AR033617A1 - Compuestos derivados espirociclicos, metodos para prepararlos y su uso como inhibidores de fosfodiesterasa-7 - Google Patents

Compuestos derivados espirociclicos, metodos para prepararlos y su uso como inhibidores de fosfodiesterasa-7

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Publication number
AR033617A1
AR033617A1 ARP020100993A ARP020100993A AR033617A1 AR 033617 A1 AR033617 A1 AR 033617A1 AR P020100993 A ARP020100993 A AR P020100993A AR P020100993 A ARP020100993 A AR P020100993A AR 033617 A1 AR033617 A1 AR 033617A1
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Argentina
Prior art keywords
lower alkyl
substituted
heteroatoms
hydrogen
optionally interrupted
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ARP020100993A
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English (en)
Inventor
Patrick Bernardellli
Pierre Ducrot
Fabrice Vergne
Edwige Lorthiois
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Warner Lambert Co
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Application filed by Warner Lambert Co filed Critical Warner Lambert Co
Publication of AR033617A1 publication Critical patent/AR033617A1/es

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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
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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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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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
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    • 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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

Compuestos de formulas (1), (2) o (3) donde: a) X1, X2, X3 y X4 son -N, siempre que no más de dos de ellos sean nitrogeno, o -C-R1; R1 es Q1, alquilo, alquenilo o alquinilo inferiores, no sustituidos o sustituidos con uno o varios grupos Q2; X5-R5, X5 es un solo enlace, alquileno, alquenileno o alquinileno inferiores, optativamente interrumpido con 1 o 2 heteroátomos de O, S, S(=O), SO2 o N, los carbonos de estos grupos son no sustituidos o sustituidos con uno o varios grupos, de SR6, OR6, NR6R7, =O, =S, o =N-R6, R6 y R7 son hidrogeno o alquilo inferiores, R5 es arilo, heteroarilo, cicloalquilo optativamente interrumpido con C(=O) o con 1, 2 o 3 heteroátomos de O, S, S(=O), SO2 o N, cicloalquenilo optativamente interrumpido con C(=O) o con 1, 2 o 3 heteroátomos de O, S, S(=O), SO2 o N, o un grupo bicíclico no sustituidos o sustituidos con uno o varios grupos de Q3, heteroarilo o alquilo inferiores optativamente sustituidos con Q3; Q1, Q2 Q3 son hidrogeno, halogeno, CN, NO2, SO3H, P(=O)(OH)2, OR2, OC(=O)R2, C(=O)OR2, SR2, S(=O)R2, C(=O)-NH-SO2-CH3, NR3R4, Q-R2, Q-NR3R4, NR2-Q-NR3R4 o NR3-Q-R2; Q es C(=NR), C(=O), C(=S) o SO2; R es hidrogeno, CN o SO2NH2 o alquilo inferior y R2, R3 y R4 son hidrogeno, alquilo inferior optativamente interrumpido con C(=O), Q4-arilo, Q4-heteroarilo, Q4-cicloalquilo optativamente interrumpido con C(=O) o con 1 o 2 heteroátomos de O, S, S(=O), SO2 o N, o Q4-cicloalquenilo optativamente interrumpido con C(=O) o con 1 o 2 heteroátomos de O, S, S(=O), SO2 o N; Q4 es (CH2)n, alquilo inferior con un heteroátomo de O, S o N, alquenilo o alquinilo inferiores, optativamente sustituidos con alquilo inferior, OR', o NR'R''; R' y R'' son hidrogeno o alquilo inferior; n es un numero entero de 0, 1, 2, 3 o 4; estos grupos son no sustituidos o sustituidos con uno o varios grupos halogeno, CN, CH3, SO3H, SO2CH3, C(=O)-NH-SO2-CH3, CF3, OR6, COOR6, C(=O)R6, NR6R7, NR6C(=O)R7, C(=O)NR6R7 o SO2NR6R7, en donde R6 y R7 son hidrogeno o alquilo inferior optativamente sustituido con uno o dos grupos de OR, COOR, o NRR8; R y R8 son hidrogeno o alquilo inferior y R6 y R7, y/o, R3 y R4, junto con el átomo de nitrogeno al cual están unidos, pueden formar un anillo heterocíclico de 4 a 8 miembros, con uno o dos heteroátomos de O, S, S(=O), SO2 o N, y que puede ser sustituido con (CH2)n-Q5, n es un numero entero de 0, 1, 2 o 3 y Q5 es un anillo heterocíclico de 4 a 8 miembros, con uno o dos heteroátomos de O, S o N y que puede ser sustituido con un alquilo o un alquilo inferior optativamente sustituido con OR', NR'R'', C(=O)NR'R'' o COOR'; R' y R'' son H o alquilo inferior optativamente sustituido con OR o COOR donde R es hidrogeno o alquilo inferior y R' y R'' junto con el átomo de nitrogeno al cual están unidos, pueden formar un anillo heterocíclico de 4 a 8 miembros, con uno o dos heteroátomos seleccionados de O, S o N; o cuando X1 y X2 ambos representan C-R1, los dos sustituyentes R1 pueden formar junto con los átomos de carbono a los cuales están unidos, un anillo heterocíclico de 5 miembros que comprende un átomo de nitrogeno y optativamente un segundo heteroátomo de O, S o N; b) X es O o NR9, donde R9 es hidrogeno, CN, OH, NH2, alquilo, alquenilo o alquinilo inferiores, no sustituidos o sustituidos con cicloalquilo optativamente interrumpido con 1 o 2 heteroátomos de O, S, S(=O), SO2 o N, cicloalquenilo optativamente interrumpido con 1 o 2 heteroátomos elegidos de O, S, S(=O), SO2 o N, arilo, heteroarilo, OR10, COOR10 o NR10R11, donde R10 y R11 son hidrogeno o alquilo inferior; c) Y es O, S o N-R12; R12 es hidrogeno, CN, OH, NH2, alquilo, alquenilo o alquinilo inferiores, no sustituidos o sustituidos con cicloalquilo optativamente interrumpido con 1 o 2 heteroátomos de O, S, S(=O), SO2 o N, cicloalquenilo optativamente interrumpido con 1 o 2 heteroátomos elegidos de O, S, S(=O), SO2 o N, arilo, heteroarilo, OR10, COOR10 o NR10R11, donde R10 y R11 son hidrogeno o alquilo inferior; d) Z es CH-NO2, O, S o NR13, donde R13 es hidrogeno, CN, OH, NH2, arilo, heteroarilo, cicloalquilo optativamente interrumpido con uno o varios heteroátomos de O, S, S(=O), SO2 o N, cicloalquenilo optativamente interrumpido con uno o varios heteroátomos de O, S, S(=O), SO2 o N, C(=O)R14, C(=O)NR14R15, OR14, o alquilo inferior, no sustituido o sustituido con uno o varios grupos que son OR14, COOR10, o NR14R15; R14 y R15 son hidrogeno o alquilo inferior, o, R14 y R15, junto con el átomo de nitrogeno al cual están unidos, pueden formar un anillo heterocíclico de 4 a 8 miembros con uno o dos heteroátomos de O, S o N, sustituido con un alquilo inferior o cuando Y es N-R12 y Z es N-R13, pueden formar juntos grupos -CH=N- o -C=C-, cuando X es N-R9 y Z es N-R13, R9 y R13 pueden formar juntos un grupo -CH=N- o un grupo -C=C-; e) Z1 es H, CH3 o NR16R17, R16 y R17 son hidrogeno, CN, arilo, heteroarilo, cicloalquilo optativamente interrumpido con uno o varios heteroátomos de O, S, S(=O), SO2 o N, cicloalquenilo optativamente interrumpido con uno o varios heteroátomos de O, S, S(=O), SO2 o N, C(=O)R14, C(=O)NR14R15, OR14, o alquilo inferior no sustituido o sustituido con uno o varios grupos de OR14, COOR14 o NR14R15; R14 y R15 son hidrogeno o alquilo inferior y R14 y R15, y/o, R16 y R17, junto con el átomo de nitrogeno al cual están unidos, pueden formar un anillo heterocíclico de 4 a 8 miembros con uno o más heteroátomos de O, S o N, sustituido con un alquilo inferior; f) A es un ciclo elegido del grupo (4), donde A1, A2, A4, A5 y A6 son O, S, C, C(=O), SO, SO2 o N-R18 y R18 es hidrogeno, arilo, heteroarilo, cicloalquilo optativamente interrumpidos con uno o varios heteroátomos de O, S, S(=O), SO2 o N, cicloalquenilo optativamente interrumpido con uno o varios heteroátomos de O, S, S(=O), SO2 o N, alquilo inferior no sustituido o sustituido con arilo, heteroarilo, cicloalquilo optativamente interrumpido con uno o varios heteroátomos de O, S, S(=O), SO2 o N, cicloalquenilo optativamente interrumpido con uno o varios heteroátomos de O, S, S(=O), SO2 o N, CN, NR19R20, C(=O)NR19R20, OR19, C(=O)R19 o C(=O)OR19 en donde R19 y R20 son hidrogeno o alquilo inferior; A3 es O, S, C, C(=O), SO, SO2 o N-R18 cuando A1 y/o A2 son C(=O) o cuando Y es O o S, R18 es lo definido anteriormente; * representa un átomo de carbono que se comparte entre el ciclo A y el ciclo de la cadena principal que contiene X y/o Y; cada carbono del ciclo A es no sustituido o sustituido con 1 o 2 grupos alquilo inferior optativamente sustituido con OR21, NR21R22, COOR21 o CONR21R22, haloalquilo inferior, CN, F, =O, SO2NR19R20, OR19, SR19, C(=O)OR19, C(=O)NR19R20 o NR19R20, donde R19 y R20 son hidrogeno o alquilo inferior optativamente sustituido con OR21, NR21R22, COOR21 o CONR21R22 en donde R21 y R22 son hidrogeno o alquilo inferior, y R19 y R20, y/o, R21 y R22, junto con el átomo de nitrogeno al cual están unidos, pueden formar un anillo heterocíclico de 4 a 8 miembros; 2 átomos del ciclo A, que no son adyacentes, pueden ser unidos por una cadena de 2, 3 o 4 átomos de carbono que puede ser interrumpida con 1 heteroátomo de O, S o N; siempre que no más de dos de los grupos A1, A2, A3, A4, A5 y A6 simultáneamente sean un heteroátomo; el ciclo A no contenga más de 2 carbonos en un estado de hibridacion sp2; cuando X es O, X2 no es C-R1, R1 es un tienilo sustituido con CN o con CN y CH3, un fenilo sustituido con CN, Cl, NO2 o CN y F, Br, F o sus tautomeros, racémicos o isomeros y sus derivados farmacéuticamente aceptables. Se usan en composiciones farmacéuticas como inhibidor de PDE7, para prevencion o tratamiento de enfermedades relacionadas con células T, enfermedades autoinmunes, osteoartritis, esclerosis multiple, enfermedad pulmonar obstructiva cronica, asma, cáncer, síndrome de inmunodeficiencia adquirida, alergia o enfermedad intestinal inflamatoria. Método para preparar los compuestos de formula (1) haciendo reaccionar una urea sustituida con una cetona cíclica.
ARP020100993A 2001-03-21 2002-03-20 Compuestos derivados espirociclicos, metodos para prepararlos y su uso como inhibidores de fosfodiesterasa-7 AR033617A1 (es)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2001/003355 WO2002076953A1 (en) 2001-03-21 2001-03-21 New spirotricyclic derivatives and their use as phosphodiesterase-7 inhibitors

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AR033617A1 true AR033617A1 (es) 2003-12-26

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US (3) US20020198198A1 (es)
EP (2) EP1373224B1 (es)
JP (1) JP4086663B2 (es)
KR (1) KR100617435B1 (es)
CN (1) CN100447136C (es)
AP (1) AP1699A (es)
AR (1) AR033617A1 (es)
AT (1) ATE367381T1 (es)
AU (1) AU2002304800B2 (es)
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PL (1) PL367058A1 (es)
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SI (1) SI1373224T1 (es)
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UA (1) UA74243C2 (es)
WO (2) WO2002076953A1 (es)
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EP1400244A1 (en) * 2002-09-17 2004-03-24 Warner-Lambert Company LLC New spirocondensed quinazolinones and their use as phosphodiesterase inhibitors
GB0230195D0 (en) * 2002-12-24 2003-02-05 Biofocus Plc Compound Libraries
US7723349B2 (en) 2003-04-24 2010-05-25 Incyte Corporation Aza spiro alkane derivatives as inhibitors of metalloproteases
JP2006219374A (ja) 2003-06-13 2006-08-24 Daiichi Asubio Pharma Co Ltd Ｐｄｅ７阻害作用を有するイミダゾトリアジノン誘導体
JP2006219373A (ja) 2003-06-13 2006-08-24 Daiichi Asubio Pharma Co Ltd Ｐｄｅ７阻害作用を有するピリジニルピラゾロピリミジノン誘導体
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