ES2608871T3 - Alafenamide hemifumarate de tenofovir - Google Patents
Alafenamide hemifumarate de tenofovir Download PDFInfo
- Publication number
- ES2608871T3 ES2608871T3 ES12753867.6T ES12753867T ES2608871T3 ES 2608871 T3 ES2608871 T3 ES 2608871T3 ES 12753867 T ES12753867 T ES 12753867T ES 2608871 T3 ES2608871 T3 ES 2608871T3
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- ES
- Spain
- Prior art keywords
- tenofovir alafenamide
- tenofovir
- hemifumarate
- alafenamide
- monofumate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- 229960004556 tenofovir Drugs 0.000 title 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title 1
- SVUJNSGGPUCLQZ-FQQAACOVSA-N tenofovir alafenamide fumarate Chemical compound OC(=O)\C=C\C(O)=O.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 SVUJNSGGPUCLQZ-FQQAACOVSA-N 0.000 abstract description 7
- 239000012535 impurity Substances 0.000 description 7
- 238000010926 purge Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 description 3
- 229960004946 tenofovir alafenamide Drugs 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- LDEKQSIMHVQZJK-GNGHXOLXSA-N propan-2-yl (2s)-2-[[[(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-phenoxyphosphoryl]amino]propanoate Chemical compound O([P@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-GNGHXOLXSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- 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
-
- 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
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
Abstract
Hemifumarato de tenofovir alafenamida.
Description
Datos TGA
[0062] Los datos de TGA se obtuvieron usando 4,161 mg de hemifumarato de tenofovir alafenamida. Se calentó a 10ºC/min en el intervalo de 25-200ºC. La muestra perdió 0,3% de peso antes de la fusión (Fig. 3). Se determinó que es una forma anhidra.
Análisis DVS
[0063] El análisis DVS se realizó utilizando 4,951 mg de hemifumarato de tenofovir alafenamida. El material se mantuvo a 25ºC en nitrógeno a humedades comprendidas entre 10% y 90% de humedad relativa; Cada etapa se equilibró durante 120 minutos. La isoterma de adsorción se muestra en la FIG. 4. Se demostró que el material era no higroscópico, y absorbía 0,65% de agua a una humedad relativa de 90%.
Purga de la impureza diastereomérica
[0064] En las síntesis anteriores de tenofovir alafenamida, una de las principales impurezas es típicamente el diastereómero 9-[(R)-2-[[(R)-[[(S)-1-(isopropoxicarbonilo)etilo]amino]fenoxifosfinilo]metoxi]propilo]adenina. La forma de hemifumarato de tenofovir alafenamida del Ejemplo 3 tiene una capacidad excepcional para purgar esta impureza diastereomérica, en comparación con la capacidad de la forma de monofumarato (descrita en la Patente de Estados Unidos nº 7.390.791). Los datos de la Tabla 2 (a continuación) demuestran que el hemifumarato de tenofovir alafenamida (Lote 2) purgó la impureza diastereomérica a menos de una décima parte de la concentración inicial, mientras que la forma de monofumarato de tenofovir alafenamida (Lote 1) sólo purgó ligeramente la impureza diastereomérica.
Tabla 2. Comparación de capacidades de purga
- Lote
- La impureza diastereomérica en material de partida Solvente Carga de ácido fumárico (equivalente molar) Producto obtenido La impureza diastereomérica de producto
- 1
- 9,3% ACN 0,9 Forma de monofumarato 7,6%
- 2
- 10,0% ACN 0,5 Forma de hemifumarato 0,65%
Estabilidad química
[0065] La estabilidad química de la forma de hemifumarato de tenofovir alafenamida se comparó con la forma de monofumarato. Como se muestra en la Tabla 3 (a continuación), en condiciones idénticas, la forma de hemifumarato de tenofovir alafenamida era químicamente más estable y exhibe una mejor estabilidad de almacenamiento a largo plazo, con significativamente menos degradación (% Deg Total. Productos) que la forma de monofumarato. Condiciones evaluadas incluyen la temperatura, la humedad relativa (RH), y el estado abierto o cerrado de la tapa del recipiente.
Tabla 3. Estabilidad química Comparación
- Condición de almacenamiento
- Puntos de tiempo (semanas) Forma de monofumarato Forma de hemifumarato
- % TA* Área normalizada
- % Total Deg. Productos % TA área normalizada Total% Deg. Productos
- 40°C/75% RH tapa cerrada
- 0 97,1 0,69 98,4 0,05
- 1
- 97,0 0,87 98,4 0,14
- 2
- 96,6 1,18 98,5 0,14
- 4
- 96,4 1,49 98,4 0,25
- 8
- 95,4 2,36 98,0 0,49
- 40°C/75% RH tapa abierta
- 0 97,1 0,69 98,4 0,05
- 1
- 96,9 0,90 98,5 0,15
- 2
- 96,6 1,10 98,5 0,14
- 4
- 96,2 1,67 98,4 0,26
- 8
- 95,0 2,74 98,1 0,50
- 70°C tapa cerrada
- 0 97,1 0,69 98,4 0,05
- 2
- 96,2 1,83 98,5 0,22
- 4
- 93,3 4,78 98,4 0,33
- TA es tenofovir alafenamida
Claims (1)
-
imagen1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161524224P | 2011-08-16 | 2011-08-16 | |
| US201161524224P | 2011-08-16 | ||
| PCT/US2012/050920 WO2013025788A1 (en) | 2011-08-16 | 2012-08-15 | Tenofovir alafenamide hemifumarate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| ES2608871T3 true ES2608871T3 (es) | 2017-04-17 |
| ES2608871T5 ES2608871T5 (es) | 2024-04-04 |
Family
ID=46785793
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES12753867T Active ES2608871T5 (es) | 2011-08-16 | 2012-08-15 | Alafenamide hemifumarate de tenofovir |
Country Status (41)
| Country | Link |
|---|---|
| US (2) | US8754065B2 (es) |
| EP (3) | EP3070088A1 (es) |
| JP (5) | JP5651275B2 (es) |
| KR (1) | KR101612642B1 (es) |
| CN (2) | CN103732594A (es) |
| AP (1) | AP3639A (es) |
| AR (1) | AR087546A1 (es) |
| AU (1) | AU2012296622C1 (es) |
| BR (1) | BR112014003420B1 (es) |
| CA (1) | CA2845553C (es) |
| CL (1) | CL2014000370A1 (es) |
| CO (1) | CO6880063A2 (es) |
| CR (1) | CR20140072A (es) |
| CY (1) | CY1118385T1 (es) |
| DK (1) | DK2744810T4 (es) |
| EA (1) | EA027768B1 (es) |
| EC (1) | ECSP14013206A (es) |
| ES (1) | ES2608871T5 (es) |
| FI (1) | FI2744810T4 (es) |
| HK (1) | HK1199026A1 (es) |
| HR (1) | HRP20161696T4 (es) |
| HU (1) | HUE031253T2 (es) |
| IL (2) | IL230949A (es) |
| IN (1) | IN2014DN01012A (es) |
| LT (1) | LT2744810T (es) |
| MA (1) | MA35350B1 (es) |
| MD (1) | MD4508C1 (es) |
| ME (1) | ME02612B (es) |
| MX (1) | MX336627B (es) |
| PE (1) | PE20141328A1 (es) |
| PL (1) | PL2744810T5 (es) |
| PT (1) | PT2744810T (es) |
| RS (1) | RS55353B2 (es) |
| SG (1) | SG2014011548A (es) |
| SI (1) | SI2744810T2 (es) |
| SM (1) | SMT201600476B (es) |
| TW (1) | TWI516499B (es) |
| UA (1) | UA115311C2 (es) |
| UY (1) | UY34262A (es) |
| WO (1) | WO2013025788A1 (es) |
| ZA (1) | ZA201400582B (es) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IN2014DN01012A (es) | 2011-08-16 | 2015-05-15 | Gilead Sciences Inc | |
| SI3333173T1 (sl) | 2011-10-07 | 2019-08-30 | Gilead Sciences, Inc. | Postopki za pripravo analogov protivirusnega nukleotida |
| US20150105350A1 (en) * | 2012-02-03 | 2015-04-16 | Gilead Sciences, Inc. | Combination therapy comprising tenofovir alafenamide hemifumarate and cobicistat for use in the treatment of viral infections |
| WO2015040640A2 (en) * | 2013-09-20 | 2015-03-26 | Laurus Labs Private Limited | An improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof |
| TWI660965B (zh) * | 2014-01-15 | 2019-06-01 | 美商基利科學股份有限公司 | 泰諾福韋之固體形式 |
| WO2015120057A1 (en) | 2014-02-05 | 2015-08-13 | Gilead Sciences, Inc. | Pharmaceutical combinations against co-infection with hiv and tuberculosis |
| CN105085571A (zh) * | 2014-05-20 | 2015-11-25 | 四川海思科制药有限公司 | 替诺福韦艾拉酚胺复合物及其制备方法和用途 |
| CN108148094A (zh) * | 2014-11-12 | 2018-06-12 | 四川海思科制药有限公司 | 一种替诺福韦艾拉酚胺富马酸盐晶型c及其制备方法和用途 |
| CN105237571B (zh) * | 2014-11-28 | 2018-03-09 | 成都苑东生物制药股份有限公司 | 9‑[(r)‑2‑[[(s)‑[[(s)‑1‑(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤的盐 |
| CN104558036A (zh) * | 2014-12-11 | 2015-04-29 | 杭州和泽医药科技有限公司 | 一种替诺福韦艾拉酚胺半反丁烯二酸盐晶型及其制备方法 |
| BR112017013858A2 (pt) | 2014-12-26 | 2018-02-27 | Univ Emory | n4-hidroxicitidina e derivados e usos antivirais relacionados aos mesmos |
| AU2015373104B2 (en) * | 2015-01-03 | 2020-07-09 | Mylan Laboratories Limited | Processes for the preparation of amorphous tenofovir alafenamide hemifumarate and a premix thereof |
| CN105669751B (zh) * | 2015-03-05 | 2018-09-21 | 洛阳聚慧医药科技有限公司 | 非环核苷酸磷酰胺类化合物及其盐的制备以及在抗病毒方面的应用 |
| GB201509431D0 (en) * | 2015-06-01 | 2015-07-15 | Equigerminal Sa | Antiviral composition |
| CZ2015384A3 (cs) | 2015-06-05 | 2016-12-14 | Zentiva, K.S. | Pevné formy Tenofovir alafenamidu |
| US9777028B2 (en) * | 2015-06-17 | 2017-10-03 | Gilead Sciences, Inc. | Co-crystals, salts and solid forms of tenofovir alafenamide |
| KR102313668B1 (ko) | 2015-06-30 | 2021-10-19 | 길리애드 사이언시즈, 인코포레이티드 | 테노포비르 및 엠트리시타빈을 포함하는 제약 제제 |
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| WO2017037608A1 (en) * | 2015-08-28 | 2017-03-09 | Laurus Labs Private Limited | Solid forms of tenofovir alafenamide and salts thereof, processes for its preparation and pharmaceutical compositions thereof |
| PL3346995T3 (pl) | 2015-11-09 | 2020-03-31 | Gilead Sciences, Inc. | Kompozycje terapeutyczne do leczenia ludzkiego wirusa niedoboru odporności |
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| CN107793451A (zh) * | 2016-08-30 | 2018-03-13 | 江苏奥赛康药业股份有限公司 | 替诺福韦艾拉酚胺半富马酸盐化合物及其药物组合物 |
| WO2018044822A1 (en) * | 2016-08-31 | 2018-03-08 | Viiv Healthcare Company | Combinations and uses and treatments thereof |
| WO2018051250A1 (en) | 2016-09-14 | 2018-03-22 | Viiv Healthcare Company | Combination comprising tenofovir alafenamide, bictegravir and 3tc |
| WO2018080903A1 (en) | 2016-10-26 | 2018-05-03 | Merck Sharp & Dohme Corp. | Antiviral aryl-amide phosphodiamide compounds |
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