ES2640049T3 - Derivados de 3,6-dihidropirimidina 2,4,5,6-sustituidos como inhibidores de la polimerasa del virus de la hepatitis B (VHB) para el tratamiento de, por ejemplo, la hepatitis crónica - Google Patents
Derivados de 3,6-dihidropirimidina 2,4,5,6-sustituidos como inhibidores de la polimerasa del virus de la hepatitis B (VHB) para el tratamiento de, por ejemplo, la hepatitis crónica Download PDFInfo
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- ES2640049T3 ES2640049T3 ES13830553.7T ES13830553T ES2640049T3 ES 2640049 T3 ES2640049 T3 ES 2640049T3 ES 13830553 T ES13830553 T ES 13830553T ES 2640049 T3 ES2640049 T3 ES 2640049T3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- 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
- A61K31/495—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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61K31/495—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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D403/14—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 three or more hetero rings
-
- 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
- C07D413/06—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 carbon chain containing only aliphatic carbon atoms
-
- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
Un compuesto de Fórmulas (I) o (Ia) **(Ver fórmula)** o un enantiómero, un diastereoisómero, un tautómero, un hidrato, un solvato o una sal farmacéuticamente aceptable del mismo, en donde: cada A es un enlace, -O-, -S- o -NR5-; cada R es -X-Z; X es -(CR7R7n)m- o -C(>=O)-; Z tiene las Fórmulas (II) o (IIa): **(Ver fórmula)** en la que cada B es -CR7R7n-; cada W es N; cada Y es -O-; cada R1 es arilo o heteroarilo; cada R2 es H, alquilo, alquenilo, alquinilo, arilo, aralquilo, heteroarilo, heteroarilalquilo, cicloalquilo, cicloalquilalquilo, heterociclilo, heterociclilalquilo o alcoxicarbonilo; cada R3 es arilo o heteroarilo; cada R4 es H o alquilo C1-4; R5 es H, alquilo, -(CR7R7a)m-C(>=O)O-R8, alquenilo o alquinilo; cada R7a y R7 son independientemente H, F, Cl, Br, alquilo, haloalquilo, -(CH2)m-OH o -(CH2)m-C(>=O)O-R8; cada R8 y R8a son independientemente H, alquilo, haloalquilo, aminoalquilo, Boc-NH-alquilo, alcoxi, -(CH2)m- OH, -(CH2)m-C(>=O)O-(CH2)m-H o -(CH2)m-OC(>=O)-(CH2)m-H; Boc es terc-butiloxicarbonilo; cada R9 es independientemente -(CR7R7n)t-OH, -(CR7R7a)m-C(>=O)O-R8, -(CR7R7a)m-C(>=O)O-(CR7R7a)m- OC(>=O)O-R8, -(CR7R7a)m-C(>=O)O-(CR7R7a)m-OC(>=O)-R8, -(CR7R7a)m- C(>=O)O-(CR7R7a)m-C(>=O)O-R8, - (CR7R7a)t-OC(>=O)-R8, triazolilo, tetrazolilo o -(CR7R7a)m-C(>=O)N(R8)2, con la condición de que cuando R9 es - (CR7R7a)tOH, R3 es arilo, furilo, imidazolilo, isoxazolilo, oxazolilo, pirrolilo, pirimidinilo, piridazinilo, tiazolilo, diazolilo, triazolilo, tetrazolilo, tienilo, pirazolilo, isotiazolilo, oxadiazolilo, tiadiazolilo, pirazinilo, piranilo o triazinilo; cada n es independientemente 1, 2 o 3; cada t es independientemente 1, 2, 3 o 4; cada m es independientemente 0, 1 o 2; y opcionalmente, cada arilo, heteroarilo, alquilo, haloalquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo, alcoxicarbonilo, aralquilo, heteroarilalquilo, aminoalquilo, alcoxi, furanilo, imidazolilo, isoxazolilo, oxazolilo, pirrolilo, pirimidinilo, piridazinilo, tiazolilo, diazolilo, triazolilo, tetrazolilo, tienilo, pirazolilo, isotiazolilo, oxadiazolilo, tiadiazolilo, pirazinilo, piranilo, triazinilo, heterociclilo y heterociclilalquilo anteriormente descritos, están independientemente sustituidos con uno o más sustituyentes que son iguales o diferentes, en donde el sustituyente es H, F, Cl, Br, I, alquilo, alcoxi, ciano, hidroxi, nitro, alquilamino, amino, trifluorometilo, trifluorometoxi, -(CR7R7a)m-C(>=O)O-R8, arilo sustituido con haloalquilo, arilo sustituido con halógeno, - (CR7R7a)m-C(>=O)N(R8a)2 o trifluorometilsulfonilo.
Description
OC(=O)O-R8, -(CR7R7a)m-C(=O)O-(CR7R7a)m-OC(=O)-R8, -(CR7R7a)t-OC(=O)-R8, triazolilo, tetrazolilo o (CR7R7a)m-C(=O)N(R8)2, con la condición de que cuando R9 es -(CR7R7a)t-OH, R3 es fenilo, furilo, imidazolilo, isoxazolilo, oxazolilo, pirrolilo, pirimidinilo, piridazinilo, tiazolilo, diazolilo, triazolilo, tetrazolilo, tienilo, pirazolilo, isotiazolilo, oxadiazolilo, tiadiazolilo, pirazinilo, piranilo o triazinilo;
5 cada m es independientemente 0, 1 o 2; y
cada t es independientemente 1, 2, 3 o 4.
10 En otras realizaciones, Z es:
8
concentración final de cada compuesto fue de 500 nmol en cada pocillo. Los medios que contenían compuesto se renovaron el día 4 después de la siembra de células. Los medios de cultivo se recogieron de las placas HepG2.2.15 el día 7 después de la siembra y se sometieron a continuación a extracción del ADN de VHB.
5 Extracción del ADN de VHB: uso del kit QIAamp 96 DNA Blood (QIAGEN 51161).
PCR para cuantificación: la mezcla de la PCR se preparó de acuerdo con el sistema PCR; la mezcla de la PCR se dispensó a las placas de reacción ópticas de 384 pocillos (especiales para cuantificación); se añadió el patrón diluido proporcionalmente; la muestra se añadió; las placas se sellaron con película óptica adhesiva; el sistema de la PCR 10 se llevó a cabo de acuerdo con los programas.
El porcentaje de inhibición de la replicación del ADN de VHB mediante los compuestos se calculó usando la siguiente ecuación:
II. Resultados del ensayo
Los porcentajes de inhibición de la replicación del ADN del VHB mediante los compuestos divulgados en el presente 20 documento se detectaron con los métodos anteriores. Los resultados se muestran en la Tabla 2:
Tab.2
- Ejemplo
- VHB ( % Inb.) (500 nmol) Ejemplo VHB ( % Inb.) (500 nmol)
- Ejemplo 1
- 75,85 Ejemplo 55 92,96
- Ejemplo 2
- 31,3 Ejemplo 60 93,96
- Ejemplo 3
- 84,5 Ejemplo 61 91,08
- Ejemplo 4
- 90 Ejemplo 66 88,79
- Ejemplo 5
- 95 Ejemplo 69 36,5
- Ejemplo 6
- 99,9 Ejemplo 70 63,6
- Ejemplo 9
- 93,1 Ejemplo 71 43,4
- Ejemplo 10
- 89,7 Ejemplo 74 91,7
- Ejemplo 11
- 95,6 Ejemplo 77 91,9
- Ejemplo 12
- 53,8 Ejemplo 78 87,9
- Ejemplo 13
- 54,5 Ejemplo 80 91,9
- Ejemplo 21
- 51,2 Ejemplo 81 91,9
- Ejemplo 23
- 45 Ejemplo 82 96,0
- Ejemplo 24
- 56,1 Ejemplo 83 36,0
- Ejemplo 25
- 91,9 Ejemplo 119 94
- Ejemplo 26
- 96,0 Ejemplo 121 48,5
- Ejemplo 27
- 91,9 Ejemplo 122 46,2
- Ejemplo 34
- 94,35 Ejemplo 123 37,55
- Ejemplo 40
- 95 Ejemplo 125 92,55
- Ejemplo 42
- 91,9 Ejemplo 126 94,65
- Ejemplo 49
- 96,2 Ejemplo 129 92
- Ejemplo 51
- 91,3 Ejemplo 133 92,61
- Ejemplo 52
- 89,51 Ejemplo 135 93,35
- Ejemplo 53
- 92,62 Ejemplo 136 95,85
- Ejemplo 54
- 91,05
159
Claims (1)
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imagen1 imagen2 imagen3 imagen4 imagen5 imagen6 imagen7 imagen8 imagen9 169imagen10 imagen11 imagen12 imagen13 imagen14 imagen15 imagen16 imagen17 imagen18 imagen19 imagen20 imagen21 imagen22 imagen23 imagen24 imagen25 imagen26 imagen27 imagen28 imagen29
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210303033 | 2012-08-24 | ||
| CN201210303033 | 2012-08-24 | ||
| CN201310116949 | 2013-04-03 | ||
| CN201310116949 | 2013-04-03 | ||
| PCT/CN2013/001001 WO2014029193A1 (en) | 2012-08-24 | 2013-08-23 | Dihydropyrimidine compounds and their application in pharmaceuticals |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2640049T3 true ES2640049T3 (es) | 2017-10-31 |
Family
ID=50149385
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES13830553.7T Active ES2640049T3 (es) | 2012-08-24 | 2013-08-23 | Derivados de 3,6-dihidropirimidina 2,4,5,6-sustituidos como inhibidores de la polimerasa del virus de la hepatitis B (VHB) para el tratamiento de, por ejemplo, la hepatitis crónica |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US9340538B2 (es) |
| EP (1) | EP2888241B1 (es) |
| JP (1) | JP6263533B2 (es) |
| KR (1) | KR102148678B1 (es) |
| CN (2) | CN103626752B (es) |
| AU (1) | AU2013305390C1 (es) |
| BR (1) | BR112015002858A2 (es) |
| CA (1) | CA2876690C (es) |
| DK (1) | DK2888241T3 (es) |
| ES (1) | ES2640049T3 (es) |
| HK (1) | HK1206027A1 (es) |
| HU (1) | HUE034919T2 (es) |
| MX (1) | MX2015002511A (es) |
| MY (1) | MY182403A (es) |
| PL (1) | PL2888241T3 (es) |
| PT (1) | PT2888241T (es) |
| RU (1) | RU2655914C9 (es) |
| SG (1) | SG11201408791TA (es) |
| TW (1) | TWI668217B (es) |
| WO (1) | WO2014029193A1 (es) |
| ZA (1) | ZA201500451B (es) |
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