 0 ó 1;e es 0, 1 ó 2;cada uno de J y L es independientemente oxigeno azufre;- 3 -R21 es hidrógeno, hidroxilo, flúor, alquilo(C1-C6), alcoxilo(C1-C6), haloalquilo(C1-C6), amino, acil(C1-C6) amino o NR26R27 en que cada uno de R26 y R27 es independientemente seleccionado entre hidrógeno, alquilo(C1-C6) y arilo(C6-C10);yR22 es hidrógeno, alquilo(C1-C6) opcionalmente sustituido con hidroxilo, halógeno, alquil(C1-C6)tio, alquil(C1-C6) sulfinilo o alquil(C1-C6)sulfonilo;o, en la fórmula II, cuando n es 1 y tanto B como D son CR5, los dos grupos R5 pueden ser considerados junto con los carbonos a los que están unidos, para formar un grupo de fórmula VI<EMI FILE="00066883_6" ID="6" IMF=JPEG >en la quelas lineas discontinuas, representan dobles enlaces opcionales;m es 0 ó 1; ycada uno de T, U, V y W es independientemente oxígeno, azufre, CO, nitrógeno o CR5R6 en el que R5 y R6 son como se definieron anteriormente;o, cuando tanto A como B son CR5, o cuando n es 1 y tanto B como D son CR5, o cuando tanto D como E son CR5, o cuando tanto E como G son CR5, los dos grupos pueden ser considerados junto con los carbonos adyacentes a los que están unidos, para formar un grupo cicloalquilo(C5-C6) opcionalmente sustituido con hidroxilo, o un grupo benzo.A method for treating or preventing IL-1 mediated morbid conditions, comprising administering together, to a mammalian animal in need of such treatment, effective amounts of an IL-1ra polypeptide or a variant thereof, and a non-steroid agent that inhibits the processing and release of IL-1. A method according to claim 1, wherein the inhibitor of the processing and release of IL-1 is a diarylsulfonylurea of formula I <EMI FILE = "00066883_1" ID = " 1 "MFI = JPEG> or a pharmaceutically acceptable salt thereof, formula in which each of R1 and R2 is independently a group of formula II <EMI FILE =" 00066883_2 "ID =" 2 "MFI = JPEG> In the that dashed lines (---) represent optional double bonds; n is 0, 1, 2 or 3; and each of A, B, D, E and G is independently oxygen, sulfur, nitrogen or CR5R6 in which each of R5 and R6 is independently selected from (1) hydrogen; (2) (C1-C6) alkyl optionally substituted with one or two groups selected from (C1-C6) alkyl, amino (C1-C6) thio, (C1-C6) alkoxy, hydroxyl, cyano, perfluoroalkyl (C1-C6) ), aryl (C6-C10), heteroaryl (C5-C9), aryl (C6-C10) amino, aryl- (C6-C10) thio, aryl (C6-C10) oxyl in which the aryl group is optionally substituted with alkoxy (C1-C6), acyl (C1-C6), carboxyl, hydroxyl or halogen; heteroaryl (C5-C9) amino, heteroaryl (C5-C9) thio, heteroaryl (C5-C9) oxyl, aryl (C6-C10) -aryl (C6-C10), cycloalkyl (C3-C6), hydroxyl, piperazinyl, aryl (C6-C10) (C1-C6) alkoxy, heteroaryl (C5-C9) alkoxy (C1-C6), acyl (C1-C6) amino, acyl (C1-C6) thio, acyl (C1-C6) oxyl, alkyl - (C1-C6) sulfinyl, aryl (C6-C10) sulfinyl, alkyl (C1-C6) sulfonyl, aryl (C6-C10) sulfonyl, amino, alkyl (C1-C6) amino and [alkyl (C1-C6)] 2amino; (3) halogen; (4) cyano; (5) amino; (6) hydroxyl; (7) perfluoroalkyl (C1-C6); (8) perfluoroalkoxy (C1-C6); (9) alkenyl (C2-C6); (10) carboxy-alkenyl- (C2-C6); (11) (C2-C6) alkynyl; (12) (C1-C6) alkyl amino; (13) [C1-C6 alkyl] 2amino; (14) (C1-C6) alkyl sulfonylamide; (15) (C1-C6) alkyl sulfinyl; (16) (C1-C6) alkyl sulfonyl; (17) aminosulfonyl; (18) (C1-C6) alkyl aminosulfinyl; (19) [C1-C6 alkyl] 2-amino sulfonyl; (20) (C1-C6) alkyl thio; (21) (C1-C6) alkoxy; (22) perfluoroalkyl-2- (C1-C6); (23) aryl - (C6-C10); (24) heteroaryl (C5-C9); (25) aryl (C6-C10) amino; (26) aryl (C6-C10) uncle; (27) aryl (C6-C10) alkoxy (C1-C6); (28) heteroaryl (C5-C9) amino; (29) heteroaryl (C5-C9) thio; (30) heteroaryl (C5-C9) oxyl; (31) cycloalkyl (C3-C6); (32) alkyl- (C1-C6) hydroxymethylene; (33) piperidil =; (34) pyridinyl; (35) thienyl; (36) furanyl; (37) (C1-C6) alkyl piperidyl; (38) acyl (C1-C6) amino; (39) acyl (C1-C6) uncle; 40) acyl (C1-C6) -oxy; (41) R7 (C1-C6) alkyl in which R7 is acyl (C1-C6) piperazino, aryl (C6-C10) piperazino, heteroaryl (C5-C9) piperazino, alkyl (C1-C6) piperazino, aryl (C6- C10) (C1-C6) alkyl piperazino, heteroaryl (C5-C9) alkyl (C1-C6) piperazino, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperidyl, (C1-C6) alkyl -piperidyl, aryl (C6-C10) piperidyl , heteroaryl (C5-C9) piperidyl, alkyl (C1-C6) piperidyl-alkyl (C1-C6), aryl (C6-C10) piperidyl-alkyl (C1-C6), heteroaryl (C5-C9) piperidyl-alkyl- ( C1-C6) or acyl (C1-C6) piperidyl; (42) a group of formula III <EMI FILE = "00066883_3" ID = "3" MFI = JPEG> in which cheese is 0 to 6; t is 0 or 1; X is oxygen or NR8 in which R8 is hydrogen, (C1-C6) alkyl or (C3-C7) cycloalkyl (C1-C6) alkyl; eY is hydrogen, hydroxyl, (C1-C6) alkyl optionally substituted with halogen, hydroxyl or cyano; (C1-C6) alkoxy, cyano, (C2-C6) alkynyl, aryl (C6-C10) in which the aryl group is optionally substituted with halogen, hydroxyl, carboxyl, (C1-C6) alkyl, (C1-C6) alkoxy ), perfluoroalkyl (C1-C6), alkoxy (C1-C6) alkyl (C1-C6) or NR9R10 in which each of R9 and R10 is independently selected from the group consisting of hydrogen and optionally substituted (C1-C6) alkyl with (C1-C6) alkyl piperidyl, aryl (C6-C10) piperidyl, heteroaryl (C5-C9) piperidyl, aryl (C6-C10), heteroaryl (C5-C9) or cycloalkyl (C3-C6); piperidyl, (C1-C6) alkyl piperidyl, aryl (C6-C10) piperidyl, heteroaryl (C5-C9) piperidyl, acyl (C1-C6) piperidyl, aryl (C6-C10), heteroaryl (C5-C9), cycloalkyl ( C3-C6), R11 (C2-C6) alkyl, (C1-C5) alkyl - (CHR11) - (C1-C6) alkyl in which R11 is hydroxyl, acyl (C1-C6), oxyl, (C1-C6) alkoxy ), piperazino, acyl (C1-C6) amino, aIquiI (C1-C6) -thio, aryl (C6-10) thio, alkyl (C1-C6) sulfinyl, aryl (C6-C10) -sulfinyl, alkyl (C1- C6) sulfoxyl, aryl (C6-10) sulfoxyl, amino, (C1-C6) alkyl, amino [[C1-C6]] 2amino, acyl (C1-C6) -piperazino, (C1-C6) alkyl piperazino, aryl (C6-C10) alkyl (C1-C6) piperazino, heteroaryl (C5-C9) alkyl (C1-C6) piperazino, morpholino, thiomorpholino, piperidino or pyrroidine; R12 (C1-C6) alkyl, (C1-C5) alkyl - (CHR12) (C1-C6) alkyl in which R12 is piperidyl or (C1-C6) alkyl piperidyl; and CH (R13) COR14 in which R14 is as defined below and R13 is hydrogen, (C1-C6) alkyl, aryl (C6-C10) (C1-C6) alkyl, heteroaryl (C5-C9) (C1-) alkyl C6), (C1-C6) alkyl thio (C1-C6) alkyl, aryl (C6-C10) thio-C1-C6 alkyl, (C1-C6) alkyl sulfinyl (C1-C6) alkyl, aryl (C6-) C10) sulfinyl (C1-C6) alkyl, (C1-C6) alkyl sulfonyl (C1-C6) alkyl, aryl (C6-C10) sulfonyl (C1-C6) alkyl, hydroxyalkyl (C1-C6), aminoalkyl ( C1-C6), alkyl (C1-C6) aminoalkyl- (C1-C6), [alkyl (C1-C6) amino] 2alkyl (C1-C6), R15R16NCOalkyl (C1-C6) or R15 OCOalkyl (C1-C6), wherein each of R15 and R16 is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, aryl (C6-C10) alkyl (C1-C6) and heteroaryl (C5-C9) (C1-C6) alkyl ); and R14 is R17O or R17R18N, in which each of R17 and R18 is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, aryl (C6-C10) alkyl (C1-C6) and heteroaryl (C5- C9) (C1-C6) alkyl; (43) a group of formula IV <EMI FILE = "00066883_4" ID = "4" IMF = JPEG> in which u is 0, 1 or 2; R19 is hydrogen, (C1 alkyl) -C6) or perfluoroalkyl (C1-C6); and R20 is hydrogen, (C1-C6) alkyl, (C1-C6) carboxy alkyl or (C6-C10) aryl (C1-C6) alkyl; and (44) a group of formula V <EMI FILE = "00066883_5" ID = "5" MFI = JPEG> in which a is 0, 1 or 2; b is 0 or 1; c is 1, 2 or 3; d is 0 or 1; e is 0, 1 or 2; each of J and L is independently sulfur oxygen; - 3 -R21 is hydrogen, hydroxyl, fluorine, (C1-C6) alkyl, (C1-C6) alkoxy, haloalkyl (C1-C6), amino, acyl (C1-C6) amino or NR26R27 in which each of R26 and R27 is independently selected from hydrogen, (C1-C6) alkyl and aryl (C6-C10); and R22 is hydrogen, alkyl (C1-C6) optionally substituted with hydroxyl, halogen, (C1-C6) alkyl thio, (C1-C6) alkyl sulfinyl or (C1-C6) alkyl sulfonyl; or, in formula II, when n is 1 and both B since D is CR5, the two R5 groups can be considered together with the carbons to which they are attached, to form a group of formula VI <EMI FILE = "00066883_6" ID = "6" IMF = JPEG> in which the broken lines , represent optional double bonds; m is 0 or 1; Each one of T, U, V and W is independently oxygen, sulfur, CO, nitrogen or CR5R6 in which R5 and R6 are as defined above; or, when both A and B are CR5, or when n is 1 and both B as D are CR5, or when both D and E are CR5, or when both E and G are CR5, the two groups can be considered together with the adjacent carbons to which they are attached, to form a cycloalkyl group (C5-C6 ) optionally substituted with hydroxyl, or a benzo group.

CO00066883A 1999-09-14 2000-09-05 TREATMENT OF COMBINATION WITH II-1RA AND COMPOUNDS THAT INHIBIT THE PROCESSING AND RELEASE OF II-1 CO5190701A1 (en)

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