AR075368A1 - Inhibidores de glicosilceramida sintasa - Google Patents

Inhibidores de glicosilceramida sintasa

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Publication number
AR075368A1
AR075368A1 ARP100100327A ARP100100327A AR075368A1 AR 075368 A1 AR075368 A1 AR 075368A1 AR P100100327 A ARP100100327 A AR P100100327A AR P100100327 A ARP100100327 A AR P100100327A AR 075368 A1 AR075368 A1 AR 075368A1
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Argentina
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alkyl
heteroaryl
haloalkyl
independently
ring
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ARP100100327A
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Exelixis Inc
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    • C07C237/00Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/00Drugs for disorders of the cardiovascular system
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    • C07D205/04Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
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    • C07D209/04Indoles; Hydrogenated indoles
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    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/36Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
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    • C07D213/02Heterocyclic 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
    • C07D213/04Heterocyclic 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
    • C07D213/24Heterocyclic 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
    • C07D213/54Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182Radicals derived from carboxylic acids
    • C07D295/185Radicals derived from carboxylic acids from aliphatic carboxylic acids
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    • C07D319/101,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/141,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/161,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07C2601/14The ring being saturated

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Abstract

Moduladores de glucosilceramida sintasa (GCS) y métodos para hacer los compuesto. Comprende además composiciones que comprenden los compuestos, N-oxidos, y/o sales farmacéuticamente aceptables de los mismos. También comprende el uso de los compuestos y composiciones para la fabricacion de medicamentos, particularmente para tratar enfermedades en las cuales GCS es un mediador o está implicado. Reivindicacion 1: Un compuesto de la formula (1), o un estereoisomero sencillo o mezcla de estereoisomeros de los mismos, N-oxidos de los mismos, y de manera adicional opcionalmente como una sal farmacéuticamente aceptable de los mismos, caracterizado porque A es isopropilo, t-butilo, cicloalquilo C3-8, heterociclilo, arilo, o heteroarilo, en donde el cicloalquilo, heterociclilo, arilo, y heteroarilo están opcionalmente sustituidos por uno, dos o tres grupos RA, en donde cada RA es independientemente RA2, alquilo C1-4, haloalquilo C1-4, arilo, arilalquilo C1-4, o alquilo C1-4-RA2, en donde el arilo del grupo arilalquilo C1-4 está opcionalmente sustituido con uno, dos o tres grupos RA2, en donde, cada RA2 es independientemente halogeno, ciano, nitro, -ORA1, -SRA1, -N(RA1)2, -C(O)RA1, -S(O)RA1, -S(O)2RA1, -S(O)N(RA1)2, -S(O)2N(RA1)2, -C(O)ORA1, -C(O)N(RA1)2, -N(RA1)C(O)RA1, -N(RA1)C(O)ORA1, -N(RA1)C(O)N(RA1)2, -N(RA1)S(O)2RA1, -N(RA1)C(=NRA1)N(RA1)2, -P(O)(ORA1)2, o -OP(O)(ORA1)2, en donde cada RA1 es independientemente hidrogeno, alquilo C1-4, o haloalquilo C1-4, o dos RA enlazados a átomos de carbono adyacentes, tomados juntos, forman -O-(G)y-O-, en donde cada G es independientemente -CH2-, -C(H)(F)-, o -CF2-, e y es 1, 2, o 3; L es -[C(RL)2]p-L1-[C(RL)2]q-, en donde p es 1, 2, o 3; q es un entero seleccionado de 0 hasta (3-p); L1 es una union u -O-; y cada RL es independientemente hidrogeno, metilo, o halometilo; R1 es -N(R10)(R11) o una porcion de la formula (2), en donde R10 es hidrogeno o alquilo C1-4; R11 es -R13,-cicloalquilo C3-6-N(R12)2, -cicloalquilo C3-6-R13, alquilo C1-4-N(R12)2, o alquilo C1-6-R13, en donde cada R12 es independientemente hidrogeno o alquilo C1-4; y R13 es (a) un anillo heterociclilo monocíclico de 4-10 miembros, bicíclico fusionado de 4-10 miembros, bicíclico puenteado de 5-10 miembros, o bicíclico espiro de 5-10 miembros, donde el anillo heterociclilo comprende uno, dos o tres átomos de nitrogeno anular, y opcionalmente comprende un átomo de oxígeno o azufre anular, o (b) un heteroarilo monocíclico de 5 o 6 miembros o un heteroarilo bicíclico fusionado de 8-10 miembros, donde el anillo heteroarilo comprende uno, dos, o tres átomos de N anulares, y opcionalmente comprende un átomo de O o S anular, en donde el heterociclilo y heteroarilo están cada uno opcionalmente sustituidos con uno, dos, o tres, grupos R13A, en donde cada grupo R13A es independientemente halogeno, ciano, nitro, alquilo C1-4, haloalquilo C1-4, arilalquilo C1-4, -ORB1, -SRB1, -N(RB1)2, -C(O)RB1, -S(O)RB1, -S(O)2RB1, -S(O)N(RB1)2, -S(O)2N(RB1)2, -C(O)ORB1, -C(O)N(RB1)2, -N(RB1)C(O)RB1, -N(RB1)C(O)ORB1, -N(RB1)C(O)N(RB1)2, o -N(RB1)S(O)2RB1, en donde cada RB1 es independientemente hidrogeno, alquilo C1-4, haloalquilo C1-4,arilo, o arilalquilo C1-4, w es 0, 1, 2, o 3; el anillo B en la definicion de R1 es (a) un anillo heterocíclico monocíclico de 4-10 miembros, bicíclico fusionado de 4-10 miembros, bicíclico puenteado de 5-10 miembros, o bicíclico espiro de 5-10 miembros, donde el anillo heterociclilo opcionalmente comprende un átomo de oxígeno o azufre anular, y opcionalmente uno, dos, o tres átomos de nitrogeno anulares adicionales, o (b) un heteroarilo monocíclico de 5 o 6 miembros o un heteroarilo bicíclico fusionado de 8-10 miembros, donde el anillo heteroarilo opcionalmente comprende un átomo de oxígeno o azufre anular, y opcionalmente uno, dos, o tres átomos de nitrogeno anulares adicionales; R20 es -RB2, hidrogeno, alquilo C1-4, haloalquilo C1-4, cicloalquilo C3-8, arilalquilo C1-4, o alquilo C1-4-RB2, donde cada RB2 es independientemente ciano, nitro, -ORB3, -SRB3, -N(RB3)2, -C(O)RB3, -S(O)RB3, -S(O)2RB3, -S(O)N(RB3)2, -S(O)2N(RB3)2, -C(O)ORB3, -C(O)N(RB3)2, -N(RB3)C(O)RB3, -N(RB3)C(O)ORB3, -N(RB3)C(O)N(RB3)2 o -N(RB3)S(O)2RB3, en donde cada RB3 es independientemente hidrogeno, alquilo C1-4, haloalquilo C1-4, arilo, o arilalquilo C1-4; o dos RB3 tomados junto con el átomo de nitrogeno al cual ambos se enlazan forman un heterociclilo o heteroarilo monocíclico saturado o no saturado, en donde el heterociclilo y heteroarilo están cada uno opcionalmente sustituidos con uno, dos, o tres grupos los cuales son cada uno independientemente alquilo C1-3, halogeno, o haloalquilo C1-4; y cada R21 es independientemente halogeno o -R20; R2 es metilo opcionalmente sustituido con uno, dos o tres grupos halo, o ambos R2 tomados junto con el átomo de carbono al cual se enlazan forman un grupo ciclopropilo; m es 1, 2, 3, 4 o 5; y cada R3 es independientemente halogeno, ciano, nitro, alquilo C1-4, haloalquilo C1-4, cicloalquilo C3-6, -ORC1, -N(RC1)2, -C(O)RC1, -S(O)RC1, -S(O)2RC1, -S(O)N(RC1)2, -S(O)2N(RC1)2, -C(O)ORC1, -C(O)N(RC1)2, -N(RC1)C(O)RC1, -N(RC1)C(O)ORC1, -N(RC1)C(O)N(RC1)2 o -N(RC1)S(O)2RC1, en donde cada RC1 es independientemente hidrogeno, alquilo C1-4, haloalquilo C1-4, arilo, o arilalquilo C1-4, o dos R3 tomados junto con los átomos en el anillo a los cuales se enlazan forman un arilo, heteroarilo, un cicloalquilo monocíclico, o un heterociclilo, cada uno opcionalmente sustituido con uno, dos, o tres grupos los cuales son cada uno independientemente alquilo C1-3, halogeno, o haloalquilo C1-4.
ARP100100327A 2009-02-06 2010-02-05 Inhibidores de glicosilceramida sintasa AR075368A1 (es)

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US15043409P 2009-02-06 2009-02-06
US28111609P 2009-11-13 2009-11-13
PCT/US2010/023168 WO2010091164A1 (en) 2009-02-06 2010-02-04 Inhibitors of glucosylceramide synthase

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DK2685986T3 (da) * 2011-03-18 2020-03-02 Genzyme Corp Glucosylceramidsyntasehæmmer
FR2985256B1 (fr) * 2011-12-30 2016-03-04 Pitty Marc Henry Derives piperazinyles pour le traitement de cancers
MA37975B2 (fr) * 2012-09-11 2021-03-31 Genzyme Corp Inhibiteurs de synthase de glucosylcéramide
RU2668166C1 (ru) 2013-12-17 2018-09-27 Стелла Фарма Корпорейшн Способ получения 2-фтор-4-бороно-l-фенилаланина и вещества-предшественника 2-фтор-4-бороно-l-фенилаланина
EP3134079A4 (en) * 2014-04-23 2017-12-20 X-RX Discovery, Inc. Substituted n-(2-(amino)-2-oxoethyl)benzamide inhibitors of autotaxin and their preparation and use in the treatment of lpa-dependent or lpa-mediated diseases
CN104311473B (zh) * 2014-05-27 2016-09-28 斯芬克司药物研发(天津)股份有限公司 一种哌啶类化合物及其制备方法
EP3318277A1 (en) 2016-11-04 2018-05-09 Institut du Cerveau et de la Moelle Epiniere-ICM Inhibitors of glucosylceramide synthase for the treatment of motor neuron diseases
WO2019126776A1 (en) 2017-12-21 2019-06-27 Lysosomal Therapeutics Inc. Crystalline substituted cyclohexyl pyrazolo[1,5-a]pyrimidinyl carboxamide compound and therapeutic uses thereof
CN114829361B (zh) * 2019-11-15 2024-07-16 柳韩洋行 具有2,3-二氢-1h-茚或2,3-二氢苯并呋喃部分的衍生物或其药学上可接受盐及含其的药物组合物
CN114746422B (zh) * 2019-11-15 2024-03-12 柳韩洋行 具有1,2,3,4-四氢萘部分的衍生物或其药学上可接受的盐以及包含它们的药物组合物
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