ES2632443T3 - Compuestos de pirrolopiridinona y procedimientos de tratamiento del VIH - Google Patents
Compuestos de pirrolopiridinona y procedimientos de tratamiento del VIH Download PDFInfo
- Publication number
- ES2632443T3 ES2632443T3 ES12833476.0T ES12833476T ES2632443T3 ES 2632443 T3 ES2632443 T3 ES 2632443T3 ES 12833476 T ES12833476 T ES 12833476T ES 2632443 T3 ES2632443 T3 ES 2632443T3
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- Prior art keywords
- methyl
- dihydro
- butoxy
- oxo
- tert
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- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 abstract description 41
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- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229950004697 lasinavir Drugs 0.000 description 1
- 229940121292 leronlimab Drugs 0.000 description 1
- 229950004188 lersivirine Drugs 0.000 description 1
- CJPLEFFCVDQQFZ-UHFFFAOYSA-N loviride Chemical compound CC(=O)C1=CC=C(C)C=C1NC(C(N)=O)C1=C(Cl)C=CC=C1Cl CJPLEFFCVDQQFZ-UHFFFAOYSA-N 0.000 description 1
- 229950006243 loviride Drugs 0.000 description 1
- 229960004710 maraviroc Drugs 0.000 description 1
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229960000884 nelfinavir Drugs 0.000 description 1
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 229940072250 norvir Drugs 0.000 description 1
- 229950006460 palinavir Drugs 0.000 description 1
- RXBWRFDZXRAEJT-SZNOJMITSA-N palinavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)C=1N=C2C=CC=CC2=CC=1)C(C)C)[C@H](O)CN1[C@@H](C[C@@H](CC1)OCC=1C=CN=CC=1)C(=O)NC(C)(C)C)C1=CC=CC=C1 RXBWRFDZXRAEJT-SZNOJMITSA-N 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229960004742 raltegravir Drugs 0.000 description 1
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- BEUUJDAEPJZWHM-COROXYKFSA-N tert-butyl n-[(2s,3s,5r)-3-hydroxy-6-[[(2s)-1-(2-methoxyethylamino)-3-methyl-1-oxobutan-2-yl]amino]-6-oxo-1-phenyl-5-[(2,3,4-trimethoxyphenyl)methyl]hexan-2-yl]carbamate Chemical compound C([C@@H]([C@@H](O)C[C@H](C(=O)N[C@H](C(=O)NCCOC)C(C)C)CC=1C(=C(OC)C(OC)=CC=1)OC)NC(=O)OC(C)(C)C)C1=CC=CC=C1 BEUUJDAEPJZWHM-COROXYKFSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 1
- 229950009860 vicriviroc Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
-
- 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
- A61K31/435—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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Un compuesto seleccionado entre el grupo que consiste en: ácido 2-(1-bencil-4-(4-clorofenil)-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)-2-(terc-butoxi)acético, ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-1-(4-fluorobencil)-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5- il)acético, ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-1-(4-metoxibencil)-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5- il)acético, ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-1-(2-metoxietil)-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acético, ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-1-isobutil-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acético, ácido (S)-2-(terc-butoxi)-2-(4-(4-clorofenil)-1-(3,4-difluorobencil)-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5- il)acético, ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-6-metil-7-oxo-1-(2-(piperidin-1-il)etil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5- il)acético, ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-6-metil-7-oxo-1-(2-(piperidin-1-il)etil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5- il)acético, ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-6-metil-7-oxo-1-((5-(trifluorometil)furan-2-il)metil)-6,7-dihidro-1H-pirrol[2,3- c]piridin-5-il)acético, ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-1-(imidazo[1,2-a]piridin-2-ilmetil)-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3- c]piridin-5-il)acético, ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-6-metil-1-((2-metiltiazol-4-il)metil)-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin- 5-il)acético, ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-1-(2-((2-hidroxi-4-metilfenil)amino)-2-oxoetil)-6-metil-7-oxo-6,7-dihidro-1Hpirrol[ 2,3-c]piridin-5-il)acético, ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-6-metil-7-oxo-1-(1-feniletil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acético, ácido 2-(1-bencil-3-bromo-4-(4-clorofenil)-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)-2-(tercbutoxi) acético, ácido 2-(1-bencil-4-(4-clorofenil)-3,6-dimetil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)-2-(terc-butoxi)acético, ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-1-((4-fluorofenil)sulfonil)-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5- il)acético, 30 ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-6-metil-7-oxo-1-tosil-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acético, ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-1-((1-(2-hidroxietil)-1H-1,2,3-triazol-4-il)metil)-6-metil-7-oxo-6,7-dihidro-1Hpirrol[ 2,3-c]piridin-5-il)acético, ácido 2-(1-bencil-6-metil-7-oxo-4-(p-tolil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)-2-(terc-butoxi)acético, ácido 2-(1- (benzo[c][1,2,5]oxadiazol-5-ilmetil)-6-metil-7-oxo-4-(p-tolil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)-2-(terc35 butoxi)acético, ácido 2-(1-(4-boronobencil)-6-metil-7-oxo-4-(p-tolil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)-2-(terc-butoxi)acético, ácido 2-(terc-butoxi)-2-(1-(4-carbamoilbencil)-6-metil-7-oxo-4-(p-tolil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5- il)acético, ácido 2-(terc-butoxi)-2-(6-metil-7-oxo-4-(p-tolil)-1-(4-((trifluorometil)tio)bencil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5- il)acético, ácido (S)-2-(terc-butoxi)-2-(1-(4-fluorobencil)-6-metil-7-oxo-4-(p-tolil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acético, ácido 2-(terc-butoxi)-2-(6-metil-7-oxo-1-(tiofen-2-ilmetil)-4-(p-tolil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acético, ácido 2-(terc-butoxi)-2-(1-(4-fluorofenetil)-6-metil-7-oxo-4-(p-tolil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acético, ácido 2-(terc-butoxi)-2-(6-metil-1-(4-(metilsulfonil)bencil)-7-oxo-4-(p-tolil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5- il)acético, ácido 2-(terc-butoxi)-2-(1-(3,4-difluorobencil)-6-metil-7-oxo-4-(p-tolil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acético, ácido 2-(terc-butoxi)-2-(1-(4-metoxibencil)-6-metil-7-oxo-4-(p-tolil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acético, ácido 2-(terc-butoxi)-2-(1,6-dimetil-7-oxo-4-(p-tolil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acético, ácido 2-(terc-butoxi)-2-(1-(4-cloro-3-fluorobencil)-6-metil-7-oxo-4-(p-tolil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5- il)acético, ácido 2-(terc-butoxi)-2-(6-metil-7-oxo-4-(p-tolil)-1-(3,4,5-trifluorobencil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5- il)acético, ácido 2-(1-(benzo[d][1,3]dioxol-5-ilmetil)-6-metil-7-oxo-4-(p-tolil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)-2-(tercbutoxi) acético, ácido 2-(terc-butoxi)-2-(1-(4-fluorofenil)-6-metil-7-oxo-4-(p-tolil)-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acético, ácido 2-(terc-butoxi)-2-(1-(2-((4-fluorofenil)amino)-2-oxoetil)-6-metil-7-oxo-4-(p-tolil)-6,7-dihidro-1H-pirrol[2,3- c]piridin-5-il)acético, ácido 2-(terc-butoxi)-2-(1-(4-fluorobencil)-4-(4-metoxifenil)-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5- il)acético, ácido 2-(terc-butoxi)-2-(1-(4-fluorobencil)-4-(4-fluorofenil)-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5- il)acético, ácido 2-(1-bencil-6-metil-4-(5-metilcroman-6-il)-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)-2-(terc-butoxi)acético, ácido 2-(1-bencil-6-metil-4-(5-metilcroman-6-il)-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)-2-(terc-butoxi)acético, ácido 2-(terc-butoxi)-2-(1,6-dimetil-4-(5-metilcroman-6-il)-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acético,
Description
que incluyen cada uno de los compuestos. Como alternativa, la combinación puede administrarse por separado de una manera secuencial en la que se administra primero un agente de tratamiento y el otro segundo o viceversa. Dicha administración secuencial puede ser próxima temporalmente o remota temporalmente. Las cantidades del compuesto o compuestos de la invención o sales de los mismos y el otro u otros agentes farmacéuticamente activos
5 y los tiempos relativos de administración se seleccionarán con el fin de conseguir el efecto terapéutico combinado deseado.
Como tal, los compuestos de la presente invención pueden usarse en combinación con uno o más agentes útiles en la prevención o tratamiento del VIH.
Ejemplos de tales agentes incluyen:
10 inhibidores nucleotídicos de la transcriptasa inversa tales como zidovudina, didanosina, lamivudina, zalcitabina, abacavir, estavudina, adefovir, adefovir dipivoxilo, fozivudina, todoxilo, emtricitabina, alovudina, amdoxovir, elvucitabina y agentes similares; inhibidores no nucleótidos de la transcriptasa inversa (que incluyen un agente que tiene actividad antioxidante, tal como immunocal, oltipraz, etc.) tal como nevirapina, delavirdina, efavirenz, lovirida, immunocal, oltipraz,
15 capravirina, lersivirina, GSK2248761, TMC-278, TMC-125, etravirina y agentes similares; inhibidores de la proteasa tales como saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir y agentes similares; Inhibidores de la entrada, unión y fusión, tales como enfuvirtide (T-20), T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068 y BMS-626529, 5-Helix y agentes similares;
20 Inhibidores de la integrasa, tales como raltegravir, elvitegravir, GSK1349572, GSK1265744 y agentes similares; inhibidores de la maduración, tales como PA-344 y PA-457 y agentes similares; e inhibidores de CXCR4 y/o CCR5, tales como vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427.857), TAK449, así como los divulgados en los documentos WO 02/74769, PCT/US03/39644, PCT/US03/39975, PCT/US03/39619, PCT/US03/39618, PCT/US03/39740 y PCT/US03/39732 y agentes similares.
25 El ámbito de las combinaciones de compuestos de esta invención con agentes VIH no se limita a los mencionados anteriormente, sino que incluye, en principio, cualquier combinación con cualquier composición farmacéutica útil para el tratamiento del VIH. Como se ha indicado, en tales combinaciones los compuestos de la presente invención y otros agentes del VIH pueden administrarse por separado o conjuntamente. Además, un agente puede ser anterior, concurrente o posterior a la administración de otro agente o agentes.
30 La presente invención puede usarse en combinación con uno o más agentes útiles como potenciadores farmacológicos así como con o sin compuestos adicionales para la prevención o tratamiento del VIH. Ejemplos de tales potenciadores farmacológicos (o refuerzos farmacocinéticos) incluyen, pero sin limitación, ritonavir, GS-9350 y SPI-452.
El ritonavir es ácido 10-hidroxi-2-metil-5-(1-metiletil)-1-1[2-(1-metiletil)-4-tiazolil]-3,6-dioxo-8,11-bis(fenilmetil)
35 2,4,7,12-tetraazatridecan-13-óico, 5-tiazolilmetil éster, [5S-(5S*,8R*,10R*,11R*)] y está disponible de Abbott Laboratories (Abbott Park, Illinois) como Norvir. Ritonavir es un inhibidor de la proteasa del VIH indicado con otros agentes antirretrovirales para el tratamiento de la infección por VIH. El ritonavir también inhibe el metabolismo del fármaco mediado por P450, así como el sistema de transporte de células de la P-glicoproteína (Pgp), dando lugar de este modo a concentraciones aumentadas de compuesto activo dentro del organismo.
40 GS-9350 es un compuesto que está siendo desarrollado por Gilead Sciences de Foster City California como un potenciador farmacológico.
SPI-452 es un compuesto que está siendo desarrollado por Sequoia Pharmaceuticals de Gaithersburg, Maryland, como un potenciador farmacológico.
En una realización de la presente invención, se usa un compuesto de la invención en combinación con ritonavir. En
45 una realización, la combinación es una combinación oral de dosis fija. En otra realización, el compuesto de la invención se formula en forma de una inyección parenteral de acción prolongada y el ritonavir se formula en forma de una composición oral. En una realización, es un kit que contiene el compuesto de la invención formulado en forma de una inyección parenteral de acción prolongada y el ritonavir se formula en forma de una composición oral. En otra realización, el compuesto de la invención se formula en forma de una inyección parenteral de acción
50 prolongada y el ritonavir se formula en forma de una composición inyectable. En una realización, es un kit que contiene el compuesto de la invención formulado en forma de una inyección parenteral de acción prolongada y el ritonavir se formula en forma de una composición inyectable.
En otra realización de la presente invención, se usa un compuesto de la invención en combinación GS-9350. En una realización, la combinación es una combinación oral de dosis fija. En otra realización, el compuesto de la invención
55 se formula en forma de una inyección parenteral de acción prolongada y el GS-9350 se formula en forma de una composición oral. En una realización, es un kit que contiene el compuesto de la invención formulado en forma de una inyección parenteral de acción prolongada y el GS-9350 se formula en forma de una composición oral. En otra realización, el compuesto de la invención se formula en forma de una inyección parenteral de acción prolongada y el
8
Etapa B
2-(terc-butoxi)-2-(4-(4-clorofenil)-1-(4-fluorobencil)-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acetato de metilo
5 Una solución de 2-(terc-butoxi)-2-(4-(4-clorofenil)-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acetato de metilo (20 mg, 0,043 mmol) en acetonitrilo (0,5 ml) se trató con cloruro 4-fluorobencilo (0,025 ml, 0,213 mmol) y Cs2CO3 (69 mg, 0,213mmol) y después se agitó a 70 °C durante 2 horas. La mezcla se diluyó con agua y después se extrajo con acetato de etilo. Los extractos combinados se lavaron con salmuera, se secaron sobre Na2SO4, se filtraron y se concentraron y se concentraron para proporcionar 2-(terc-butoxi)-2-(4-(4-clorofenil)-1-(4-fluorobencil)-6
10 metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acetato de metilo en forma de un sólido de color amarillo claro que se usó sin ninguna purificación adicional. CLEM (m/z) ES+ = 511 (M+1).
Etapa C
Ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-1-(4-fluorobencil)-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5il)acético
El compuesto del título se preparó de una manera similar a la que se describe en el ejemplo 1 y se aisló en forma de
15 un sólido de color blanco (6,1 mg, 0,012 mmol, rendimiento del 29 %) después de purificación por cromatografía de fase inversa (MeCN al 10-90 %/H2O-TFA al 0,1 %, 12 min). RMN 1H (400 MHz, CLOROFORMO-d) ppm 7,58 -7,67 (m, 1 H) 7,43 -7,51 (m, 2 H) 7,37 -7,44 (m, 1 H) 7,24 -7,33 (m, 2 H) 6,97 -7,05 (m, 3 H) 5,96 -6,02 (m, 1 H) 5,75 -5,86 (m, 2 H) 5,30 -5,36 (m, 1 H) 3,67 (s, 3 H) 1,00 (s, 9 H); CLEM (m/z) ES+ = 497 (M+1).
Ejemplo 3
20 Ácido 2-(terc-butoxi)-2-(4-(4-clorofenil)-1-(4-metoxibencil)-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acético
El compuesto del título se preparó de una manera similar a la que se describe en el ejemplo 2 a partir de 2-(tercbutoxi)-2-(4-(4-clorofenil)-6-metil-7-oxo-6,7-dihidro-1H-pirrol[2,3-c]piridin-5-il)acetato de metilo y cloruro de 4metoxibencilo. RMN 1H (400 MHz, CLOROFORMO-d) ppm 7,57 -7,64 (m, 1 H) 7,43 -7,49 (m, 2 H) 7,37 -7,43 (m, 1
25 H) 7,24 -7,29 (m, 2 H) 6,99 -7,06 (m, 1 H) 6,83 -6,90 (m, 2 H) 5,93 -6,00 (m, 1 H) 5,70 -5,83 (m, 2 H) 5,30 -5,36 (m, 1 H) 3,79 (s, 3 H) 3,68 (s, 3 H) 1,01 (s, 9 H); CLEM (m/z) ES+ = 509 (M+1).
42
(continuación)
- Número de compuesto (de la tabla 1)
- Ensayo VIH de MT4 CI50 (µM)
- 15
- 1,62
- 16
- 1,80
- 17
- 1,20
- 18
- 50,00
- 19
- 0,08
- 20
- 0,16
- 21
- 2,70
- 22
- 8,70
- 23
- 1,50
- 24
- 0,04
- 25
- 0,22
- 26
- 2,25
- 27
- 3,85
- 28
- 0,08
- 29
- 0,17
- 30
- 1,10
- 31
- 0,11
- 32
- 0,08
- 33
- 0,21
- 34
- 0,77
- 35
- 1,00
- 36
- 0,06
- 37
- 0,67
- 38
- 0,07
- 39
- 1,36
- 40
- 0,50
- 41
- 0,01
- 42
- 0,54
- 43
- 1,10
- 44
- 0,05
- 45
- 0,08
- 46
- 0,09
- 47
- 0,04
- 48
- 0,03
- 49
- 0,04
- 50
- 0,23
110
Claims (1)
-
imagen1 imagen2 imagen3
Applications Claiming Priority (3)
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| US201161537649P | 2011-09-22 | 2011-09-22 | |
| US201161537649P | 2011-09-22 | ||
| PCT/US2012/055838 WO2013043553A1 (en) | 2011-09-22 | 2012-09-18 | Pyrrolopyridinone compounds and methods for treating hiv |
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| Publication Number | Publication Date |
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| ES2632443T3 true ES2632443T3 (es) | 2017-09-13 |
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| ES12833476.0T Active ES2632443T3 (es) | 2011-09-22 | 2012-09-18 | Compuestos de pirrolopiridinona y procedimientos de tratamiento del VIH |
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| EP (1) | EP2757887B1 (es) |
| ES (1) | ES2632443T3 (es) |
| WO (1) | WO2013043553A1 (es) |
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| BR112012033689A2 (pt) | 2010-07-02 | 2019-09-24 | Gilead Sciences Inc | derivados de ácido 2-quinolinil-acético como compostos de hiv antivirais |
| SG186820A1 (en) | 2010-07-02 | 2013-02-28 | Gilead Sciences Inc | Napht- 2 -ylacetic acid derivatives to treat aids |
| ES2615734T3 (es) | 2011-04-21 | 2017-06-08 | Gilead Sciences, Inc. | Compuestos de benzotiazol y su uso farmacéutico |
| WO2013097052A1 (en) * | 2011-12-30 | 2013-07-04 | Abbott Laboratories | Bromodomain inhibitors |
| US9376392B2 (en) | 2012-01-04 | 2016-06-28 | Gilead Sciences, Inc. | 2-(tert-butoxy)-2-(7-methylquinolin-6-yl) acetic acid derivatives for treating AIDS |
| US9284323B2 (en) | 2012-01-04 | 2016-03-15 | Gilead Sciences, Inc. | Naphthalene acetic acid derivatives against HIV infection |
| MX2014005002A (es) | 2012-04-20 | 2014-07-09 | Gilead Sciences Inc | Derivados de acido benzotiazol-6-il acetico y su uso para tratar una infeccion por vih. |
| TW201441197A (zh) | 2013-01-31 | 2014-11-01 | Shionogi & Co | Ｈｉｖ複製抑制劑 |
| MX366703B (es) | 2013-03-15 | 2019-07-22 | Incyte Holdings Corp | Heterociclos tricíclicos como inhibidores de la proteína bet. |
| EP2821082A1 (en) | 2013-07-05 | 2015-01-07 | Laboratoire Biodim | Method of producing an inactivated lentivirus, especially HIV, vaccine, kit and method of use |
| EP3019502B1 (en) | 2013-07-08 | 2017-05-17 | Incyte Holdings Corporation | Tricyclic heterocycles as bet protein inhibitors |
| WO2015081189A1 (en) | 2013-11-26 | 2015-06-04 | Incyte Corporation | Bicyclic heterocycles as bet protein inhibitors |
| US9399640B2 (en) | 2013-11-26 | 2016-07-26 | Incyte Corporation | Substituted pyrrolo[2,3-c]pyridines and pyrazolo[3,4-c]pyridines as BET protein inhibitors |
| WO2015095492A1 (en) | 2013-12-19 | 2015-06-25 | Incyte Corporation | Tricyclic heterocycles as bet protein inhibitors |
| ES2654242T3 (es) | 2014-02-12 | 2018-02-12 | Viiv Healthcare (No.5) Limited | Macrociclos de benzotiazol como inhibidores de la réplica del virus de la inmunodeficiencia humana |
| WO2015126758A1 (en) | 2014-02-18 | 2015-08-27 | Bristol-Myers Squibb Company | Imidazopyrimidine macrocycles as inhibitors of human immunodeficiency virus replication |
| US9409922B2 (en) | 2014-02-18 | 2016-08-09 | Bristol-Myers Squibb Company | Imidazopyridine macrocycles as inhibitors of human immunodeficiency virus replication |
| EP3152215A1 (en) | 2014-02-18 | 2017-04-12 | ViiV Healthcare UK (No.5) Limited | Pyrazolopyrimidine macrocycles as inhibitors of human immunodeficiency virus replication |
| US9273067B2 (en) | 2014-02-19 | 2016-03-01 | Bristol-Myers Squibb Company | Pyrazolopyrimidine macrocycles as inhibitors of human immunodeficiency virus replication |
| KR102702503B1 (ko) | 2014-04-23 | 2024-09-05 | 인사이트 홀딩스 코포레이션 | BET 단백질의 저해제로서의 1H-피롤로[2,3-c]피리딘-7(6H)-온 및 피라졸로[3,4-c]피리딘-7(6H)-온 |
| WO2015174511A1 (ja) | 2014-05-16 | 2015-11-19 | 塩野義製薬株式会社 | Ｈｉｖ複製阻害作用を有する３環性複素環誘導体 |
| UY36217A (es) | 2014-07-21 | 2016-02-29 | Viiv Healthcare Uk Ltd | Compuestos piridona sustituídos, composiciones farmacéuticas y métodos de uso. |
| WO2016044130A1 (en) | 2014-09-15 | 2016-03-24 | Incyte Corporation | Tricyclic heterocycles for use as bet protein inhibitors |
| MA43120A (fr) | 2015-05-29 | 2018-09-05 | Shionogi & Co | Dérivé tricyclique contenant de l'azote présentant une activité inhibitrice de la réplication du vih |
| US20170121347A1 (en) | 2015-10-29 | 2017-05-04 | Incyte Corporation | Amorphous solid form of a bet protein inhibitor |
| PH12021551886A1 (en) | 2016-06-20 | 2023-07-17 | Incyte Corp | Crystalline solid forms of a bet inhibitor |
| JP2019522014A (ja) | 2016-07-25 | 2019-08-08 | ヴィーブ ヘルスケア ユーケー リミテッド | インドリン誘導体 |
| EP3509642A1 (en) | 2016-09-12 | 2019-07-17 | ST IP Holding AG | Formulations of 4-methyl-5-(pyrazin-2-yl)-3h-1, 2-dithiole-3-thione, and methods of making and using same |
| WO2018047002A1 (en) * | 2016-09-12 | 2018-03-15 | St Ip Holding Ag | Formulations of 4-methyl-5-(pyrazin-2-yl)-3h-1.2-dithiole-3-thione, taste-modified formulations, and methods of making and using same |
| WO2018047013A1 (en) * | 2016-09-12 | 2018-03-15 | St Ip Holding Ag | Formulations of 4-methyl-5-(pyrazin-2-yl)-3h-1, 2-dithiole-3-thione, and methods of making and using same |
| CA3036630A1 (en) | 2016-09-12 | 2018-03-15 | St Ip Holding Ag | Formulations of 4-methyl-5-(pyrazin-2-yl)-3h-1,2-dithiole-3-thione, taste-modified formulations, and methods of making and using same |
| AU2018389763B2 (en) * | 2017-12-20 | 2023-02-23 | Pi Industries Ltd. | Pyrazolopyridine-diamides, their use as insecticide and processes for preparing the same. |
| US11135220B1 (en) | 2020-04-08 | 2021-10-05 | St Ip Holding Ag | Methods of treating viral infections with formulated compositions comprising 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione |
| US11833155B2 (en) | 2020-06-03 | 2023-12-05 | Incyte Corporation | Combination therapy for treatment of myeloproliferative neoplasms |
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| US4107288A (en) | 1974-09-18 | 1978-08-15 | Pharmaceutical Society Of Victoria | Injectable compositions, nanoparticles useful therein, and process of manufacturing same |
| US5145684A (en) | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
| UA72611C2 (uk) * | 2000-05-17 | 2005-03-15 | Орто-Макнейл Фармацевтикал, Інк. | Похідні заміщеного піролопіридинону, корисні як інгібітори фосфодіестерази |
| US20040110785A1 (en) | 2001-02-02 | 2004-06-10 | Tao Wang | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
| JPWO2002074769A1 (ja) | 2001-03-19 | 2004-07-08 | 小野薬品工業株式会社 | トリアザスピロ［５．５］ウンデカン誘導体を有効成分として含有する薬剤 |
| AR045595A1 (es) * | 2003-09-04 | 2005-11-02 | Vertex Pharma | Composiciones utiles como inhibidores de proteinas quinasas |
| US20070142414A1 (en) | 2005-12-16 | 2007-06-21 | Pharmacia Italia S.P.A. | N-substituted pyrrolopyridinones active as kinase inhibitors |
| KR20100097156A (ko) * | 2007-11-16 | 2010-09-02 | 베링거 인겔하임 인터내셔날 게엠베하 | 사람 면역결핍 바이러스 복제의 억제제 |
| WO2009062308A1 (en) * | 2007-11-16 | 2009-05-22 | Boehringer Ingelheim International Gmbh | Inhibitors of human immunodeficiency virus replication |
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| US9012642B2 (en) | 2015-04-21 |
| WO2013043553A1 (en) | 2013-03-28 |
| EP2757887A4 (en) | 2015-05-27 |
| EP2757887A1 (en) | 2014-07-30 |
| US20140343092A1 (en) | 2014-11-20 |
| EP2757887B1 (en) | 2017-04-26 |
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