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AR048528A1 - COMPOUNDS DERIVED FROM QUINOLINA AS AN ANTAGONIST OF THE PGD2 RECEPTOR FOR THE TREATMENT OF INFLAMMATORY DISEASES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. - Google Patents

COMPOUNDS DERIVED FROM QUINOLINA AS AN ANTAGONIST OF THE PGD2 RECEPTOR FOR THE TREATMENT OF INFLAMMATORY DISEASES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.

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Publication number
AR048528A1
AR048528A1 ARP050101369A ARP050101369A AR048528A1 AR 048528 A1 AR048528 A1 AR 048528A1 AR P050101369 A ARP050101369 A AR P050101369A AR P050101369 A ARP050101369 A AR P050101369A AR 048528 A1 AR048528 A1 AR 048528A1
Authority
AR
Argentina
Prior art keywords
aromatic
group
ring
alkyl
optionally substituted
Prior art date
Application number
ARP050101369A
Other languages
Spanish (es)
Inventor
Shomir Ghosh
Amy M Elder
Kenneth G Carson
Kevin T Sprott
Sean Harrison
Frederick Hicks
Original Assignee
Millennium Pharm Inc
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Publication date
Application filed by Millennium Pharm Inc filed Critical Millennium Pharm Inc
Publication of AR048528A1 publication Critical patent/AR048528A1/en

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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P37/02—Immunomodulators
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    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P37/08—Antiallergic agents
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • General Chemical & Material Sciences (AREA)
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Abstract

Se describe el uso de dichos compuestos para inhibir el receptor acoplado a proteína G mencionados como molécula homologa al receptor quimioatrayante expresado en Th2, o simplemente ôCRTH2ö para el tratamiento de trastornos inflamatorios. Las variables en la Formula Estructural (1) se definen en la presente. Reivindicacion 1: Un compuesto de formula (1), o una sal farmacéuticamente aceptable del mismo, donde: El anillo A es un aromático monocíclico opcionalmente sustituido; R es -X1-R1; Rx ES -X2-R4; cada uno de X1 y X2 son independientemente -S(O)2-, -C(O)-, o -C(O)NH-; R1 es: A) un grupo aromático o grupo heteroaromático que 5-6 átomos en el anillo, condensado a un anillo heterocíclico monocíclico no aromático o anillo monocíclico aromático o heteroaromático donde el anillo heterocíclico no aromático, el anillo aromático, o el anillo heteroaromático están o opcionalmente sustituido; o B) un grupo aromático o grupo heteroaromático que tiene 5-6 átomos en el anillo, sustituido con: i) T1-V-T-Ry; ii) T1-V-T-M-Ry; o iii) V-R9, donde R9 es un grupo carbocíclico o heterocíclico no aromático opcionalmente sustituido; y donde el grupo aromático o heteroaromático que tiene 5-6 átomos en el anillo está opcionalmente sustituido también con 1-2 grupos seleccionados independientemente representados por Rz; cada Rz se selecciona independientemente entre halogeno, haloalquilo, Ro, -ORo, -O(haloalquilo), -SRo; -NO2, -CN, -N(R')2, -NR'CO2Ro, -NR??C(O)Ro, -NR??NR'C(O)Ro, -N(R??)C(O)N(R')2, -NR'NR??C(O)N(R??)2, -NR??NR'CO2Ro, -C(O)C(O)Ro, -C(O)CH2(O)Ro, -CO2Ro, -C(O)Ro, -C(O)N(Ro)2, -OC(O)Ro, -OC(O)N(Ro)2, -S(O)2Ro, -SO2N(R')2, -S(O)Ro, -NR'SO2N(R')2, -NR'SO2Ro, -C(=S)N(R')2 y -C(=NH)-N(R')2; cada R' es independientemente hidrogeno, alquilo, -C(O)ORo, S(O)2Ro o -C(O)Ro; cada Ro es independientemente hidrogeno o un grupo alquilo, grupo heterocíclico no aromático o grupo aromático y el alquilo, el grupo heterocíclico no aromático y el grupo aromático representados por Ro están opcionalmente sustituidos con uno o más grupos seleccionados independientemente representados por R ; R es R+, -OR+, -O(haloalquilo), -SR+; -NO2, -CN, -N(R+)2, -NHCO2R+, -NHC(O)R+, -NHNHC(O)R+, -NHC(O)N(R+)2, - NHNHC(O)N(R+)2, -NHNHCO2R+, -C(O)C(O)R+, -C(O)CH2(O)R+, -CO2R+, -C(O)R+, -C(O)N(R+)2, -OC(O)R+, -OC(O)N(R+)2, -S(O)2R+, -SO2N(R+)2, -S(O)R+, -NHSO2N(R+)2, -NHSO2R+, -C(=S)N(R+)2 y -C(=NH)-N(R+)2; R+ es -H, un grupo alquilo C1-3, un grupo heteroarilo monocíclico, un grupo heterocíclico no aromático o un grupo fenilo opcionalmente sustituido con alquilo, haloalquilo, alcoxi, haloalcoxi, halo, -CN, -NO2, amina, alquilamina o dialquilamina; o -N(R+)2 es un grupo heterocíclico no aromático, con la condicion de que los grupos heterocíclicos no aromáticos representados por R+ y -N(R+)2 que comprenden una amina de anillo secundario están opcionalmente acilados o alquilados; V es un enlace covalente, -O-, -C(O)-, -N(R')-, -S-, -S(O)-, -C(O)NR5-, - NR5C(O)-, -S(O)2NR5, -NR5S(O)2- o -S(O)2-; T es alquileno C1-10 de cadena lineal; T1 es un enlace covalente o un alquileno C1-10 de cadena lineal, donde T y T1 juntos no contienen más de 10 átomos de carbono y donde T y T1 están opcional e independientemente sustituidos en cualquiera de uno o más de los átomos de carbono sustituibles con haluro, alquilo, gem dialquilo, gem dihalo, haloalquilo, alcoxi, haloalcoxi, espiro cicloalquilo, nitrogeno opcionalmente N-sustituido que contiene un grupo heterocíclico no aromático espiro, amina, alquilamina, dialquilamina, alcoxi o hidroxilo; M es un grupo opcionalmente sustituido seleccionado entre grupo aromático monocíclico, heteroaromático, carbocíclico monocíclico no aromático o heterocíclico; Ry es -C(O)OR5, -C(O)R5, -OC(O)R5, -C(O)N(R5)2, -NR5C(O)R5, -NR5C(O)OR5, -S(O)2R5, -S(O)2COR5, -S(O)2N(R5)2, -NR5S(O)2R5, -NR5S(O)2R5, -S(O)2OR5, -S(O)OR5, -S(O)R5, -SR5, -C(O)NR5S(O)2R5, -CN, -NR5C(O)N(R5)2, -OC(O)N(R5)2, -N(R5)2, - OR5, un grupo heterocíclico no aromático opcionalmente sustituido o un grupo heteroarilo opcionalmente sustituido; con la condicion de que T es C2-10 cuando V es un enlace covalente y T es C2-10 cuando V es -O-, -S- o -N(R??)- y Ry es -CN, -OH, -SH, - N(R5)2; cada R5 es independientemente -H, alquilo, haloalquilo, hidroxialquilo, carboxialquilo, -C(O)OCH2C6H5, -S(O)2CH3, -C(O)OH, -C(O)OMe, -C(O)OEt, C(O)NH2, bencilo, pirrolidinilo, morfolinilo o -N(R5)2 es un grupo heterocíclico no aromático que contiene nitrogeno; R2 es alquilo C1-3; R3 es un grupo monocíclico o bicíclico opcionalmente sustituido seleccionado entre un grupo aromático, heteroaromático, carbocíclico no aromático y heterocíclico no aromático; y R4 es alquilo C1-3 o hidroxialquilo C1-3. Reivindicacion 48: El método de la reivindicacion 46 donde la enfermedad, trastorno o síntoma inflamatorio es rinitis alérgica o asma alérgica. Reivindicacion 53: Un método para preparar un compuesto producto representado por la formula estructural (2), a partir de un compuesto de partida representado por la formula estructural (3), comprendiendo dicho método la etapa de reducir el carbonilo de la amida del compuesto de partida para formar un intermedio y después ciclar el intermedio para formar el compuesto producto, donde -C(O)ORz es un grupo protector de amida.The use of said compounds to inhibit the G-protein coupled receptor mentioned as a homologous molecule to the chemoattractant receptor expressed in Th2, or simply "CRTH2" for the treatment of inflammatory disorders is described. The variables in the Structural Formula (1) are defined herein. Claim 1: A compound of formula (1), or a pharmaceutically acceptable salt thereof, wherein: Ring A is an optionally substituted monocyclic aromatic; R is -X1-R1; Rx ES -X2-R4; each of X1 and X2 are independently -S (O) 2-, -C (O) -, or -C (O) NH-; R1 is: A) an aromatic group or heteroaromatic group that 5-6 atoms in the ring, condensed to a non-aromatic monocyclic heterocyclic ring or aromatic or heteroaromatic monocyclic ring where the non-aromatic heterocyclic ring, aromatic ring, or heteroaromatic ring are or optionally substituted; or B) an aromatic group or heteroaromatic group having 5-6 ring atoms, substituted with: i) T1-V-T-Ry; ii) T1-V-T-M-Ry; or iii) V-R9, where R9 is an optionally substituted non-aromatic carbocyclic or heterocyclic group; and where the aromatic or heteroaromatic group having 5-6 ring atoms is optionally also substituted with 1-2 independently selected groups represented by Rz; each Rz is independently selected from halogen, haloalkyl, Ro, -ORo, -O (haloalkyl), -SRo; -NO2, -CN, -N (R ') 2, -NR'CO2Ro, -NR ?? C (O) Ro, -NR ?? NR'C (O) Ro, -N (R ??) C ( O) N (R ') 2, -NR'NR ?? C (O) N (R ??) 2, -NR ?? NR'CO2Ro, -C (O) C (O) Ro, -C (O ) CH2 (O) Ro, -CO2Ro, -C (O) Ro, -C (O) N (Ro) 2, -OC (O) Ro, -OC (O) N (Ro) 2, -S (O ) 2Ro, -SO2N (R ') 2, -S (O) Ro, -NR'SO2N (R') 2, -NR'SO2Ro, -C (= S) N (R ') 2 and -C (= NH) -N (R ') 2; each R 'is independently hydrogen, alkyl, -C (O) ORo, S (O) 2Ro or -C (O) Ro; each Ro is independently hydrogen or an alkyl group, non-aromatic heterocyclic group or aromatic group and the alkyl, the non-aromatic heterocyclic group and the aromatic group represented by Ro are optionally substituted with one or more independently selected groups represented by R; R is R +, -OR +, -O (haloalkyl), -SR +; -NO2, -CN, -N (R +) 2, -NHCO2R +, -NHC (O) R +, -NHNHC (O) R +, -NHC (O) N (R +) 2, - NHNHC (O) N (R +) 2, -NHNHCO2R +, -C (O) C (O) R +, -C (O) CH2 (O) R +, -CO2R +, -C (O) R +, -C (O) N (R +) 2, -OC (O) R +, -OC (O) N (R +) 2, -S (O) 2R +, -SO2N (R +) 2, -S (O) R +, -NHSO2N (R +) 2, -NHSO2R +, -C ( = S) N (R +) 2 and -C (= NH) -N (R +) 2; R + is -H, a C1-3 alkyl group, a monocyclic heteroaryl group, a non-aromatic heterocyclic group or a phenyl group optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, halo, -CN, -NO2, amine, alkylamine or dialkylamine ; or -N (R +) 2 is a non-aromatic heterocyclic group, with the proviso that the non-aromatic heterocyclic groups represented by R + and -N (R +) 2 comprising a secondary ring amine are optionally acylated or alkylated; V is a covalent bond, -O-, -C (O) -, -N (R ') -, -S-, -S (O) -, -C (O) NR5-, - NR5C (O) - , -S (O) 2NR5, -NR5S (O) 2- or -S (O) 2-; T is C1-10 straight chain alkylene; T1 is a covalent bond or a C1-10 straight chain alkylene, where T and T1 together contain no more than 10 carbon atoms and where T and T1 are optionally and independently substituted on any one or more of the substitutable carbon atoms with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, alkoxy, haloalkoxy, cycloalkyl spiro, optionally N-substituted nitrogen containing a non-aromatic spiro, amine, alkylamine, dialkylamine, alkoxy or hydroxyl heterocyclic group; M is an optionally substituted group selected from monocyclic, heteroaromatic, non-aromatic or heterocyclic monocyclic aromatic group; Ry is -C (O) OR5, -C (O) R5, -OC (O) R5, -C (O) N (R5) 2, -NR5C (O) R5, -NR5C (O) OR5, -S (O) 2R5, -S (O) 2COR5, -S (O) 2N (R5) 2, -NR5S (O) 2R5, -NR5S (O) 2R5, -S (O) 2OR5, -S (O) OR5 , -S (O) R5, -SR5, -C (O) NR5S (O) 2R5, -CN, -NR5C (O) N (R5) 2, -OC (O) N (R5) 2, -N ( R5) 2, - OR5, an optionally substituted non-aromatic heterocyclic group or an optionally substituted heteroaryl group; with the proviso that T is C2-10 when V is a covalent bond and T is C2-10 when V is -O-, -S- or -N (R ??) - and Ry is -CN, -OH, -SH, - N (R5) 2; each R5 is independently -H, alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, -C (O) OCH2C6H5, -S (O) 2CH3, -C (O) OH, -C (O) OMe, -C (O) OEt, C (O) NH2, benzyl, pyrrolidinyl, morpholinyl or -N (R5) 2 is a non-aromatic heterocyclic group containing nitrogen; R2 is C1-3 alkyl; R3 is an optionally substituted monocyclic or bicyclic group selected from an aromatic, heteroaromatic, non-aromatic carbocyclic and non-aromatic heterocyclic group; and R4 is C1-3 alkyl or C1-3 hydroxyalkyl. Claim 48: The method of claim 46 wherein the inflammatory disease, disorder or symptom is allergic rhinitis or allergic asthma. Claim 53: A method for preparing a product compound represented by the structural formula (2), from a starting compound represented by the structural formula (3), said method comprising the step of reducing the carbonyl of the amide of the compound of starting to form an intermediate and then cycling the intermediate to form the product compound, where -C (O) ORz is an amide protecting group.

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