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Isatuximab
(A chain)
QVQLVQSGAE VAKPGTSVKL SCKASGYTFT DYWMQWVKQR PGQGLEWIGT IYPGDGDTGY
AQKFQGKATL TADKSSKTVY MHLSSLASED SAVYYCARGD YYGSNSLDYW GQGTSVTVSS
ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS
GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG
PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN
STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE
LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW
QQGNVFSCSV MHEALHNHYT QKSLSLSPGK
(B chain)
QVQLVQSGAE VAKPGTSVKL SCKASGYTFT DYWMQWVKQR PGQGLEWIGT IYPGDGDTGY
AQKFQGKATL TADKSSKTVY MHLSSLASED SAVYYCARGD YYGSNSLDYW GQGTSVTVSS
ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS
GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG
PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN
STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE
LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW
QQGNVFSCSV MHEALHNHYT QKSLSLSPGK
(C chain)
DIVMTQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD
RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(D chain)
DIVMTQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD
RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: A22-A96, A147-A203, A223-C214, A229-B229, A232-B232, A264-A324, A370-A428, B22-B96, B147-B203, B223-D214, B264-B324, B370-B428, C23-C88, C134-C194, D23-D88, D134-D194)
Isatuximab
イサツキシマブ (遺伝子組換え)
APPROVED USFDA 2020/3/2, Sarclisa
EU APPROVED 2020/5/30
JAPAN APPROVED 2020/6/29
CAS 1461640-62-9
| Antineoplastic, Anti-CD38 antibody | |
| Disease | Multiple myeloma |
|---|
Isatuximab, sold under the brand name Sarclisa, is a monoclonal antibody (mAb) medication for the treatment of multiple myeloma.[4][3]
The most common side effects include neutropenia (low levels of neutrophils, a type of white blood cell), infusion reactions, pneumonia (infection of the lungs), upper respiratory tract infection (such as nose and throat infections), diarrhoea and bronchitis (inflammation of the airways in the lungs).[3]
Isatuximab is an anti-CD38 mAb intended to treat relapsed or refractory multiple myeloma.[5] It entered in Phase II trials for multiple myeloma[6] and T-cell leukemia in 2015.[7]
Medical uses
In the United States it is indicated, in combination with pomalidomide and dexamethasone, for the treatment of adults with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.[8][9][10]
In the European Union it is indicated, in combination with pomalidomide and dexamethasone, for the treatment of adults with relapsed and refractory multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor (PI) and have demonstrated disease progression on the last therapy.[3]
History
It was granted orphan drug designation for multiple myeloma by the European Medicines Agency (EMA) in April 2014, and by the U.S. Food and Drug Administration (FDA) in December 2016.[3][11]
Researchers started a Phase I study with isatuximab in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM). The results during the Phase I trial showed that 26 out of the 45 patients discontinued the treatment due to progression of the disease. The patients had already been heavily pretreated. The latter lead to a manageable safety profile where the dose of isatuximab in combination with pomalidomide and dexamethasone would be capped to the maximum of 10 mg/kg weekly every two weeks for future studies.[12]
Based on the remarkable findings during the Phase I trial, a Phase II trial was launched where researchers investigated isatuximab as a single agent in patients with MM. The heavily pretreated patients reacted well to the single administration of isatuximab during Phase II of the trial.[13]
A Phase III combination trial for plasma cell myeloma is comparing pomalidomide and dexamethasone with and without isatuximab is in progress with an estimated completion date of 2021.[medical citation needed]
Additionally, two Phase III trials were added in 2017. The first trial highlights whether there is an added value in the combination of isatuximab with bortezomib, lenalidomide and dexamethasone. The latter will be tested in patients with newly diagnosed MM who are not qualified for a transplant (IMROZ trial). The second trial evaluates the combinations of isatuximab with carfilzomib and dexamethasone compared to carfilzomib with dexamethasone. The second trial was designed for patients who were previously treated with one to three prior lines (IKEMA). There is currently[when?] no treatment for MM, however promising improvements have been made and the study is still ongoing.[14][15]
In March 2020, it was approved for medical use in the United States.[8][9][10]
The U.S. Food and Drug Administration (FDA) approved isatuximab-irfc in March 2020, based on evidence from a clinical trial (NCT02990338) of 307 subjects with previously treated multiple myeloma.[10] The trial was conducted at 102 sites in Europe, North America, Asia, Australia and New Zealand.[10]
The trial evaluated the efficacy and side effects of isatuximab-irfc in subjects with previously treated multiple myeloma.[10] Subjects were randomly assigned to receive either isatuximab-irfc (in combination with pomalidomide and low-dose dexamethasone) or active comparator (pomalidomide and low-dose dexamethasone).[10] Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity.[10] Both subjects and health care providers knew which treatment was given.[10] The trial measured the time patients lived without the cancer growing (progression-free survival or PFS).[10]
It was approved for medical use in the European Union in May 2020.[3]
Structure and reactivity
The structure of isatuximab consists of two identical immunoglobulin kappa light chains and also two equal immunoglobulin gamma heavy chains. Chemically, isatuximab is similar to the structure and reactivity of daratumumab, hence both drugs show the same CD38 targeting. However, isatuximab shows a more potent inhibition of its ectozyme function. The latter gives potential for some non-cross reactivity. Isatuximab shows action of an allosteric antagonist with the inhibition of the CD38 enzymatic activity. Additionally, isatuximab shows potential where it can induce apoptosis without cross linking.[16] Lastly, Isatuximab reveals direct killing activity when a larger increase in apoptosis is detected in CD38 expressing cancer cells. Furthermore, isatuximab demonstrated a dose dependent inhibition of CD38 enzymatic activity. However, daratumumab with the same experimental conditions shows a more limited inhibition without a dose response.[17]
Reactions
Isatuximab binds uniquely to an epitope on the CD38 receptor and is the only CD38 antibody which can start apoptosis directly.[18] Isatuximab binds to a different CD38 epitope amino-acid sequence than does the anti-CD38 monoclonal antibody daratumumab.[19] The binding with the CD38 receptor is mainly via the gamma heavy chains and are more potent than other CD38 antibodies such as daratumumab which can inhibit the enzymatic activity of CD38. Moreover, isatuximab inhibits the hydrolase activity of CD38.[medical citation needed]
The antibodies show signs of improving antitumor immunity by eliminating regulatory T cells, B cells and myeloid-derived suppressor cells. The difference in binding between isatuximab and daratumumab is in the recognition of the different amino acid groups. Isatuximab identifies 23 amino acids of CD38 to the contrary with daratumumab who has 27. The residue of Glu233 has a flexible sidechain and faces the N-terminal of Asp1 residue in the isatuximab light chain. The latter light chain of isatuximab is also flexible which makes the interaction between CD38/Glu233 and the Asp1 weaker than the other interactions between CD38 and isatuximab. The caspase-dependent apoptotic pathway and the lysosomal mediated cell death pathway in MM cells is induced by isatuximab. The MM cell death follows the downstream reactions of the lysosomal activation. The latter also activates the production of reactive oxygen species.[20]
Available forms
Isatuximab or isatuximab-irfc is available as a drug in an intravenous infusion form. Injection doses are 100 mg/5 mL (20 mg/mL) solution in single-dose vial or 500 mg/25 mL (20 mg/mL) solution in single-dose vial.[4]
Mechanism of action
Cancer of the blood that is distinguished by an overproduction of malignant plasma cells in the bone marrow is called multiple myeloma. The myeloma cells are marked with uniformed overexpression of CD38 surface glycoproteins. Although these proteins are also expressed on other myeloid and lymphoid cells, the extent is relatively minor compared to myeloma cells. The fact that CD38 glycoproteins carry out various important cellular functions, and that they are plentiful on the surface of myeloma cells, has made them an appealing target for multiple myeloma treatment.[21] CD38 was first described as an activation marker, but later the molecule displayed functions in adhesion to endothelial CD31 proteins, e.g. as an aiding component of the synapse complex, as well as an ectoenzyme implicated in the metabolism of extracellular NAD+ and cytoplasmic NADP. The tumour cells can evade the immune system, possibly due to adenosine, an immunosuppressive molecule that arises as a product of the ectoenzymatic activity of CD38.[22]
Isatuximab-irfc is an IgG1-derived monoclonal antibody that selectively binds to the CD38 that exists on the exterior of hematopoietic and multiple myeloma cells (as well as other tumor cells). This drug induces apoptosis of tumor cells and activates immune effector mechanisms such as complement dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). Isatuximab-irfc is able to stimulate natural killer (NK) cells in the absence of CD38-positive target tumor cells and blocks CD38-positive T-regulatory cells.[4] Furthermore, the NADase activity of CD38 is adjusted by isatuximab, similarly to other CD38 antibodies. Contrarily to daratumumab however, isatuximab can incite apoptosis directly without cross-linking, and in its binding epitope.[23] According to the FDA, isatuximab-irfc alone has reduced ADCC and direct tumor cell killing activity in vitro in comparison to when it is combined with pomalidomide. As well as increased anti-tumor activity as opposed to isatuximab-irfc or pomalidomide only in a human multiple myeloma xenograft model.[4]
Metabolism and toxicity
Metabolism
Isatuximab-irfc is likely to be metabolized through catabolic pathways into smaller peptides. When isatuximab is at a constant state it is expected that the ≥99% elimination will occur approximately two months after the last dose was administered. The clearance percentage diminished when the dosages were increased over time, as well as when multiple doses were administered. However, the elimination of isatuximab-irfc did not differ when applied as a single agent or as a combination therapy.[4]
Toxicity
A dose-limiting toxicity (DLT) has characterized been characterized as the development of any of the following: grade ≥ 3 non-hematologic toxicity; grade 4 neutropenia or grade 4 thrombocytopenia lasting more than 5 days; grade ≥ 2 allergic reactions or hypersensitivity (i.e., infusion reactions); or any other toxicity considered to be dose-limiting by the investigators or sponsor. Grade ≤ 2 infusion reactions were excluded from the DLT definition, because, with suitable care, patients that suffered a grade 2 infusion reaction prior to completion of the infusion were able to finalize isatuximab administration.[23]
There is no recommended reduced dose of isatuximab-irfc. In the eventuality of hematological toxicity it may be necessary to delay administration so that the blood count may be recovered.[4] Although there is no counteracting agent for isatuximab, clinical experience with overdoses is seemingly nonexistent as well. Overdose symptoms will probably be in line with the side effects attached to isatuximab. Therefore, infusion reactions, gastrointestinal disturbances and an elevated risk of infections may occur. It is necessary to carefully monitor the patient in case of an overdose and to employ clinically indicated symptomatic and supportive procedures.[21]
No studies have been conducted with isatuximab concerning carcinogenicity, genotoxicity or fertility.[4]
Pregnancy
When given to pregnant women isatuximab-irfc can cause fetal injury, due to the mechanism of action. It can precipitate depletion of immune cells as well as decreased bone density in the fetus. Pregnant women are therefore notified of the potential risks to a fetus, and women that are able to reproduce are advised to use effective contraceptives during treatment and at least five months subsequent to the last dose of isatuximab-irfc.
Furthermore, it is not recommended to combine isatuximab-irfc with pomalidomide in women that are carrying a child, because pomalidomide may cause birth defects and death of the unborn child.[4]
Indications
Isatuximab is indicated as a CD38-directed cytolytic antibody. By inhibiting the enzymatic activity of CD38.
The binding of isatuximab to CD38 on multiple myeloma (MM) cells leads to a trigger to several mechanisms leading to direct apoptosis of target cancer cells. The triggered pathways are the caspase-dependent apoptotic and the lysosome-mediated cell death pathway in MM cells.[24]
It is used in a combination with dexamethasone and pomalidomide. The drug is thus to treat patients with multiple myeloma. Restrictions for the use of isatuximab is that the patients have to be adults who have at least received two previous treatments with lenalidomide and a proteasome inhibitor.[4]
Isatuximab is currently[when?] also being tested in a Phase II trial as a monotherapy against refractory/recurrent systemic light-chain amyloidosis.[24]
Efficacy and side effects
Efficacy
A Phase III study of patients with refractory and relapsed MM, who were resistant to lenalidomide and a proteasome inhibitor, and could not have received daratumumab, another anti-CD38 monoclonal antibody was published in 2019 (ICARIA-MM). The addition of isatuximab to pomalidomide and dexamethasone improved progression free survival to 11.5 months compared to 6.5 months, with an overall response rate of 63%.[25]
Side effects
Adverse reactions to isatuximab-irfc may include neutropenia, infusion-related reactions and/or secondary primary malignancies.[4] Of these three the most commonly occurring ones are the infusion-related reactions.[24] Examples of the most frequent symptoms of infusion-related reactions are dyspnea, cough, chills, and nausea, while the severest signs and symptoms included hypertension and dyspnea.[4]
Effects on animals
The activity of isatuximab has been researched in mouse tumor models. It has been proven that isatuximab leads to antitumor activity in MM cells. Furthermore, the combination of isatuximab and pomalidomide will lead to an extra enhanced antitumor activity in MM cells. Thus, pomalidomide in vivo and in vitro leads to an increase of the activity of isatuximab.[24]
Animal studies in reproduction toxicity have not yet been carried out. So, the risks of birth defects and miscarriage risks are unknown.[4]
Names
Isatuximab is the United States Adopted Name (USAN).[26]
It was developed by ImmunoGen and Sanofi-Aventis with the development name SAR-650984.
References
- ^ Jump up to:a b “Sarclisa Australian prescription medicine decision summary”. Therapeutic Goods Administration (TGA). 14 May 2020. Retrieved 16 August 2020.
- ^ “Isatuximab (Sarclisa) Use During Pregnancy”. Drugs.com. 25 March 2020. Retrieved 25 June 2020.
- ^ Jump up to:a b c d e f “Sarclisa EPAR”. European Medicines Agency (EMA). 24 March 2020. Retrieved 25 June 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ Jump up to:a b c d e f g h i j k l “Sarclisa- isatuximab injection, solution, concentrate”. DailyMed. 2 March 2020. Retrieved 26 March 2020.
- ^ ImmunoGen, Inc. Announces Data Presentations at Upcoming 57th ASH Annual Meeting and Exposition
- ^ Martin T (2015). “A Dose Finding Phase II Trial of Isatuximab (SAR650984, Anti-CD38 mAb) As a Single Agent in Relapsed/Refractory Multiple Myeloma”. Blood. 126 (23): 509. doi:10.1182/blood.V126.23.509.509.
- ^ “Safety and Efficacy of Isatuximab in Lymphoblastic Leukemia”. ClinicalTrials.gov. Retrieved 4 March 2020.
- ^ Jump up to:a b “FDA approves isatuximab-irfc for multiple myeloma”. U.S. Food and Drug Administration (FDA). 2 March 2020. Retrieved 2 March 2020.
This article incorporates text from this source, which is in the public domain. - ^ Jump up to:a b “FDA Approves New Therapy for Patients with Previously Treated Multiple Myeloma”. U.S. Food and Drug Administration (FDA) (Press release). 2 March 2020. Retrieved 4 March 2020. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b c d e f g h i “Drug Trials Snapshots: Sarclisa”. U.S. Food and Drug Administration(FDA). 2 March 2020. Retrieved 25 March 2020. This article incorporates text from this source, which is in the public domain.
- ^ “Isatuximab Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 4 March 2020.
- ^ Mikhael J, Richardson P, Usmani SZ, Raje N, Bensinger W, Karanes C, et al. (July 2019). “A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma”. Blood. 134 (2): 123–133. doi:10.1182/blood-2019-02-895193. PMC 6659612. PMID 30862646.
- ^ Martin T (7 December 2015). “A Dose Finding Phase II Trial of Isatuximab (SAR650984, Anti-CD38 mAb) As a Single Agent in Relapsed/Refractory Multiple Myeloma”. ASH.
- ^ Orlowski RZ, Goldschmidt H, Cavo M, Martin TG, Paux G, Oprea C, Facon T (20 May 2018). “Phase III (IMROZ) study design: Isatuximab plus bortezomib (V), lenalidomide (R), and dexamethasone (d) vs VRd in transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM)”. Journal of Clinical Oncology. 36 (15_suppl): TPS8055. doi:10.1200/JCO.2018.36.15_suppl.TPS8055.
- ^ Moreau P, Dimopoulos MA, Yong K, Mikhael J, Risse ML, Asset G, Martin T (January 2020). “Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA Phase III study design”. Future Oncology. 16 (2): 4347–4358. doi:10.2217/fon-2019-0431. PMID 31833394.
- ^ Rajan AM, Kumar S (July 2016). “New investigational drugs with single-agent activity in multiple myeloma”. Blood Cancer Journal. 6 (7): e451. doi:10.1038/bcj.2016.53. PMC 5030378. PMID 27471867.
- ^ Martin T, Baz R, Benson DM, Lendvai N, Wolf J, Munster P, et al. (June 2017). “A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma”. Blood. 129 (25): 3294–3303. doi:10.1182/blood-2016-09-740787. PMC 5482100. PMID 28483761.
- ^ Martin TG, Corzo K, Chiron M (2019). “Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab”. Cells. 8 (12): 1522. doi:10.3390/cells8121522. PMC 6953105. PMID 31779273.
- ^ Dhillon S (2020). “Isatuximab: First Approval”. Drugs. 80 (9): 905–912. doi:10.1007/s40265-020-01311-1. PMID 32347476. S2CID 216597315.
- ^ Martin TG, Corzo K, Chiron M, Velde HV, Abbadessa G, Campana F, et al. (November 2019). “Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab”. Cells. 8 (12): 1522. doi:10.3390/cells8121522. PMC 6953105. PMID 31779273.
- ^ Jump up to:a b “Isatuximab”. Drugbank. 20 May 2019.
- ^ Morandi F, Horenstein AL, Costa F, Giuliani N, Pistoia V, Malavasi F (28 November 2018). “CD38: A Target for Immunotherapeutic Approaches in Multiple Myeloma”. Frontiers in Immunology. 9: 2722. doi:10.3389/fimmu.2018.02722. PMC 6279879. PMID 30546360.
- ^ Jump up to:a b Martin T, Strickland S, Glenn M, Charpentier E, Guillemin H, Hsu K, Mikhael J (March 2019). “Phase I trial of isatuximab monotherapy in the treatment of refractory multiple myeloma”. Blood Cancer Journal. 9 (4): 41. doi:10.1038/s41408-019-0198-4. PMC 6440961. PMID 30926770.
- ^ Jump up to:a b c d Martin TG, Corzo K, Chiron M, Velde HV, Abbadessa G, Campana F, et al. (November 2019). “Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab”. Cells. 8 (12): 1522. doi:10.3390/cells8121522. PMC 6953105. PMID 31779273.
- ^ Attal, Michel; Richardson, Paul G; Rajkumar, S Vincent; San-Miguel, Jesus; Beksac, Meral; Spicka, Ivan; Leleu, Xavier; Schjesvold, Fredrik; Moreau, Philippe; Dimopoulos, Meletios A; Huang, Jeffrey Shang-Yi (2019). “Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study”. The Lancet. 394 (10214): 2096–2107. doi:10.1016/s0140-6736(19)32556-5. ISSN 0140-6736. PMID 31735560. S2CID 208049235.
- ^ Statement On A Nonproprietary Name Adopted By The USAN Council – Isatuximab, American Medical Association
External links
- “Isatuximab”. Drug Information Portal. U.S. National Library of Medicine.
- Clinical trial number NCT02990338 for “Multinational Clinical Study Comparing Isatuximab, Pomalidomide, and Dexamethasone to Pomalidomide and Dexamethasone in Refractory or Relapsed and Refractory Multiple Myeloma Patients (ICARIA-MM)” at ClinicalTrials.gov
| Isatuximab (pale blue) binding CD38 (purple). PDB: 4CMH | |
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Chimeric (mouse/human) |
| Target | CD38 |
| Clinical data | |
| Trade names | Sarclisa |
| Other names | SAR-650984, isatuximab-irfc |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a620023 |
| License data | US DailyMed: Sarclisa |
| Pregnancy category | AU: C[1]US: N (Not classified yet)[2] |
| Routes of administration | Intravenous |
| Drug class | Antineoplastic |
| ATC code | None |
| Legal status | |
| Legal status | AU: S4 (Prescription only) [1]US: ℞-onlyEU: Rx-only [3] |
| Identifiers | |
| CAS Number | 1461640-62-9 |
| DrugBank | DB14811 |
| ChemSpider | none |
| UNII | R30772KCU0 |
| KEGG | D11050 |
| Chemical and physical data | |
| Formula | C6456H9932N1700O2026S44 |
| Molar mass | 145190.99 g·mol−1 |
////////Isatuximab, Sarclisa, 2020APPROVALS, JAPAN 2020, US 2020, EU 2020, PEPTIDE, SANOFI , イサツキシマブ (遺伝子組換え) ,
Borofalan (10B)
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Borofalan (10B), ボロファラン (10B), 硼[10B]法仑
APPROVED JAPAN, 2020/3/25, Steboronine
Antineoplastic, Diagnostic aid, Radioactive agent
(2S)-2-amino-3-(4-(10B)dihydroxy(10B)phenyl)propanoic acid
| Formula | C9H12BNO4 |
|---|---|
| CAS | 80994-59-8 |
| Mol weight | 209.0069 |
- 4-(Borono-10B)-L-phenylalanine
- (10B)-4-Borono-L-phenylalanine
- Borofalan (10b)
- L-(p-[10B]Boronophenyl)alanine
- L-4-[10B]Boronophenylalanine
- p-[10B]Borono-L-phenylalanine
- L-Phenylalanine, 4-borono-10B-
Marketed Head and neck cancer - Originator Stella Pharma
- Developer Osaka University; Stella Pharma; Sumitomo Heavy Industries
- Class Antineoplastics; Borates; Propionic acids; Radiopharmaceuticals
- Mechanism of Action Ionising radiation emitters
- Phase IIGlioma
- Phase I Haemangiosarcoma; Malignant melanoma
- 20 May 2020 Launched for Head and neck cancer (Inoperable/Unresectable, Late-stage disease, Locally recurrent) in Japan (IV)
- 25 Mar 2020 Registered for Head and neck cancer (Inoperable/Unresectable, Late-stage disease, Locally recurrent) in Japan (IV) – First global approval
- 03 Mar 2020 Chemical structure information added
- Melting Point (Experimental)Value: 285-298 °C (decomp) Hattori, Yoshihide; Tetrahedron Letters 2008, VOL49(33), PG 4977-4980
- SP ROT -5.2 ° Conc: 0.50 g/100mL; Solv: hydrochloric acid 589.3 nm; Temp: 25 °C, Hattori, Yoshihide; Tetrahedron Letters 2008, VOL49(33), PG 4977-4980
Borofalan (10B)
4-[(10B)Borono]-L-phenylalanine
C9H1210BNO4 : 208.21
[80994-59-8]
With the development of atomic science, radiation therapy such as cobalt hexahydrate, linear accelerator, and electron beam has become one of the main methods of cancer treatment. However, traditional photon or electron therapy is limited by the physical conditions of the radiation itself. While killing the tumor cells, it also causes damage to a large number of normal tissues on the beam path. In addition, due to the sensitivity of tumor cells to radiation, traditional radiation therapy For the more radiation-resistant malignant tumors (such as: glioblastoma multiforme, melanoma), the treatment effect is often poor.
In order to reduce the radiation damage of normal tissues around the tumor, the concept of target treatment in chemotherapy has been applied to radiation therapy; and for tumor cells with high radiation resistance, it is currently actively developing with high relative biological effects (relative Biological effectiveness, RBE) radiation sources, such as proton therapy, heavy particle therapy, neutron capture therapy. Among them, neutron capture therapy combines the above two concepts, such as boron neutron capture therapy, by the specific agglomeration of boron-containing drugs in tumor cells, combined with precise neutron beam regulation, providing better radiation than traditional radiation. Cancer treatment options.
Boron Neutron Capture Therapy (BNCT) is a high-capture cross-section of thermal neutrons using boron-containing ( 10 B) drugs, with 10 B(n,α) 7 Li neutron capture and nuclear splitting reactions. Two heavy charged particles of 4 He and 7 Li are produced. The average energy of the two charged particles is about 2.33 MeV, which has high linear energy transfer (LET) and short range characteristics. The linear energy transfer and range of α particles are 150 keV/μm and 8 μm, respectively, while the 7 Li heavy particles are For 175 keV/μm, 5 μm, the total range of the two particles is equivalent to a cell size, so the radiation damage caused to the organism can be limited to the cell level, when the boron-containing drug is selectively aggregated in the tumor cells, with appropriate The sub-radiation source can achieve the purpose of locally killing tumor cells without causing too much damage to normal tissues.
Since the effectiveness of boron neutron capture therapy depends on the concentration of boron-containing drugs in the tumor cell position and the number of thermal neutrons, it is also called binary cancer therapy; thus, in addition to the development of neutron sources, The development of boron-containing drugs plays an important role in the study of boron neutron capture therapy.
4-( 10 B)dihydroxyboryl-L-phenylalanine (4-( 10 B)borono-L-phenylalanine, L- 10 BPA) is currently known to be able to utilize boron neutron capture therapy (boron neutron capture therapy) , BNCT) An important boron-containing drug for the treatment of cancer.
Therefore, various synthetic methods of L-BPA have been developed. As shown in the following formula (A), the prior art L-BPA synthesis method includes two methods of forming a bond (a) and a bond (b):
Among them, the method for synthesizing L-BPA by forming the bond (a) is to try to introduce a substituent containing a dihydroxylboryl group or a borono group into the skeleton of the phenylalanine, thereby the pair of the amide substituent. The position forms a carbon-boron bond to produce L-BPA.
J. Org. Chem. 1998, 63, 8019 discloses a method for the cross-coupling reaction of (S)-4-iodophenylalanine with a diboron compound by palladium-catalyzed amine end treatment. Amine-protected (S)-4-iodophenylalanine (eg (S)-N-tert-butoxycarbonyl-4-iodophenylalanine ((S)-N-Boc-4-) Iodophenylalanine)) is prepared by cross-coupling with a diboron compound such as bis(pinacolato diboron) to give (S)-N-tert-butoxycarbonyl-4-pentanoylboryl phenylalanine The amine-terminated (S)-4-boranyl ester phenylalanine of the acid ((S)-N-Boc-4-pinacolatoborono phenylalanine); afterwards, the protecting group on the amine end and the boronic end are removed. The above substituents complete the preparation of L-BPA.
However, since the selected 10 B-doped divaleryl diboron is not a commercially available compound, this method requires additional pretreatment of the preparation of the borating agent, resulting in a high process complexity and a long time consuming process. It is impossible to prepare a high yield of L-BPA. In addition, the carboxylic acid group of the protected (S)-4-iodophenylalanine at the amine end needs to be protected by a substituent to form a benzyl ester group to increase the process yield to 88%; however, The preparation of L-BPA in this manner also requires an additional step of deprotecting the carboxylic acid group, which in turn increases the process complexity of L-BPA.
Accordingly, the method provided in this document not only involves pre-treatment of the preparation of the borating agent, but also requires a large amount of process time and synthesis steps to complete the steps of protecting and deprotecting the carboxylic acid group, and is not advantageous as an industry. The main method of synthesizing L-BPA.
On the other hand, a method for synthesizing L-BPA by forming a bond (b) is a coupling reaction of an amino acid with a boron-containing benzyl fragment or a boron-containing benzaldehyde fragment. To synthesize L-BPA. Biosci. Biotech. Biochem. 1996, 60, 683 discloses an enantioselective synthesis of L-BPA which gives the hands of a cyclic ethers of boronic acid and L-proline The chiral derivatives from L-valine are subjected to a coupling reaction to produce L-BPA. However, this method requires the formation of a cyclic ether compound of boric acid from 4-boronobenzylbromide, followed by a coupling reaction with a chiral derivative of L-proline, and in the latter stage. The amino acid undergoes an undesired racemization in the synthesis step, so that the method requires an enzymatic resolution step to reduce the yield to obtain L-BPA having a certain optical purity.
Accordingly, the method provided in the literature still includes the steps of pretreatment of the preparation of the borating agent and post-treatment of the enzymatic resolution, so that the process involved in the method is complicated and takes a long time, and cannot be obtained. High yield of L-BPA.
In addition, L- 10 BPA (4-( 10 B)borono-L-phenylalanine, 4-( 10 B)dihydroxyboryl-L-phenylalanine) containing 10 boron is currently known to accumulate in tumor cells. The key factor is to use the thermal neutron beam to irradiate the boron element accumulated in the tumor cells to kill the tumor cells by capturing the high-energy particles generated by the reaction, thereby achieving the purpose of treating cancer. Therefore, 10 boron can promote the treatment of L- 10 BPA by boron neutron capture treatment.
However, the boron element present in nature contains about 19.9% of 10 boron and about 80.1% of 11 boron. Therefore, many researchers are still actively developing methods that can be applied to the synthesis of L-BPA, especially for the synthesis of 10- boron-rich L-BPA.
J.Org.Chem.1998,63,8019 additionally provides a method of synthesizing 10 boronated agents, since the method involves multiple steps, it is easy to greatly reduce the boron content of 10 10 boron enriched material in the manufacturing process. Therefore, the method provided in this document is not suitable for the synthesis of 10- boron-rich L-BPA.
Another example is the Biosci.Biotech.Biochem.1996,60,683, before the enzymatic resolution step is not performed, the method provided by the articles could not be obtained with a certain L-BPA optical purity; 10 and the method for preparing boronated agents when also relates to multi-step, resulting in conversion of boron-rich material 10 occurs during the manufacturing process. Therefore, the method provided in this document is also not suitable for the synthesis of 10- boron-rich L-BPA.
Furthermore, Bull. Chem. Soc. Jpn. 2000, 73, 231 discloses the use of palladium to catalyze 4-iodo-L-phenylalanine with 4,4,5,5-tetramethyl-1,3,2 A method in which a dioxonium pentoxide (common name: pinacolborane) is subjected to a coupling reaction. However, this document does not mention how to prepare articles 10 boron enriched L-BPA using this method, and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane not a commercial 10 The compounds available in the literature are not suitable for the synthesis of 10- boron-rich L-BPA.
In addition, Synlett. 1996, 167 discloses a method for coupling a iodophenylborate with a zinc derivative of L-serine zinc derivatives, which involves first preparing phenyl iodoborate. The ester and the preparation of a zinc derivative of L-type serine acid, etc., result in a lower yield of the produced L-BPA. In addition, since the 10- boron-rich triiodide 10 boron and 1,3-diphenylpropane-1,3-diol selected for this method are not commercially available compounds, the methods provided in this document are also provided. Still not suitable for the synthesis of 10- boron-rich L-BPA.
SYN
Repub. Korean Kongkae Taeho Kongbo, 2018060319,
PAPER
Research and Development in Neutron Capture Therapy, Proceedings of the International Congress on Neutron Capture Therapy, 10th, Essen, Germany, Sept. 8-13, 2002 (2002), 1-8.
PAPER
European Journal of Pharmaceutical Sciences (2003), 18(2), 155-163
https://www.sciencedirect.com/science/article/abs/pii/S0928098702002567
PAPER
Tetrahedron Letters (2008), 49(33), 4977-4980
PATENT
WO 2004009135
PATENT
US 20130331599
PATENT
WO 2017028751
https://patents.google.com/patent/WO2017028751A1/en
Example 1
Before preparing (S)-N-tert-butoxycarbonyl-4-dihydroxyborylphenylalanine from (S)-N-tert-butoxycarbonyl-4-iodophenylalanine, it is necessary to reveal Process for preparing (S)-N-tert-butoxycarbonyl-4-iodophenylalanine by using (S)-4-iodophenylalanine as a starting material and a process for preparing 10 tributyl borate with 10 boric acid.
1. Preparation of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine from (S)-4-iodophenylalanine
Please refer to the following reaction formula I, which is (S)-4-iodophenylalanine in a solvent of 1,4-dioxane (1,4-dioxane) and water (H 2 O) with hydrogen peroxide. Sodium (NaOH) and di-tert-butyl dicarbonate (Boc 2 O) are reacted to obtain a chemical reaction formula of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine.
In the preparation process, two reaction vessels were selected for the reaction.
The specific operation process is as follows:
1. Set up a reaction using a 3L three-neck bottle.
2. (S)-4-iodo-L-phenylalanine (200.00 g, 687.10 mmol, 1.00 eq) was added to the reaction system.
3. Add 1,4-dioxane (1.00 L) and water (1.00 L) to the reaction system, respectively.
4. Sodium hydroxide (68.71 g, 1.72 mol, 2.50 eq) was added to the reaction system, the solution gradually became clear, and the temperature rose slightly to 19 °C.
5. When the system is cooled to 0-10 ° C, di-tert-butyl dicarbonate (254.93 g, 1.17 mol, 268.35 mL, 1.70 eq) is added to the reaction system, and the temperature of the reaction system is naturally raised to 10 to 30 ° C and Stir at room temperature (about 30 ° C) for 8 hours.
6. The reaction was detected using high performance liquid chromatography (HPLC) until the starting of the reaction.
7. The temperature of the control system is less than 40 ° C, and the 1,4-dioxane in the reaction solution is concentrated.
8. The reaction system was lowered to room temperature (about 25 ° C), 100 mL of water was added, and the pH was adjusted to 1.8-2 with hydrochloric acid (2M (ie, molarity, M)).
9. Extract three times with ethyl acetate (2 L).
10. Combine the organic phases and wash twice with saturated brine (1 L).
11. The organic phase was dried over sodium sulfate (200 g).
12. Continue drying in an oven (40-45 ° C) to give (S)-N-tert-butoxycarbonyl-4-iodo-L-phenylalanine (250.00 g, 626.28 mmol, HPLC analysis, yield 93.00 %, purity 98%).
The prepared (S) -N- tert-butoxycarbonyl-4-iodo-phenylalanine was -L- Hydrogen 1 nuclear magnetic resonance spectrum analysis (1 HNMR) as follows:
1 H NMR: (400 MHz DMSO-d 6 )
δ 7.49 (d, J = 7.8 Hz, 2H), 6.88 (d, J = 7.8 Hz, 2H), 5.80 (d, J = 5.9 Hz, 1H), 3.68 (d, J = 5.5 Hz, 1H), 3.00-2.90 (m, 1H), 2.87-2.75 (m, 1H), 1.35-1.15 (m, 9H).
Second, tributyl borate 10 was prepared from boronic acid 10
See the following reaction formulas II, 10 as boric acid (H 2 SO 4) is reacted with sulfuric acid in a solvent (butan-1-ol), and toluene (Toluene) in n-butanol, to obtain 10 tributyl borate (10 The chemical reaction formula of B(OBu) 3 ).
The specific operation process is as follows:
1. Set up a reaction device R1 using a 3L three-necked bottle, and configure a water separator on the device.
2. 10 boric acid (150.00 g, 2.46 mol, 1.00 eq) was added to the reaction R1 at room temperature (about 25 ° C).
3. Add n-butanol (1.00 L) to the reaction R1 at room temperature (about 25 ° C) and stir, and most of the boric acid cannot be dissolved.
4. Toluene (1.00 L) was added to the reaction R1 at room temperature (about 25 ° C) and stirred.
5. Concentrated sulfuric acid (4.82 g, 49.16 mmol, 2.62 mL, 0.02 eq) was added dropwise to the reaction at room temperature (about 25 ° C), at which time a large amount of solid remained undissolved.
6. The reaction system was heated to 130 ° C, and the water was continuously removed, stirred for 3.5 hours, and water (about 140 g) was formed in the water separator. The solids were all dissolved, and the solution changed from colorless to brown. .
7. TLC (DCM: MeOH = 5:1, Rf = 0.43, bromocresol green).
8. Distill off most of the toluene at atmospheric pressure.
9. After most of the toluene is distilled off, the temperature of the system is lowered to 20 to 30 ° C, and the reaction liquids of the two reactions are combined, and the apparatus is changed for distillation.
10. Oil bath external temperature 108-110 ° C pump distillation under reduced pressure, Kelvin thermometer 45 ° C, distilled n-butanol.
11. Oil bath external temperature 108-110 ° C oil pump distillation under reduced pressure, the residual butanol was distilled off.
12. Oil bath external temperature 118-120 ° C oil pump vacuum distillation, Kelvin thermometer 55 ° C, began to produce products.
13. The temperature is raised to 135-140 ° C oil pump vacuum distillation, the product is completely distilled.
14. The product is obtained as a colorless liquid 10 tributyl borate (830.00g, 3.62mol, yield 73.58%).
The results of the 1 H NMR analysis of the obtained tributyl 10 borate were as follows:
1 H NMR: (400 MHz CDCl 3 )
δ 3.82-3.68 (m, 6H), 1.57-1.42 (m, 6H), 1.34 (qd, J = 7.4, 14.9 Hz, 6H), 0.95-0.80 (m, 9H).
Three, -N- tert-butoxycarbonyl-4-iodo-phenylalanine was prepared (S) of (S) -N- tert-butoxycarbonyl-4-hydroxy-10-yl -L- phenylalanine boron
Please refer to the following reaction formula III, which is (S)-N-tert-butoxycarbonyl-4-iodophenylalanine with tributyl 10 borate, t-butyl magnesium chloride (t-BuMgCl) and bis (2-A) yl aminoethyl) ether (BDMAEE) reaction, to produce (S) -N- tert-butoxycarbonyl group -4- (10 B) dihydroxyboryl -L- phenylalanine chemical reaction.
In the preparation process, two reaction vessels were selected for the reaction.
The specific operation process is as follows:
1. Set up a reaction using a 3L three-neck bottle.
2. Tributyl 10 borate (187.60 g, 87.98 mmol, 3.20 eq) was placed in the reaction system at room temperature (about 22 ° C).
3. Sodium hydride (20.45 g, 511.24 mmol, purity 60%, 2.00 eq) was added to the reaction system at room temperature (about 22 ° C). The reaction solution was a suspension and stirred at room temperature (about 22 ° C). 5 minutes.
4. Bis(2-methylaminoethyl)ether (327.73 g, 2.04 mol, 8.00 eq) was added to the reaction at room temperature (about 22 ° C).
5. N-tert-Butoxycarbonyl-4-iodo-L-phenylalanine (100.00 g, 255.62 mmol, 1.00 eq) was added to the reaction system at room temperature (about 22 ° C), and a large amount of solid was not dissolved.
6. Lower the temperature of the reaction system to 0-5 ° C, add t-butyl magnesium chloride (1.7 M, 1.20 L, 2.04 mol, 8.00 eq) to the reaction, control the temperature between 0-10 ° C, the dropping time is about It is 1.5 hours.
7. After the completion of the charging, the temperature of the reaction system was naturally raised to room temperature (20 to 30 ° C) and stirred at this temperature for 12 hours.
8. Using high performance liquid chromatography (HPLC) to detect about 9.00% of the remaining material.
9. When the temperature of the reaction system was lowered to -5 to 0 ° C, it was quenched by dropwise addition of 500 mL of water.
10. Lower the temperature of the system to 0-5 ° C, add methyl tert-butyl ether (500 mL) to the reaction system and adjust the pH to 2.9-3.1 (using a pH meter) with 37% HCl (about 500 mL). Exothermic, the temperature of the control system is between 0-15 °C.
11. The aqueous phase obtained by liquid separation was extracted once with methyl tert-butyl ether (500 mL), and the obtained organic phases were combined to give an organic phase of about 1.1 L.
12. Slowly add a sodium hydroxide aqueous solution (1 M, 400 mL) to the obtained organic phase, exotherm during the dropwise addition, and control the system temperature between 0-15 °C.
13. After the completion of the dropwise addition, the pH of the system was about 10, and the pH was adjusted to between 12.10 and 12.6 with an aqueous sodium hydroxide solution (4M). (measured with a pH meter)
14. Dispensing.
15. The aqueous phase 1 obtained after liquid separation was extracted once with n-butanol (500 ml) to obtain aqueous phase 2.
16. Combine the aqueous phase 2 of the two reaction vessels.
17. Adjust the pH of the aqueous phase to 2.9-3.1 with 37% HCl, stir for about 40 minutes, and precipitate a large amount of solid.
18. Filtration gave a white solid which was washed once with dichloromethane (50 mL).
19. At 25 ° C, the precipitated solid was slurried with dichloromethane (150 mL) and stirred for 10 min.
20. A white solid was filtered to give (S) -N- tert-butoxycarbonyl group -4- (10 B) dihydroxyboryl -L- phenylalanine (75.00g, 240.82mmol, by HPLC analysis, a yield of 47.11% , purity 99%).
The prepared (S) -N- tert-butoxycarbonyl group -4- (10 B) results dihydroxyboryl -L- phenylalanine 1 HNMR was as follows:
1 H NMR: (400 MHz DMSO-d 6 )
Δ12.55 (br.s., 1H), 7.91 (s, 2H), 7.66 (d, J = 7.5 Hz, 2H), 7.17 (d, J = 7.5 Hz, 2H), 4.08-4.01 (m, 1H) ), 3.61-3.53 (m, 1H), 2.98 (dd, J = 4.2, 13.9 Hz, 1H), 2.79 (dd, J = 10.4, 13.5 Hz, 1H), 1.79-1.67 (m, 1H), 1.35- 1.17 (m, 9H).
Preparation of L- 10 BPA from (S)-N-tert-Butoxycarbonyl-4-dihydroxyboryl-L-phenylalanine
See the following reaction scheme IV, which is (S) -N- tert-butoxycarbonyl group -4- (10 B) of amine end dihydroxyboryl -L- phenylalanine deprotection of the chemical reaction, to obtain L- 10 BPA.
The specific operation process is as follows:
1. Set up a reaction using a 1L three-neck bottle.
2. room temperature (20-30 deg.] C) to (S) -N- tert-butoxycarbonyl group -4- (10 B) dihydroxyboryl -L- phenylalanine (67.00g, 217.31mmol, 1.00eq) was added the reaction In the system.
3. room temperature (20-30 deg.] C) water (23.75mL) and acetone (Acetone, 420.00mL) were added dropwise to the reaction flask, stirred (S) -N- tert-butoxycarbonyl group -4- (10 B) dihydroxy Boronyl-L-phenylalanine.
4. Concentrated hydrochloric acid (23.93 g, 656.28 mmol, 23.46 mL, 3.02 eq) was added dropwise to the reaction system at room temperature (20-30 ° C). After the addition was completed, the reaction system was heated to 55-60 ° C and stirred for 4.5 hours.
5. HPLC detection until the reaction of the starting material is completed.
6. The temperature is controlled below 40 ° C, and the acetone in the reaction system is concentrated.
7. Lower the concentrated system to below 15 °C, adjust the pH of the system to about 1.5 with sodium hydroxide solution (4M) (pH meter detection), stir for 40 minutes and continue to adjust the pH of the system to 6.15 using sodium hydroxide solution (4M). ～6.25, a large amount of white solid precipitated, which was filtered to give a white solid, and rinsed with acetone (200mL).
8. Obtained as a white solid L- 10 BPA (36.00 g, 171.17 mmol, HPLC, yield 78.77%, purity 99%).
The analytical results obtained by the L- 10 BPA 1 HNMR are as follows:
1 H NMR: (400 MHz D 2 O, CF 3 COOH)
δ 7.44 (d, J = 7.9 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 4.06 (dd, J = 5.7, 7.5 Hz, 1H), 3.11-3.01 (m, 1H), 2.98 -2.87 (m, 1H).
xample 6
Preparation of (S)-N-tert-butoxycarbonyl-4-dihydroxyboryl-L-phenylalanine from (S)-N-tert-butoxycarbonyl-4-iodophenylalanine
Please refer to the following reaction formula VII, which is a reaction of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine with tributyl borate and t-butylmagnesium chloride (t-BuMgCl) to obtain (S The chemical reaction formula of -N-tert-butoxycarbonyl-4-dihydroxyboryl-L-phenylalanine.
The specific operation process is as follows:
1. Construct a reaction unit with a 250 mL three-neck bottle.
2. Tributyl borate (17.65 g, 76.68 mmol, 3.00 eq) was placed in a 250 mL reaction flask at 20-30 °C.
3. Sodium hydride (1.02 g, 25.56 mmol, 1.00 eq) was added to a 250 mL reaction vial at 20-30 °C.
4. (S)-N-tert-Butoxycarbonyl-4-iodo-L-phenylalanine (10.00 g, 25.56 mmol, 1.00 eq) was added to a 250 mL reaction vial at 20-30 °C.
5. Reduce the temperature of the reaction system to 0 ° C under nitrogen atmosphere, slowly add t-butyl magnesium chloride (1.7 M in THF, 120 mL, 8.00 eq) to the reaction, the dropping time is about 30 minutes, and the control temperature is 0. Between °C and 10 °C.
Stir at 20.20 ~ 30 ° C for 20 hours.
7. HPLC detection of the basic reaction of the raw materials, leaving only about 0.7% of the raw materials.
8. At a temperature of 0 ° C, 5 mL of water was added dropwise to the reaction to quench it. After complete quenching, stirring was continued for 10 minutes.
9. Cool down to 0 ° C, add methyl tert-butyl ether (50 mL) to the reaction and adjust the pH to 3 with 37% HCl (about 50 mL) (detected with a pH meter), adjust the pH during the process to exotherm, control the temperature at 0 Between °C and 15 °C.
12. The aqueous phase obtained by liquid separation was extracted once with methyl t-butyl ether (50 mL) and the organic phases were combined.
12. Add NaOH solution (1M, 55mL) to the obtained organic phase to adjust the pH to between 12.10-12.6. The process is exothermic and the temperature is controlled between 0 °C and 15 °C.
13. Liquid separation, the obtained aqueous phase was extracted once with n-butanol (50 mL), and most of the impurities were extracted and removed.
14. The aqueous phase obtained by liquid separation was adjusted to pH 3 with 37% HCl and stirred for about 30 minutes to precipitate a white solid.
15. Filtration gave a white solid which was washed once with dichloromethane (50 mL).
16. The precipitated solid was slurried with 25 mL of dichloromethane at 25 ° C and stirred for 10 minutes.
17. Filtration of (S)-N-tert-butoxycarbonyl-4-dihydroxyboryl-L-phenylalanine (6.8 g, HPLC, yield: 83.15%, purity 98%).
Example 7
Please continue to refer to Reaction Scheme VII. The specific operation process is as follows:
1. Construct a reaction unit with a 250 mL three-neck bottle.
2. Tributyl borate (8.82 g, 38.34 mmol, 3.00 eq) was added to a 250 mL reaction vial at 20-30 °C.
3. Sodium hydride (511.25 mg, 12.78 mmol, 1.00 eq) was added to a 250 mL reaction vial at 20-30 °C.
4. (S)-N-tert-Butoxycarbonyl-4-iodo-L-phenylalanine (5.00 g, 12.78 mmol, 1.00 eq) was added to a 250 mL reaction vial at 20-30 °C.
5. The temperature of the reaction system was lowered to 0 ° C under nitrogen atmosphere, and t-butyl magnesium chloride (1.7 M in THF, 60 mL, 8.00 eq) was added dropwise to the reaction, the dropwise addition time was about 30 minutes, and the control temperature was 0 ° C. -10 ° C between.
Stir at 6.20 ~ 30 ° C for 22 hours.
7. HPLC detection of the raw material reaction is completed.
8. At a temperature of 0 ° C, 2.5 mL of water was added dropwise to the reaction to quench it. After complete quenching, stirring was continued for 10 minutes.
9. Cool down to 0 ° C, add methyl tert-butyl ether (25 mL) to the reaction and adjust the pH to 3 with 37% HCl (about 25 mL) (detected with a pH meter), adjust the pH during the process to exotherm, control the temperature at 0 Between °C and 15 °C.
12. The aqueous phase obtained by liquid separation was extracted once with methyl t-butyl ether (25 mL) and the organic phases were combined.
12. Add NaOH solution (1M, 30mL) to the obtained organic phase to adjust the pH to between 12.10-12.6. The process is exothermic and the temperature is controlled between 0 °C and 15 °C.
13. Liquid separation, the obtained aqueous phase was extracted once with n-butanol (25 ml), and most of the impurities were extracted and removed.
14. The aqueous phase obtained by liquid separation was adjusted to pH 3 with 37% HCl and stirred for about 30 minutes to precipitate a white solid.
15. Filtration gave a white solid which was washed once with dichloromethane (25 mL).
16. The precipitated solid was slurried with 15 mL of dichloromethane at 25 ° C and stirred for 10 minutes.
17. Filtration gave (S)-N-tert-butoxycarbonyl-4-dihydroxyboryl-L-phenylalanine (3.4 g, obtained by HPLC, yield: 85.26%, purity 98%).
Bis(2-methylaminoethyl)ether is a complexing agent for Mg, which can reduce the occurrence of side reactions in the reaction. The reactions of Examples 6 and 7 were carried out without adding bis(2-methylaminoethyl)ether. The analysis showed that the iodine impurity in the reaction of Example 6 was about 17%, and the iodine impurity in the reaction of Example 7 was observed. About 28%. Therefore, it has been proved from the side that the addition of bis(2-methylaminoethyl)ether can protect the reaction from reducing iodine.
The BPA or 10 BPA obtained in the above examples were analyzed by chiral HPLC, and the ratio of the L-enantiomer to the D-enantiomer was 100:0.
The boron-containing drug L-BPA for neutron capture therapy disclosed in the present invention is not limited to the contents described in the above examples. The above-mentioned embodiments are only examples for convenience of description, and the scope of the claims should be determined by the claims.
PATENT
KR 2018060319
PATENT
WO 2019163790
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019163790
///////////Borofalan (10B), Borofalan, Steboronine, JAPAN 2020, 2020 APPROVALS, ボロファラン (10B), ボロファラン , 硼[10B]法仑 ,
B(C1=CC=C(C=C1)CC(C(=O)O)N)(O)O
Tepotinib hydrochloride
Tepotinib hydrochloride
CS-977;Tepotinib;Veledimex;MSC2156119;EMD-1214063
3-[1-[[3-[5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl]phenyl]methyl]-6-oxopyridazin-3-yl]benzonitrile;hydrate;hydrochloride
Benzonitrile, 3-(1,6-dihydro-1-((3-(5-((1-methyl-4-piperidinyl)methoxy)-2-pyrimidinyl)phenyl)methyl)-6-oxo-3-pyridazinyl)-, hydrochloride, hydrate
3- (1- {3- [5- (1-methylpiperidin-4-ylmethoxy) pyrimidine) -2-yl] -benzyl} -6-oxo-1,6-dihydro-pyridazin-3-yl) -benzonitrileтепотиниб [Russian] [INN]تيبوتينيب [Arabic] [INN]特泊替尼 [Chinese] [INN]
- 3-[1,6-Dihydro-1-[[3-[5-[(1-methyl-4-piperidinyl)methoxy]-2-pyrimidinyl]phenyl]methyl]-6-oxo-3-pyridazinyl]benzonitrile
- 3-{1-[(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile
- EMD 1214063
- MSC 2156119
| Formula | C29H28N6O2. HCl. H2OC29H28N6O2FREE |
|---|---|
| CAS | 1946826-82-9 HCL.H2OCAS No. FREE 1100598-32-0 |
| Mol weight | 547.0478492.57 FREE |
JAPAN 25/3 2020 APPROVED, Tepmetko
| Antineoplastic, Receptor tyrosine kinase inhibitor |
SYN
Bioorganic & Medicinal Chemistry Letters, 25(7), 1597-1602; 2015
PATENT
WO 2009006959
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009006959
Example 40
The preparation of the compound 3- (1- {3- [5- (1-Methyl-piperidin-4-ylmethoxy) -pyrimidin-2-yl] -benzyl} -6-oxo-1,6-dihydro-pyridazin-3 -yl) -benzonitrile (“A257”) takes place analogously to the following scheme
40.1 17.7 g (67.8 mmol) triphenyl are added to a suspension of 13.0 g (56.5 mmol) 3- (5-hydroxypyrimidin-2-yl) -benzoic acid methyl ester and 13.4 g (62.1 mmol) N-Boc-piperidinemethanol in 115 ml THF -phosphine and cooled to 5 ° C. To the suspension kept at this temperature, 13.3 ml (67.8 mmol) of diisopropylazodicarboxylate are added dropwise with stirring within 45 minutes. The reaction mixture is stirred for 1 hour at room temperature. Then a further 22.2 g (84.7 mmol) triphenylphosphine and 16.6 ml (84.7 mmol)
Diisopropyl azodicarboxylate added. The reaction mixture turns 18
Stirred for hours at room temperature and concentrated in vacuo. The resulting solid is filtered off with suction, washed with diethyl ether and chromatographed on a silica gel column with dichloromethane / methanol as the mobile phase: 4- [2- (3-methoxycarbonyl-phenyl) -pyrimidin-5-yloxymethyl] -piperidine-1-carboxylic acid tert .-butyl ester as lemon yellow crystals;
166 ° C .; ESI 428.
40.2 To a suspension of 1.71 g (3.99 mmol) of 4- [2- (3-methoxycarbonyl-phenyl) -pyrimidin-5-yloxymethyl] -piperidine-1-carboxylic acid tert-butyl ester in 20 ml of THF are added under nitrogen 25 ml (25 mmol) of a 1 M solution of diisobutylaluminum hydride in THF were added dropwise. The reaction mixture is stirred at room temperature for 1 hour, and 1 ml of a saturated sodium sulfate solution is added. The resulting precipitate is filtered off with suction and washed with THF and hot 2-propanol. The filtrate is evaporated and recrystallized from tert-butyl methyl ether: {3- [5- (1-Methyl-piperidin-4-ylmethoxy) -pyrimidin-2-yl] -phenyl} -methanol as beige crystals; Mp 175 ° C; ESI 314.
40.3 To a solution of 313 mg (1.00 mmol) {3- [5- (1-methyl-piperidin-4-ylmethoxy) -pyrimidin-2-yl] -phenyl} -methanol in 2 ml THF are successively added 264 mg (1.30 mmol) 3- (6-oxo-1, 6-dihydro-pyridazin-3-yl) benzonitrile and 397 mg (1.5 mmol) triphenylphosphine are added. The reaction mixture is cooled in an ice bath and
294 μl (1.5 mmol) of diisopropylazodicarboxylate are added dropwise with stirring. The
The reaction mixture is stirred for 18 hours at room temperature and evaporated. The residue is chromatographed on a silica gel column using dichloromethane / methanol. The product-containing fractions are combined, evaporated, the residue digested with tert-butyl methyl ether, filtered off with suction and dried in vacuo: 3- (1- {3- [5- (1-methylpiperidin-4-ylmethoxy) pyrimidine) -2-yl] -benzyl} -6-oxo-1,6-dihydro-pyridazin-3-yl) -benzonitrile as colorless crystals; M.p. 177 ° C; ESI 493;
1 H-NMR (de-DMSO): δ [ppm] = 1.33 (m, 2H), 1.75 (m, 3H), 1.89 (m, 2H), 2.17 (S, 3H), 2.80 (m, 2H), 4.05 (d, J = 6.1 Hz 1 2H), 5.45 (s, 2H) 1 7.16 (d, J = 10 Hz, 1 H), 7.49 (m, 2H), 7.73 (t, J = 7.8 Hz, 1H ), 7.93 (d, J = 7.8 Hz, 1H) 1 8.17 (d, J = 10 Hz, 1H), 8.24 (m, 2H), 8.38 (m, 2H), 8.64 (s, 2H).
The hemisulfate, citrate, tartrate, sulfate, succinate and hydrochloride are obtained from “A257” by salt formation.
PATENT
WO 2009007074
PAPER
Bioorganic & Medicinal Chemistry Letters (2015), 25(7), 1597-1602.
https://www.sciencedirect.com/science/article/abs/pii/S0960894X15000955
PAPER
Molecules (2019), 24(6), 1173/1-1173/16.
https://www.mdpi.com/1420-3049/24/6/1173
Scheme 1. Reagents and conditions: a) PdCl2(PPh3)2, Na2CO3, ethanol/toluene/water, 90 °C, 8 h; b) SOCl2, CHCl3, reflux; c) SeO2, dioxane:H2O = 10:1, reflux, 12 h; d) NaOH, −30 °C; e) NaH, DMF/THF, 0 °C—room temperature, 12 h; f) dry ethanol, reflux; g) NaOH, DMF/H2O, 60 °C, 8 h, N2.
Scheme 2. Reagents and conditions: a) N,N-diisopropylethylamine, dry CH2Cl2, 0 °C—room temperature, 6 h; b) PdCl2(PPh3)2, Na2CO3, ethanol/toluene/water, 90 °C, 8 h; c) 10% aq. HCl, MeOH, reflux; d) K2CO3, dry DMF, 80 °C, 12 h; e) NaOH, DMF/H2O, 60 °C, 8 h, N2; f) PPh3, DIAD, THF, 0 °C—room temperature; g) SOCl2, CHCl3, reflux; h) 35% formaldehyde, NaBH4, MeOH.
Scheme 3. Reagents and conditions: a) PdCl2(PPh3)2, Na2CO3, ethanol/toluene/water, 90 °C, 8 h; b) NaBH4, MeOH, 0 °C—room temperature, 1 h; c) SOCl2, CHCl3, reflux; d) K2CO3, dry DMF, 80 °C, 12 h; e) 31a–31b: NaOH, DMF/H2O, 60 °C, 8 h, N2; f) 31c–31g: NaH, dry DMF, 0 °C—room temperature, 5 h.
Scheme 4. Reagents and conditions: a) K2CO3, dry DMF, 80 °C, 12 h; b) PdCl2(PPh3)2, Na2CO3, DME/DMF/water, 89 °C, 12 h; c) NaOH, DMF/H2O, 60 °C, 8 h, N2.
Scheme 5. Reagents and conditions: a) K2CO3, dry DMF, 80 °C, 12 h; b) PdCl2(PPh3)2, Na2CO3, DME/DMF/water, 89 °C, 12 h; c) NaOH, DMF/H2O, 60 °C, 8 h, N2.
///////////Tepotinib, Tepotinib hydrochloride, Tepmetko, JAPAN 2020, 2020 APPROVALS, тепотиниб , تيبوتينيب , 特泊替尼 , EMD 1214063, MSC 2156119
CN1CCC(CC1)COC2=CN=C(N=C2)C3=CC=CC(=C3)CN4C(=O)C=CC(=N4)C5=CC=CC(=C5)C#N.O.Cl
Tirabrutinib
Tirabrutinib
チラブルチニブ塩酸塩
GS-4059
ONO-4059
6-amino-9-[(3R)-1-but-2-ynoylpyrrolidin-3-yl]-7-(4-phenoxyphenyl)purin-8-one
| Formula | C25H22N6O3. HCl |
|---|---|
| CAS | 1439901-97-9 HCL1351636-18-4FREE FORM |
| Mol weight | 490.9415 |
JAPAN APPROVED 2020/3/25 Velexbru
Antineoplastic, Bruton’s tyrosine kinase inhibitor
8H-Purin-8-one,6-amino-7,9-dihydro-9-((3R)-1-(1-oxo-2-butyn-1-yl)-3-pyrrolidinyl)-7-(4-phenoxyphenyl)
6-Amino-9-((3R)-1-(2-butynoyl)-3-pyrrolidinyl)-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one
Tirabrutinib (Velexbru®) is an orally administered, small molecule, Bruton’s tyrosine kinase (BTK) inhibitor being developed by Ono Pharmaceutical and its licensee Gilead Sciences for the treatment of autoimmune disorders and haematological malignancies. Tirabrutinib irreversibly and covalently binds to BTK in B cells and inhibits aberrant B cell receptor signalling in B cell-related cancers and autoimmune diseases. In March 2020, oral tirabrutinib was approved in Japan for the treatment of recurrent or refractory primary central nervous system lymphoma. Tirabrutinib is also under regulatory review in Japan for the treatment of Waldenström’s macroglobulinemia and lymphoplasmacytic lymphoma. Clinical development is underway in the USA, Europe and Japan for autoimmune disorders, chronic lymphocytic leukaemia, B cell lymphoma, Sjogren’s syndrome, pemphigus and rheumatoid arthritis. This article summarizes the milestones in the development of tirabrutinib leading to the first approval of tirabrutinib for the treatment of recurrent or refractory primary central nervous system lymphoma in Japan.
PATENT
WO 2011152351
https://patents.google.com/patent/WO2011152351A1/en
Example 19 (2) : 6-amino-9-[(3R) -1- (2-butinoyl) -3-pyrrolidinyl] -7- (4-phenoxyphenyl) -7,9-dihydro-8H-purine- 8-on
TLC: Rf 0.68 (ethyl acetate: methanol = 9: 1);
1 H-NMR (CDCl 3 ): δ 1.94-2.03, 2.23-2.39, 2.80-3.01, 3.50-3.63, 3.67-3.80, 3.86-4.02, 4.03-4.18, 4.23-4.33, 4.42-4.51, 5.11-5.25, 7.04-7.23, 7.34-7.45, 8.20-8.23.
PATENT
WO 2013081016
WO 2015193740
WO 2015181633
WO 2015185998
WO 2016024228
WO 2016024231
WO 2016163531
WO 2016024227
WO 2017033113
PATENT
US 20170035881
https://patents.google.com/patent/US20170035881A1/en
PATENT WO 2017033113
https://patents.google.com/patent/WO2017033113A1/en
///////Tirabrutinib, japan 2020, 2020 approvals, Velexbru , チラブルチニブ塩酸塩 , GS 4059, ONO 4059,
CC#CC(=O)N1CCC(C1)N2C3=NC=NC(=C3N(C2=O)C4=CC=C(C=C4)OC5=CC=CC=C5)N
Berotralstat
Berotralstat
CAS 1809010-50-1
DIHCl 1809010-52-3
Molecular Formula, C30-H26-F4-N6-O, Molecular Weight, 562.5684
1-(3-(Aminomethyl)phenyl)-N-(5-((R)-(3-cyanophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide
1H-Pyrazole-5-carboxamide, 1-(3-(aminomethyl)phenyl)-N-(5-((R)-(3-cyanophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-
To treat patients with hereditary angioedema
FDA APPROVED 12/4/2020, Orladeyo, 110MG CAPSULE 0RAL
New Drug Application (NDA): 214094
Company: BIOCRYST PHARMACEUTICALS INC
New Drug Application (NDA): 214094
Company: BIOCRYST PHARMACEUTICALS INC
Berotralstat Hydrochloride
1-[3-(Aminomethyl)phenyl]-N-(5-{(1R)-(3-cyanophenyl)[(cyclopropylmethyl)amino]methyl}-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide dihydrochloride
C30H26F4N6O▪2HCl : 635.48
[1809010-52-3]
Berotralstat, also known as BCX-7353, is a kallikrein inhibitor. BCX7353 is a synthetic, once-daily, small molecule drug that can be taken as an oral capsule to treat HAE attacks and for prophylaxis.
Hereditary angioedema (HAE) is rare disorder caused by a SERPING1 gene mutation that triggers severe swelling of the skin and upper airway. Treatment options for HAE with deficient and dysfunctional C1-inhibitor are expanding to include small-molecule drugs that inhibit protein interactions in the kallikrein-kinin system
Serine proteases make up the largest and most extensively studied group of proteolytic enzymes. Their critical roles in physiological processes extend over such diverse areas as blood coagulation, fibrinolysis, complement activation, reproduction, digestion, and the release of physiologically active peptides. Many of these vital processes begin with cleavage of a single peptide bond or a few peptide bonds in precursor protein or peptides. Sequential limited proteolytic reactions or cascades are involved in blood clotting, fibrinolysis, and complement activation. The biological signals to start these cascades can be controlled and amplified as well. Similarly, controlled proteolysis can shut down or inactivate proteins or peptides through single bond cleavages.
Kallikreins are a subgroup of serine proteases. In humans, plasma kallikrein (KLKB1) has no known homologue, while tissue kallikrein-related peptidases (KLKs) encode a family of fifteen closely related serine proteases. Plasma kallikrein participates in a number of pathways relating to the intrinsic pathway of coagulation, inflammation, and the complement system.
Coagulation is the process by which blood forms clots, for example to stop bleeding. The physiology of coagulation is somewhat complex insofar as it includes two separate initial pathways, which converge into a final common pathway leading to clot formation. In the final common pathway, prothrombin is converted into thrombin, which in turn converts fibrinogen into fibrin, the latter being the principal building block of cross- linked fibrin polymers which form a hemostatic plug. Of the two initial pathways upstream of the final common pathway, one is known as the contact activation or intrinsic pathway, and the other is known as the tissue factor or extrinsic pathway.
The intrinsic pathway begins with formation of a primary complex on collagen by high-molecular- weight kininogen (HMWK), prekallikrein, and FXII (Factor XII; Hageman factor). Prekallikrein is converted to kallikrein, and FXII is activated to become FXIIa. FXIIa then converts Factor XI (FXI) into FXIa, and FXIa in turn activates Factor IX (FIX), which with its co-factor F Villa form the“tenase” complex, which activates Factor X (FX) to FXa. It is FXa which is responsible for the conversion of prothrombin into thrombin within the final common pathway.
Prekallikrein, the inactive precursor of plasma kallikrein, is synthesized in the liver and circulates in the plasma bound to FDVTWK or as a free zymogen. Prekallikrein is cleaved by activated factor XII(FXIIa) to release activated plasma kallikrein (PK). Activated plasma kallikrein displays endopeptidase activity towards peptide bonds after arginine (preferred) and lysine. PK then generates additional FXIIa in a feedback loop which in turn activates factor XI (FXI) to FXIa to connect to the common pathway. Although the initial activation of the intrinsic pathway is through a small amount of FXIIa activating a small amount of PK, it is the subsequent feedback activation of FXII by PK that controls the extent of activation of the intrinsic pathway and hence downstream coagulation. Hathaway, W. E., et al. (1965) Blood 26:521-32.
Activated plasma kallikrein also cleaves HMWK to release the potent vasodilator peptide bradykinin. It is also able to cleave a number of inactive precursor proteins to generate active products, such as plasmin (from plasminogen) and urokinase (from prourokinase). Plasmin, a regulator of coagulation, proteolytically cleaves fibrin into fibrin degradation products that inhibit excessive fibrin formation.
Patients who have suffered acute myocardial infarction (MI) show clinical evidence of being in a hypercoagulable (clot-promoting) state. This hypercoagulability is
paradoxically additionally aggravated in those receiving fibrinolytic therapy. Increased generation of thrombin, as measured by thrombin-antithrombin III (TAT) levels, is observed in patients undergoing such treatment compared to the already high levels observed in those receiving heparin alone. Hoffmeister, H. M. et al. (1998) Circulation 98:2527-33. The increase in thrombin has been proposed to result from plasmin-mediated activation of the intrinsic pathway by direct activation of FXII by plasmin.
Not only does the fibrinolysis-induced hypercoagulability lead to increased rates of reocclusion, but it is also probably responsible, at least in part, for failure to achieve complete fibrinolysis of the clot (thrombus), a major shortcoming of fibrinolytic therapy (Keeley, E. C. et al. (2003) Lancet 361 : 13-20). Another problem in fibrinolytic therapy is the accompanying elevated risk of intracranial hemorrhage. Menon, V. et al. (2004) (Chest l26:549S-575S; Fibrinolytic Therapy Trialists’ Collaborative Group (1994) Lancet 343 :311-22. Hence, an adjunctive anti -coagulant therapy that does not increase the risk of bleeding, but inhibits the formation of new thrombin, would be greatly beneficial. Plasma kallikrein inhibitors also have therapeutic potential for treating hereditary angioedema (HAE). HAE is is a serious and potentially life-threatening rare genetic illness, caused by mutations in the Cl -esterase inhibitor (C1INH) gene, located on chromosome 1 lq. HAE is inherited as an autosomal dominant condition, although one quarter of diagnosed cases arise from a new mutation. HAE has been classed as an orphan disease in Europe, with an estimated prevalence of 1 in 50,000. Individuals with HAE experience recurrent acute attacks of painful subcutaneous or submucosal edema of the face, larynx, gastrointestinal tract, limbs or genitalia which, if untreated, may last up to 5 days. Attacks vary in frequency, severity and location and can be life-threatening. Laryngeal attacks, with the potential for asphyxiation, pose the greatest risk. Abdominal attacks are especially painful, and often result in exploratory procedures or unnecessary surgery. Facial and peripheral attacks are disfiguring and debilitating.
HAE has a number of subtypes. HAE type I is defined by CllNH gene mutations which produce low levels of Cl -inhibitor, whereas HAE type II is defined by mutations which produce normal levels of ineffective Cl protein. HAE type III has separate pathogenesis, being caused by mutations in the F12 gene which codes for the serine protease known as Factor XII. Diagnostic criteria for distinguishing the subtypes of HAE, and distinguishing HAE from other angioedemas, can be found in Ann Allergy Asthma Immunol 2008; l00(Suppl2): S30-S40 and J Allergy Clin Immunol 2004; 114: 629-37, incorporated herein by reference.
Current treatments for HAE fall into two main types. Older non-specific treatments including androgens and antifibrinolytics are associated with significant side effects, particularly in females. Newer treatments are based on an understanding of the molecular pathology of the disease, namely that CllNH is the most important inhibitor of kallikrein in human plasma and that CllNH deficiency leads to unopposed activation of the kallikrein- bradykinin cascade, with bradykinin the most important mediator of the locally increased vascular permeability that is the hallmark of an attack. All of the currently available targeted therapies are administered by intravenous or subcutaneous injection. There is currently no specific targeted oral chronic therapy for HAE.
Therefore, a need exists to develop inhibitors of PK that can tip the balance of fibrinolysis/thrombosis at the occluding thrombus toward dissolution, thereby promoting reperfusion and also attenuating the hypercoagulable state, thus preventing thrombus from reforming and reoccluding the vessel. In particular, the creation of plasma kallikrein inhibitors that are specific and capable of being formulated for in vivo use could lead to a new class of therapeutics. Thus, what is needed are improved compositions and methods for preparing and formulating plasma kallikrein inhibitors.
For example, in patients with angioedema conditions, small polypeptide PK inhibitor DX-88 (ecallantide) alleviates edema in patients with hereditary angioedema (HAE). Williams, A. et al. (2003) Transfus. Apher. Sci. 29:255-8; Schneider, L. et al.
(2007) J Allergy Clin Immunol. 120:416-22; and Levy, J. H. et al. (2006) Expert Opin. Invest. Drugs 15: 1077-90. A bradykinin B2 receptor antagonist, Icatibant, is also effective in treating HAE. Bork, K. et al. (2007) J. Allergy Clin. Immunol. 119:1497-1503. Because plasma kallikrein generates bradykinin, inhibition of plasma kallikrein is expected to inhibit bradykinin production.
For example, in coagulation resulting from fibrinolytic treatment (e.g., treatment with tissue plasminogen activator or streptokinase), higher levels of plasma kallikrein are found in patients undergoing fibrinolysis. Hoffmeister, H. M. et al. (1998) J. Cardiovasc. Pharmacol. 31 :764-72. Plasmin-mediated activation of the intrinsic pathway has been shown to occur in plasma and blood and was markedly attenuated in plasma from individuals deficient in any of the intrinsic pathway components. Ewald, G. A. et al. (1995) Circulation 91 :28-36. Individuals who have had an acute MI were found to have elevated levels of activated plasma kallikrein and thrombin. Hoffmeister, H. M., et al. (1998) Circulation 98:2527-33.
DX-88 reduced brain edema, infarct volume, and neurological deficits in an animal model of ischemic stroke. Storini, C. et al. (2006) J Pharm. Exp. Ther. 318:849-854. Cl- inhibitor reduced infarct size in a mouse model of middle cerebral artery occlusion
(MCAO). De Simoni, M. G. et al. (2004) Am. J. Pathol. 164: 1857-1863; and Akita, N. et al. (2003) Neurosurgery 52:395-400). B2 receptor antagonists were found to reduce the infarct volume, brain swelling, and neutrophil accumulation and were neuroprotective in an MCAO animal model. Zausinger, S. et al. (2003 ) Acta Neurochir. Suppl. 86:205-7;
Lumenta, D. B. et al. (2006) Brain Res. 1069:227-34; Ding-Zhou, L. et al. (2003) Br. J Pharmacol. 139: 1539-47.
Regarding blood loss during cardiopulmonary bypass (CPB), it has been found that the kallikrein-kinin (i.e., contact) system is activated during CABG. Wachtfogel, Y. T. (1989) Blood 73:468. Activation of the contact system during CPB results in up to a 20- fold increase in plasma bradykinin. Cugno, M. et al. (2006) Chest 120:1776-82; and Campbell, D. J. et al. (2001 ) Am. J. Physiol. Reg. Integr. Comp. Physiol. 281 : 1059-70.
Plasma kallikrein inhibitors P8720 and PKSI-527 have also been found to reduce joint swelling in rat models of arthritis. De La Cadena, R. A. et al. (1995) FASEB J. 9:446- 52; Fujimori, Y. (1993) Agents Action 39:42-8. It has also been found that inflammation in animal models of arthritis was accompanied by activation of the contact system. Blais, C. Jr. et al. (1997) Arthritis Rheum. 40: 1327-33.
Additionally, plasma kallikrein inhibitor P8720 has been found to reduce inflammation in an acute and chronic rat model of inflammatory bowel disease (IBD). Stadnicki, A. et al. (1998) FASEB J. 12:325-33; Stadnicki, A. et al. (1996) Dig. Dis. Sci.
41 :9l2-20; and De La Cadena, R. A., et al. (1995) FASEB J. 9:446-52. The contact system is activated during acute and chronic intestinal inflammation. Sartor, R. B. et al. (1996) Gastroenterology 110: 1467-81. It has been found that B2 receptor antagonist, an antibody to high molecular weight kininogen, or reduction in levels of kininogen reduced clinicopathology in animal models of IBD. Ibid !; Arai, Y. et al. (1999) Dig. Dis. Sci.
44:845-51; and Keith, J. C. et al. (2005) Arthritis Res. Therapy 7 :R769-76.
H-D-Pro-Phe-Arg-chloromethylketone (CMK), an inhibitor of PK and FXII and a physiological inhibitor (Cl -inhibitor), has been found to reduce vascular permeability in multiple organs and reduce lesions in lipopolysaccharide (LPS)- or bacterial-induced sepsis in animals. Liu, D. et al. (2005) Blood 105:2350-5; Persson, K. et al. (2000) J. Exp. Med. 192: 1415-24. Clinical improvement was observed in sepsis patients treated with Cl- inhibitor. Zeerleder, S. et al. (2003) Clin. Diagnost. Lab. Immunol. 10:529-35; Caliezi, C., et al. (2002) Crit. Care Med. 30:1722-8; and Marx, G. et al. (1999) Intensive Care Med.
25: 1017-20. Fatal cases of septicemia are found to have a higher degree of contact activation. Martinez-Brotons, F. et al. (1987) Thromb. Haemost. 58:709-713; and Kalter, E. S. et al. (1985) J. Infect. Dis. 151 : 1019-27.
It has also been found that prePK levels are higher in diabetics, especially those with proliferative retinopathy, and correlate with fructosamine levels. Gao, B.-B., et al. (2007) Nature Med. 13: 181-8; and Kedzierska, K. et al. (2005) Archives Med. Res. 36:539- 43. PrePK is also found to be highest in those with a sensorimotor neuropathy. Christie,
M. et al. (1984) Thromb. Haemostas. (Stuttgart) 52:221-3. PrePK levels are elevated in diabetics and are associated with increased blood pressure. PrePK levels independently correlate with the albumin excretion rate and are elevated in diabetics with
macroalbuminuria, suggesting prePK may be a marker for progressive nephropathy. Jaffa, A. A. et al. (2003) Diabetes 52: 1215-21. Bl receptor antagonists have been found to decrease plasma leakage in rats treated with streptozotocin. Lawson, S. R. et al. (2005)
Eur. J. Pharmacol. 514:69-78. Bl receptor antagonists can also prevent streptozotocin- treated mice from developing hyperglycemia and renal dysfunction. Zuccollo, A. et al. (1996) Can. J. Physiol. Pharmacol. 74:586-9.
PATENT
WO 2015134998
https://patents.google.com/patent/WO2015134998A1/en
PATENT
WO 2020092898
https://patents.google.com/patent/WO2020092898A1/en
Example 1 : Synthetic protocol for racemic compound 54e
Reproduced from WO 2015/134998 and U.S. Patent Application Publication No. 2017/0073314 A1 (both incorporated by reference)
Preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide
(54e)
Step-l : Preparation of 3-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (54b)
To a solution of 3-formylbenzonitrile (54a) (29 g, 217 mmol) in tetrahydrofuran (200 mL) cooled to 0 °C was added freshly prepared Grignard reagent (52c) (245 mL, 221 mmol, ~ 0.9 M in THF) stirred at 0 °C for 1 h, and room temperature for 18 h. The reaction mixture was quenched with 1 N HC1 (aq. 440 mL), stirred for 3 h, neutralized with NaOH (2 N, aq.) to pH = ~ 8. The reaction mixture was extracted with ethyl acetate (600, 300 mL). The combined extracts were washed with brine (120 mL), dried over MgS04, filtered and concentrated in vacuum. The crude product was purified by flash column
chromatography [silica gel, eluting with hexanes/ethyl acetate (1 :0 to 1 : 1) to give 3-((3- amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (54b) (36.28 g) as a brown gum which was used as such for next step; MS (ES+) 265.3 (M+23).
Step-2: Preparation of tert-butyl 3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2- fluorophenylcarbamoyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54c)
To a solution of 3-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (54b) (24.682 g, 102 mmol) in DMF (480 mL) was added l-(3-((tert- butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxylic acid (lOd) (35.0 g, 91 mmol), N-ethyl-N-isopropylpropan-2-amine (132 mL, 758 mmol), bromotripyrrolidin-l-ylphosphonium hexafluorophosphate(V) (PyBrOP, 42.8 g, 91 mmol) and stirred at room temperature for 19 h. The reaction mixture was diluted with ethyl acetate (1000 mL), washed with water (500, 400 mL), brine (400 mL), dried over MgS04, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography [silica gel, eluting with hexanes/ethyl acetate (1 :0 to 1 : 1)] to afford tert- butyl 3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3- (trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54c) (4.583 g, 5% for two steps) as a yellow solid; ¾ NMR (300 MHz, DMSO-i¾) d 10.57 (s, 1H), 7.81 (t, J= 1.7 Hz, 1H), 7.73 – 7.66 (m, 2H), 7.64 – 7.19 (m, 10H), 6.25 (d, J= 4.0 Hz, 1H), 5.78 (d, J= 4.0 Hz, 1H), 4.19 (d, J= 6.1 Hz, 2H), 1.37 (s, 9H); 19F NMR (282 MHz, DMSO-i¾) d -60.81 , -123.09; MS (ES+) 632.3 (M+23).
Step-3: Preparation of tert-butyl 3-(5-(5-((3- cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3- (trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54d)
To a solution of tert-butyl 3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2- fluorophenylcarbamoyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54c) (1.333 g, 2.187 mmol) in dichloromethane (40 mL) at 0°C was added thionyl chloride (0.340 mL, 4.59 mmol) and warmed to room temperature over 2 h. The reaction mixture was quenched with triethyl amine (2.0 mL, 14.35 mmol) stirred at room temperature for 1 h. It was then treated with cyclopropylmethanamine (4.30 mL, 48.0 mmol), concentrated to remove most of dichloromethane followed by addition of acetonitrile (30 mL), stirring at 70 °C for 14 h, and concentration in vacuum to dryness. The residue was treated with chlorofrom (200 mL), washed with water (100 mL), dried over MgS04 followed by filtration and
concentration. The crude product was purified by flash column chromatography [silica gel eluting with hexanes/ethyl acetate (1 :0 to 2: 1)] to afford tert-butyl 3-(5-(5-((3- cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3- (trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54d) (184 mg, 13%) as colorless gum; ¾ NMR (300 MHz, DMSO-ά) d 10.56 (s, 1H), 7.89 (t, J= 1.7 Hz, 1H), 7.77 – 7.71 (m, 1H), 7.70 – 7.30 (m, 10H), 7.22 (dd, J= 10.3, 8.5 Hz, 1H), 4.93 (s, 1H), 4.19 (d, J= 6.2 Hz, 2H), 2.26 (d, J= 6.6 Hz, 2H), 1.37 (s, 9H), 1.00 – 0.80 (m, 1H), 0.45 – 0.28 (m, 2H), 0.12 – -0.01 (m, 2H); 19F NMR (282 MHz, DMSO-i¾) d -60.80 , -123.20; MS (ES+) 663.4 (M+l). Step-4: Preparation of l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (54e)
To a solution of tert-butyl 3-(5-(5-((3- cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3- (trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54d) (161 mg, 0.243 mmol) in 1,4- Dioxane (18 mL) was added hydrogen chloride (2.60 mL, 10.40 mmol, 4 M in l,4-dioxane) and stirred at room temperature for 16 h. the reaction mixture was treated with hexanes, decanted, washed with hexanes, and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluting with chloroform/CMA80 (1 :0 to 2:1)] to afford l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (54e). The pure product was dissolved in methanol (10 mL) and added 4 N HC1 (aq. 0.14 mL) followed by concentration in vacuum to dryness to give HC1 salt of l-(3- (aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2- fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (54e) (74 mg, 48%) white solid; ¾ NMR (300 MHz, DMSO- d, D20 ex NMR) d 8.13 (t, J = 1.7 Hz, 1H), 7.98 – 7.84 (m, 3H), 7.73 – 7.64 (m, 3H), 7.63 – 7.48 (m, 4H), 7.44 (dd, J = 10.2, 8.6 Hz, 1H),
5.75 (s, 1H), 4.12 (s, 2H), 2.76 (d, J = 7.2 Hz, 2H), 1.17 – 0.94 (m, 1H), 0.68 – 0.47 (m, 2H), 0.34-0.24 (m, 2H); 19F NMR (282 MHz, DMSO- d) d -60.82, -120.02; MS (ES+): 563.3 (M+l); Analysis calculated for C30H26F4N6O2.O HCT3.0 H2O: C, 52.26; H, 4.97; N, 12.19; Found: C, 52.26; H, 5.00; N, 11.72.
Example 2: Separation of enantiomers of racemic compound 54e
Reproduced from WO 2015/134998 and U.S. Patent Application Publication No. 2017/0073314 A1 (both incorporated by reference)
Compound I (free base) Separation of (+)-l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lFl-pyrazole-5-carboxamide (Compound I), and (-)-l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lFl-pyrazole-5-carboxamide ((-
)-enantiomer)
Isomers of Racemic l-(3-(aminomethyl)phenyl)-N-(5-((3- cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lF[- pyrazole-5-carboxamide (54e) (0.4 g) were separated by using preparative SFC method using the following conditions to furnish:
Preparative SFC Method used:
Column 20mm x 25.0 cm ChromegaChiral CCS from
Regis Technologies (Morton Grove, IL)
CO2 Co-solvent (Solvent B) Methanol: Isopropanol (1 : 1) with 1%
Isopropylamine
Isocratic Method 20 % Co-solvent at 80 mL/min
System Pressure 200 bar
Column Temperature 25 °C
Sample Diluent Methanol: Isopropanol
Chiral Purity of peaks was determined by following Analytical SFC Method:
Column 4.6 x 100 mm ChiralPak AS from Chiral
Technologies (West Chester, PA)
CO2 Co-solvent (Solvent B) Methanol: Isopropanol (1 : 1) with 0.1%
Isopropylamine
Isocratic Method 5-65 % Co-solvent Gradient at 4 mL/min System Pressure 100 bar
Column Temperature 25 °C
Sample Diluent Methanol
Peak-l (Compound I) 2.1 min 144 mg >95% ee (UV 254)
98.6 % purity (UV 254)
Peak-2 ((-)-enantiomer) 2.4 min 172 mg 95.5 % ee (UV 254)
96.5 % purity (UV 254) 1. Peak-l assigned as (+)-l-(3-(aminomethyl)phenyl)-N-(5-((3- cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3- (trifluoromethyl)-lH-pyrazole-5-carboxamide (Compound I) (144 mg, >95%ee) free base as white solid; Optical rotation: [O]D = (+) 6.83 [CH3OH, 1.2]; ‘H NMR (300 MHz, DMSO-£¾) d 10.53 (s, 1H, D2O exchangeable), 7.88 (t, J= 1.7 Hz, 1H), 7.77 – 7.71 (m, 1H), 7.67 (dt, 7= 7.7, 1.4 Hz, 1H), 7.63 (dd, J= 7.5, 2.1 Hz, 1H), 7.56 (s, 1H), 7.54 – 7.47 (m, 2H), 7.47 – 7.38 (m, 2H), 7.34 (ddt, J= 8.6, 5.9, 2.8 Hz, 2H), 7.22 (dd, J= 10.3, 8.5 Hz, 1H), 4.93 (s, 1H), 3.77 (s, 2H), 2.31 – 2.21 (m, 2H), 0.97 – 0.80 (m, 1H), 0.42 – 0.33 (m, 2H), 0.10 – -0.02 (m, 2H); 19F NMR (282 MHz, DMSO-Ts) d -60.73 , -123.20; MS (ES+) 563.3 (M+l), 561.3 (M-l). To a solution of free base mixture of (+)-l-(3-(aminomethyl)phenyl)-N-(5-((3- cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3- (trifluoromethyl)-lH-pyrazole-5-carboxamide (Compound I) (120 mg) in methanol (15 mL) was added hydrogen chloride (0.969 mL, 1.938 mmol), stirred at room temperature for 10 min, evaporated to dryness to afford (+)-l-(3- (aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2- fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (Compound I) (100 mg) hydrochloride salt as white solid; ¾ NMR (300 MHz, DMSO-Ts) d 10.84 (s, 1H, D2O exchangeable), 10.44 (s, 2H, D2O exchangeable), 8.44 (s, 3H, D2O exchangeable), 8.30 (s, 1H, D2O exchangeable), 8.09 (d, J= 7.9 Hz, 1H), 7.99 (d, J = 6.8 Hz, 1H), 7.91 – 7.83 (m, 1H), 7.80 – 7.50 (m, 7H), 7.42 (dd, J= 10.3, 8.6 Hz, 1H), 5.78 (d, J= 6.9 Hz, 1H), 4.13 (d, J= 5.7 Hz, 2H), 2.88 – 2.62 (m, 2H), 1.42 – 0.99 (m, 1H), 0.73 – 0.46 (m, 2H), 0.32 (d, J= 4.4 Hz, 2H); 19F NMR (282 MHz, DMSO-i¾) d -60.81 , -119.99; MS (ES+): MS (ES+) 563.3 (M+l), MS (ES-) 561.3 (M-l), 597.3 (M+Cl); Analysis calculated for C30H26F4N6O 2HC1 l.75H20: C, 54.02; H, 4.76; Cl, 10.63; N, 12.60; Found: C, 54.12; H, 4.83; Cl, 10.10; N, 11.97. Peak-2 assigned as (-)-l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide ((-)-enantiomer) (172 mg, 95.5 % ee) as free base was repurified by flash column chromatography (silica gel 12 g, eluting 0-30% MeOH in chloroform for 15 min) to afford (-)-l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide ((-)-enantiomer) free base as an off-white solid; Optical rotation: [O]D = (-) 5.44
[CH3OH, 1.25]; ¾ NMR (300 MHz, DMSO-i¾) d 7.88 (t, J= 1.6 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.70 – 7.61 (m, 2H), 7.57 (s, 1H), 7.54 – 7.47 (m, 2H), 7.45 – 7.41 (m,
2H), 7.34 (ddq, J= 8.7, 6.1, 3.5, 2.8 Hz, 2H), 7.22 (dd, J= 10.3, 8.5 Hz, 1H), 4.93 (s, 1H), 3.78 (s, 2H), 2.25 (d, J= 6.9 Hz, 2H), 0.90 (ddd, J= 9.8, 8.0, 5.2 Hz, 1H), 0.47 – 0.29 (m, 2H), 0.04 (dd, J= 5.0, 1.5 Hz, 2H); 19F NMR (282 MHz, DMSO-i¾) d -60.73 , -123.19; MS (ES+) 563.3 (M+l), MS (ES-), 561.3 (M-l). To a solution of free base of (-)-l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide ((-)-enantiomer) (0.124 g, 0.220 mmol) in methanol (15 mL) was added hydrogen chloride (1.102 mL, 2.204 mmol), stirred at room temperature for 10 min, evaporated to dryness to afford (-)-l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide ((-)-enantiomer) (0.121 g) hydrochloride salt as an off-white solid; Ή NMEE ¾ NMR (300 MHz, DMSO-i¾) d 10.82 (s, 1H, D20 exchangeable), 10.36 (s, 2H, D2O exchangeable), 8.38 (s, 3H, D2O exchangeable), 8.27 (s, 1H), 8.06 (d, J= 7.9 Hz, 1H), 7.98 (d, J= 6.7 Hz, 1H), 7.87 (d, J= 7.7 Hz, 1H), 7.78 – 7.49 (m, 7H), 7.48 – 7.37 (m, 1H), 5.78 (s, 1H), 4.13 (d, j= 5.7 Hz, 2H), 2.72 (s, 2H), 1.14 (s, 1H), 0.56 (d, j= 7.7 Hz, 2H), 0.31 (d, J= 5.0 Hz, 2H); 19F NMR (282 MHz, DMSO-i¾) d -60.82 , -120.03; MS (ES+): MS (ES+) 563.3 (M+l), MS (ES-), 561.3 (M-l), 597.2 (M+Cl); Analysis calculated for C30H26F4N6O.2HCI. I .75H2O: C, 54.02; H, 4.76; Cl, 10.63; N, 12.60; Found: C, 54.12; H, 4.83; Cl, 10.10; N, 11.97.
Example 3 : Preparation of a Seed Crystal of Compound I*2
A solution of Compound I ( see Example 2) in methyl tert-butyl ether (MTBE) (1 equiv) is added to a solution of HC1 (aq) (2 equiv) in methanol (cold), followed by heating to about 30°C, and keeping it at about 30°C for not longer than 5 hours while stirring at about 115 rpm. Compound I bis(HCl) is collected by filtration and dried. The crystalline material obtained can be used as a seed for the crystallization protocol described in
Example 4. Example 4: Large-Scale Synthetic & Crystallization Protocol for Compound I*2(HC1 )
Compound I (free base) Compound I bis(HCI)
37% Aqueous hydrochloric acid (38.1 kg, 32.3 L, 2.14 equiv.) was charged to a clean and empty crystallization vessel, methanol (228.9 kg, 39.5 equiv.) was added, and the contents were cooled to -7 ± 3°C. A solution of Compound I free base (approx. 101.8 kg; 180.9 moles) in MTBE (approx. 1,300 L) was filtered through a polish filter into the crystallization vessel at temperature -5 ± 5°C. After rinse with MTBE, pre-weighed Compound I»2(HCl) seed crystals (1.39 kg, 0.012 equiv.; Example 3) were charged to the crystallization vessel via the manhole. The vessel content was heated to 30-33°C, and the agitation speed was set to 25-50 rpm. After confirmed crystallization, the slurry was agitated for another three to four hours. The product slurry was transferred to centrifuge and isolated by centrifugation. The product was washed with MTBE (585 L). After dry spinning the wet product, Compound I*2(HC1), it was discharged from the centrifuge, and the product was dried at < 40°C under vacuum in a cone drier. Product Compound I»2(HCl) yield: 100 kg; 157.4 mol; approx. 85%.
‘H NMR (300 MHz, DMSO-c/i,) data is shown in the following table:
19F NMR (282 MHz, DMSO- is) data is shown in the following table:
Compound I has two basic sites. The conjugate acid of the primary amine was calculated to have a pKa value of 8.89, and the conjugate acid of the secondary amine was calculated to have a pKa value of 7.86.
The XRPD pattern of Compound I»2(HCl) is shown in Fig. 1. Compound I»2(HCl) has characteristic peaks in its XRPD pattern at values of two theta (°2Q) of 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.01, 23.31, 24.64, and 30.31. TG-IR analysis indicated two, distinct weight loss regions: the first was completed by 125 °C while the second began at approximately 208 °C. IR analysis of the off gasses from this experiment detected only trace amounts of water at the initial weight loss while HC1 gas was detected at the 208°C event. No other solvents were detected in the sample. Thus, it was determined that Compound I*2(HC1) initially loses water when heated and, when heated to above 200°C, the salt begins to break apart and HC1 gas is evolved. The IR signal for all these events is very weak indicating that they are occurring over a range and not at a specified temperature. An exemplary TG-IR spectrum is shown in Fig. 2.
REFERENCES
1: Sohtome Y, Sodeoka M. Development of Chaetocin and S-Adenosylmethionine Analogues as Tools for Studying Protein Methylation. Chem Rec. 2018 Dec;18(12):1660-1671. doi: 10.1002/tcr.201800118. Epub 2018 Oct 16. Review. PubMed PMID: 30324709.
2: Bensussen A, Torres-Sosa C, Gonzalez RA, Díaz J. Dynamics of the Gene Regulatory Network of HIV-1 and the Role of Viral Non-coding RNAs on Latency Reversion. Front Physiol. 2018 Sep 28;9:1364. doi: 10.3389/fphys.2018.01364. eCollection 2018. PubMed PMID: 30323768; PubMed Central PMCID: PMC6172855.
////////berotralstat, Orladeyo, BIOCRYST, APPROVALS 2020, FDA 2020, ORPHAN DRUG, CX-7353, CX 7353,
NCc1cccc(c1)n2nc(cc2C(=O)Nc3cc(ccc3F)[C@H](NCC4CC4)c5cccc(c5)C#N)C(F)(F)F
Viltolarsen
Viltolarsen
维托拉生
ビルトラルセン
| Formula | C244H381N113O88P20 |
|---|---|
| CAS | 2055732-84-6 |
| Mol weight | 6924.8155 |
APPROVED FDA 2020/8/12, Viltepso
APPROVED JAPAN PMDA 2020/3/25, VILTEPSO
- NCNP-01
- NS-065
- NS-065/NCNP-01
- WHO 10771
- WHO-10771
| NAME | DOSAGE | STRENGTH | ROUTE | LABELLER | MARKETING START | MARKETING END | ||
|---|---|---|---|---|---|---|---|---|
| Viltepso | Injection, solution | 250 mg/1 | Intravenous | Ns Pharma, Inc. | 2020-08-13 | Not applicable |  |
SYNWatanabe N, Nagata T, Satou Y, Masuda S, Saito T, Kitagawa H, Komaki H, Takagaki K, Takeda S: NS-065/NCNP-01: An Antisense Oligonucleotide for Potential Treatment of Exon 53 Skipping in Duchenne Muscular Dystrophy. Mol Ther Nucleic Acids. 2018 Dec 7;13:442-449. doi: 10.1016/j.omtn.2018.09.017.
| PATENT NUMBER | PEDIATRIC EXTENSION | APPROVED | EXPIRES (ESTIMATED) | |
|---|---|---|---|---|
| US9079934 | No | 2011-08-31 | 2031-08-31 | |
Viltolarsen
all-P-ambo-[2′,3′-Azanediyl-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-seco](2′-N→5′)(CCTCCGGTTC TGAAGGTGTT C)
C244H381N113O88P20 : 6924.82
[2055732-84-6]
Viltolarsen, sold under the brand name Viltepso, is a medication used for the treatment of Duchenne muscular dystrophy (DMD).[3][4][2] Viltolarsen is an antisense oligonucleotide.[3][2]
The most common side effects include upper respiratory tract infection, injection site reaction, cough, and pyrexia (fever).[3][4][2]
Viltolarsen was approved for medical use in the United States in August 2020.[3][4] After golodirsen was approved in December 2019, viltolarsen is the second approved targeted treatment for people with this type of mutation in the United States.[3][5] Approximately 8% of people with DMD have a mutation that is amenable to exon 53 skipping.[3]
Medical uses
Viltolarsen is indicated for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping.[3][2]
DMD is a rare genetic disorder characterized by progressive muscle deterioration and weakness.[3] It is the most common type of muscular dystrophy.[3] DMD is caused by mutations in the DMD gene that results in an absence of dystrophin, a protein that helps keep muscle cells intact.[3] The first symptoms are usually seen between three and five years of age and worsen over time.[3] DMD occurs in approximately one out of every 3,600 male infants worldwide; in rare cases, it can affect females.[3]
Adverse effects
The most common side effects include upper respiratory tract infection, injection site reaction, cough, and pyrexia (fever).[3][4][2]
Although kidney toxicity was not observed in the clinical studies, the clinical experience is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides.[3]
History
Viltolarsen was evaluated in two clinical studies with a total of 32 participants, all of whom were male and had genetically confirmed DMD.[3] The increase in dystrophin production was established in one of those two studies, a study that included sixteen DMD participants, with eight participants receiving viltolarsen at the recommended dose.[3] In the study, dystrophin levels increased, on average, from 0.6% of normal at baseline to 5.9% of normal at week 25.[3] Trial 1 provided data for evaluation of the benefits of viltolarsen.[4] The combined populations from both trials provided data for evaluation of the side effects of viltolarsen.[4] Trial 1 was conducted at six sites in the United States and Canada and Trial 2 was conducted at five sites in Japan.[4] All participants in both trials were on a stable dose of corticosteroids for at least three months before entering the trials.[4]
The U.S. Food and Drug Administration (FDA) concluded that the applicant’s data demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in people with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping.[3] A clinical benefit of the drug has not been established.[3] In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies.[3]
The application for viltolarsen was granted priority review designation and the FDA granted the approval to NS Pharma, Inc.[3]
References
- ^ https://www.drugs.com/pregnancy/viltolarsen.html
- ^ Jump up to:a b c d e f “Viltepso- viltolarsen injection, solution”. DailyMed. 12 August 2020. Retrieved 18 August 2020.
- ^ Jump up to:a b c d e f g h i j k l m n o p q r s t u “FDA Approves Targeted Treatment for Rare Duchenne Muscular Dystrophy Mutation”. U.S. Food and Drug Administration (FDA) (Press release). 12 August 2020. Retrieved 12 August 2020. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b c d e f g h “Drug Trials Snapshots: Viltepso”. U.S. Food and Drug Administration. 12 August 2020. Retrieved 18 August 2020. This article incorporates text from this source, which is in the public domain.
- ^ Anwar S, Yokota T (August 2020). “Golodirsen for Duchenne muscular dystrophy”. Drugs of Today. 56 (8): 491–504. doi:10.1358/dot.2020.56.8.3159186. PMID 33025945.
Further reading
- Dhillon S (July 2020). “Viltolarsen: First Approval”. Drugs. 80 (10): 1027–1031. doi:10.1007/s40265-020-01339-3. PMID 32519222. S2CID 219542850.
- Dzierlega K, Yokota T (June 2020). “Optimization of antisense-mediated exon skipping for Duchenne muscular dystrophy”. Gene Ther. 27 (9): 407–416. doi:10.1038/s41434-020-0156-6. PMID 32483212. S2CID 219157034.
- Hwang J, Yokota T (October 2019). “Recent advancements in exon-skipping therapies using antisense oligonucleotides and genome editing for the treatment of various muscular dystrophies”. Expert Rev Mol Med. 21: e5. doi:10.1017/erm.2019.5. PMID 31576784.
- Roshmi RR, Yokota T (October 2019). “Viltolarsen for the treatment of Duchenne muscular dystrophy”. Drugs Today. 55 (10): 627–639. doi:10.1358/dot.2019.55.10.3045038. PMID 31720560.
External links
- “Viltolarsen”. Drug Information Portal. U.S. National Library of Medicine (NLM).
- Clinical trial number NCT02740972 for “Safety and Dose Finding Study of NS-065/NCNP-01 in Boys With Duchenne Muscular Dystrophy (DMD)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Viltepso |
| Other names | NS-065/NCNP-01 |
| AHFS/Drugs.com | Monograph |
| License data | US DailyMed: Viltolarsen |
| Pregnancy category | US: N (Not classified yet)[1] |
| Routes of administration | Intravenous |
| Drug class | Antisense oligonucleotide |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only [2]In general: ℞ (Prescription only) |
| Identifiers | |
| CAS Number | 2055732-84-6 |
| DrugBank | DB15005 |
| ChemSpider | 71115970 |
| UNII | SXA7YP6EKX |
| KEGG | D11528 |
| ChEMBL | ChEMBL4298062 |
| Chemical and physical data | |
| Formula | C244H381N113O88P20 |
| Molar mass | 6924.910 g·mol−1 |
//////////Viltolarsen, Viltepso, 维托拉生 , FDA 2020, EU 2020, APPROVALS 2020, NCNP-01, NS-065, NS-065/NCNP-01, WHO 10771, WHO-10771, ビルトラルセン
Pemigatinib
Pemigatinib
INCB054828
| Formula | C24H27F2N5O4 |
|---|---|
| CAS | 1513857-77-62379919-96-5 HCL |
| Mol weight | 487.4991 |
2020/4/17FDA APPROVED, PEMAZYRE
佩米替尼 [Chinese] [INN]
3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,6-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one
2H-Pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-8-(4-morpholinylmethyl)-
3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one
- Originator Incyte Corporation
- Developer Incyte Corporation; Innovent Biologics
- ClassAntineoplastics; Ethers; Fluorobenzenes; Morpholines; Pyridines; Pyrimidinones; Pyrroles; Small molecules
- Mechanism of Action Type 1 fibroblast growth factor receptor antagonists; Type 3 fibroblast growth factor receptor antagonists; Type 4 fibroblast growth factor receptor antagonists; Type-2 fibroblast growth factor receptor antagonists
- Orphan Drug Status Yes – Myeloproliferative disorders; Lymphoma; Cholangiocarcinoma
- MarketedCholangiocarcinoma
- Phase IIBladder cancer; Lymphoma; Myeloproliferative disorders; Solid tumours; Urogenital cancer
- Phase I/IICancer
- 05 Nov 2020Preregistration for Cholangiocarcinoma (Late-stage disease, Metastatic disease, First line therapy, Inoperable/Unresectable) in Japan (PO) in November 2020
- 05 Nov 2020Incyte Corporation stops enrolment in the FIGHT-205 trial for Bladder cancer due to regulatory feedback
- 26 Oct 2020Preregistration for Cholangiocarcinoma (Second-line therapy or greater, Inoperable/Unresectable, Late-stage disease, Metastatic disease) in Canada (PO)
Pemigatinib, also known as INCB054828, is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) types 1, 2, and 3 (FGFR1/2/3), with potential antineoplastic activity. FGFR inhibitor INCB054828 binds to and inhibits FGFR1/2/3, which may result in the inhibition of FGFR1/2/3-related signal transduction pathways. This inhibits proliferation in FGFR1/2/3-overexpressing tumor cells.
Pemigatinib (INN),[2] sold under the brand name Pemazyre, is a medication for the treatment of adults with previously treated, unresectable locally advanced or metastatic bile duct cancer (cholangiocarcinoma) with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.[3][4] Pemigatinib works by blocking FGFR2 in tumor cells to prevent them from growing and spreading.[3]
Pemigatinib belongs to a group of medicines called protein kinase inhibitors.[5] It works by blocking enzymes known as protein kinases, particularly those that are part of receptors (targets) called fibroblast growth factor receptors (FGFRs).[5] FGFRs are found on the surface of cancer cells and are involved in the growth and spread of the cancer cells.[5] By blocking the tyrosine kinases in FGFRs, pemigatinib is expected to reduce the growth and spread of the cancer.[5]
The most common adverse reactions are hyperphosphatemia and hypophosphatemia (electrolyte disorders), alopecia (spot baldness), diarrhea, nail toxicity, fatigue, dysgeusia (taste distortion), nausea, constipation, stomatitis (sore or inflammation inside the mouth), dry eye, dry mouth, decreased appetite, vomiting, joint pain, abdominal pain, back pain and dry skin.[3][4] Ocular (eye) toxicity is also a risk of pemigatinib.[3][4]
Medical uses
Cholangiocarcinoma is a rare form of cancer that forms in bile ducts, which are slender tubes that carry the digestive fluid bile from the liver to gallbladder and small intestine.[3] Pemigatinib is indicated for the treatment of adults with bile duct cancer (cholangiocarcinoma) that is locally advanced (when cancer has grown outside the organ it started in, but has not yet spread to distant parts of the body) or metastatic (when cancer cells spread to other parts of the body) and who have tumors that have a fusion or other rearrangement of a gene called fibroblast growth factor receptor 2 (FGFR2).[3] It should be used in patients who have been previously treated with chemotherapy and whose cancer has a certain type of abnormality in the FGFR2 gene.[6]
History
Pemigatinib was approved for use in the United States in April 2020 along with the FoundationOne CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection.[3][4][7]
The approval of pemigatinib in the United States was based on the results the FIGHT-202 (NCT02924376) multicenter open-label single-arm trial that enrolled 107 participants with locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement who had received prior treatment.[3][4][6] The trial was conducted at 67 sites in the United States, Europe, and Asia.[6] During the clinical trial, participants received pemigatinib once a day for 14 consecutive days, followed by 7 days off, in 21-day cycles until the disease progressed or the patient experienced an unreasonable level of side effects.[3][4][6] To assess how well pemigatinib was working during the trial, participants were scanned every eight weeks.[3] The trial used established criteria to measure how many participants experienced a complete or partial shrinkage of their tumors during treatment (overall response rate).[3] The overall response rate was 36% (95% CI: 27%, 45%), with 2.8% of participants having a complete response and 33% having a partial response.[3] Among the 38 participants who had a response, 24 participants (63%) had a response lasting six months or longer and seven participants (18%) had a response lasting 12 months or longer.[3][4]
The U.S. Food and Drug Administration (FDA) granted the application for pemigatinib priority review, breakthrough therapy and orphan drug designations.[3][4][8][9] The FDA granted approval of Pemazyre to Incyte Corporation.[3]
On 24 August 2018, orphan designation (EU/3/18/2066) was granted by the European Commission to Incyte Biosciences Distribution B.V., the Netherlands, for pemigatinib for the treatment of biliary tract cancer.[5] On 17 October 2019, orphan designation EU/3/19/2216 was granted by the European Commission to Incyte Biosciences Distribution B.V., the Netherlands, for pemigatinib for the treatment of myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2.[10]
PATENT
US 20200281907
| The present disclosure is directed to, inter alia, methods of treating cancer in a patient in need thereof, comprising administering pemigatinib, which is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidin-2-one, having the structure shown below: |
Pemigatinib is described in U.S. Pat. No. 9,611,267, the entirety of which is incorporated herein by reference. Pemigatinib is further described in US Publication Nos.: 2019/0337948 and 2020/0002338, the entireties of which are incorporated herein by reference.
| Provided herein is a method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises administering a therapeutically effective amount of pemigatinib to the patient while avoiding the concomitant administration of a CYP3A4 perpetrator. |
Example 1. Synthesis of Pemigatinib
Step 1: 4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde
| A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (CAS #958230-19-8, Lakestar Tech, Lot: 124-132-29: 3.0 g, 17 mmol) and ethylamine (10M in water, 8.3 mL, 83 mmol) in 2-methoxyethanol (20 mL, 200 mmol) was heated to 130° C. and stirred overnight. The mixture was cooled to room temperature then concentrated under reduced pressure. The residue was treated with 1N HCl (30 mL) and stirred at room temperature for 1 h then neutralized with saturated NaHCO 3 aqueous solution. The precipitate was collected via filtration then washed with water and dried to provide the desired product (2.9 g, 92%). LC-MS calculated for C 10H 12N 3O [M+H] + m/z: 190.1; found: 190.1. |
Step 2: 5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine
| A mixture of 4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (7.0 g, 37 mmol), 2,6-difluoro-3,5-dimethoxyaniline (9.1 g, 48 mmol) and [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid (Aldrich, cat #21360: 2 g, 7 mmol) in xylenes (250 mL) was heated to reflux with azeotropic removal of water using Dean-Stark for 2 days at which time LC-MS showed the reaction was complete. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (500 mL) and then 2.0 M lithium tetrahydroaluminate in THF (37 mL, 74 mmol) was added slowly and the resulting mixture was stirred at 50° C. for 3 h then cooled to room temperature. The reaction was quenched by addition of water, 15% aqueous NaOH and water. The mixture was filtered and washed with THF. The filtrate was concentrated and the residue was washed with CH 2Cl 2 and then filtered to get the pure product (11 g, 82%). LC-MS calculated for C 18H 21F 2N 4O 2[M+H] + m/z: 363.2; found: 363.1. |
Step 3: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one
| A solution of triphosgene (5.5 g, 18 mmol) in tetrahydrofuran (30 mL) was added slowly to a mixture of 5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine (5.6 g, 15 mmol) in tetrahydrofuran (100 mL) at 0° C. and then the mixture was stirred at room temperature for 6 h. The mixture was cooled to 0° C. and then 1.0 M sodium hydroxide in water (100 mL, 100 mmol) was added slowly. The reaction mixture was stirred at room temperature overnight and the formed precipitate was collected via filtration, washed with water, and then dried to provide the first batch of the purified desired product. The organic layer in the filtrate was separated and the aqueous layer was extracted with methylene chloride. The combined organic layer was concentrated and the residue was triturated with methylene chloride then filtered and dried to provide another batch of the product (total 5.5 g, 92%). LC-MS calculated for C 19H 19F 2N 4O 3[M+H] + m/z: 389.1; found: 389.1. |
Step 4: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one
| To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (900 mg, 2.32 mmol) in N,N-dimethylformamide (20 mL) cooled to 0° C. was added sodium hydride (185 mg, 4.63 mmol, 60 wt % in mineral oil). The resulting mixture was stirred at 0° C. for 30 min then benzenesulfonyl chloride (0.444 mL, 3.48 mmol) was added. The reaction mixture was stirred at 0° C. for 1.5 h at which time LC-MS showed the reaction completed to the desired product. The reaction was quenched with saturated NH 4Cl solution and diluted with water. The white precipitate was collected via filtration then washed with water and hexanes, dried to afford the desired product (1.2 g, 98%) as a white solid which was used in the next step without further purification. LC-MS calculated for C 25H 23F 2N 4O 5S [M+H] + m/z: 529.1; found: 529.1. |
Step 5: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde
| To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro2H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidin-2-one (1.75 g, 3.31 mmol) in tetrahydrofuran (80 mL) at −78° C. was added freshly prepared lithium diisopropylamide (1M in tetrahydrofuran (THF), 3.48 mL, 3.48 mmol). The resulting mixture was stirred at −78° C. for 30 min then N,N-dimethylformamide (1.4 mL, 18 mmol) was added slowly. The reaction mixture was stirred at −78° C. for 30 min then quenched with water and extracted with EtOAc. The organic extracts were combined then washed with water and brine. The organic layer was dried over Na 2SO 4 and concentrated. The residue was purified by flash chromatography eluted with 0 to 20% EtOAc in DCM to give the desired product as a white solid (1.68 g, 91%). LC-MS calculated for C 26H 23F 2N 4O 6S (M+H) + m/z: 557.1; found: 556.9. |
Step 6: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one
| To a solution 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde (1.73 g, 3.11 mmol) in dichloromethane (50 mL) was added morpholine (0.95 mL, 11 mmol), followed by acetic acid (2 mL, 30 mmol). The resulting yellow solution was stirred at room temperature overnight then sodium triacetoxyborohydride (2.3 g, 11 mmol) was added. The mixture was stirred at room temperature for 3 h at which time LC-MS showed the reaction went to completion to the desired product. The reaction was quenched with saturated NaHCO 3 then extracted with ethyl acetate (EtOAc). The organic extracts were combined then washed with water and brine. The organic layer was dried over Na 2SO 4 and concentrated. The residue was purified by flash chromatography eluted with 0 to 40% EtOAc in DCM to give the desired product as a yellow solid (1.85 g, 95%). LC-MS calculated for C 30H 32F 2N 5O 6S (M+H) + m/z: 628.2; found: 628.0. |
Step 7: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidin-2-one (pemigatinib)
| To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidin-2-one (1.5 g, 2.4 mmol) in tetrahydrofuran (40 mL) was added tetra-n-butylammonium fluoride (1M in THF, 7.2 mL, 7.2 mmol). The resulting solution was stirred at 50° C. for 1.5 h then cooled to room temperature and quenched with water. The mixture was extracted with dichloromethane (DCM) and the organic extracts were combined then washed with water and brine. The organic layer was dried over Na 2SO 4 and concentrated. The residue was purified by flash chromatography eluted with 0 to 10% MeOH in DCM to give the desired product as a white solid, which was further purified by prep HPLC (pH=2, acetonitrile/H 2O). LC-MS calculated for C 24H 28F 2N 5O 4 (M+H) + m/z: 488.2; found: 488.0. 1H NMR (500 MHz, DMSO) δ 12.09 (s, 1H), 8.06 (s, 1H), 7.05 (t, J=8.1 Hz, 1H), 6.87 (s, 1H), 4.78 (s, 2H), 4.50 (s, 2H), 4.17 (q, J=6.8 Hz, 2H), 3.97 (br, 2H), 3.89 (s, 6H), 3.65 (br, 2H), 3.37 (br, 2H), 3.15 (br, 2H), 1.37 (t, J=6.8 Hz, 3H). |
PATENT
WO 2019213506
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019213506
PATENT
WO 2019213544
The present disclosure is directed to, inter alia, solid forms, including crystalline forms and amorphous forms, of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)- 1 ,3,4,7 -tetrahydro-2H-pyrrolo [3 ‘,2’ : 5 ,6]pyrido [4,3 -d]pyrimidin-2-one
(Compound 1), and processes and intermediates for preparing the compound. The structure of Compound 1 is shown below.
Compound 1
Compound 1 is described in US Patent No. 9,611,267, the entirety of which is incorporated herein by reference.
Example 1
Synthesis of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-l^, 4,7-tetrahydro-2H-pyrrolo[3f,2f:5,6]pyrido[4r3-d]pyrimidin-2-one (Compound 1) Scheme 1.
Step 1: Synthesis of 4-((4-chloro-5-(l, 3-dioxolan-2-yl)-l-(phenylsulfonyl)-lH-pyrrolo[2, 3-b ] pyridin-2-yl) methyl) morpholine
To a l-L flask was added 4-chloro-5-(l,3-dioxolan-2-yl)-l-(phenylsulfonyl)-lH-pyrrolo [2,3-b] pyridine (50.0 g, 137 mmol) (see, e.g., Example 2) and tetrahydrofuran (THF, 266 g, 300 mL) under N2. To this mixture at -70 °C was added 2.0 M lithium
diisopropylamide in THF/heptane/ethyl benzene (77.4 g, 95 mL, 190 mmol, 1.4 eq.). The mixture was stirred at -70 °C for 1 h. To the mixture was added /V- formyl morpholine (29.7 g, 258 mmol, 1.9 eq.) in THF (22. 2 g, 25 mL) dropwise. The reaction was done in 30 min after addition. LC/MS showed that the desired product, 4-chloro-5-(l, 3-dioxolan-2-yl)-l-(phenylsulfonyl)- 1 //-pyrrolo [2, 3-61 pyridine-2-carbaldehyde, was formed cleanly. The reaction was quenched with acetic acid (16.4 g, 15.6 mL, 274 mmol, 2.0 eq.) and the dry ice cooling was removed. To the mixture was added morpholine (33.7 g, 33.5 mL, 387 mmol, 2.83 eq.) followed by acetic acid (74.0 g, 70 mL, 1231 mmol, and 9.0 eq.) at 0 °C (internal temperature rose from 0 °C to 18 °C) and stirred overnight. Sodium triacetoxyborohydride (52.50 g, 247.7 mmol, 1.8 eq.) was added and the reaction mixture temperature rose from 20 °C to 32 °C. The mixture was stirred at room temperature for 30 min. HPLC & LC/MS indicated the reaction was complete. Water (100 g, 100 mL) was added followed by 2.0 M sodium carbonate (Na2C03) in water (236 g, 200 mL, 400 mmol, 2.9 eq.) slowly (off gas!). The mixture was stirred for about 30 min. The organic layer was separated and water (250 g, 250 mL) and heptane (308 g, 450 mL) were added. The resulting slurry was stirred for 1 h and the solid was collected by filtration. The wet cake was washed with heptane twice (75.00 mL x 2, 51.3 g x 2) before being dried in oven at 50 °C overnight to give the desired product, 4-((4-chloro-5-( 1 3-dioxolan-2-yl)- 1 -(phenylsulfonyl)- 1 //-pyrrolo|2.3-6 |pyridin-2-yl)methyl)morpholine as a light brown solid (52.00 g, 81.8 % yield): LCMS calculated for C21H23CIN2O5S [M+H]+: 464.00; Found: 464.0; ftf NMR ^OO MHz, DMSO-de) d 8.48 (s, 1 H), 8.38 (m, 2H), 7.72 (m, 1H), 7.64 (m, 2H), 6.83 (s, 1H), 6.13 (s, 1H), 4.12 (m, 2H), 4.00 (m, 2H), 3.92 (s, 2H), 3.55 (m, 4H), 2.47 (m, 4H).
Step 2: Synthesis of 4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-lH-pyrrolo[2, 3-b] pyridine-5 -carbaldehyde
To a 2 L reactor with a thermocouple, an addition funnel, and a mechanical stirrer was charged 4-((4-chloro-5 -(1 ,3 -dioxolan-2-yl)- 1 -(phenylsulfonyl)- 1 //-pyrrolo [2,3 -6]pyridin-2-yl)methyl)morpholine (20.00 g, 43.1 mmol) and dichloromethane (265 g, 200 mL) at room temperature. The resulting mixture was stirred at room temperature (internal temperature
was 19.5 °C) to achieve a solution. To the resulting solution was added an aqueous hydrochloric acid solution (0.5 M, 240 g, 200.0 ml, 100 mmol, 2.32 eq.) at room temperature in 7 min. After over 23 h agitations at room temperature, the bilayer reaction mixture turned into a thick colorless suspension. When HPLC showed the reaction was complete, the slurry was cooled to 0-5 °C and aqueous sodium hydroxide solution (1 N, 104 g, 100 mL, 100 mmol, and 2.32 eq.) was added in about 10 min to adjust the pH of the reaction mixture to 10-11. «-Heptane (164 g, 240 mL) was added and the reaction mixture and the mixture were stirred at room temperature for 1 h. The solid was collected by filtration and the wet cake was washed with water (2 x 40 mL), heptane (2 x 40 ml) before being dried in oven at 50 °C under vacuum to afford the desired product, 4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)- 1 //-pyrrolo|2.3-/i |pyridine-5-carbaldehyde as a light brown solid (16.9 g, 93% yield): LCMS calculated for C19H19CIN3O4S [M+H]+: 420.00; Found: 420.0; ¾ NMR (400 MHz, DMSO-de) d 10.33 (s, 1H), 8.76 (s, 1 H), 8.42 (m, 2H), 7.74 (m, 1H), 7.65 (m, 2H), 6.98 (s, 1H), 3.96 (m, 2H), 3.564 (m, 4H), 2.51 (m, 4H).
Step 3: Synthesis ofN-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-lH-pyrrolo [2, 3-h] pyridin-5-yl) methyl) -2, 6-difluoro-3,5-dimethoxyaniline
To a 2-L reactor equipped with a thermocouple, a nitrogen inlet and mechanical stirrer were charged AOV-dimethyl formamide (450 mL, 425 g), 4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)- 1 //-pyrrolo|2.3-6 |pyridine-5-carbaldehyde (30.0 g, 71.45 mmol) and 2,6-difluoro-3,5-dimethoxyanihne (14.2 g, 75.0 mmol). To this suspension (internal temperature 20 °C) was added chlorotrimethylsilane (19.4 g, 22. 7 mL, 179 mmol) dropwise in 10 min at room temperature (internal temperature 20-23 °C). The suspension changed into a solution in 5 min after the chlorotrimethylsilane addition. The solution was stirred at room temperature for 1.5 h before cooled to 0-5 °C with ice-bath. Borane-THF complex in THF (1.0 M, 71.4 mL, 71.4 mmol, 64.2 g, 1.0 eq.) was added dropwise via additional funnel over 30 min while maintaining temperature at 0-5 °C. After addition, the mixture was stirred for 4 h. Water (150 g, 150 mL) was added under ice-bath cooling in 20 min, followed by slow addition of ammonium hydroxide solution (28% N¾, 15.3 g, 17 ml, 252 mmol, 3.53 eq.) to pH 9-10 while maintaining the temperature below 10 °C. More water (250 mL, 250 g) was added through the additional funnel. The slurry was stirred for 30 min and the solids were collected by filtration. The wet cake was washed with water (90 g x 2, 90 ml x 2) and heptane (61.6 g x2, 90 ml x 2). The product w as suction dried overnight to give the desired product LG-((4-chloro-2-(morphohnomethyl)-l-(phenylsulfonyl)-li/-pyrrolo[2,3-Z>]pyridin-5-yl)methyl)-2,6- difluoro-3,5-dimethoxyaniline (41.6 g, 96% yield): LCMS calculated for C27H28ClF2N405S[M+H]+: 593.10; Found: 593.1 ; ¾ NMR (400 MHz, DMSO-d6) 5 8.36 (m, 2H), 8.28 (s, 1H), 7.72 (m, 1H), 7.63 (m, 2H), 6.78 (s, 1H), 6.29 (m, 1H), 5.82 (m, 1H), 4.58 (m, 2H), 3.91 (s, 2H), 3.76 (s, 6H), 3.56 (m, 4H), 2.47 (m, 4H).
Step 4: Synthesis of l-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-lH-pyrrolo [2, 3-b ] pyridin-5-yl) methyl)-! -(2, 6-difluoro-3, 5-dimethoxyphenyl)-3-ethylurea
To a 2-L, 3-neck round bottom flask fitted with a thermocouple, a nitrogen bubbler inlet, and a magnetic stir were charged /V-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-li/-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline (67.0 g, 113 mmol) and acetonitrile (670 ml, 527 g). The suspension was cooled to 0-5 °C.
To the mixture was charged ethyl isocyanate (17.7 mL, 15.9 g, 224 mmol, 1.98 eq.) over 30 sec. The temperature stayed unchanged at 0.7 °C after the charge. Methanesulfonic acid (16.1 mL, 23.9 g, 248 mmol, 2.2 eq.) was charged dropwise over 35 min while maintaining the temperature below 2 °C. The mixture was warmed to room temperature and stirred overnight. At 24 h after addition showed that the product was 93.7%, unreacted SM was 0.73% and the major impurity (bis-isocyanate adduct) was 1.3%. The mixture was cooled with an ice-bath and quenched with sodium hydroxide (NaOH) solution (1.0M, 235 mL, 244 g, 235 mmol, 2.08 eq.) over 20 min and then saturated aqueous sodium bicarbonate
(NaHCCh) solution (1.07 M, 85 mL, 91 g, 0.091 mol, 0.80 eq.) over 10 min. Water (550 mL, 550 g) was added and the liquid became one phase. The mixture was stirred for 2 h and the solids were collected by filtration, washed with water (165 mL, 165 g) to give l-((4-chloro-2-(morpholinomethyl)- 1 -(phenylsulfonyl)- 1 //-pyrrolo| 2.3-6 |p\ ri din-5 -y l (methy l )- 1 -(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea ( 70.3 g, 93.7% yield).
The crude l-((4-chloro-2-(morpholinomethyl)-l -(phenylsulfonyl)- li/-pyrrolo [2, 3-61 pyridin-5-yl) methyl)- 1 -(2, 6-difluoro-3, 5-dimethoxyphenyl)-3-ethylurea (68.5 g, 103 mmol) was added in to acetonitrile (616 mL, 485 g). The mixture was heated 60-65 °C and an amber colored thin suspension was obtained. The solid was filtered off with celite and the celite was washed with acetonitrile (68.5 mL, 53.8 g). To the pale yellow filtrate was added water (685 g, 685 ml) to form a slurry. The slurry was stirred overnight at room temperature and filtered. The solid was added to water (685 mL, 685 g) and stirred at 60 °C for 2 h. The solid was filtered and re-slurred in heptane (685 mL, 469 g) overnight. The product was dried in an oven at 50 °C under vacuum for 48 h to afford l-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)- 1 //-pyrrolo|2.3-6 |pyridin-5-yl)methyl)- 1 -(2.6-difluoro-3.5-
dimethoxyphenyl)-3-ethylurea as a colorless solid (62.2 g, 90.8% yield, 99.9% purity by HPLC area%). KF was 0.028%. Acetonitrile (by ‘H NMR) was about 1.56%, DCM (by ‘H NMR) 2.0%: LCMS calculated for C30H33CIF2N5O6S [M+H]+: EM: 664.17; Found: 664.2; ¾ NMR (400 MHz, DMSO-de) d 8.33 (m, 2H), 8.31 (s, 1H), 7.72 (m, 1H), 7.64 (m, 1H), 6.96 (m, 2H), 6.73 (s, 1H), 6.43 (m, 1H), 4.87 (s, 2H), 3.90 (s, 2H), 3.77 (s, 6H), 3.54 (m, 4H),
3.03 (m, 2H), 2.46 (m, 4H), 0.95 (m, 3H).
Step 5: Synthesis of 3-(2, 6-difluoro-3, 5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-l, 3, 4, 7-tetrahydro-2H-pyrrolo[ 3 2’:5, 6 ]pyrido[ 4, 3-d]pyrimidin-2-one
To a 2000 mL flask equipped with a thermal couple, a nitrogen inlet, and a mechanical stirrer were charged dry l-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-1 //-pyrrolo| 2.3-6 |pyridin-5-yl)methyl)- 1 -(2.6-dinuoro-3.5-dimetho\yphenyl)-3-ethylurea (30.0 g, 45.2 mmol, KF=0. l l%) and tetrahydrofuran (1200 mL, 1063 g). To this suspension at room temperature was charged 1.0 M lithium hexamethyldisilazide in THF (62.3 mL, 55.5 g, 62.3 mmol, 1.38 eq). The mixture turned into a solution after the base addition. The reaction mixture was stirred for 2 h and HPLC shows the starting material was not detectable. To this mixture was added 1.0 M hydrochloric acid (18.1 mL, -18.1 g. 18.1 mmol, 0.4 eq.). The solution was concentrated to 600 mL and water (1200 mL, 1200 g) was added. Slurry was formed after water addition. The slurry was stirred for 30 min at room temperature and the solid was collected by filtration. The wet cake was washed with water twice (60 mLx2,
60 gx2) and dried at 50 °C overnight to give 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-l,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4, 3-d]pyrimidin-2-one as a light brown solid (26.58 g, as-is yield 93.7%): THF by ‘H NMR 0.32%, KF 5.26%, adjusted yield was 88.5%: LCMS calculated for C30H32F2N5O6S [M+H]+: EM: 628.20; Found: 628.2; ¾ NMR (400 MHz, DMSO-de) d 8.41 (m, 2H), 8.07 (s, 1H), 7.70 (m, 1H), 7.63 (m, 2H), 7.05 (m, 1H), 6.89 (s, 1H), 4.76 (s, 2H), 4.09 (m, 2H), 3.93 (s, 2H), 3.89 (s, 6H), 3.60 (m, 4H), 2.50 (m, 4H), 1.28 (m, 3H).
Step 6: Synthesis of 3-( 2, 6-difluoro-3, 5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-1,3, 4, 7 -tetrahydro-2H-pyrrolo [ 3 ‘, 2 5, 6 ]pyrido[ 4, 3-dJpyrimidin-2-one
To a stirring suspension of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholinomethyl)-7-(phenylsulfonyl)-l,3,4,7-tetrahydro-2i/-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (10.0 g, 15.93 mmol) in l,4-dioxane (100 ml, 103 g) in a 500 mL flask equipped with a nitrogen inlet, a condenser, a thermocouple and a heating mantle was added 1 M aqueous sodium hydroxide (63.7 ml, 66.3 g, 63.7 mmol). The reaction mixture was heated at 75 °C for 18 h. LCMS showed the reaction was complete. Water (100 mL, 100 g) was added to give a thick suspension. This slurry was stirred at room temperature for 1 h and filtered. The cake was washed with water (3 x 10 mL, 3 x 10 g) and heptane (2 x 10 mL, 2 x 6.84 g). The cake was dried overnight by pulling a vacuum through the filter cake and then dried in an oven at 50 °C under vacuum overnight to give 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-l,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5, 6]pyrido[4,3-d]pyrimidin-2-one (6.8 g, 87.6% yield): LCMS calculated for C24H28F2N5O4 [M+H]+: 488.20; Found: 488.2.
PATENT
US 20130338134
https://patents.google.com/patent/US20130338134A1/en
Step 1: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one
- [0832]
- [0833]
To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (Example 49, Step 3: 900 mg, 2.32 mmol) in N,N-dimethylformamide (20 mL) cooled to 0° C. was added sodium hydride (185 mg, 4.63 mmol, 60 wt % in mineral oil). The resulting mixture was stirred at 0° C. for 30 min then benzenesulfonyl chloride (0.444 mL, 3.48 mmol) was added. The reaction mixture was stirred at 0° C. for 1.5 h at which time LC-MS showed the reaction completed to the desired product. The reaction was quenched with saturated NH4Cl solution and diluted with water. The white precipitate was collected via filtration then washed with water and hexanes, dried to afford the desired product (1.2 g, 98%) as a white solid which was used in the next step without further purification. LC-MS calculated for C25H23F2N4O5S [M+H]+ m/z: 529.1; found: 529.1.
Step 2: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde
- [0834]
- [0835]
To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (1.75 g, 3.31 mmol) in tetrahydrofuran (80 mL) at −78° C. was added freshly prepared lithium diisopropylamide (1M in tetrahydrofuran (THF), 3.48 mL, 3.48 mmol). The resulting mixture was stirred at −78° C. for 30 min then N,N-dimethylformamide (1.4 mL, 18 mmol) was added slowly. The reaction mixture was stirred at −78° C. for 30 min then quenched with water and extracted with EtOAc. The organic extracts were combined then washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography eluted with 0 to 20% EtOAc in DCM to give the desired product as a white solid (1.68 g, 91%). LC-MS calculated for C26H23F2N4O6S (M+H)+ m/z: 557.1; found: 556.9.
Step 3: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one
- [0836]
- [0837]
To a solution 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde (1.73 g, 3.11 mmol) in dichloromethane (50 mL) was added morpholine (0.95 mL, 11 mmol), followed by acetic acid (2 mL, 30 mmol). The resulting yellow solution was stirred at room temperature overnight then sodium triacetoxyborohydride (2.3 g, 11 mmol) was added. The mixture was stirred at room temperature for 3 h at which time LC-MS showed the reaction went to completion to the desired product. The reaction was quenched with saturated NaHCO3 then extracted with ethyl acetate (EtOAc). The organic extracts were combined then washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography eluted with 0 to 40% EtOAc in DCM to give the desired product as a yellow solid (1.85 g, 95%). LC-MS calculated for C30H32F2N5O6S (M+H)+ m/z: 628.2; found: 628.0.
Step 4: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one
- [0838]
To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (1.5 g, 2.4 mmol) in tetrahydrofuran (40 mL) was added tetra-n-butylammonium fluoride (1M in THF, 7.2 mL, 7.2 mmol). The resulting solution was stirred at 50° C. for 1.5 h then cooled to room temperature and quenched with water. The mixture was extracted with dichloromethane (DCM) and the organic extracts were combined then washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography eluted with 0 to 10% MeOH in DCM to give the desired product as a white solid, which was further purified by prep HPLC (pH=2, acetonitrile/H2O). LC-MS calculated for C24H28F2N5O4 (M+H)+ m/z: 488.2; found: 488.0. 1H NMR (500 MHz, DMSO) δ 12.09 (s, 1H), 8.06 (s, 1H), 7.05 (t, J=8.1 Hz, 1H), 6.87 (s, 1H), 4.78 (s, 2H), 4.50 (s, 2H), 4.17 (q, J=6.8 Hz, 2H), 3.97 (br, 2H), 3.89 (s, 6H), 3.65 (br, 2H), 3.37 (br, 2H), 3.15 (br, 2H), 1.37 (t, J=6.8 Hz, 3H).
PATENTS
| Publication Number | Title | Priority Date | Grant Date |
|---|---|---|---|
| US-2013338134-A1 | Substituted tricyclic compounds as fgfr inhibitors | 2012-06-13 | |
| US-2017137424-A1 | Substituted tricyclic compounds as fgfr inhibitors | 2012-06-13 | |
| US-2019127376-A1 | Substituted tricyclic compounds as fgfr inhibitors | 2012-06-13 | |
| US-9611267-B2 | Substituted tricyclic compounds as FGFR inhibitors | 2012-06-13 | 2017-04-04 |
| WO-2014007951-A2 | Substituted tricyclic compounds as fgfr inhibitors | 2012-06-13 |
| Publication Number | Title | Priority Date | Grant Date |
|---|---|---|---|
| JP-6336665-B2 | Substituted tricyclic compounds as FGFR inhibitors | 2012-06-13 | 2018-06-06 |
| JP-6545863-B2 | Substituted tricyclic compounds as FGFR inhibitors | 2012-06-13 | 2019-07-17 |
| JP-6711946-B2 | Substituted tricyclic compounds as FGFR inhibitors | 2012-06-13 | 2020-06-17 |
| TW-201402574-A | Substituted tricyclic compounds as FGFR inhibitors | 2012-06-13 | |
| US-10131667-B2 | Substituted tricyclic compounds as FGFR inhibitors | 2012-06-13 | 2018-11-20 |
| Publication Number | Title | Priority Date | Grant Date |
|---|---|---|---|
| JP-2015521600-A | Substituted tricyclic compounds as FGFR inhibitors | 2012-06-13 | |
| JP-2017222709-A | Substituted tricyclic compounds as FGFR inhibitors | 2012-06-13 | |
| JP-2018135377-A | Substituted tricyclic compounds as FGFR inhibitors | 2012-06-13 | |
| JP-2019178156-A | Substituted tricyclic compounds as FGFR inhibitors | 2012-06-13 | |
| JP-6301321-B2 | Substituted tricyclic compounds as FGFR inhibitors | 2012-06-13 | 2018-03-28 |
| Publication Number | Title | Priority Date | Grant Date |
|---|---|---|---|
| EP-3176170-A1 | Substituted tricyclic compounds as fgfr inhibitors | 2012-06-13 | |
| EP-3176170-B1 | Substituted tricyclic compounds as fgfr inhibitors | 2012-06-13 | 2018-11-14 |
| EP-3495367-A1 | Substituted tricyclic compounds as fgfr inhibitors | 2012-06-13 | |
| ES-2704744-T3 | Substituted tricyclic compounds as FGFR inhibitors | 2012-06-13 | 2019-03-19 |
| HU-E031916-T2 | Substituted tricyclic compounds as fgfr inhibitors | 2012-06-13 |
| Publication Number | Title | Priority Date | Grant Date |
|---|---|---|---|
| DK-2861595-T5 | Substituted tricyclic compounds as FGFR inhibitors | 2012-06-13 | 2018-01-15 |
| DK-3176170-T3 | Substituted tricyclic relations as fgfr inhibitors | 2012-06-13 | 2019-01-28 |
| EP-2861595-A2 | Substituted tricyclic compounds as fgfr inhibitors | 2012-06-13 | |
| EP-2861595-B1 | Substituted tricyclic compounds as fgfr inhibitors | 2012-06-13 | 2016-12-21 |
| EP-2861595-B9 | Substituted tricyclic compounds as fgfr inhibitors | 2012-06-13 | 2017-06-21 |
| Publication Number | Title | Priority Date | Grant Date |
|---|---|---|---|
| WO-2019191707-A1 | Heterocyclic compounds as immunomodulators | 2018-03-30 | |
| AU-2013287176-A1 | Substituted tricyclic compounds as FGFR inhibitors | 2012-06-13 | |
| CA-2876689-A1 | Substituted tricyclic compounds as fgfr inhibitors | 2012-06-13 | |
| CN-107383009-B | Substituted tricyclic compounds as FGFR inhibitors | 2012-06-13 | 2020-06-09 |
| DK-2861595-T3 | Substituted tricyclic compounds as fgfr inhibitors | 2012-06-13 | 2017-02-13 |
| Publication Number | Title | Priority Date | Grant Date |
|---|---|---|---|
| WO-2019213544-A2 | Solid forms of an fgfr inhibitor and processes for preparing the same | 2018-05-04 | |
| WO-2019213544-A3 | Solid forms of an fgfr inhibitor and processes for preparing the same | 2018-05-04 | |
| TW-202003511-A | Heterocyclic compounds as immunomodulators | 2018-03-30 | |
| US-10669271-B2 | Heterocyclic compounds as immunomodulators | 2018-03-30 | 2020-06-02 |
| US-2019300524-A1 | Heterocyclic compounds as immunomodulators | 2018-03-30 |
| Publication Number | Title | Priority Date | Grant Date |
|---|---|---|---|
| TW-201946630-A | Salts of an FGFR inhibitor | 2018-05-04 | |
| TW-202003516-A | Solid forms of an FGFR inhibitor and processes for preparing the same | 2018-05-04 | |
| US-2019337948-A1 | Solid forms of an fgfr inhibitor and processes for preparing the same | 2018-05-04 | |
| US-2020002338-A1 | Salts of an fgfr inhibitor | 2018-05-04 | |
| WO-2019213506-A1 | Salts of an fgfr inhibitor | 2018-05-04 |
| Publication Number | Title | Priority Date | Grant Date |
|---|---|---|---|
| WO-2019227007-A1 | Tricyclic heterocyclic compounds as sting activators | 2018-05-25 | |
| TW-201946626-A | Heterocyclic compounds as immunomodulators | 2018-05-11 | |
| US-10618916-B2 | Heterocyclic compounds as immunomodulators | 2018-05-11 | 2020-04-14 |
| US-2019345170-A1 | Heterocyclic compounds as immunomodulators | 2018-05-11 | |
| WO-2019217821-A1 | Tetrahydro-imidazo[4,5-c]pyridine derivatives as pd-l1 immunomodulators | 2018-05-11 |
| Publication Number | Title | Priority Date | Grant Date |
|---|---|---|---|
| US-2020040009-A1 | Tricyclic heteraryl compounds as sting activators | 2018-07-31 | |
| WO-2020028565-A1 | Tricyclic heteraryl compounds as sting activators | 2018-07-31 | |
| WO-2020028566-A1 | Heteroaryl amide compounds as sting activators | 2018-07-31 | |
| WO-2019238873-A1 | A method of precision cancer therapy | 2018-06-13 | |
| US-2019359608-A1 | Tricyclic heterocyclic compounds as sting activators | 2018-05-25 |
| Title | Priority Date | Grant Date | |
|---|---|---|---|
| WO-2020131627-A1 | Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of fgfr tyrosine kinases | 2018-12-19 | |
| WO-2020131674-A1 | 7-((3,5-dimethoxyphenyl)amino)quinoxaline derivatives as fgfr inhibitors for treating cancer | 2018-12-19 | |
| WO-2020081898-A1 | Non-invasive urinary biomarkers for the detection of urothelial carcinoma of the bladder | 2018-10-20 | |
| US-2020115378-A1 | Dihydropyrido[2,3-d]pyrimidinone compounds as cdk2 inhibitors | 2018-10-11 | |
| US-2020039994-A1 | Heteroaryl amide compounds as sting activators | 2018-07-31 |
References
- ^ “Pemigatinib (Pemazyre) Use During Pregnancy”. Drugs.com. 11 August 2020. Retrieved 24 September 2020.
- ^ World Health Organization (2018). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 80”. WHO Drug Information. 32 (3): 479. hdl:10665/330907.
- ^ Jump up to:a b c d e f g h i j k l m n o “FDA Approves First Targeted Treatment for Patients with Cholangiocarcinoma, a Cancer of Bile Ducts”. U.S. Food and Drug Administration (FDA) (Press release). 17 April 2020. Retrieved 17 April 2020. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b c d e f g h “FDA grants accelerated approval to pemigatinib for cholangiocarcinoma”. U.S. Food and Drug Administration (FDA). 17 April 2020. Retrieved 20 April 2020. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b c d e “EU/3/18/2066”. European Medicines Agency (EMA). 19 December 2018. Retrieved 20 April 2020. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b c d “Drug Trials Snapshot: Pemazyre”. U.S. Food and Drug Administration (FDA). 17 April 2020. Retrieved 5 May 2020. This article incorporates text from this source, which is in the public domain.
- ^ “Pemazyre: FDA-Approved Drugs”. U.S. Food and Drug Administration (FDA). Retrieved 21 April 2020.
- ^ “Pemigatinib Orphan Drug Designation and Approval”. U.S. Food and Drug Administration (FDA). Retrieved 19 April 2020.
- ^ “Pemigatinib Orphan Drug Designation and Approval”. U.S. Food and Drug Administration (FDA). Retrieved 19 April 2020.
- ^ “EU/3/19/2216”. European Medicines Agency (EMA). 23 January 2020. Retrieved 19 April 2020. This article incorporates text from this source, which is in the public domain.
Further reading
- Roskoski R (January 2020). “The role of fibroblast growth factor receptor (FGFR) protein-tyrosine kinase inhibitors in the treatment of cancers including those of the urinary bladder”. Pharmacol. Res. 151: 104567. doi:10.1016/j.phrs.2019.104567. PMID 31770593.
External links
- “Pemigatinib”. Drug Information Portal. U.S. National Library of Medicine.
- “Pemigatinib”. National Cancer Institute.
- Clinical trial number NCT02924376 for “Efficacy and Safety of Pemigatinib in Subjects With Advanced/Metastatic or Surgically Unresectable Cholangiocarcinoma Who Failed Previous Therapy – (FIGHT-202)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Pemazyre |
| Other names | INCB054828 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a620028 |
| License data | US DailyMed: Pemigatinib |
| Pregnancy category | US: N (Not classified yet)[1] |
| Routes of administration | By mouth |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only |
| Identifiers | |
| IUPAC name[show] | |
| CAS Number | 1513857-77-6 |
| PubChem CID | 86705695 |
| DrugBank | DB15102 |
| ChemSpider | 68007304 |
| UNII | Y6BX7BL23K |
| KEGG | D11417 |
| ChEMBL | ChEMBL4297522 |
| Chemical and physical data | |
| Formula | C24H27F2N5O4 |
| Molar mass | 487.508 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES[hide]CCN1C2=C3C=C(NC3=NC=C2CN(C1=O)C4=C(C(=CC(=C4F)OC)OC)F)CN5CCOCC5 | |
| InChI[hide]InChI=1S/C24H27F2N5O4/c1-4-30-21-14(11-27-23-16(21)9-15(28-23)13-29-5-7-35-8-6-29)12-31(24(30)32)22-19(25)17(33-2)10-18(34-3)20(22)26/h9-11H,4-8,12-13H2,1-3H3,(H,27,28)Key:HCDMJFOHIXMBOV-UHFFFAOYSA-N |
/////////Pemigatinib, 佩米替尼 , PEMAZYRE, FDA 2020, 2020 APPROVALS, INCB054828, INCB 054828, Orphan Drug Status, Myeloproliferative disorders, Lymphoma, Cholangiocarcinoma, INCYTE
O=C1N(CC)C2=C3C(NC(CN4CCOCC4)=C3)=NC=C2CN1C5=C(F)C(OC)=CC(OC)=C5F.[H]Cl
RALOXIFENE
Keoxifene hydrochloride, Raloxifene hydrochloride, LY-139481(free base), LY-156758, Optruma, Loxifen, EvistaTitle: RaloxifeneCAS Registry Number: 84449-90-1CAS Name: [6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoneAdditional Names: keoxifeneManufacturers’ Codes: LY-139481Molecular Formula: C28H27NO4SMolecular Weight: 473.58Percent Composition: C 71.01%, H 5.75%, N 2.96%, O 13.51%, S 6.77%Literature References: Nonsteroidal, selective estrogen receptor modulator (SERM). Prepn: C. D. Jones, EP62503; idem,US4418068 (1982, 1983 both to Lilly); idemet al.,J. Med. Chem.27, 1057 (1984). Review of pharmacology and toxicology: J. Buelke-Sam et al.,Reprod. Toxicol.12, 217-221 (1998); of clinical pharmacology and pharmacokinetics: D. Hochner-Celnikier, Eur. J. Obstet. Gynecol. Reprod. Biol.85, 23-29 (1999); of clinical efficacy in osteoporosis: D. Agnusdei, ibid. 43-46. Clinical effect on risk of breast cancer: S. R. Cummings et al.,J. Am. Med. Assoc.281, 2189 (1999); on reduction of fracture risk: B. Ettinger et al.,ibid.282, 637 (1999).Properties: Crystals from acetone, mp 143-147°. uv max (ethanol): 290 nm (e 34000).Melting point: mp 143-147°Absorption maximum: uv max (ethanol): 290 nm (e 34000)
Derivative Type: HydrochlorideCAS Registry Number: 82640-04-8Manufacturers’ Codes: LY-156758Trademarks: Evista (Lilly)Molecular Formula: C28H27NO4S.HClMolecular Weight: 510.04Percent Composition: C 65.94%, H 5.53%, N 2.75%, O 12.55%, S 6.29%, Cl 6.95%Properties: Crystals from methanol/water, mp 258°. uv max (ethanol): 286 nm (e 32800).Melting point: mp 258°Absorption maximum: uv max (ethanol): 286 nm (e 32800)
Therap-Cat: Antiosteoporotic.Keywords: Antiosteoporotic; Selective Estrogen Receptor Modulator (SERM).
Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids.[4] For osteoporosis it is less preferred than bisphosphonates.[4] It is also used to reduce the risk of breast cancer in those at high risk.[4] It is taken by mouth.[4]
Common side effects include hot flashes, leg cramps, swelling, and joint pain.[4] Severe side effects may include blood clots and stroke.[4] Use during pregnancy may harm the baby.[4] The medication may worsen menstrual symptoms.[5] Raloxifene is a selective estrogen receptor modulator (SERM) and therefore a mixed agonist–antagonist of the estrogen receptor (ER).[4] It has estrogenic effects in bone and antiestrogenic effects in the breasts and uterus.[4]
Raloxifene was approved for medical use in the United States in 1997.[4] It is available as a generic medication.[4][6] A month supply in the United Kingdom costs the NHS about 3.50 £ as of 2019.[6] In the United States the wholesale cost of this amount is about $16.[7] In 2017, it was the 330th most commonly prescribed medication in the United States, with more than 900 thousand prescriptions.[8
Medical uses
Raloxifene is used for the treatment and prevention of osteoporosis in postmenopausal women.[9] It is used at a dosage of 60 mg/day for both the prevention and treatment of osteoporosis.[10] In the case of either osteoporosis prevention or treatment, supplemental calcium and vitamin D should be added to the diet if daily intake is inadequate.[11]
Raloxifene is used to reduce the risk of breast cancer in postmenopausal women. It is used at a dosage of 60 mg/day for this indication.[10] In the Multiple Outcomes of Raloxifene (MORE) clinical trial, raloxifene decreased the risk of all types of breast cancer by 62%, of invasive breast cancer by 72%, and of invasive estrogen receptor-positive breast cancer by 84%.[12] Conversely, it does not reduce the risk of estrogen receptor-negative breast cancer.[12] There were no obvious differences in effectiveness of raloxifene in the MORE trial for prevention of breast cancer at a dosage of 60 mg/m2/day relative to 120 mg/m2/day.[12] In the Study of Tamoxifen and Raloxifene (STAR) trial, 60 mg/day raloxifene was 78% as effective as 20 mg/day tamoxifen in preventing non-invasive breast cancer.[13] Women with undetectable levels of estradiol (<2.7 pg/mL) have a naturally low risk of breast cancer and, in contrast to women with detectable levels of estradiol, do not experience significant benefit from raloxifene in terms of reduction of breast cancer risk.[12]
Contraindications
Raloxifene is contraindicated in lactating women or women who are or who may become pregnant.[14] It also may be of concern to women with active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis.[15]
Side effects
Common side effects of raloxifene include hot flashes (25–28% vs. 18–21% for placebo),[12] vaginal dryness, and leg cramps (generally mild; 5.5% vs. 1.9% for placebo).[14][1][16] Raloxifene does not cause breast tenderness, endometrial hyperplasia, menstrual bleeding, or endometrial cancer.[17] It does not appear to affect cognition or memory.[15][12] Raloxifene is a teratogen; i.e., it can cause developmental abnormalities such as birth defects.
Raloxifene may infrequently cause serious blood clots to form in the legs, lungs, or eyes.[1] Other reactions experienced include leg swelling/pain, trouble breathing, chest pain, and vision changes. Black box warnings were added to the label of raloxifene in 2007 warning of increased risk of death due to stroke for postmenopausal women with documented coronary heart disease or at increased risk for major coronary events, as well as increased risk for deep vein thrombosis and pulmonary embolism.[14] The risk of venous thromboembolism with raloxifene is increased by several-fold in postmenopausal women (RR = 3.1).[18][12] Raloxifene has a lower risk of thromboembolism than tamoxifen.[13] In the MORE trial, raloxifene caused a 40% decrease in risk of cardiovascular events in women who were at increased risk for coronary artery disease, although there was no decrease in cardiovascular events for the group as a whole.[12]
A report in September 2009 from Health and Human Services’ Agency for Healthcare Research and Quality suggests that tamoxifen and raloxifene, used to treat breast cancer, significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects.[19]
A recent human case report in July 2016 suggests that raloxifene may in fact, at some point, also stimulate breast cancer growth leading to a reduction of advanced breast cancer disease upon the withdrawal of the drug.[20]
Unlike other SERMs, such as tamoxifen, raloxifene has no risk of uterine hyperplasia or endometrial cancer (RR = 0.8).[1][18][13]
Raloxifene does not increase the incidence of breast pain or tenderness in postmenopausal women.[16][21]
Overdose
Raloxifene has been studied in clinical trials across a dosage range of 30 to 600 mg/day, and was well-tolerated at all dosages.[16]
Pharmacology
Pharmacodynamics
Mechanism of action
Raloxifene is a selective estrogen receptor modulator (SERM) and hence is a mixed agonist and antagonist of the estrogen receptor (ER) in different tissues.[4] It has estrogenic activity in some tissues, such as bone and the liver, and antiestrogenic activity in other tissues, such as the breasts and uterus.[4] Its affinity (Kd) for the ERα is approximately 50 pM, which is similar to that of estradiol.[16] Relative to estradiol, raloxifene has been reported to possess about 8 to 34% of the affinity for the ERα and 0.5 to 76% of the affinity for the ERβ.[22][23] Raloxifene acts as a partial agonist of the ERα and as a pure antagonist of the ERβ.[24][25] In contrast to the classical ERs, raloxifene is an agonist of the G protein-coupled estrogen receptor (GPER) (EC50 = 10–100 nM), a membrane estrogen receptor.[26][27]
Clinical effects
Raloxifene has antiestrogenic effects in the mammary glands in preclinical studies.[16] In accordance, raloxifene reduces breast density in postmenopausal women, a known risk factor for breast cancer.[28] It does not stimulate the uterus in postmenopausal women, and results in no increase in risk of endometrial thickening, vaginal bleeding, endometrial hyperplasia, or endometrial cancer.[29][16][21] At the same time, raloxifene has minimal antiestrogenic effect in the uterus in premenopausal women.[29] This may possibly be due to inadequate tissue exposure of the uterus to raloxifene in these estrogen-rich individuals.[29]
In premenopausal women, raloxifene increases levels of follicle-stimulating hormone (FSH) and estradiol.[12] Conversely, in postmenopausal women, raloxifene has been found to reduce levels of the gonadotropins, luteinizing hormone (LH) and FSH, while not affecting levels of estradiol.[12][29] Raloxifene also decreases prolactin levels in postmenopausal women.[29] In men, raloxifene has been found to disinhibit the hypothalamic–pituitary–gonadal axis (HPG axis) and thereby increase total testosterone levels.[30][31][32][33] Due to the simultaneous increase in sex hormone-binding globulin (SHBG) levels however, free testosterone levels often remain unchanged in men during therapy with raloxifene.[30]
Raloxifene has estrogenic effects on liver protein synthesis.[12] It increases SHBG levels in both pre- and postmenopausal women as well as in men.[12][30] The medication decreases levels of total and low-density lipoprotein (LDL) cholesterol, C-reactive protein, apolipoprotein B, and homocysteine.[12][29] Conversely, it has little effect on levels of triglycerides and high-density lipoprotein (HDL).[12] Raloxifene has been shown to inhibit the oxidation of LDL cholesterol in vitro.[16] The medication has been found to decrease insulin-like growth factor 1 (IGF-1) levels in pre- and postmenopausal women as well as in men.[31] It has also been found to increase insulin-like growth factor binding protein 3 (IGFBP-3) levels in pre- and postmenopausal women.[12] Due to activation of estrogen receptors in the liver, raloxifene has procoagulatory effects, such as decreasing levels of fibrinogen and influencing levels of other coagulation factors.[12][29][16] For these reasons, raloxifene increases the risk of thrombosis.[12][29]
Raloxifene increases bone mineral density in postmenopausal women but decreases it in premenopausal women.[12] In the MORE trial, the risk of vertebral fractures was decreased by 30%, and bone mineral density was increased in the spine (by 2.1% at 60 mg, 2.4% at 120 mg) and femoral neck (2.6% at 60 mg, 2.7% at 120 mg).[18] It has been found to possess estrogenic effects in adipose tissue in postmenopausal women, promoting a shift from an android fat distribution to a gynoid fat distribution.[34][35] The medication has been found to increase levels of leptin, an adipokine.[12]
AbsorptionPharmacokinetics
The absorption of raloxifene is approximately 60%.[1][2] However, due to extensive first-pass metabolism, the absolute bioavailability of raloxifene is only 2.0%.[1][2] Raloxifene is rapidly absorbed from the intestines upon oral administration.[1] Peak plasma levels of raloxifene occur 0.5 to 6 hours after an oral dose.[1][2]
Distribution
Raloxifene is widely distributed throughout the body.[1] There is extensive distribution of raloxifene into the liver, serum, lungs, and kidneys.[1] The volume of distribution of raloxifene with a single 30 to 150 mg oral dose is approximately 2348 L.[1][36] Both raloxifene and its metabolites show high plasma protein binding (>95%), including to both albumin and α1 acid glycoprotein, but not to sex hormone-binding globulin.[1][2]
Metabolism
Raloxifene is metabolized in the liver and undergoes enterohepatic recycling.[2] It is metabolized exclusively by glucuronidation and is not metabolized by the cytochrome P450 system.[1][2] Less than 1% of radiolabeled material in plasma comprises unconjugated raloxifene.[2] The metabolites of raloxifene include several glucuronides.[1] The elimination half-life of raloxifene after a single dose is 27.7 hours (1.2 days), whereas its half-life at steady state at a dosage of 60 mg/day is 15.8 to 86.6 hours (0.7–3.6 days), with an average of 32.5 hours (1.4 days).[1][2] The extended half-life of raloxifene is attributed to enterohepatic recirculation and its high plasma protein binding.[1] Raloxifene and its glucuronide conjugates are interconverted by reversible metabolism and enterohepatic recycling, which prolongs the elimination half-life of raloxifene with oral administration.[2] The medication is deconjugated into its active form in a variety of tissues, including liver, lungs, spleen, bone, uterus, and kidneys.[1]
Elimination
Raloxifene is mainly excreted in bile and is eliminated in feces.[1][2] Less than 0.2% of a dose is excreted unchanged in urine and less than 6% of a dose is excreted in urine as glucuronide conjugates.[2]
Chemistry
See also: List of selective estrogen receptor modulators and Benzothiophene
Raloxifene hydrochloride has the empirical formula C28H27NO4S•HCl, which corresponds to a molecular weight of 510.05 g/mol. Raloxifene hydrochloride is an off-white to pale-yellow solid that is slightly soluble in water.[14]
Raloxifene is a benzothiophene derivative and is structurally distinct from the triphenylethylene SERMs like tamoxifen, clomifene, and toremifene.[37] It is the only benzothiophene SERM to have been marketed.[37] A benzothiophene SERM that was not marketed is arzoxifene (LY-353381).[38] Bazedoxifene (Duavee, Viviant) and pipendoxifene (ERA-923) are structurally related to raloxifene but are technically not benzothiophenes and instead are indoles.[38]
History
Raloxifene was approved in the United States for the prevention of postmenopausal osteoporosis in 1997, the treatment of postmenopausal osteoporosis in 1999, and to prevent or reduce the risk of breast cancer in certain postmenopausal women in 2007.[39][40][41][42] It received orphan designation in 2005.[39]
Society and culture
A bottle of raloxifene.
Names
Raloxifene is the generic name of the drug and its INN and BAN, while raloxifène is its DCF and raloxifene hydrochloride is its USAN, BANM, and JAN.[43][44][45][46] It has also been known by the name keoxifene.[43][44][46]
Raloxifene is sold mainly under the brand name Evista and to a lesser extent the brand name Optruma.[46][44] It is also sold under a variety of other brand names in various countries.[46]
Availability
Raloxifene is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, elsewhere throughout Europe, Australia, New Zealand, South Africa, Latin America, Southern, Eastern, and Southeastern Asia, and elsewhere in the world such as in Israel and Egypt.[46][44]
Raloxifene is provided in the form of 60 mg oral tablets.[10]
Controversy
An editorial in Lancet Oncology criticized the way that research about the medication for breast cancer prevention was released.[47]
Research
Clinical studies of raloxifene for metastatic breast cancer in women have been conducted but found little effectiveness at 60 mg/day in those previously treated with tamoxifen, though modest effectiveness has been observed at higher doses.[12][48] In contrast to tamoxifen, raloxifene is not approved for the treatment of breast cancer.[49]
Raloxifene has been studied in men for a variety of uses, such as for treatment of schizophrenia, prostate cancer, and osteoporosis.[50][51][52][53][54][33][32][55][56][57][58] It has been studied in combination with castration and bicalutamide, a nonsteroidal antiandrogen, for the treatment of prostate cancer.[58][55]
Raloxifene has been studied as an adjunct in the treatment of schizophrenia in postmenopausal women.[59] A 2017 meta-analysis concluded that it was safe and effective for this indication, although further studies with larger sample sizes are needed for confirmation.[59] It may be effective in women with less severe symptoms.[59]
A tissue-selective estrogen-receptor complex (TSEC) of estradiol and raloxifene has been studied in postmenopausal women.[60]
Raloxifene (60 mg/day) was reported to be effective in the treatment of pubertal gynecomastia in adolescent boys in a small retrospective chart review.[61][62][63] Other SERMs are also known to be effective in the treatment of gynecomastia.[64]
Raloxifene has been reported to augment the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs).[65]
June 18th 2020, Exscalate4CoV, the private-public consortium supported by the EU’s Horizon 2020 programme for research and innovation, led by Dompé farmaceutici and currently representing 18 partners (including Fraunhofer Institute, CINECA, Chelonia Applied Science, Swiss Institute of Bioinformatics and others) has requested access to clinical trials for the use of Raloxifene in Covid 19 patients. Raloxifene, already proven effective against Mers and Sars in precliinical tests, has been indicated as effective against Sars-Cov2 by the “in-silico” research conducted by the consortium which has shown efficacy in countering the replication of the virus in cells. The IP for its use against Sars-Cov2 has already been protected on May 6 2020 in the name Dompé farmaceutici, Fraunhofer Institute and KU Leuven, to facilitate the largest possible access. Raloxifene would be used in mildly symptomatic Covid19 patients to halt the spread of infection. This result emerged from the first virtual (in silico) screening conducted on the Consortium’s supercomputers of more than 400.000 molecules (safe-in-man drugs and natural products) made available by Dompé farmaceutici and the partner Fraunhofer (IME) to the Consortium. The molecules were prioritized if in clinical stage or already on the market. 7.000 molecules with certain promising characteristics were tested.
SYN
Jones, Charles D.; Jevnikar, Mary G.; Pike, Andrew J.; Peters, Mary K.; Black, Larry J.; Thompson, Allen R.; Falcone, Julie F.; Clemens, James A. (1984). “Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride (LY 156758), a remarkably effective estrogen antagonist with only minimal intrinsic estrogenicity”. Journal of Medicinal Chemistry 27 (8): 1057–66.doi:10.1021/jm00374a021. PMID 6431104.
syn 1
EP 0062053; GB 2097788
Keoxifene has been synthesized using the following process: A portion of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-pipendinoethoxy)benzoyl]benzo[b]thiophene hydrochloride (I) was combined with denatured alcohol and 5N sodium hydroxide, and stirred under a nitrogen atmosphere. The reaction mixture was evaporated to dryness under vacuum, and the residue dissolved in water and washed with diethyl ether. The water layer was degassed under vacuum, and then nitrogen was bubbled through it to remove all traces of ether. The mixture was then acidified with 1N hydrochloric acid, and then made basic with excess sodium bicarbonate The precipitate was collected by filtration and washed with cold water to obtain crude product, which was purified on a column of silica gel. The column was eluted first with 700 ml of 5% methanol in chloroform, followed by 1l of 10% methanol in chloroform. The impurities came off first, and the product-containing fractions were combined and evaporated under vacuum to obtain a yellow oil. The oil was dissolved in acetone seeded and chilled in a freezer to obtain the purified product.
syn2
J Label Compd Radiopharm 1995,36(1),43
The synthesis of radiolabeled raloxifene has been reported: The esterification of 3,5-dibromo-4-hydroxybenzoic acid (I) with methanol/HCl gives the corresponding methyl ester (II), which is condensed with 1-(2-chloroethyl)piperidine (III) by means of K2CO3 in DMF yielding 3,5-dibromo-4-[2-(1-piperidyl)ethoxy]benzoic acid methyl ester (IV). The hydrolysis of (IV) with NaOH in methanol affords the corresponding free acid (V), which by treatment of SOCl2 in toluene is converted to the acyl chloride (VI). The Friedel-Crafts condensation of (VI) with 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (VII) by means of AlCl3 in dichloromethane gives [3,5-dibromo-4-[2-(1-piperidinyl)ethoxy]phenyl]-[6-methoxy-2-(4-methoxy phenyl)benzo[b]thien-3-yl]methanone (VIII), which is demethylated with AlCl3 and ethylmercaptane to dibromoraloxifene (IX). Finally, this compound is submitted to hydrogenolysis with tritium over Pd/C in methanol.
syn 3
Bioorg Med Chem Lett 1997,7(8),993
The two major metabolites of raloxifene, the glucuronide conjugates (VI) and (VIII) are synthesized as follows: The partial silylation of raloxifene (I) with tert-butyldimethylsilyl chloride (TBDMS-Cl) by means of dimethylaminopyridine (DMAP) in THF/DMF gives a mixture of the monosilylated compounds (II) and (III), which are separated by chromatography. Compounds (II) and (III) are independently condensed with methyl 1,2,3,4-tetra-O-acetyl-D-glucuronate (IV) by means of BF3.OEt2 in dichloromethane yielding protected glucuronides (V) and (VII), respectively. Finally, both compounds are deprotected by a treatment first with LiOH in dioxane to hydrolyzed the ester groups, and then with tetrabutylammonium fluoride in THF to eliminate the silyl groups, thus obtaining the desired metabolites (VI) and (VIII), respectively.
syn 4
Tetrahedron Lett 1999,40(28),5155
Two related new syntheses of raloxifene have been described: 1) The acylation of N-(6-methoxy-1-benzothiophen-2-yl)-N,N-dimethylamine (I) with 4-fluorobenzoyl chloride (II) by heating at 100 C in chlorobenzene gives the 3-acyl derivative (III), which is condensed with 4-methoxyphenylmagnesium bromide (IV) in THF yielding 3-(4-fluorobenzoyl)-6-methoxy-2-(4-methoxyphenyl)-1-benzothiophene (V). The condensation of (V) with 1-(2-hydroxyethyl)piperidine (VI) by means of NaH in DMF affords the ether (VII), which is finally demethylated with AlCl3 and ethanethiol. 2) The intermediate (III) can also be condensed first with 1-(2-hydroxyethyl)piperidine (VI) by means of NaH as before giving the piperidinoethyl ether (VIII), which is then condensed with the Grignard reagent (IV) affording the previously reported ether (VII).
syn
Org Chem Ind J, Volume: 14( 3)
A GREEN PROCESS FOR DEMETHYLATION REACTION IN SYNTHESIS OF RALOXIFENE HYDROCHLORIDEAuthors : Ramadas Chavakula *, Chakradhar Saladi J S, Narayana Rao Mutyalaa , Vijaya Raju Maddalaa and Raghu Babu Kb
A green process for demethylation reaction in synthesis of raloxifene hydrochloride by using aluminium chloride and odorless decanethiol as demethylation agent instead of aluminium chloride and ethanethiol (foul smell) under normal conditions is described.
Raloxifene hydrochloride [1], is an estrogen agonist/antagonist, commonly referred to as a Selective Estrogen Receptor Modulator (SERM) [1,2] that belongs to the benzothiophene class of compounds. Raloxifene decreases the resorption of bone and reduces the biochemical markers of bone turnover to the premenopausal range [3–5]. Raloxifene hydrochloride may also lower the chance of developing a certain type of breast cancer (invasive breast cancer) in post-menopausal women [6,7]. It can be synthesized [3] directly from aroylation of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene [2] by the acid chloride(4) of 4-[2-(1-piperidinyl)ethoxy]benzoic acid hydrochloride [3] in the presence of AlCl3 followed by addition of ethanethiol (FIG. 1).
Experimental Section
4-[2-(1-Piperidinyl)ethoxy]benzoic acid hydrochloride [3] and 6-methoxy-2-(4-methoxyphenyl) benzo[b] thiophene [2] were prepared by procedures reported previously [3]. Decanethiol was from commercial source. All melting points are uncorrected and were determined in capillary tubes on an Electothermal melting point apparatus. 1H NMR spectra were recorded on a Brucker ADVANCE 400 MHz spectrometer, using DMSO-d6 as solvent and TMS as internal standard. Electrospray ionization mass spectroscopy was performed using an ion trap mass spectrometer (Model 6310 Agilent). All reactions were monitored and checked by Thin Layer Chromatography (TLC) using methanol and spots examined by a UV lamp.
Preparation of [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl][4-[2-(1-piperidyl)ethoxy]phenyl] methanone hydrochloride (Raloxifene hydrochloride) [1]
To a solution of 4-[2-(1-piperidinyl)ethoxy]benzoic acid hydrochloride (3) (14.3 g, 0.05 mol) in methylene dichloride (400 mL) and pyridine (0.5 mL) at 25ºC to 35ºC, thionyl chloride (23.8 g, 0.20 mol) was added dropwise under argon for 15-30 minute. The reaction mixture was stirred for 2 hr. at 40ºC to 45ºC. Excess thionyl chloride and solvent were removed in vacuum at 40◦C to afford 15.0 g of the crude acid chloride hydrochloride salt [4]. The crude solid acid chloride hydrochloride [4] was dissolved in methylene dichloride (150 mL), cooled to 0ºC to 10ºC, 6-methoxy-2-(4-methoxyphenyl)benzo[b] thiophene [2] (10.8 g, 0.04 mol) was added. Then, anhydrous aluminium chloride (37.0 g, 0.28 mol) was added portion wise over a period of 30 min and then the mixture was allowed to warm to 30ºC and stirred for 2 hr at 25-35ºC. Then decanethiol (28.0 g, 0.16 mol) was added and stirred for 2 hr. at 25-35ºC. The reaction mixture was quenched with mixture of methanol (100 mL), ice (200 g) and Conc. HCl (15 mL) and stirred for 1 hr. at 25-35ºC. The precipitated solid was collected, washed with water (100 mL X 2) and dried at 65ºC for 4 h to afford 20.0 g of crude compound 1, which was crystallized from methanol/water (23/1, vol/vol) to yield 13.6 g of compound 1 (53.3 %yield) as a white solid, MP 258-260°C, liter 3, 258°C ; 1H NMR: δ 1.34, 1.72 [2H, m, (CH2CH2)2CH2], 1.76 [4H, m, N(CH2CH2)2], 2.96 (2H, m, N-CH2), 3.43 [4H, m, N(CH2CH2)2], 4.44 (2H, m, O-CH2), 6.67 (2H, d, Ar), 6.85 (1H, d, Ar), 6.95 (2H, d, Ar), 7.18 (2H, d, Ar), 7.25 (1H, d, Ar), 7.35 (1H, s, Ar), 7.70 (2H, d, Ar), 9.77 (1H, s, OH), 9.82 (1H, s, OH), 10.16 (1H, brs, NH), MS (ESI): m/z 474.6 (M +H). “This procedure has been scaled up using 250g of compound 1.”
Results and Discussion
Commonly used thiols like ethanethiol and benzyl mercaptan in demethylation reactions have a foul smell making them difficult and unpleasant to use in the laboratory without fume hoods. The problem becomes even worse in industry on a large scale. Odorless substitutes are therefore always required. Few papers [8,9] discuss the use of long chain thiols to minimize odor, so we used this work as a basis for choosing a long chain thiol for our demethylation reaction. We now report a new, highly active demethylation reagent, an aluminum chloride and decanethiol, characterized by rapid action under mild conditions, easy workup of the reaction product, and high yield (FIG. 2.).
Figure 2: Synthesis of Raloxifene hydrochloride.
Conclusion
In conclusion, we have found that decanethiol is odorless thiol compared to ethanethiol. We believe that removing the foul-smelling thiols and use of these odorless thiols will greatly improve the greenchemistry.
References
- Grese TA, Dodge JA. Selective Estrogen Receptor Modulators (SERMs). Curr Pharm Des. 1998;4:71-92.
- Bryant HU, Dere WH. Selective estrogen receptor modulators: an alternative to hormone replacement therapy. Proc Soc Exp Biol Med. 1998;217:45-52.
- Jones CD, Jevnikar MG, Pike AJ, et al. Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo [b] thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl) benzo [b] thien-3-yl]-[4-[2-(1-piperidinyl) ethoxy] phenyl] methanone hydrochloride (LY 156758), a remarkably effective estrogen antagonist with only minimal intrinsic estrogenicity. J Med Chem. 1984;27:1057-66.
- Sato M, Grese TA, Dodge JA, et al. Emerging therapies for the prevention or treatment of postmenopausal osteoporosis. J Med Chem. 1999;42:1-24.
- Draper MW, Flowers DE, Huster WJ, et al. A controlled trial of raloxifene (LY139481) HCl: impact on bone turnover and serum lipid profile in healthy postmenopausal women. J Bone Miner Res. 1996;11:835-42.
paper
https://www.sciencedirect.com/science/article/abs/pii/S0223523412001122
syn
https://www.tandfonline.com/doi/abs/10.1080/00397911.2014.943348?journalCode=lsyc20
Piperidine Nucleophilic Substitution Without Solvent: An Efficient Synthesis of RaloxifeneYewei Yang,Tao Zhang,Wenhai Huang &Zhenrong Shen Pages 3271-3276 |
Mild and high-yielding synthesis is described for raloxifene via piperdine nucleophilic substitution of a new raloxifene intermediate 3-aroyl-2-aryl-substituted benzo[b]thiophenes, which is obtained by acylation of para-substituted benzoyl chlorides and 2-arylbenzo[b]thiophenes. The key step is solvent free and offers valuable advantages, such as low cost, and is suitable for industrial production.
Keywords: Friedel–Crafts acylation, green chemistry, nucleophiles, raloxifene, SERM
The improved synthesis of raloxifene 1 was accomplished as shown in Scheme 2. Methyl p-hydroxybenzoate 2, 1-bromo-2-chloroethane, and K2CO3 were refluxed in acetone, yielding compound 3 in 94% yield. Without prior purification, 3 was hydrolyzed to the corresponding p-substituted benzoyl acids 4 in 100% yield. The application of general reaction conditions of methanol as solvent and hydrochloric as acid would afford the substitution impurity 4-(2-methoxyethoxy)-benzoic acid. To control this impurity during reaction, various solvents such as alcohol, ethyl acetate, acetone, and tetrahydrofuran (THF) were screened, and THF gave the best result from the view of impurity formation and yield. Compound 4 is a solid and was easily isolated from THF by adding water. Then 4 was transferred to acid chlorides 5 and substantially reacted with benzothiophene 6 using AlCl3 in dichloromethane at 50 C to afford aroylated benzothiophene 7 in two steps, with yield of 95% (79% from method A[8] and 65.5% from method B[3]). With the requisite 7 in hand, we next examined piperidine nucleophilic substitution to produce the desired beno[b]thien-3-yl ketones 8. In general using reaction conditions A (acetone, NaI, K2CO3, reflux, 70%) and B (acetonitrile, NaI, K2CO3, reflux, 85%), impurity formation was observed from the beginning of the reaction. We screened various conditions and were delighted to found that using excess piperidine at reflux temperature gave negligible impurity formation. Piperidine was not only reagent but also solvent. The isolated product 8 was stable and was converted into the desired raloxifene 1 as reported. In conclusion, we have developed a viable alternative route for the synthesis of raloxifene. The new synthesis would have been better able to support the increase in bulk demand for this drug for the chemoprevention of breast cancer and novel formulations. Our synthetic route has several advantages: the use of difunctionalized coumpunds 5 as key intermediate makes Friedel–Crafts acylation and nucleophilic substitution highly efficient. The using of piperine as reagent and solvent avoids the large waste streams derived from neutralization reaction of sodium hydride. The cost of the new route is less than the current route of manufacture.
Preparation of [4-(2-Chloro-ethoxy)-phenyl]-[6-methoxy-2- (4-methoxy-phenyl)-benzo[b]thiophen-3-yl]-methanone (7) Under an N2 atmosphere, 5 was added to a mixture of 6 (20.25 g, 75 mmol) and AlCl3 (13.30 g, 100 mmol) in DCM (2 mL), and the mixture was stirred for 12 h. The reaction was monitored by TLC (n-hexane/EtOAc, 4:1). After the reaction was judged complete, the reaction mixture was allowed to cool. The crude mixture was poured into H2O and extracted with EtOAc. The organic layer was separated and concentrated. The residue was crystallized from EtOAc to give the product 7 (32.26 g, 95%): yellow solid crystals; mp 119–120 C; IR (KBr) nmax: 2960, 2835, 1647, 1599, 1472, 1251, 1169, 1032, 830 cm1 ; 1 H NMR (400 MHz, CDCl3) d 7.76 (d, J ¼ 8.8 Hz, 2H), 7.53 (d, J ¼ 8.8 Hz, 1H), 7.32 (d, J ¼ 8.4 Hz, 2H), 7.31 (s, 1H), 6.95 (dd, J ¼ 8.4, 2.4 Hz, 1H), 6.75 (dd, J ¼ 9.2, 7.2 Hz, 4H), 4.20 (t, J ¼ 4.0 Hz,2H), 3.87 (s, 3H), 3.78 (t, J ¼ 6.0 Hz, 2H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) d 193.1, 162.1, 159.7, 157.6, 142.7, 139.9, 133.8, 132.3, 130.9, 130.2, 130.1, 125.9, 123.9, 114.8, 114.1, 113.9, 104.4, 67.8, 55.6, 55.2, 41.5; MS (EI) m/z (%):452 (Mþ, 100.0), 437 (13.0), 297 (25.0), 183 (39.0), 121 (44.0). HRMS m/z (EI) calcd. for C25H22ClO4S: (MþH) þ: 453.0927; found: 453.0933.
Preparation of [6-Methoxy-2-(4-methoxy-phenyl)-benzo[b] thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (8) Under an N2 atmosphere, a mixture of 7 (8.50 g, 19 mmol) and piperdine (30 ml) was stirred under reflux for 12 h. The reaction was monitored by TLC (n-hexane/EtOAc, 4:1). After the reaction was judged complete, the reaction mixture was allowed to cool. The mixture was concentrated for recovery of piperidine. EtOAc was added and the residue was washed with saturated NaHCO3 aqueous solution. The organic layer was separated and concentrated to give the product 8 (8.80 g, 94%): yellow viscous oil; IR (KBr) nmax: cm1 2933, 1645, 1597, 1535, 1501, 1470, 1249, 1164, 1030, 827; 1 H NMR (400 MHz, CDCl3) d7.76 (d, J ¼ 8.8 Hz, 2H), 7.52 (d, J ¼ 8.8 Hz, 1H), 7.33 (d, J ¼ 8.8 Hz, 2H), 7.30 (d, J ¼ 2.4 Hz, 1H), 6.94 (dd, J ¼ 8.8, 2.0 Hz, 1H), 6.75 (dd, J ¼ 7.2, 5.2 Hz, 4H), 4.08 (t, J ¼ 6.0 Hz, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 2.71 (t, J ¼ 6.0 Hz, 2H), 2.46 (s, 4H), 1.60–1.54 (m, 4H), 1.43–1.41 (m, 2H).13C NMR (100 MHz, CDCl3) d 193.2, 163.0, 159.7, 157.6, 142.4, 140.1, 133.9, 132.3, 130.6, 130.4, 130.2, 126.0, 124.0, 114.8, 114.2, 114.1, 104.5, 66.3, 57.7, 55.6, 55.2, 55.1, 25.9, 24.1. MS (EI) m/z (%): 501 (Mþ, 100.0), 452 (12.0), 402 (21.0), 297 (24.0), 98 (100.0). HRMS m/z (EI) calcd. for C30H32NO4S: (MþH) þ: 502.2052; found: 502.2055.REFERENCES 1. Clemett, D.; Spencer, C. M. Drugs 2000, 60 (2), 379–411. 2. Land, S. R. JAMA 2007, 298 (9), 973–973. 3. Dadiboyena, S. Eur. J. Med. Chem. 2012, 51, 17–34. 4. Schmid, C. R.; Sluka, J. P.; Duke, K. M. Tetrahedron Lett. 1999, 40 (4), 675–678. 5. Bradley, D. A.; Godfrey, A. G.; Schmid, C. R. Tetrahedron Lett. 1999, 40 (28), 5155–5159. 6. Shinde, P. S.; Shinde, S. S.; Renge, A. S.; Patil, G. H.; Rode, A. B.; Pawar, R. R. Lett. Org. Chem. 2009, 6 (1), 8–10.7. Sach, N. W.; Richter, D. T.; Cripps, S.; Tran-Dube, M.; Zhu, H. C.; Huang, B. W.; Cui, J.; Sutton, S. C. Org. Lett. 2012, 14 (15), 3886–889. 8. Jones, C. D.; Jevnikar, M. G.; Pike, A. J.; Peters, M. K.; Black, L. J.; Thompson, A. R.; Falcone, J. F.; Clemens, J. A. J. Med. Chem. 1984, 27 (8), 1057–1066. 9. Grese, T. A.; Cho, S.; Finley, D. R.; Godfrey, A. G.; Jones, C. D.; Lugar, C. W.; Martin, M. J.; Matsumoto, K.; Pennington, L. D.; Winter, M. A.; Adrian, M. D.; Cole, H. W.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.; Short, L. L.; Glasebrook, A. L.; Bryant, H. U. J. Med. Chem. 1997, 40 (2), 146–167.
synChapter 2 – 1-Substituted PiperidinesAuthor links open overlay panelRubenVardanyan
https://doi.org/10.1016/B978-0-12-805157-3.00002-8Piperidine-Based Drug DiscoveryHeterocyclic Drug Discovery2017, Pages 83-1011-Substituted Piperidines
Ruben Vardanyan, in Piperidine-Based Drug Discovery, 2017
Raloxifene (7685)
Raloxifene (Evista) (1.3.4) is a second-generation selective estrogen receptor modulator that functions as an estrogen antagonist on breast and uterine tissues, and an estrogen agonist on bone. Raloxifene is an antiresorptive agent, a new representative of a class of drugs that prevent the loss of bone mass, i.e., used to treat osteoporosis and similar diseases in postmenopausal women and those postmenopausal women at increased risk of invasive breast cancer [41–53].
It was shown that raloxifene can have some affect on cognition, mental health, sleep, and sexual function in menopausal women [54]. Raloxifene was used also as an adjuvant treatment in postmenopausal women with schizophrenia [55].
The first reported synthesis of the raloxifene scaffold consists in Friedel-Crafts aroylation in 1,2-dichloroethane and using AlCl3 as a catalyst by coupling of 4-(2-(piperidin-1-yl)ethoxy)benzoyl chloride (2.3.15) with benzothiophene derivative (2.3.16) followed by alkaline hydrolysis of mesyl groups, which give the desired raloxifene (2.3.4) [56–58] (Scheme 2.9).
The key intermediate – 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (2.3.16) – was prepared by the cyclization-rearrangement of 1-(4-methoxyphenyl)-2-((3-methoxyphenyl)thio)ethan-1-one (2.3.20) induced by polyphosphoric acid (PPA). This rearrangement (Kost rearrangement [59]) is general for 3-(R-substituted)indoles, -benzofurans, and -benzothiophenes, which are converted to the corresponding 2-isomers by heating with PPA.
The synthesis started from thiophenol (2.3.18) and bromoketone (2.3.19), which were coupled in presence of KOH in ethanol/water solution. Obtained (2.3.20) was heated with PPA to give a mixture that is easily separable by crystallization isomeric 2-phenylbenzo[b]thiophenes (2.3.21) and (2.3.22), where preferable, isomer (2.3.22) predominates. Cleavage of the methoxy groups in (2.3.22) was done conveniently with pyridine hydrochloride to give (2.3.23), which was easily converted to mesylate (2.3.16) with methanesulfonyl chloride in pyridine and 4-dimethylaminopyridine as a catalyst (Scheme 2.10).
The second reagent—4-(2-(piperidin-1-yl)ethoxy)benzoyl chloride (2.3.15)—was prepared starting with 4-hydroxybenzoate (2.3.24), which with 1-(2-chloroethyl)piperidine (2.3.25) in anhydrous DMF, and K2CO3 or sodium hydride, gave methyl 4-(2-(piperidin-1-yl)ethoxy)benzoate (2.3.26) hydrolyzed in MeOH/water NaOH solution. The acid (2.3.26) was converted to its chloride (2.3.15) with SOCl2 in 1,2-dichloroethane and a catalytic amount of DMF (Scheme 2.11).
Another novel convenient synthesis of raloxifene (2.3.4) have been proposed [60]. According to this method anisaldehyde (2.3.28) was transformed to corresponding cyanohydrin (2.3.29) using a mixture of sodium cyanide ethanol containing triethylamine through which HCl gas was passed over 30 minutes at 5–10°C.
Gaseous HCl was added to the solution of prepared cyanohydrin (2.3.29) in ethanol at room temperature over 30 minutes in order to give p-methoxybenzaldehyde cyanohydrin iminoether hydrochloride (2.3.30). Then, hydrogen sulfide was bubbled into a solution of the methyl imidate (2.3.30) and triethylamine in methanol at 0°C to give α-(4-methoxy phenyl)-α-hydroxy-N,N dimethylthioacetamide (2.3.31).
To the obtained α-hydroxythioamide (2.3.31) dissolved-in-methylene chloride methanesulfonic acid was slowly added, which transformed the starting material to 2-N,N-dimethylamino-6-methoxy benzo[β]thiophene (2.3.32).
The obtained 2-dimethylaminobenzothiophene (2.3.32) and known 4-(2-piperidinoethoxy)-benzoyl chloride (2.3.15) were partially dissolved in chlorobenzene and the mixture was warmed in a 100–105°C to give 2-(4-methoxyphenyl)-6-methoxy-3-[4-(piperidinoethoxy)benzoyl]-benzo[β]thiophene (2.3.33). 4-Methoxyphenylmagnesium bromide (2.3.34) in THF was added to chilled to 0°C prepared compound (2.3.33) in THF, which gave 2-(4-methoxyphenyl)-6-methoxy-3-[4-(piperidinoethoxy)benzoyl] benzo[β] thiophene (2.3.35). To the prepared benzothiophene (2.3.35) suspended in chlorobenzene was added AlCl3, followed by the addition of n-propanethiol, and the mixture was heated at 35°C. After the workup with aqueous HCl, the desired raloxifene (2.3.4) was separated [60] (Scheme 2.12).
There exist plenty of modifications for these two approaches, as reviewed in [61,62].
References
- ^ Jump up to:a b c d e f g h i j k l m n o p q r s t u v w Morello, Karla C.; Wurz, Gregory T.; DeGregorio, Michael W. (2003). “Pharmacokinetics of Selective Estrogen Receptor Modulators”. Clinical Pharmacokinetics. 42 (4): 361–372. doi:10.2165/00003088-200342040-00004. ISSN 0312-5963. PMID 12648026. S2CID 13003168.
- ^ Jump up to:a b c d e f g h i j k l m n o p q Hochner-Celnikier D (1999). “Pharmacokinetics of raloxifene and its clinical application”. Eur. J. Obstet. Gynecol. Reprod. Biol. 85 (1): 23–9. doi:10.1016/s0301-2115(98)00278-4. PMID 10428318.
- ^ Jeong, Eun Ju; Liu, Yong; Lin, Huimin; Hu, Ming (2005-03-15). “Species- and Disposition Model-Dependent Metabolism of Raloxifene in Gut and Liver: Role of UGT1A10”. Drug Metabolism and Disposition. ASPET. 33 (6): 785–794. doi:10.1124/dmd.104.001883. PMID 15769887. S2CID 24273998.
- ^ Jump up to:a b c d e f g h i j k l m “Raloxifene Hydrochloride Monograph for Professionals”. Drugs.com. American Society of Health-System Pharmacists. Retrieved 22 March 2019.
- ^ Yang, Z. D.; Yu, J.; Zhang, Q. (August 2013). “Effects of raloxifene on cognition, mental health, sleep and sexual function in menopausal women: a systematic review of randomized controlled trials”. Maturitas. 75 (4): 341–348. doi:10.1016/j.maturitas.2013.05.010. ISSN 1873-4111. PMID 23764354.
- ^ Jump up to:a b British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 736–737. ISBN 9780857113382.
- ^ “NADAC as of 2019-02-27”. Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
- ^ “Raloxifene Hydrochloride – Drug Usage Statistics”. ClinCalc. Retrieved 11 April 2020.
- ^ “Raloxifene: MedlinePlus Drug Information”. medlineplus.gov. Retrieved 2018-11-07.
- ^ Jump up to:a b c Mosby (5 March 2013). Mosby’s Drug Reference for Health Professions – E-Book. Elsevier Health Sciences. pp. 1379–. ISBN 978-0-323-18760-2.
- ^ Ohta, Hiroaki; Hamaya, Etsuro; Taketsuna, Masanori; Sowa, Hideaki (January 2015). “Quality of life in Japanese women with postmenopausal osteoporosis treated with raloxifene and vitamin D: post hoc analysis of a postmarketing study”. Current Medical Research and Opinion. 31 (1): 85–94. doi:10.1185/03007995.2014.975339. ISSN 1473-4877. PMID 25299349. S2CID 24671531.
- ^ Jump up to:a b c d e f g h i j k l m n o p q r s t Fabian CJ, Kimler BF (March 2005). “Selective estrogen-receptor modulators for primary prevention of breast cancer”. J. Clin. Oncol. 23 (8): 1644–55. doi:10.1200/JCO.2005.11.005. PMID 15755972.
- ^ Jump up to:a b c Kirby I. Bland; Edward M. Copeland; V. Suzanne Klimberg; William J Gradishar (29 June 2017). The Breast E-Book: Comprehensive Management of Benign and Malignant Diseases. Elsevier Health Sciences. pp. 231–. ISBN 978-0-323-51187-2.
- ^ Jump up to:a b c d Raloxifene label Last updated 09/2007]
- ^ Jump up to:a b Gizzo S, Saccardi C, Patrelli TS, Berretta R, Capobianco G, Di Gangi S, Vacilotto A, Bertocco A, Noventa M, Ancona E, D’Antona D, Nardelli GB (2013). “Update on raloxifene: mechanism of action, clinical efficacy, adverse effects, and contraindications”. Obstet Gynecol Surv. 68 (6): 467–81. doi:10.1097/OGX.0b013e31828baef9. PMID 23942473. S2CID 9003157.
- ^ Jump up to:a b c d e f g h Goldstein, S. R. (2000). “A pharmacological review of selective oestrogen receptor modulators”. Human Reproduction Update. 6 (3): 212–224. doi:10.1093/humupd/6.3.212. ISSN 1355-4786. PMID 10874566.
- ^ Seeman E (2001). “Raloxifene”. J. Bone Miner. Metab. 19 (2): 65–75. doi:10.1007/s007740170043. PMID 11281162.
- ^ Jump up to:a b c Park, W (2002). “Selective estrogen receptor modulators (SERMS) and their roles in breast cancer prevention”. Trends in Molecular Medicine. 8 (2): 82–88. doi:10.1016/S1471-4914(02)02282-7. ISSN 1471-4914. PMID 11815274.
- ^ Agency for Healthcare Research and Quality, Rockville, MD. (September 2009). “Medications Effective in Reducing Risk of Breast Cancer But Increase Risk of Adverse Effects”. Retrieved 2009-09-14.
- ^ Lemmo, W (2016). “Anti-Estrogen Withdrawal Effect With Raloxifene? A Case Report”. Integrative Cancer Therapies. Published Online Before Print July 13 (3): 245–249. doi:10.1177/1534735416658954. PMC 5739193. PMID 27411856.
- ^ Jump up to:a b Haskell, Sally G. (2003). “Selective Estrogen Receptor Modulators”. Southern Medical Journal. 96 (5): 469–476. doi:10.1097/01.SMJ.0000051146.93190.4A. ISSN 0038-4348. PMID 12911186. S2CID 40607634.
- ^ Weatherman, Ross V; Clegg, Nicola J; Scanlan, Thomas S (2001). “Differential SERM activation of the estrogen receptors (ERα and ERβ) at AP-1 sites”. Chemistry & Biology. 8(5): 427–436. doi:10.1016/S1074-5521(01)00025-4. ISSN 1074-5521. PMID 11358690.
- ^ Escande A, Pillon A, Servant N, Cravedi JP, Larrea F, Muhn P, Nicolas JC, Cavaillès V, Balaguer P (May 2006). “Evaluation of ligand selectivity using reporter cell lines stably expressing estrogen receptor alpha or beta”. Biochem. Pharmacol. 71 (10): 1459–69. doi:10.1016/j.bcp.2006.02.002. PMID 16554039.
- ^ Greene, G. L.; Shiau, A. K.; Nettles, K. W. (2004). “A Structural Explanation for ERα/ERβ SERM Discrimination”. New Molecular Mechanisms of Estrogen Action and Their Impact on Future Perspectives in Estrogen Therapy (46): 33–45. doi:10.1007/978-3-662-05386-7_3. ISBN 978-3-662-05388-1. PMID 15248503.
- ^ Barkhem, Tomas; Carlsson, Bo; Nilsson, Yvonne; Enmark, Eva; Gustafsson, Jan-Åke; Nilsson, Stefan (1998). “Differential Response of Estrogen Receptor α and Estrogen Receptor β to Partial Estrogen Agonists/Antagonists”. Molecular Pharmacology. 54 (1): 105–112. doi:10.1124/mol.54.1.105. ISSN 0026-895X. PMID 9658195.
- ^ Prossnitz ER, Arterburn JB (July 2015). “International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators”. Pharmacol. Rev. 67 (3): 505–40. doi:10.1124/pr.114.009712. PMC 4485017. PMID 26023144.
- ^ Petrie WK, Dennis MK, Hu C, Dai D, Arterburn JB, Smith HO, Hathaway HJ, Prossnitz ER (2013). “G protein-coupled estrogen receptor-selective ligands modulate endometrial tumor growth”. Obstet Gynecol Int. 2013: 472720. doi:10.1155/2013/472720. PMC 3863501. PMID 24379833.
- ^ Jeon-Hor, Chen; et al. (September 15, 2003). “Reduction of Breast Density Following Tamoxifen Treatment Evaluated by 3-D MRI: Preliminary Study”. Magn Reson Imaging. 29 (1): 91–8. doi:10.1016/j.mri.2010.07.009. PMC 3005955. PMID 20832226.
- ^ Jump up to:a b c d e f g h Draper, Michael W.; Chin, William W. (2003). “Molecular and Clinical Evidence for the Unique Nature of Individual Selective Estrogen Receptor Modulators”. Clinical Obstetrics and Gynecology. 46 (2): 265–297. doi:10.1097/00003081-200306000-00008. ISSN 0009-9201. PMID 12808380. S2CID 5132467.
- ^ Jump up to:a b c Corona G, Rastrelli G, Ratrelli G, Maggi M (February 2015). “The pharmacotherapy of male hypogonadism besides androgens”. Expert Opin Pharmacother. 16 (3): 369–87. doi:10.1517/14656566.2015.993607. PMID 25523084. S2CID 8891640.
- ^ Jump up to:a b Duarte FH, Jallad RS, Bronstein MD (November 2016). “Estrogens and selective estrogen receptor modulators in acromegaly”. Endocrine. 54 (2): 306–314. doi:10.1007/s12020-016-1118-z. PMID 27704479. S2CID 10136018.
- ^ Jump up to:a b Birzniece V, Sutanto S, Ho KK (April 2012). “Gender difference in the neuroendocrine regulation of growth hormone axis by selective estrogen receptor modulators”. J. Clin. Endocrinol. Metab. 97 (4): E521–7. doi:10.1210/jc.2011-3347. PMID 22319035.
- ^ Jump up to:a b Uebelhart B, Herrmann F, Pavo I, Draper MW, Rizzoli R (September 2004). “Raloxifene treatment is associated with increased serum estradiol and decreased bone remodeling in healthy middle-aged men with low sex hormone levels”. J. Bone Miner. Res. 19 (9): 1518–24. doi:10.1359/JBMR.040503. PMID 15312253. S2CID 36104038.
- ^ Xu, Beibei; Lovre, Dragana; Mauvais-Jarvis, Franck (2016). “Effect of selective estrogen receptor modulators on metabolic homeostasis”. Biochimie. 124: 92–97. doi:10.1016/j.biochi.2015.06.018. ISSN 0300-9084. PMID 26133657.
In healthy postmemopausal women, raloxifene treatment for one year prevented body weight gain and abdominal adiposity by promoting a shift from an android to gynoid fat distribution [46].
- ^ Francucci, C. M.; Pantaleo, D.; Iori, N.; Camilletti, A.; Massi, F.; Boscaro, M. (2014). “Effects of raloxifene on body fat distribution and lipid profile in healthy post-menopausal women”. Journal of Endocrinological Investigation. 28 (9): 623–631. doi:10.1007/BF03347261. ISSN 0391-4097. PMID 16218045. S2CID 28467435.
These results […] suggest, for the first time, that RLX promotes the shift from android to gynoid fat distribution, and prevents the uptrend of abdominal adiposity and body weight compared with untreated women.
- ^ Snyder KR, Sparano N, Malinowski JM (September 2000). “Raloxifene hydrochloride”. Am J Health Syst Pharm. 57 (18): 1669–75, quiz 1676–8. doi:10.1093/ajhp/57.18.1669. PMID 11006795.
- ^ Jump up to:a b Eric S. Orwoll; Michael Bliziotes (2 August 2002). Osteoporosis: Pathophysiology and Clinical Management. Springer Science & Business Media. pp. 320–. ISBN 978-1-59259-278-4.
- ^ Jump up to:a b Stuart Silverman; Bo Abrahamsen (29 December 2015). The Duration and Safety of Osteoporosis Treatment: Anabolic and Antiresorptive Therapy. Springer. pp. 24–. ISBN 978-3-319-23639-1.
- ^ Jump up to:a b Institute of Medicine; Board on Health Sciences Policy; Committee on Accelerating Rare Diseases Research and Orphan Product Development (3 April 2011). Rare Diseases and Orphan Products: Accelerating Research and Development. National Academies Press. pp. 113–. ISBN 978-0-309-15806-0.
- ^ Reducing Breast Cancer Risk with Drugs. Am Cncl on Science, Health. pp. 10–. GGKEY:CBEALLAHP8W.
- ^ Sydney Lou Bonnick (10 November 2007). Bone Densitometry for Technologists. Springer Science & Business Media. pp. 277–. ISBN 978-1-59259-992-9.
- ^ Jie Jack Li; Douglas S. Johnson (27 March 2013). Modern Drug Synthesis. John Wiley & Sons. pp. 2–. ISBN 978-1-118-70124-9.
- ^ Jump up to:a b J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 1063–. ISBN 978-1-4757-2085-3.
- ^ Jump up to:a b c d Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 909–. ISBN 978-3-88763-075-1.
- ^ I.K. Morton; Judith M. Hall (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 245–. ISBN 978-0-7514-0499-9.
- ^ Jump up to:a b c d e “Raloxifene”.
- ^ Thelancetoncology (2006). “A STARring role for raloxifene?”. Lancet Oncol. 7 (6): 443. doi:10.1016/S1470-2045(06)70701-X. PMID 16750489.
- ^ Provinciali N, Suen C, Dunn BK, DeCensi A (October 2016). “Raloxifene hydrochloride for breast cancer risk reduction in postmenopausal women”. Expert Rev Clin Pharmacol. 9 (10): 1263–1272. doi:10.1080/17512433.2016.1231575. PMID 27583816. S2CID 26047863.
- ^ James F. Holland; Raphael E. Pollock (2010). Holland-Frei Cancer Medicine 8. PMPH-USA. pp. 743–. ISBN 978-1-60795-014-1.
- ^ Blum A, Hathaway L, Mincemoyer R, Schenke WH, Csako G, Waclawiw MA, Panza JA, Cannon RO (2000). “Hormonal, lipoprotein, and vascular effects of the selective estrogen receptor modulator raloxifene in hypercholesterolemic men”. Am. J. Cardiol. 85 (12): 1491–4, A7. doi:10.1016/s0002-9149(00)00802-x. PMID 10856400.
- ^ Doran PM, Riggs BL, Atkinson EJ, Khosla S (2001). “Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men”. J. Bone Miner. Res. 16 (11): 2118–25. doi:10.1359/jbmr.2001.16.11.2118. PMID 11697809. S2CID 28216610.
- ^ Dimaraki EV, Symons KV, Barkan AL (2004). “Raloxifene decreases serum IGF-I in male patients with active acromegaly”. Eur. J. Endocrinol. 150 (4): 481–7. doi:10.1530/eje.0.1500481. PMID 15080777.
- ^ Duschek EJ, Gooren LJ, Netelenbos C (2004). “Effects of raloxifene on gonadotrophins, sex hormones, bone turnover and lipids in healthy elderly men” (PDF). Eur. J. Endocrinol. 150 (4): 539–46. doi:10.1530/eje.0.1500539. PMID 15080785.
- ^ Smith MR, Fallon MA, Lee H, Finkelstein JS (2004). “Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial”. J. Clin. Endocrinol. Metab. 89 (8): 3841–6. doi:10.1210/jc.2003-032058. PMID 15292315.
- ^ Jump up to:a b Ho TH, Nunez-Nateras R, Hou YX, Bryce AH, Northfelt DW, Dueck AC, Wong B, Stanton ML, Joseph RW, Castle EP (2017). “A Study of Combination Bicalutamide and Raloxifene for Patients With Castration-Resistant Prostate Cancer”. Clin Genitourin Cancer. 15 (2): 196–202.e1. doi:10.1016/j.clgc.2016.08.026. PMID 27771244. S2CID 19043552.
- ^ Khodaie-Ardakani MR, Khosravi M, Zarinfard R, Nejati S, Mohsenian A, Tabrizi M, Akhondzadeh S (2015). “A Placebo-Controlled Study of Raloxifene Added to Risperidone in Men with Chronic Schizophrenia”. Acta Med Iran. 53 (6): 337–45. PMID 26069170.
- ^ Weickert TW, Weinberg D, Lenroot R, Catts SV, Wells R, Vercammen A, O’Donnell M, Galletly C, Liu D, Balzan R, Short B, Pellen D, Curtis J, Carr VJ, Kulkarni J, Schofield PR, Weickert CS (2015). “Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia”. Mol. Psychiatry. 20 (6): 685–94. doi:10.1038/mp.2015.11. PMC 4444978. PMID 25980345.
- ^ Jump up to:a b Fujimura, Tetsuya; Takayama, Kenichi; Takahashi, Satoru; Inoue, Satoshi (2018). “Estrogen and Androgen Blockade for Advanced Prostate Cancer in the Era of Precision Medicine”. Cancers. 10 (2): 29. doi:10.3390/cancers10020029. ISSN 2072-6694. PMC 5836061. PMID 29360794.
- ^ Jump up to:a b c Wang Q, Dong X, Wang Y, Li X (2017). “Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a meta-analysis of randomized controlled trials”. Arch Womens Ment Health. 21 (1): 31–41. doi:10.1007/s00737-017-0773-2. PMID 28849318. S2CID 4524617.
- ^ Carneiro AL, de Cassia de Maio Dardes R, Haidar MA (July 2012). “Estrogens plus raloxifene on endometrial safety and menopausal symptoms–semisystematic review”. Menopause. 19 (7): 830–4. doi:10.1097/gme.0b013e31824a74ce. PMID 22549172. S2CID 196380398.
- ^ Nordt CA, DiVasta AD (2008). “Gynecomastia in adolescents”. Curr. Opin. Pediatr. 20 (4): 375–82. doi:10.1097/MOP.0b013e328306a07c. PMID 18622190. S2CID 205834072.
- ^ Leung KC, Leung AC (2017). “Gynecomastia in Infants, Children, and Adolescents”. Recent Pat Endocr Metab Immune Drug Discov. 10 (2): 127–137. doi:10.2174/1872214811666170301124033. PMID 28260521.
- ^ Lawrence SE, Faught KA, Vethamuthu J, Lawson ML (July 2004). “Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia”. J. Pediatr. 145 (1): 71–6. doi:10.1016/j.jpeds.2004.03.057. PMID 15238910.
- ^ Kanakis, G. A.; Nordkap, L.; Bang, A. K.; Calogero, A. E.; Bártfai, G.; Corona, G.; Forti, G.; Toppari, J.; Goulis, D. G.; Jørgensen, N. (2019). “EAA clinical practice guidelines—gynecomastia evaluation and management”. Andrology. 7 (6): 778–793. doi:10.1111/andr.12636. ISSN 2047-2919. PMID 31099174.
- ^ Sugiyama, Nobuhiro; Barros, Rodrigo P.A.; Warner, Margaret; Gustafsson, Jan-Åke (2010). “ERβ: recent understanding of estrogen signaling”. Trends in Endocrinology & Metabolism. 21 (9): 545–552. doi:10.1016/j.tem.2010.05.001. ISSN 1043-2760. PMID 20646931. S2CID 43001363.
Further reading
- Barrett-Connor E (2001). “Raloxifene: risks and benefits”. Ann N Y Acad Sci. 949 (1): 295–303. Bibcode:2001NYASA.949..295B. doi:10.1111/j.1749-6632.2001.tb04036.x. PMID 11795366. S2CID 41412601.
- Heringa M (2003). “Review on raloxifene: profile of a selective estrogen receptor modulator”. Int J Clin Pharmacol Ther. 41 (8): 331–45. doi:10.5414/cpp41331. PMID 12940590.
- Sporn MB, Dowsett SA, Mershon J, Bryant HU (2004). “Role of raloxifene in breast cancer prevention in postmenopausal women: clinical evidence and potential mechanisms of action”. Clin Ther. 26 (6): 830–40. doi:10.1016/s0149-2918(04)90127-0. PMID 15262454.
- Vogel VG (2009). “The NSABP Study of Tamoxifen and Raloxifene (STAR) trial”. Expert Rev Anticancer Ther. 9 (1): 51–60. doi:10.1586/14737140.9.1.51. PMC 2785111. PMID 19105706.
- Wickerham DL, Costantino JP, Vogel VG, Cronin WM, Cecchini RS, Ford LG, Wolmark N (2009). “The use of tamoxifen and raloxifene for the prevention of breast cancer”. Recent Results Cancer Res. Recent Results in Cancer Research. 181: 113–9. doi:10.1007/978-3-540-69297-3_12. ISBN 978-3-540-69296-6. PMC 5110043. PMID 19213563.
- Vogel VG (2011). “Update on raloxifene: role in reducing the risk of invasive breast cancer in postmenopausal women”. Breast Cancer: Targets and Therapy. 3: 127–37. doi:10.2147/BCTT.S11288. PMC 3846694. PMID 24367182.
- Yang ZD, Yu J, Zhang Q (2013). “Effects of raloxifene on cognition, mental health, sleep and sexual function in menopausal women: a systematic review of randomized controlled trials”. Maturitas. 75 (4): 341–8. doi:10.1016/j.maturitas.2013.05.010. PMID 23764354.
External links
- “Raloxifene”. Drug Information Portal. U.S. National Library of Medicine.
///////Keoxifene hydrochloride, Raloxifene hydrochloride, LY-139481, LY 156758, Optruma, Loxifen, Evista
TUCATINIB
Tucatinib
ツカチニブ;
N6-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-N4-(3-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}phenyl)quinazoline-4,6-diamine
| Formula | C26H24N8O2 |
|---|---|
| CAS | 937263-43-9 |
| Mol weight | 480.5212 |
To treat advanced unresectable or metastatic HER2-positive breast cancer
Drug Trials Snapshot
FDA APPROVED 4/17/2020 Tukysa
- ARRY 380
- ARRY-380
- ONT 380
- ONT-380
Tucatinib (INN),[1] sold under the brand name Tukysa, is a small molecule inhibitor of HER2 for the treatment of HER2-positive breast cancer.[2][3] It was developed by Array BioPharma and licensed to Cascadian Therapeutics (formerly Oncothyreon, subsequently part of Seattle Genetics).[4]
Common side effects are diarrhea, palmar-plantar erythrodysesthesia (burning or tingling discomfort in the hands and feet), nausea, fatigue, hepatotoxicity (liver damage), vomiting, stomatitis (inflammation of the mouth and lips), decreased appetite, abdominal pain, headache, anemia and rash.[5][6] Pregnant or breastfeeding women should not take Tucatinib because it may cause harm to a developing fetus or newborn baby.[5]
Tucatinib was approved for medical use in Australia in August 2020.[7]
Medical uses
Tucatinib is a kinase inhibitor indicated in combination with trastuzumab and capecitabine for treatment of adults with advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.[8]
Clinical trials
Two early stage clinical trials have reported encouraging results, both of which had options to enroll subjects with central nervous system (CNS) metastases.[2][9][10][11][12][10] HER2CLIMB is a Phase 2 randomized, double-blinded, placebo-controlled study of tucatinib in combination with trastuzumab and capecitabine in patients with pretreated, unresectable locally advanced or metastatic HER2-positive breast cancer.[13]
History
In April 2020, the U.S. Food and Drug Administration (FDA) approved tucatinib in combination with chemotherapy (trastuzumab and capecitabine) for the treatment of adults with advanced forms of HER2-positive breast cancer that can’t be removed with surgery, or has spread to other parts of the body, including the brain, and who have received one or more prior treatments.[5][6][14]
The FDA collaborated with the Australian Therapeutic Goods Administration (TGA), Health Canada, Health Sciences Authority (HSA, Singapore) and Swissmedic (SMC, Switzerland) on the review.[5] This was the first Project Orbis partnership between the FDA, HSA and Swissmedic.[5] As of 17 April 2020, the application is still under review at the other agencies.[5]
Tucatinib is a kinase inhibitor meaning it blocks a type of enzyme (kinase) and helps prevent the cancer cells from growing.[5] Tucatinib is approved for treatment after adults have taken one or more anti-HER2-based regimens in the metastatic setting.[5] The FDA approved tucatinib based on the results of the HER2CLIMB trial (NCT02614794) enrolling 612 subjects who had HER2-positive advanced unresectable or metastatic breast cancer and had prior treatment with trastuzumab, pertuzumab and ado-trastuzumab emtansine (T-DM1).[5][6] Subjects with previously treated and stable brain metastases, as well as those with previously treated and growing or untreated brain metastases, were eligible for the clinical trial, and 48% of enrolled subjects had brain metastases at the start of the trial.[5]
Subjects received either tucatinib 300 mg twice daily plus trastuzumab and capecitabine (tucatinib arm, n=410) or placebo plus trastuzumab and capecitabine (control arm, n=202).[6] The primary endpoint was progression-free survival (PFS), or the amount of time when there was no growth of the tumor, assessed by a blinded independent central review, evaluated in the initial 480 randomized patients.[5][6] The median PFS in subjects who received tucatinib, trastuzumab, and capecitabine was 7.8 months (95% CI: 7.5, 9.6) compared to 5.6 months (95% CI: 4.2, 7.1) in those subjects who received placebo, trastuzumab, and capecitabine (HR 0.54; 95% CI: 0.42, 0.71; p<0.00001).[5][6] Overall survival and PFS in subjects with brain metastases at baseline were key secondary endpoints.[5] The median overall survival in subjects who received tucatinib, trastuzumab, and capecitabine was 21.9 months (95% CI: 18.3, 31.0) compared to 17.4 months (95% CI: 13.6, 19.9) in subjects who received placebo, trastuzumab, and capecitabine (HR: 0.66; 95% CI: 0.50, 0.87; p=0.00480).[5][6] The median PFS in subjects with brain metastases at baseline who received tucatinib, trastuzumab and capecitabine was 7.6 months (95% CI: 6.2, 9.5) compared to 5.4 months (95% CI: 4.1, 5.7) in subjects who received placebo, trastuzumab and capecitabine (HR: 0.48; 0.34, 0.69; p<0.00001).[5][6]
The FDA granted the application for tucatinib priority review, breakthrough therapy, fast track, and orphan drug designations.[5][6][15] The FDA granted approval of Tukysa to Seattle Genetics, Inc.[5]
SYN
Recently, the Mao team reported a new route for the efficient synthesis of Tucatinib.
The results were published on Synthesis (DOI: 10.1055/s-0037-1610706).
Previously, the synthesis report route of Tucatinib was published by Array BioPharma in a patent document (WO 2007059257, 2007). The synthetic route reported in the patent is shown in the figure below:
Using 4-nitro-2-cyanoaniline as the raw material, the first step is to condense with DMF-DMA to prepare imine 3 (yield 87%); subsequent catalytic hydrogenation of palladium on carbon to reduce the nitro group to obtain the amine 4 (90% yield); followed by 1,1&39;-thiocarbonyldiimidazole (TCDI) and The amino alcohol undergoes condensation to prepare the thiourea derivative 5 (yield is only 34%); further with the intermediate 6 to undergo ring-closure reaction to obtain the key intermediate 7 (yield 62%) ; Finally, under the action of p-toluenesulfonic acid, intramolecular dehydration and ring closure to form oxazoline, complete the synthesis of the target compound tucatinib.
Reverse synthesis analysis
The author broke the bond of Tucatinib from two points a and b and split them into three fragments. : Thioether oxazoline 17, nitrobenzene 3 and the key fragment of the original research route 6.
Preparation of key fragment 6
4-nitro-3-methylphenol 8 as a starting point The material, with pyridine derivative 9, undergoes aromatic affinity substitution reaction to prepare aryl ether 10 (yield 64%); then it is condensed with DMF-DMA, and then treated with hydroxylamine hydrochloride. The step yield was 81% to obtain the oxime derivative 12; subsequently, the ring was closed under the treatment of trifluoroacetic anhydride, the mostAfter palladium-catalyzed hydrogenation to reduce the nitro group, the key aniline triazole 6 was successfully prepared, with a total yield of 32.8%.
aromatic ring skeleton construction
fragment 3 was synthesized according to the method reported in the literature. The estimated aromatic ring fragment was then constructed with the aniline triazole 6 prepared above:
Compound 6 and fragment 3 were cyclized in acetic acid , 14 was successfully prepared, and finally the nitro group was reduced by palladium-catalyzed hydrogenation to obtain the key arylamine 15 with a two-step yield of 76.4%.
Fragment 17 and Tucatinib synthesis
amino alcohol and 1,1&39;-thiocarbonyl diimidazole (TCDI) The ring is closed to obtain 16, which is then treated with methyl trifluoromethanesulfonate to obtain oxazoline 17, with a total yield of 67.23% in the two steps.
oxazoline17 and arylamine 15 in the presence of cesium carbonate, heated in DMF for 20 hours, and finally completed the synthesis of Tucatinib with a yield of 76%.
Comparison of the new route and the patent route
The yield of the last step of the patent is unknown, starting with key intermediates 3 and 6, total income The rate is less than 19%.
The overview of the new route is as follows:
Correspondingly, starting from the intermediate 3 and 6, the total yield of the new route There is a significant improvement to 39%. Moreover, the purity of the product and other aspects also meet the requirements of API.
Comment
Tucatinib (Tukysa) Tucatinib/Tucatinib as a small-molecule oral tyrosine kinase (TKI) inhibitor for HER2 Positive breast cancer has highly specific targeting selectivity. The study of the new synthetic route
effectively improves the production efficiency in terms of ensuring the purity of the compound, and the raw materials used are relatively simple and easy to obtain.
Medicinal chemists have completed the research and development and synthesis of compounds (from 0 to 1), while process chemists have optimized the synthetic routes and processes, so that the compounds can be prepared more simply, efficiently, economically and environmentally.
SYN PATENT
CN 111825604
PAPER
Synthesis (2019), 51(13), 2660-2664
Abstract
A new and improved synthetic route to tucatinib is described that involves three key intermediates. The first of these, 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, was prepared on a 100 g scale in 33% yield over five steps and 99% purity. Next, N 4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)quinazoline-4,6-diamine was isolated in 67% yield over three steps and >99% purity. Then, 4,4-dimethyl-2-(methylthio)-4,5-dihydrooxazole trifluoromethanesulfonate was prepared under mild conditions in 67% yield over two steps. Finally, tucatinib was obtained in 17% yield over nine steps and in >99% purity (HPLC). Purification methods used to isolate the product and the intermediates involved in the route are also reported.
References
- ^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75”. WHO Drug Information. 30 (1): 161. hdl:10665/331046.
- ^ Jump up to:a b “ONT-380 Active Against CNS Mets in HER2-Positive Breast Cancer”. Cancer Network. 15 December 2015. Retrieved 17 April 2020.
- ^ Martin M, López-Tarruella S (October 2018). “Emerging Therapeutic Options for HER2-Positive Breast Cancer”. American Society of Clinical Oncology Educational Book. American Society of Clinical Oncology. Annual Meeting. 35 (36): e64–70. doi:10.1200/EDBK_159167. PMID 27249772.
- ^ “Tucatinib” (PDF). Statement on a Nonproprietary Name Adopted by the USAN Council.
- ^ Jump up to:a b c d e f g h i j k l m n o p q “FDA Approves First New Drug Under International Collaboration, A Treatment Option for Patients with HER2-Positive Metastatic Breast Cancer”. U.S. Food and Drug Administration (FDA) (Press release). 17 April 2020. Retrieved 17 April 2020. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b c d e f g h i “FDA approves tucatinib for patients with HER2-positive metastatic brea”. U.S. Food and Drug Administration (FDA). 17 April 2020. Retrieved 20 April 2020. This article incorporates text from this source, which is in the public domain.
- ^ “Tukysa”. Therapeutic Goods Administration (TGA). 21 August 2020. Retrieved 22 September 2020.
- ^ “Tukysa (tucatinib) tablets, for oral use” (PDF). Seattle Genetics. Retrieved 17 April2020.
- ^ “Oncothyreon Inc. Announces Data For ONT-380 In HER2-Positive Breast Cancer Patients With And Without Brain Metastases At The San Antonio Breast Cancer Symposium”. BioSpace (Press release). 9 December 2015. Retrieved 18 April 2020.
- ^ Jump up to:a b Borges VF, Ferrario C, Aucoin N, Falkson CI, Khan QJ, Krop IE, et al. “Efficacy results of a phase 1b study of ONT-380, a CNS-penetrant TKI, in combination with T-DM1 in HER2+ metastatic breast cancer (MBC), including patients (pts) with brain metastases”. Journal of Clinical Oncology. 2016 ASCO Annual Meeting.
- ^ “SABCS15: Promising phase 1 results lead to phase 2 for ONT-380 in HER2+ breast cancer”. Colorado Cancer Blogs. Retrieved 10 June 2016.
- ^ “A Study of Tucatinib (ONT-380) Combined With Capecitabine and/or Trastuzumab in Patients With HER2+ Metastatic Breast Cancer”. ClinicalTrials.gov. 31 December 2013. Retrieved 18 April 2020.
- ^ “A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer (HER2CLIMB)”. ClinicalTrials.gov. Retrieved 18 April 2020.
- ^ “Tukysa: FDA-Approved Drugs”. U.S. Food and Drug Administration (FDA). Retrieved 20 April 2020.
- ^ “Tucatinib Orphan Drug Designation and Approval”. U.S. Food and Drug Administration(FDA). 24 December 1999. Retrieved 20 April 2020.
External links
- “Tucatinib”. Drug Information Portal. U.S. National Library of Medicine.
- “Tucatinib”. National Cancer Institute.
- Clinical trial number NCT02614794 for “A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer (HER2CLIMB)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Tukysa |
| Other names | ONT-380, ARRY-380 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a620032 |
| License data | US DailyMed: Tucatinib |
| Pregnancy category | AU: DUS: N (Not classified yet) |
| Routes of administration | By mouth |
| ATC code | None |
| Legal status | |
| Legal status | AU: S4 (Prescription only)US: ℞-only |
| Identifiers | |
| CAS Number | 937263-43-9 |
| PubChem CID | 51039094 |
| DrugBank | DB11652 |
| ChemSpider | 34995558 |
| UNII | 234248D0HH |
| KEGG | D11141 |
| ChEMBL | ChEMBL3989868 |
| Chemical and physical data | |
| Formula | C26H24N8O2 |
| Molar mass | 480.532 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES[hide]CC1=C(C=CC(=C1)NC2=NC=NC3=C2C=C(C=C3)NC4=NC(CO4)(C)C)OC5=CC6=NC=NN6C=C5 | |
| InChI[hide]InChI=1S/C26H24N8O2/c1-16-10-17(5-7-22(16)36-19-8-9-34-23(12-19)28-15-30-34)31-24-20-11-18(4-6-21(20)27-14-29-24)32-25-33-26(2,3)13-35-25/h4-12,14-15H,13H2,1-3H3,(H,32,33)(H,27,29,31)Key:SDEAXTCZPQIFQM-UHFFFAOYSA-N |
| NAME | DOSAGE | STRENGTH | ROUTE | LABELLER | MARKETING START | MARKETING END | ||
|---|---|---|---|---|---|---|---|---|
| Tukysa | Tablet | 150 mg/1 | Oral | Seattle Genetics, Inc. | 2020-04-17 | Not applicable | | |
| Tukysa | Tablet | 150 mg | Oral | Seattle Genetics, Inc. | 2020-08-27 | Not applicable |  | |
| Tukysa | Tablet | 50 mg/1 | Oral | Seattle Genetics, Inc. | 2020-04-17 | Not applicable | | |
| Tukysa | Tablet | 50 mg | Oral | Seattle Genetics, Inc. | 2020-10-08 | Not applicable | |
Showing 1 to 4 of 4 entries
///////tucatinib, FDA 2020, TUKSYA, 2020 APROVALS, ARRY 380, ONT 380, ツカチニブ ,
Ripretinib
Ripretinib
リプレチニブ;
| Formula | C24H21BrFN5O2 |
|---|---|
| CAS | 1442472-39-0 |
| Mol weight | 510.3582 |
Antineoplastic, Receptor tyrosine kinase inhibitor
US FDA APPROVED 2020/5/15 QUINLOCK
| NAME | DOSAGE | STRENGTH | ROUTE | LABELLER | MARKETING START | MARKETING END | ||
|---|---|---|---|---|---|---|---|---|
| Qinlock | Tablet | 50 mg | Oral | Deciphera Pharmaceuticals. Llc | Not applicable | Not applicable | | |
| Qinlock | Tablet | 50 mg/1 | Oral | Deciphera Pharmaceuticals, LLC | 2020-05-15 | Not applicable | |
SYN
Ripretinib, sold under the brand name Qinlock, is a medication for the treatment of adults with advanced gastrointestinal stromal tumor (GIST), a type of tumor that originates in the gastrointestinal tract.[3] It is taken by mouth.[3] Ripretinib is a kinase inhibitor, meaning it works by blocking a type of enzyme called a kinase, which helps keep the cancer cells from growing.[3]
The most common side effects include alopecia (hair loss), fatigue, nausea, abdominal pain, constipation, myalgia (muscle pain), diarrhea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (a skin reaction in the palms and soles) and vomiting.[3][4] Alopecia is a unique side effect to ripretinib, which is not seen with other tyrosine kinase inhibitors used to treat GISTs.
Ripretinib was approved for medical use in the United States in May 2020,[3] and in Australia in July 2020.[1] Ripretinib is the first new drug specifically approved in the United States as a fourth-line treatment for advanced gastrointestinal stromal tumor (GIST).
Medical uses
Ripretinib is indicated for the treatment of adults with advanced gastrointestinal stromal tumor (GIST), a type of tumor that originates in the gastrointestinal tract, who have received prior treatment with three or more kinase inhibitor therapies, including imatinib.[3] GIST is type of stomach, bowel, or esophagus tumor.[4]
Adverse effects
The most common side effects include alopecia (hair loss), fatigue, nausea, abdominal pain, constipation, myalgia (muscle pain), diarrhea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (a skin reaction in the palms and soles) and vomiting.[3][4]
Ripretinib can also cause serious side effects including skin cancer, hypertension (high blood pressure) and cardiac dysfunction manifested as ejection fraction decrease (when the muscle of the left ventricle of the heart is not pumping as well as normal).[3][4]
Ripretinib may cause harm to a developing fetus or a newborn baby.[3][4]
History
Ripretinib was approved for medical use in the United States in May 2020.[3][5][6][4]
The approval of ripretinib was based on the results of an international, multi-center, randomized, double-blind, placebo-controlled clinical trial (INVICTUS/NCT03353753) that enrolled 129 participants with advanced gastrointestinal stromal tumor (GIST) who had received prior treatment with imatinib, sunitinib, and regorafenib.[3][7] The trial compared participants who were randomized to receive ripretinib to participants who were randomized to receive placebo, to determine whether progression free survival (PFS) – the time from initial treatment in the clinical trial to growth of the cancer or death – was longer in the ripretinib group compared to the placebo group.[3] During treatment in the trial, participants received ripretinib 150 mg or placebo once a day in 28-day cycles, repeated until tumor growth was found (disease progression), or the participant experienced intolerable side effects.[3][7] After disease progression, participants who were randomized to placebo were given the option of switching to ripretinib.[3][7] The trial was conducted at 29 sites in the United States, Australia, Belgium, Canada, France, Germany, Italy, the Netherlands, Poland, Singapore, Spain, and the United Kingdom.[4]
The major efficacy outcome measure was progression-free survival (PFS) based on assessment by blinded independent central review (BICR) using modified RECIST 1.1 in which lymph nodes and bone lesions were not target lesions and a progressively growing new tumor nodule within a pre-existing tumor mass must meet specific criteria to be considered unequivocal evidence of progression.[7] Additional efficacy outcome measures included overall response rate (ORR) by BICR and overall survival (OS).[7] The trial demonstrated a statistically significant improvement in PFS for participants in the ripretinib arm compared with those in the placebo arm (HR 0.15; 95% CI: 0.09, 0.25; p<0.0001).[7]
The U.S. Food and Drug Administration (FDA) granted the application for ripretinib priority review and fast track designations, as well as breakthrough therapy designation and orphan drug designation.[3][8] The FDA granted approval of Qinlock to Deciphera Pharmaceuticals, Inc.[3]
The FDA collaborated with the Australian Therapeutic Goods Administration (TGA) and Health Canada on the review of the application as part of Project Orbis.[3][7] The FDA approved ripretinib three months ahead of schedule.[3][7] As of May 2020, the review of the applications was ongoing for the Australian TGA and for Health Canada.[3][7]
Names
Ripretinib is the International nonproprietary name (INN) and the United States Adopted Name (USAN).[9][10]
| PATENT NUMBER | PEDIATRIC EXTENSION | APPROVED | EXPIRES (ESTIMATED) | |
|---|---|---|---|---|
| US8940756 | No | 2012-06-07 | 2032-06-07 | |
| US8461179 | No | 2012-06-07 | 2032-06-07 | |
| US8188113 | No | 2010-07-27 | 2030-07-27 | |
PATENT
US 8461179
PATENT
WO 2013184119
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013184119
[0125] Example A13: A mixture of Example C5 (2.191 g, 7.94 mmol), Example Bl (1.538 g, 8.33 mmol) and KF on alumina (40 wt%) (9.22 g, 63.5 mmol) in DMA (40 mL) was sonicated for 2 h. The mixture was filtered through a shallow bed of silica gel and rinsed well with EtOAc. The filtrate was washed with satd. NaHC03 (lx), 5% LiCl (2x), then brine (lx), dried (MgS04), and concentrated to dryness to afford 3-(5-amino-2-bromo-4-fluorophenyl)-7-chloro-l -ethyl- l,6-naphthyridin-2(lH)-one (2.793 g, 89% yield) as a brown solid. 1H NMR (400 MHz, DMSO-<¾): δ 8.77 (s, 1 H), 8.00 (s, 1 H), 7.74 (s, 1 H), 7.37 (d, 1 H), 6.77 (d, 1 H), 5.45 (s, 2 H), 4.27 (q, 2 H), 1.20 (t, 3 H); MS (ESI) m z: 398.0 [M+H]+.
[0126] Example A14: A suspension of Example A13 (1.50 g, 3.78 mmol) in dioxane (15 mL) was treated with methylamine (40% in water) (26.4 mL, 303 mmol) in a pressure tube and heated to 100°C overnight. The mixture was cooled to RT, treated with a large amount of brine, then diluted with EtOAc until all of the solids dissolved. The layers were separated, the aqueous layer extracted with additional EtOAc (lx) and the combined organics were washed with satd. NaHC03 (lx), dried (MgS04) and concentrated to dryness. The resulting solid was suspended in MeCN/H20, frozen and lyophilized to afford 3-(5-amino-2-bromo-4-fluorophenyl)-l-ethyl-7-(methylamino)-l,6-naphthyridin-2(lH)-one (1.32g, 89% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-<¾): δ 8.37 (s, 1 H), 7.62 (s, 1 H), 7.30 (d, 1 H), 6.99 (q, 1 H), 6.73 (d, 1 H), 6.21 (s, 1 H), 5.33 (s, 2 H), 4.11 (q, 2 H), 2.84 (d, 3 H), 1.19 (t, 3 H); MS (ESI) m/z: 393.0 [M+H]+.
[0263] Example 31: A mixture of Example A14 (0.120 g, 0.307 mmol) and TEA (0.043 mL, 0.307 mmol) in THF (3.0 mL) was treated with phenyl isocyanate (0.040 g, 0.337 mmol) and stirred at RT for 4 h. Over the course of the next 4 days the mixture was treated with additional phenyl isocyanate (0.056 mL) and stirred at RT. The resulting solid was filtered, rinsed with THF, then triturated with MeOH to afford l-(4-bromo-5-(l-ethyl-7-(methylamino)-2-oxo- 1 ,2-dihydro- 1 ,6-naphthyridin-3 -yl)-2-fluorophenyl)-3 -phenylurea (101 mg, 64.5% yield) as a bright white solid. 1H NMR (400 MHz, DMSO-<¾): δ 9.09 (s, 1 H), 8.68 (s, 1 H), 8.41 (s, 1 H), 8.17 (d, 1 H), 7.70 (s, 1 H), 7.65 (d, 1 H), 7.41 (d, 2 H), 7.27 (m, 2 H), 7.03 (m, 1 H), 6.96 (t, 1 H), 6.23 (s, 1 H), 4.13 (q, 2 H), 2.86 (d, 3 H), 1.20 (t, 3 H); MS (ESI) m/z: 510.1 [M+H]+.
References
- ^ Jump up to:a b c “Qinlock Australian Prescription Medicine Decision Summary”. Therapeutic Goods Administration (TGA). 21 July 2020. Retrieved 17 August 2020.
- ^ “Ripretinib (Qinlock) Use During Pregnancy”. Drugs.com. 10 August 2020. Retrieved 17 August 2020.
- ^ Jump up to:a b c d e f g h i j k l m n o p q r s t “FDA Approves First Drug for Fourth-Line Treatment of Advanced Gastrointestinal Stromal Tumors”. U.S. Food and Drug Administration (FDA) (Press release). 15 May 2020. Retrieved 15 May 2020. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b c d e f g “Drug Trial Snapshot: Qinlock”. U.S. Food and Drug Administration (FDA). 15 May 2020. Retrieved 2 June 2020. This article incorporates text from this source, which is in the public domain.
- ^ “FDA Grants Full Approval of Deciphera Pharmaceuticals’ Qinlock (ripretinib) for the Treatment of Fourth-Line Gastrointestinal Stromal Tumor”. Deciphera Pharmaceuticals, Inc. (Press release). 15 May 2020. Retrieved 15 May 2020.
- ^ “Qinlock: FDA-Approved Drugs”. U.S. Food and Drug Administration (FDA). Retrieved 15 May 2020.
- ^ Jump up to:a b c d e f g h i “FDA approves ripretinib for advanced gastrointestinal stromal tumor”. U.S. Food and Drug Administration (FDA). 15 May 2020. Retrieved 18 May 2020. This article incorporates text from this source, which is in the public domain.
- ^ “Ripretinib Orphan Drug Designation and Approval”. U.S. Food and Drug Administration (FDA). 2 October 2014. Retrieved 15 May 2020.
- ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81”. WHO Drug Information. 33 (1): 106. hdl:10665/330896. License: CC BY-NC-SA 3.0 IGO.
- ^ “Ripretinib” (PDF). United States Adopted Name (USAN) Drug Finder. Retrieved 17 May 2020.
Further reading
- Schneeweiss M, Peter B, Bibi S, et al. (May 2018). “The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis”. Haematologica. 103 (5): 799–809. doi:10.3324/haematol.2017.179895. PMC 5927976. PMID 29439183.
External links
- “Ripretinib”. Drug Information Portal. U.S. National Library of Medicine.
- “Ripretinib”. NCI Drug Dictionary. National Cancer Institute.
- “Ripretinib”. National Cancer Institute.
- Clinical trial number NCT03353753 for “Phase 3 Study of DCC-2618 vs Placebo in Advanced GIST Patients Who Have Been Treated With Prior Anticancer Therapies (invictus)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Pronunciation | rip re’ ti nib |
| Trade names | Qinlock |
| Other names | DCC-2618 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a620035 |
| License data | US DailyMed: Ripretinib |
| Pregnancy category | AU: D[1]US: N (Not classified yet)[2]Use should be avoided |
| Routes of administration | By mouth |
| ATC code | None |
| Legal status | |
| Legal status | AU: S4 (Prescription only) [1]US: ℞-only [3] |
| Identifiers | |
| IUPAC name[show] | |
| CAS Number | 1442472-39-0 |
| PubChem CID | 71584930 |
| DrugBank | DB14840 |
| ChemSpider | 67886378 |
| UNII | 9XW757O13D |
| KEGG | D11353 |
| ChEMBL | ChEMBL4216467 |
| Chemical and physical data | |
| Formula | C24H21BrFN5O2 |
| Molar mass | 510.367 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES[hide]CCN1C(=O)C(=CC2=C1C=C(NC)N=C2)C1=C(Br)C=C(F)C(NC(=O)NC2=CC=CC=C2)=C1 | |
| InChI[hide]InChI=1S/C24H21BrFN5O2/c1-3-31-21-12-22(27-2)28-13-14(21)9-17(23(31)32)16-10-20(19(26)11-18(16)25)30-24(33)29-15-7-5-4-6-8-15/h4-13H,3H2,1-2H3,(H,27,28)(H2,29,30,33)Key:CEFJVGZHQAGLHS-UHFFFAOYSA-N |
////////////Ripretinib, QINLOCK, リプレチニブ , 2020 APPROVALS, FDA 2020
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 
