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Etrasimod
Etrasimod
- APD334
- C26H26F3NO3
- 457.493
1206123-37-6
2-[(3R)-7-{[4-cyclopentyl-3-(trifluoromethyl)phenyl]methoxy}-1H,2H,3H,4H-cyclopenta[b]indol-3-yl]acetic acid
| Etrasimod arginine | MXE5EMA09L | 1206123-97-8 | GVPVVOSNDUAUKM-BPGOJFKZSA-N |
Name: Etrasimod arginine
CAS#: 1206123-97-8 (arginine)
Chemical Formula: C32H40F3N5O5
Exact Mass: 631.30
Molecular Weight: 631.700
FDA APPROVED, To treat moderately to severely active ulcerative colitis in adults,
| 10/12/2023 |
Etrasimod, sold under the brand name Velsipity, is a medication that is used for the treatment of ulcerative colitis (UC).[1] It is a selective sphingosine-1-phosphate (S1P) receptor modulator that modifies the activity of the immune system.[1] It is taken by mouth.[1]
Etrasimod was discovered by Arena Pharmaceuticals, with subsequent development by Pfizer.[2]
Etrasimod is a synthetic next-generation selective Sphingosine 1-phosphate (S1P) receptor modulator that targets the S1P1,4,5 with no detectable activity on S1P2 and S1P3 receptors. S1P receptors are membrane-derived lysophospholipid signaling molecules that are involved in the sequestration of circulating peripheral lymphocytes in lymph nodes.1 Therefore, S1P receptor modulators like etrasimod were investigated in treating immune-mediated diseases like ulcerative colitis where a high level of inflammatory T cells is present in the gastrointestinal tract, thus causing diffuse mucosal inflammation.1 In fact, it has been observed that antigen-activated T cells within peripheral lymphoid organs can transiently downregulate S1P receptor levels to facilitate immune cells trafficking into the intestinal mucosa.2
Etrasimod was approved on October 13, 2023, by the FDA under the brand name VELSIPITY for the treatment of adults with moderately to severely active ulcerative colitis. This approval was based on favorable results obtained from Pfizer’s Elevate UC Phase III registrational program, consisting of the Elevate UC 52 and Elevate UC 12 clinical trials, that investigates the efficacy of a 2-mg daily dose regimen of etrasimod, with a 32% and 26% remission rate observed in UC 52 and UC 12 trials respectively.4
Medical uses
Etrasimod is used for the treatment of moderate to severe ulcerative colitis.[1]
Mechanism of action
It works by causing T cells to become trapped in the lymph nodes, preventing them from entering the bloodstream, from where they would travel to other tissues in the body and mediate inflammation.[3][4][5][6][7][8]
Society and culture
Legal status
Velsipity was approved by the US Food and Drug Administration (FDA) in October 2023.[1][9][10]
Names
Etrasimod is the international nonproprietary name.[11]
SYN
ACS Med. Chem. Lett.2014, 5, 12, 1313–1317
Publication Date:November 4, 2014
https://doi.org/10.1021/ml500389m
APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.
APD334 is the second eluting enantiomer (most retained) with a retention time of 48.4 minutes. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.75 (m, 4H), 1.79-1.92 (m, 2H), 1.95-2.16 (m, 3H), 2.39 (dd, J = 16.0, 8.8 Hz, 1H), 2.61-2.83 (m, 4H), 3.23-3.34 (m, 1H), 3.45-3.56 (m, 1H), 5.14 (s, 2H), 6.74 (dd, J = 8.7, 2.4 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.74 (s, 1H), 10.50 (s, 1H), 12.24 (bs, 1H). 13C APT NMR (100 MHz, DMSO-d6): δ up (C, CH2): 23.1, 25.5, 35.5, 35.6, 68.6, 117.0, 124.7 (q, J = 273 Hz), 124.2, 126.8 (q, J = 28 Hz), 128.7, 136.1, 136.2, 144.6, 147.0, 151.9, 173.4; down (CH, CH3): 35.0, 40.5, 102.1, 110.0, 112.4, 124.1 (q, J = 5.7 Hz), 128.4, 131.7. 19F NMR (400 MHz, DMSO-d6) δ ppm -57.4. LCMS (ESI+): calcd for C26H27F3NO3+ [M+H] 458.19; found, 458.4. HRMS (ESI-): calcd for C26H25F3NO3- [M-H] 456.1792; found, 456.1776.
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| Skeletal formula of etrasimod | |
| Clinical data | |
|---|---|
| Trade names | Velsipity |
| Other names | APD334, APD-334 |
| License data | US DailyMed: Etrasimod |
| Routes of administration | By mouth |
| Drug class | Sphingosine-1-phosphate receptor modulator |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Pharmacokinetic data | |
| Protein binding | 97.9%[medical citation needed] |
| Metabolism | Liver (CYP2C8, 2C9, 3A4)[medical citation needed] |
| Elimination half-life | 30 hours[medical citation needed] |
| Excretion | Feces (82%), kidneys (5%)[medical citation needed] |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1206123-37-6as arginine: 1206123-97-8 |
| PubChem CID | 44623998 |
| DrugBank | DB14766as arginine: DBSALT003430 |
| ChemSpider | 52084233as arginine: 57643656 |
| UNII | 6WH8495MMHas arginine: MXE5EMA09L |
| KEGG | D10930as arginine: D10931 |
| ChEMBL | ChEMBL3358920 |
| Chemical and physical data | |
| Formula | C26H26F3NO3 |
| Molar mass | 457.493 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
References
- ^ Jump up to:a b c d e f Pfizer (12 October 2023). “Velsipity (etrasimod) tablets, for oral use” (PDF). U.S. Food and Drug Administration (FDA). Retrieved 18 October 2023.
- ^ Bayer M (2 May 2023). “Pfizer tosses newly acquired meds out of the Arena”. Fierce Biotech. Retrieved 13 October 2023.
- ^ Atreya R, Neurath MF (April 2023). “The sphingosine-1-phosphate receptor agonist etrasimod in ulcerative colitis”. Lancet. 401 (10383): 1132–1133. doi:10.1016/S0140-6736(23)00228-3. PMID 36871570.
- ^ Sandborn WJ, Vermeire S, Peyrin-Biroulet L, Dubinsky MC, Panes J, Yarur A, et al. (April 2023). “Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies”. Lancet. 401 (10383): 1159–1171. doi:10.1016/S0140-6736(23)00061-2. PMID 36871574.
- ^ Dal Buono A, Gabbiadini R, Alfarone L, Solitano V, Repici A, Vetrano S, et al. (July 2022). “Sphingosine 1-Phosphate Modulation in Inflammatory Bowel Diseases: Keeping Lymphocytes Out of the Intestine”. Biomedicines. 10 (7). doi:10.3390/biomedicines10071735. PMC 9313037. PMID 35885040.
- ^ Argollo M, Furfaro F, Gilardi D, Roda G, Allocca M, Peyrin-Biroulet L, et al. (April 2020). “Modulation of sphingosine-1-phosphate in ulcerative colitis”. Expert Opin Biol Ther. 20 (4): 413–420. doi:10.1080/14712598.2020.1732919. PMID 32093531.
- ^ Al-Shamma H, Lehmann-Bruinsma K, Carroll C, Solomon M, Komori HK, Peyrin-Biroulet L, et al. (June 2019). “The Selective Sphingosine 1-Phosphate Receptor Modulator Etrasimod Regulates Lymphocyte Trafficking and Alleviates Experimental Colitis”. J Pharmacol Exp Ther. 369 (3): 311–317. doi:10.1124/jpet.118.254268. PMID 30872391.
- ^ Peyrin-Biroulet L, Christopher R, Behan D, Lassen C (May 2017). “Modulation of sphingosine-1-phosphate in inflammatory bowel disease”. Autoimmun Rev. 16 (5): 495–503. doi:10.1016/j.autrev.2017.03.007. PMID 28279838.
- ^ Brooks M (13 October 2023). “FDA Approves New Drug for Ulcerative Colitis”. Medscape. Retrieved 13 October 2023.
- ^ https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/216956Orig1s000ltr.pdf
- ^ World Health Organization (2017). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 78”. WHO Drug Information. 31 (3). hdl:10665/330961.
/////////Etrasimod, APD334, Velsipity, FDA 2023, APPROVALS 2023
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Motixafortide
Motixafortide
- 4F-benzoyl-TN-14003
- BKT-140
- BKT140
- BL-8040
Protein Chemical FormulaC97H144FN33O19S2
Protein Average Weight2159.6 Da
UNIIDA9G065962CAS number664334-36-5>Motixafortide sequence RRXCYXKKPYRXCR
| Motixafortide acetate | 2639893-42-6 | GMUZYOKQKWMETH-AQDOTSTFSA-N |
fda approved,9/8/2023,
мотиксафортид[Russian]
موتيكسافورتيد[Arabic]
莫替福肽[Chinese]
Motixafortide is a peptide inhibitor of CXCR4 used to mobilize hematopoietic stem cells prior to collection and autologous transplantation in multiple myeloma patients.
To use with filgrastim (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma
Motixafortide, sold under the brand name Aphexda, is a medication used for the treatment of multiple myeloma.[1] Motixafortide is a hematopoietic stem cell mobilizer and a CXCR4 antagonist.[1] It is given by subcutaneous injection.[1]
Motixafortide was approved for medical use in the United States in September 2023.[2][3]
Motixafortide is a cyclic peptide hematopoietic stem cell mobilizer used to improve stem cell collection prior to autologous transplantation.3 Hematopoietic stem cell transplantation (HSCT) is commonly employed in the context of hematologic cancers – high-dose chemotherapy regimens destroy cancerous blood cells, which are then replaced via infusion of the patient’s own stem cells (i.e. an autologous transplant).4 Similar in mechanism to the previously approved plerixafor, motixafortide is an inhibitor of C-X-C Motif Chemokine Receptor 4 (CXCR4), a protein that helps to anchor stem cells to bone marrow matrix.3 When administered alongside filgrastim, another agent used to aid in stem cell collection, motixafortide enabled the collection of an adequate number of stem cells in ~92% of patients within two apheresis procedures, compared to ~26% of patients receiving only filgrastim.1
Motixafortide was approved by the FDA in September 2023, in combination with filgrastim, for use in stem cell mobilization prior to autologous stem cell transplant in patients with multiple myeloma.5 It has also been investigated alongside pembrolizumab for the treatment of pancreatic cancer.2
Medical uses
Motixafortide is indicated in combination with filgrastim, a granulocyte-colony stimulating factor (G-CSF), to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in people with multiple myeloma.[1][2]
Society and culture
Names
Motixafortide is the international nonproprietary name.[4]
| Clinical data | |
|---|---|
| Trade names | Aphexda |
| Other names | BL-8040 |
| License data | US DailyMed: Motixafortide |
| Routes of administration | Subcutaneous |
| Drug class | Antineoplastic |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| CAS Number | 664334-36-5as acetate: 2639893-42-6 |
| PubChem CID | 91865076 |
| DrugBank | DB14939 |
| ChemSpider | 64854351 |
| UNII | DA9G065962as acetate: 3ZPX60DV8A |
| KEGG | D12281as acetate: D12282 |
| ChEBI | CHEBI:145536 |
| Chemical and physical data | |
| Formula | C97H144FN33O19S2 |
| Molar mass | 2159.55 g·mol−1 |
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References
- ^ Jump up to:a b c d e “Aphexda- motixafortide injection, powder, lyophilized, for solution”. DailyMed. 4 September 2023. Archived from the original on 14 September 2023. Retrieved 13 September 2023.
- ^ Jump up to:a b “Aphexda approval letter” (PDF). 8 September 2023. Archived from the original (PDF) on 14 September 2023.
This article incorporates text from this source, which is in the public domain. - ^ “BioLineRx Announces FDA Approval of Aphexda (motixafortide) in Combination with Filgrastim (G-CSF) to Mobilize Hematopoietic Stem Cells for Collection and Subsequent Autologous Transplantation in Patients with Multiple Myeloma” (Press release). BioLineRx Ltd. 11 September 2023. Retrieved 13 September 2023 – via PR Newswire.
- ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82”. WHO Drug Information. 33 (3). hdl:10665/330879.
Further reading
- Crees ZD, Rettig MP, Jayasinghe RG, Stockerl-Goldstein K, Larson SM, Arpad I, et al. (April 2023). “Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial”. Nature Medicine. 29 (4): 869–879. doi:10.1038/s41591-023-02273-z. PMC 10115633. PMID 37069359.</ref>
External links
- Clinical trial number NCT03246529 for “A Phase III, Safety, Tolerability and Efficacy of Combination Treatment of BL-8040 and G-GSF as Compared to Placebo and G-CSF for thE MobilizatioN of HematopoiEtic Stem Cells for Autologous TransplantatIon in SubjectS With MM (GENESIS)” at ClinicalTrials.gov
/////fda 2023, approvals 2023, Motixafortide, 4F-benzoyl-TN-14003, BKT-140, BKT140, BL 8040, Aphexda, мотиксафортид, موتيكسافورتيد , 莫替福肽 ,
Evobrutinib
Evobrutinib
429.5 g/mol,C25H27N5O2
- Evobrutinib
- 1415823-73-2
- Evobrutinib [INN]
- 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one
- MSC2364447C
- MSC2364447C
- M-2951
- MSC-2364447C
- ZA45457L1K
- 1-[4-[[[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino]methyl]piperidin-1-yl]prop-2-en-1-one
- M2951
Evobrutinib is under investigation in clinical trial NCT03934502 (Effect of Meal Composition and Timing on Evobrutinib Bioavailability).
Evobrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, evobrutinib inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways, which leads to the inhibition of the growth of malignant B-cells that overexpress BTK. BTK, a member of the Src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in B-lymphocyte development, activation, signaling, proliferation and survival.
Evobrutinib is in clinical development to investigate its potential as a treatment for multiple sclerosis (MS). It is an oral, highly selective inhibitor of Bruton’s tyrosine kinase (BTK) which is important in the development and functioning of various immune cells including B lymphocytes and macrophages.
Evobrutinib is designed to inhibit primary B cell responses such as proliferation and antibody and cytokine release, without directly affecting T cells. BTK inhibition is thought to suppress autoantibody-producing cells, which preclinical research suggests may be therapeutically useful in certain autoimmune diseases.
U.S. Patent No. 9073947 discloses a pyrimidine derivative of Evobrutinib which chemically named as l-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)
piperidin-l-yl)prop-2-en-l-one and pharmaceutically acceptable salts, solvates and pharmaceutical compositions thereof.
U.S. Patent No. 9073947 and ‘Journal of Medicinal Chemistry 2019, 62(17), 7643-7655’ discloses process for the preparation of Evobrutinib which involves column purifications and lyophilisation methods to provide Evobrutinib with low yield, which is not viable at large scale production.
https://www.frontiersin.org/articles/10.3389/fnume.2021.820235/full
Radiosynthesis of [11C]Evobrutinib. [11C]Evobrutinib was synthesized similarly to the Tolebrutinib example above with the following exceptions. First, the precursor 5-(4-phenoxyphenyl)-N4-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine (4) (1 mg, 2.7 μmol) was used and the crude reaction mixture after the carbonylation reaction was purified by semi-preparative HPLC (column: Luna C18(2), 5 μ (250 x 9.6 mm); mobile phase: 44% MeCN in 200 mM ammonium formate; flow rate: 5 ml/min; UV: 254 nm). The [11C]1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one ([11C]evobrutinib) was isolated between the 15.5 and 18 min mark of the chromatogram and this sample was collected into a dilution flask that contained 50 ml of a 2 mg/ml sodium ascorbate aqueous solution. This solution was transferred to an HLB light (30 mg) SPE cartridge. After transfer, the cartridge was eluted with 1 ml of ethanol into the sterile product vial that contained 4 ml of sterile saline. Using this method, 2.2 ± 0.6 GBq (81.4 ± 22.2 mCi) [11C]evobrutinib was isolated (n = 3), and the product was analyzed via reverse phase HPLC using the following methods. Method A described above and Method B (Isocratic and molar activity): column: Luna C18(2) 3-μm (250×4.6 mm); mobile phase Isocratic: 36% acetonitrile in aqueous 0.1% TFA; flow rate: 1.3 ml/min; UV: 254 nm. Method A was used to confirm chemical identity using a co-injection of non-radioactive standard. Radiochemical purity and molar activity were determined by Method B. [11C]Evobrutinib was confirmed by co-injection with a verified non-radioactive reference standard. Am was determined using a 4-point standard curve (analytical HPLC peak area) (Y) vs. standard concentration (X: in nmol) by comparison with an evobrutinib reference standard of known concentration (2.3 mg in 1 ml). The isolated [11C] evobrutinib was co-eluted with a non-radioactive reference standard. The sample was >99% radiochemically pure, >95% chemically pure (HPLC, UV: 254 nm), with a molar activity of 496.5 ± 74 GBq/μmol (13.4 Ci/μmol) The overall synthesis time from the end of cyclotron bombardment was 37–46 min.
Patent
U.S. Patent No. 9073947
PAPER
Journal of Medicinal Chemistry 2019, 62(17), 7643-7655
https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00794
Step 4
To a 20 mL vial was added 5-(4-phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine (210.00 mg, 0.56 mmol, 1.00 equiv), sodium bicarbonate (70.48 mg, 0.84 mmol, 1.50 equiv), THF (8.00 mL, 98.74 mmol, 176.55 equiv), and water (0.80 mL, 44.41 mmol, 79.40 equiv). The mixture was cooled to 0 °C on an ice bath. Acryloyl chloride (0.15 mL, 1.83 mmol) was then added dropwise. The ice bath was removed, and the reaction was stirred at room temperature for 12 h before it was purified by silica gel chromatography (25 g KPNH silica, 0–100% methanol/ethyl acetate) to afford the title compound (A18) (21 mg, 8.7% yield) was synthesized with a similar protocol to prepared as described in the main body of the article. 1H NMR (DMSO-d6) δ 7.93 (s, 1 H), 7.40–7.08 (m, 9H), 6.76 (dd, J = 4 Hz, 1 H), 6.04 (d, J = 4 Hz, 1 H), 5.61 (d, J = 4 Hz, 1 H), 5.43 (s, 2H), 4.34 (d, J = 12 Hz, 1 H), 3.98 (d, J = 8 Hz, 1 H), 3.12 (m, 2H), 2.95 (m, 1 H), 2.56 (m, 1 H), 1.81 (m, 1 H), 1.59 (m, 2H), 0.92 (m, 2H). [ES-MS] (ESI+): m/z calcd for C25H28N5O2 [M + H]+ 430, found 430.
PATENT
Examples:
Example-1: Preparation of tert-butyl 4-(((6-amino-5-chloropyrimidin-4-yl)amino) met hy 1 jpiperid ine- 1 -carboxylate
Tert-butyl-4-(aminomethyl)piperidine-l -carboxylate (81 ml) and 1,8-diazabicyclo [5.4.0]undec-7-ene (60.34 g) were added to a mixture of 5,6-dichloropyrimidin-4-amine (50 g) in N,N-dimethylformamide (500 ml) at 25-35°C. Heated the mixture to 90-95°C and stirred for 22 hrs. Cooled the mixture to 25-30°C. Water was added to the mixture at 25-35°C and stirred for 5 hrs. Filtered the precipitated solid, washed with water and n-heptane and dried to get the title compound. Yield: 73.0 gms; Purity by HPLC: 98.7%
Example-2: Preparation of tert-butyl 4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl) amino)methyl)piperidine-l-carboxylate
(4-Phenoxyphenyl)boronic acid (75.12 g) was added to a mixture of tert-butyl 4-(((6-amino-5-chloropyrimidin-4-yl)amino)methyl)piperidine-l-carboxylate(100 g), 2-di cyclo hexylphosphino-2′,6′-dimethoxybiphenyl (12 g) and potassium carbonate (121.28 g) in 1,4-di oxane (1000 ml) at 25-30°C and stirred for 30 minutes under nitrogen atmosphere. Palladium acetate (1.96 g) was added to the mixture at 25-30°C. Heated the mixture to 100-105°C and stirred for 3 hrs. Cooled the mixture to 25-30°C. Water and ethyl acetate were added to the mixture at 25-35°C and stirred for 30 minutes. Filtered the mixture by using hyflow bed. Organic layer was separated from the filtrate. Organic layer was treated with carbon powder and distilled-off the solvent under reduced pressure, n-heptane (800 ml) was added to the obtained compound. Heated the mixture to 60-65°C and stirred for 90 minutes. Cooled the mixture to 25-30°C and stirred for 2 hrs. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound. Yield: 120 gms, Purity by HPEC: 97.6% Example-3: Preparation of 5-(4-phenoxyphenyl)-N4-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine
Tert-butyl-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl) piperidine- 1 -carboxylate (200 g) in methanol (600 ml) was cooled to 0-5°C. Hydrochloric acid in ethyl acetate (500 ml) was slowly added to the mixture at 0-5°C. Mixture allowed to warm to 25-30°C and stirred for 20 hours. Water was added to the mixture and treated the mixture with aqueous ammonia solution. Dichloromethane was added to the mixture at 25-30°C and stirred for 10 minutes. Layers were separated and distilled-off the organic layer under reduce pressure. Obtained compound was treated with isopropyl ether and dried to get the title compound. Yield: 150 gms, Purity by HPLC: 76.4%
Example-4: Preparation of Evobrutinib
Sodium bicarbonate (23.86 g) and water (301 ml) were added to the mixture of 5-(4-phenoxyphenyl)-N4-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine (70 g) in tetrahydrofuran (2800 ml). Cooled the mixture to 0-5°C. Acryloyl chloride (23.62 g) was slowly added to the mixture. Mixture allowed to warm to 25-30°C and stirred for 20 hrs. Distilled-off the solvent from the mixture under reduced pressure. Ethyl acetate and water were added to the mixture and stirred for 10 minutes. Both the layers were separated. Organic layer was treated with aqueous hydrochloric acid solution and carbon powder. Distilled-off the organic layer under reduced pressure. Isopropyl ether was added to the mixture at 25-30°C and stirred for 14 hrs. Filtered the mixture and washed with isopropyl ether. Dried to get the title compound.
Yield: 41.8 gms, Purity by HPLC: 97.6%
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//////////PHASE 3, MSC2364447C, M-2951, MSC-2364447C, ZA45457L1K, M2951, M 2951, Evobrutinib
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Zuranolone
Zuranolone
CAS 1632051-40-1
FDA APPROVED 8/4/2023, To treat postpartum depression
Press Release
WeightAverage: 409.574
Monoisotopic: 409.272927379Chemical FormulaC25H35N3O2
- SAGE 217
- SAGE-217
- SAGE217
Zuranolone, sold under the brand name Zurzuvae, is a medication used for the treatment of postpartum depression.[1][2] It is taken by mouth.[1]
The most common side effects include drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection.[1][2] An orally active inhibitory pregnane neurosteroid, zuranolone acts as a positive allosteric modulator of the GABAA receptor.[6][7][8]
Zuranolone was approved for medical use in the United States for the treatment of postpartum depression in August 2023.[2] It was developed by Sage Therapeutics and Biogen.[9]
Medical uses
Zuranolone is indicated for the treatment of postpartum depression.[1][2]
Adverse effects
The most common side effects include drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis (cold-like symptoms), and urinary tract infection.[2]
The US FDA label contains a boxed warning noting that zuranolone can impact a person’s ability to drive and perform other potentially hazardous activities.[2] Use of zuranolone may cause suicidal thoughts and behavior.[2] Zuranolone may cause fetal harm.[2]
History
Zuranolone was developed as an improvement on the intravenously administered neurosteroid brexanolone, with high oral bioavailability and a biological half-life suitable for once-daily administration.[7][10] Its half-life is around 16 to 23 hours, compared to approximately 9 hours for brexanolone.[4][5]
The efficacy of zuranolone for the treatment of postpartum depression in adults was demonstrated in two randomized, double-blind, placebo-controlled, multicenter studies.[2] The trial participants were women with postpartum depression who met the Diagnostic and Statistical Manual of Mental Disorders criteria for a major depressive episode and whose symptoms began in the third trimester or within four weeks of delivery.[2] In study 1, participants received 50 mg of zuranolone or placebo once daily in the evening for 14 days.[2] In study 2, participants received another zuranolone product that was approximately equal to 40 mg of zuranolone or placebo, also for 14 days.[2] Participants in both studies were monitored for at least four weeks after the 14-day treatment.[2] The primary endpoint of both studies was the change in depressive symptoms using the total score from the 17-item Hamilton depression rating scale (HAMD-17), measured at day 15.[2] Participants in the zuranolone groups showed significantly more improvement in their symptoms compared to those in the placebo groups.[2] The treatment effect was maintained at day 42—four weeks after the last dose of zuranolone.[2]
Society and culture
Zuranolone is the international nonproprietary name.[11]
Legal status
Zuranolone was approved by the US Food and Drug Administration (FDA) for the treatment of postpartum depression in August 2023.[2][12] The FDA granted the application for zuranolone priority review and fast track designations.[2] Approval of Zurzuvae was granted to Sage Therapeutics, Inc.[2]
Zuranolone has also been under development for the treatment of major depressive disorder, but the application for this use was given a Complete Response Letter (CRL) by the FDA due to insufficient evidence of effectiveness.[13]
Research
In a randomized, placebo-controlled phase III trial to assess its efficacy and safety for the treatment of major depressive disorder, subjects in the zuranolone group (50 mg oral zuranolone once daily for 14 days) experienced statistically significant and sustained improvements in depressive symptoms (as measured by HAM-D score) throughout the treatment and follow-up periods of the study.[14]
Other investigational applications include insomnia, bipolar depression, essential tremor, and Parkinson’s disease.[15][6][16]
syn
PATENT
WO2022020363
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022020363&_cid=P11-LLRZ9A-38538-1
Example 1. Synthesis of 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (Compound 1).
[00488] To a suspension of K2CO3 (50 mg, 0.36 mmol) in THF (5 mL) was added 1H-pyrazole-4-carbonitrile (100 mg, 0.97 mmol) and 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[ ^]phenanthren-17-yl)ethan-1-one (50 mg, 0.12 mmol). The mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into 5 mL H2O and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase preparative HPLC to afford Compound 1 as a white solid (9 mg, 17.4% yield).1H NMR (500 MHZ, CDCl3) δ (ppm) 7.87 (1H, s), 7.82 (1H, s), 5.02 (1H, AB), 4.2 (1H, AB), 2.61 (1H, t), 2.16-2.24 (1H, m), 2.05 (1H, dxt), 1.70-1.88 (6H, m), 1.61-1.69 (2H, m), 1.38-1.52 (6H, m), 1.23-1.38 (5H, m), 1.28 (3H, s), 1.06-1.17 (3H, m), 0.67 (3H, s). LCMS: rt=2.24 min, m/z=410.1 [M+H]+.
PAPER
Journal of Medicinal Chemistry (2017), 60(18), 7810-7819
https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00846
Certain classes of neuroactive steroids (NASs) are positive allosteric modulators (PAM) of synaptic and extrasynaptic GABAA receptors. Herein, we report new SAR insights in a series of 5β-nor-19-pregnan-20-one analogues bearing substituted pyrazoles and triazoles at C-21, culminating in the discovery of 3α-hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217, 3), a potent GABAA receptor modulator at both synaptic and extrasynaptic receptor subtypes, with excellent oral DMPK properties. Compound 3 has completed a phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial and is currently being studied in parallel phase 2 clinical trials for the treatment of postpartum depression (PPD), major depressive disorder (MDD), and essential tremor (ET).
3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19- nor-5β-pregnan-20-one (3). Yield: 28 g (49%) as an off-white solid. LC-MS: tR = 1.00 min, m/z = 410 (M + 1). 1 H NMR (400 MHz, CDCl3): δ 7.86 (s, 1H), 7.80 (s, 1H), 5.08−4.84 (m, 2H), 2.70−2.55 (m, 1H), 2.25−2.15 (m, 1H), 2.10−2.00 (m, 1H), 1.88−1.59 (m, 7H), 1.53−1.30 (m, 15H), 1.25−1.00 (m, 3H), 0.67 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 13.92 (CH3), 23.20, 24.44, 25.54, 25.78, 26.15 (5 × CH2), 26.69 (CH3), 31.43, 34.61 (2 × CH2), 34.77, 37.71 (2 × CH), 39.26 (CH2), 40.35 (CH), 41.21 (CH2), 41.75 (CH), 45.56 (C), 56.04, 61.24 (2 × CH), 61.78 (CH2), 72.14 (C), 93.25 (C), 113.35 (CN), 136.16, 142.49 (2 × CH), 202.23 (CO). HRMS m/z 410.2803 calcd for C25H36N3O2 + 410.2802
PATENT
WO2014169833
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014169833&_cid=P11-LLRZJ9-40598-1
Synthetic Procedures
The compounds of the invention can be prepared in accordance with methods described in the art (Upasmi et al., J. Med. Chem. 1997, 40:73-84; and Hogenkamp et al., J. Med. Chem. 1997, 40:61- 72) and using the appropriate reagents, starting materials, and purification methods known to those skilled in the art. In some embodiments, compounds described herein can be prepared using methods shown in general Schemes 1-4, comprising a nucleophilic substitution of 19-nor pregnane bromide with a neucleophile. In certain embodiments, the nucleophile reacts with the 19-nor pregnane bromide in the presence of K2CO3 in THF.
Synthesis of compound SA-B. Compound SA (50 g, 184 mmol) and palladium black (2.5 g) in tetrahydrofuran (300 mL) and concentrated hydrobromic acid (1.0 mL) was hydrogenated with 10 atm hydrogen. After stirring at room temperature for 24h, the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to afford the crude compound. Recrystallization from acetone gave compound SA-B (42.0 g, yield: 83.4%) as white powder.
1H NMR: (400 MHz, CDCl3) δ 2.45-2.41 (m, 1H), 2.11-3.44 (m, 2H), 3.24 (s, 3H), 2.18-2.15 (m, 1H), 2.01-1.95 (m, 1H), 1.81-1.57 (m, 7H), 1.53-1.37 (m, 7H), 1.29-1.13 (m, 3H), 1.13-0.90 (m, 2H), 0.89 (s, 3H).
Synthesis of compound SA-C. A solution of SA-B (42.0 g, 153.06 mmol) in 600 mL anhydrous toluene was added dropwise to the methyl aluminum bis(2,6-di-tert-butyl-4-methylphenoxide (MAD) (459.19 mmol, 3.0 eq, freshly prepared) solution under N2 at -78°C. After the addition was completed, the reaction mixture was stirred for 1 hr at -78°C. Then 3.0 M MeMgBr (153.06 mL, 459.19 mmol) was slowly added dropwise to the above mixture under N2 at -78°C. Then the reaction mixture was stirred for 3 hr at this temperature. TLC (Petroleum ether/ethyl acetate = 3:1) showed the reaction was completed. Then saturated aqueous NH4Cl was slowly added dropwise
to the above mixture at -78°C. After the addition was completed, the mixture was filtered, the filter cake was washed with EtOAc, the organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated, purified by flash Chromatography on silica gel (Petroleum ether/ ethyl acetate20:1 to 3:1) to afford compound SA-C (40.2 g, yield: 90.4%) as white powder. 1H NMR: (400 MHz, CDCl3) δ 2.47-2.41 (m, 1H), 2.13-2.03 (m, 1H), 1.96-1.74 (m, 6H), 1.70-1.62 (m, 1H), 1.54-1.47 (m, 3H), 1.45-1.37 (m, 4H), 1.35-1.23 (m, 8H), 1.22-1.10 (m, 2H), 1.10-1.01 (m, 1H), 0.87 (s, 3H).
Synthesis of compound SA-D. To a solution of PPh3EtBr (204.52 g, 550.89 mmol) in THF (500 mL) was added a solution of t-BuOK (61.82 g, 550.89 mmol) in THF (300 mL) at 0°C. After the addition was completed, the reaction mixture was stirred for 1 h 60 °C, then SA-C (40.0 g, 137.72 mmol) dissolved in THF (300 mL) was added dropwise at 60°C. The reaction mixture was heated to 60 °C for 18 h. The reaction mixture was cooled to room temperature and quenched with Sat. NH4Cl, extracted with EtOAc (3*500 mL). The combined organic layers were washed with brine, dried and concentrated to give the crude product, which was purified by a flash column chromatography (Petroleum ether/ ethyl acetate50:1 to 10:1) to afford compound SA-D (38.4 g, yield:92%) as a white powder. 1H NMR: (400 MHz, CDCl3) δ 5.17-5.06 (m, 1H), 2.42-2.30 (m, 1H), 2.27-2.13 (m, 2H), 1.89-1.80 (m, 3H), 1.76-1.61 (m, 6H), 1.55-1.43 (m, 4H), 1.42-1.34 (m, 3H), 1.33-1.26 (m, 6H), 1.22-1.05 (m, 5H), 0.87 (s, 3H).
Synthesis of compound SA-E. To a solution of SA-D (38.0 g, 125.62 mmol) in dry THF (800 mL) was added dropwise a solution of BH3.Me2S (126 mL, 1.26 mol) under ice-bath. After the addition was completed, the reaction mixture was stirred for 3 h at room temperature (14-20 °C). TLC (Petroleum ether/ ethyl acetate3:1) showed the reaction was completed. The mixture was cooled to 0 °C and 3.0 M aqueous NaOH solution (400 mL) followed by 30% aqueous H2O2 (30%, 300 mL) was added. The mixture was stirred for 2 h at room temperature (14-20 °C), and then filtered, extracted with EtOAc (3*500 mL). The combined organic layers were washed with saturated aqueous Na2S2O3, brine, dried over Na2SO4 and concentrated in vacuum to give the crude product (43 g , crude) as colorless oil. The crude product was used in the next step without further purification.
Synthesis of compound SA-F. To a solution of SA-E (43.0 g, 134.16 mmol) in dichloromethane (800 mL) at 0 °C and PCC (53.8 g, 268.32 mmol) was added portion wise. Then the reaction mixture was stirred at room temperature (16-22 °C) for 3 h. TLC (Petroleum ether/ ethyl acetate3:1) showed the reaction was completed, then the reaction mixture was filtered, washed with DCM. The organic phase was washed with saturated aqueous Na2S2O3, brine, dried over Na2SO4 and concentrated in vacuum to give the crude product. The crude product was purified by a flash column chromatography (Petroleum ether/ ethyl acetate50:1 to 8:1) to afford compound SA-F (25.0 g, yield:62.5%, over two steps) as a white powder. 1H NMR (SA-F): (400 MHz, CDCl3) δ 2.57-2.50 (m, 1H), 2.19-2.11 (m, 4H), 2.03-1.97 (m, 1H), 1.89-1.80 (m, 3H), 1.76-1.58 (m, 5H), 1.47-1.42 (m, 3H), 1.35-1.19 (m, 10H), 1.13-1.04 (m, 3H), 0.88-0.84 (m, 1H), 0.61 (s, 3H).
Synthesis of compound SA. To a solution of SA-F (10 g, 31.4 mmol) and aq. HBr (5 drops, 48% in water) in 200 mL of MeOH was added dropwise bromine (5.52 g, 34.54 mmol). The reaction mixture was stirred at 17 °C for 1.5 h. The resulting solution was quenched with saturated aqueous NaHCO3 at 0°C and extracted with EtOAc (150 mLx2). The combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel eluted with (PE: EA=15:1 to 6:1) to afford compound SA (9.5 g, yield: 76.14%) as a white solid. LC/MS: rt 5.4 mm ; m/z 379.0, 381.1, 396.1.
To a suspension of K2CO3 (50 mg, 0.36mmol) in THF (5 mL) was added ethyl 1H-pyrazole-4-carbonitrile (100 mg, 0.97 mmol ) and SA (50 mg,0.12 mmol). The mixture was stirred at rt for 15h. The reaction mixture was poured in to 5 mL H2O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid (9mg, 17.4%). 1H NMR (500 MHz, CDCl3), δ (ppm) 7.87 (1H, s),
7.82 (1H, s), 5.02 (1H, AB), 4.92 (1H, AB), 2.61 (1H, t), 2.16-2.24 (1H, m), 2.05 (1H, dXt), 1.70-1.88 (6H, m), 1.61-1.69 (2H, m), 1.38-1.52 (6H, m), 1.23-1.38 (5H, m), 1.28 (3H, s), 1.06-1.17 (3H, m), 0.67 (3H, s). LCMS: rt = 2.24 mm, m/z = 410.1 [M+H]+.
PATENT
WO2020150210
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References
- ^ Jump up to:a b c d e “Zurzuvae (zuranolone) capsules, for oral use, [controlled substance schedule pending]” (PDF). Archived (PDF) from the original on 5 August 2023. Retrieved 5 August 2023.
- ^ 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 Oral Treatment for Postpartum Depression”. U.S. Food and Drug Administration (FDA) (Press release). 4 August 2023. Retrieved 4 August 2023. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b “Zuranolone”. DrugBank Online.
- ^ Jump up to:a b Cerne R, Lippa A, Poe MM, Smith JL, Jin X, Ping X, et al. (2022). “GABAkines – Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors”. Pharmacology & Therapeutics. 234: 108035. doi:10.1016/j.pharmthera.2021.108035. PMC 9787737. PMID 34793859. S2CID 244280839.
- ^ Jump up to:a b Faden J, Citrome L (2020). “Intravenous brexanolone for postpartum depression: what it is, how well does it work, and will it be used?”. Therapeutic Advances in Psychopharmacology. 10: 2045125320968658. doi:10.1177/2045125320968658. PMC 7656877. PMID 33224470.
- ^ Jump up to:a b “SAGE 217”. AdisInsight. Archived from the original on 29 March 2019. Retrieved 10 February 2018.
- ^ Jump up to:a b Blanco MJ, La D, Coughlin Q, Newman CA, Griffin AM, Harrison BL, et al. (2018). “Breakthroughs in neuroactive steroid drug discovery”. Bioorganic & Medicinal Chemistry Letters. 28 (2): 61–70. doi:10.1016/j.bmcl.2017.11.043. PMID 29223589.
- ^ Martinez Botella G, Salituro FG, Harrison BL, Beresis RT, Bai Z, Blanco MJ, et al. (2017). “Neuroactive Steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217): A Clinical Next Generation Neuroactive Steroid Positive Allosteric Modulator of the (γ-Aminobutyric Acid)A Receptor”. Journal of Medicinal Chemistry. 60 (18): 7810–7819. doi:10.1021/acs.jmedchem.7b00846. PMID 28753313.
- ^ Saltzman J (4 August 2023). “FDA approves postpartum depression pill from two Cambridge drug firms”. The Boston Globe. Archived from the original on 6 August 2023. Retrieved 5 August 2023.
- ^ Althaus AL, Ackley MA, Belfort GM, Gee SM, Dai J, Nguyen DP, et al. (2020). “Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator”. Neuropharmacology. 181: 108333. doi:10.1016/j.neuropharm.2020.108333. PMC 8265595. PMID 32976892.
- ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82”. WHO Drug Information. 33 (3). hdl:10665/330879.
- ^ “FDA Approves Zurzuvae (zuranolone), the First and Only Oral Treatment Approved for Women with Postpartum Depression, and Issues a Complete Response Letter for Major Depressive Disorder” (Press release). Biogen Inc. 4 August 2023. Retrieved 4 August 2023 – via GlobeNewswire.
- ^ McKenzie H. “Sage Hints at Difficult Decisions After Zuranolone’s Rejection in MDD”.
- ^ Clayton AH, Lasser R, Parikh SV, Iosifescu DV, Jung J, Kotecha M, et al. (May 2023). “Zuranolone for the Treatment of Adults With Major Depressive Disorder: A Randomized, Placebo-Controlled Phase 3 Trial”. The American Journal of Psychiatry: appiajp20220459. doi:10.1176/appi.ajp.20220459. PMID 37132201. S2CID 258461851.
- ^ Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, Doherty J, Jonas J, Li S, et al. (2021). “Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial”. JAMA Psychiatry. 78 (9): 951–959. doi:10.1001/jamapsychiatry.2021.1559. PMC 8246337. PMID 34190962.
- ^ Bullock A, Kaul I, Li S, Silber C, Doherty J, Kanes SJ (2021). “Zuranolone as an oral adjunct to treatment of Parkinsonian tremor: A phase 2, open-label study”. Journal of the Neurological Sciences. 421: 117277. doi:10.1016/j.jns.2020.117277. PMID 33387701. S2CID 229333842.
External links
- Clinical trial number NCT04442503 for “A Study to Evaluate the Efficacy and Safety of SAGE-217 in Participants With Severe Postpartum Depression (PPD)” at ClinicalTrials.gov
- Clinical trial number NCT02978326 for “A Study to Evaluate SAGE-217 in Participants With Severe Postpartum Depression” at ClinicalTrials.gov
/////////Zuranolone, FDA 2023, APPROVALS 2023, Zurzuvae, postpartum depression , SAGE 217, SAGE-217, SAGE217
[H][C@@]1(CC[C@@]2([H])[C@]3([H])CC[C@]4([H])C[C@](C)(O)CC[C@]4([H])[C@@]3([H])CC[C@]12C)C(=O)CN1C=C(C=N1)C#N
EIDD-2173, ATI-2173, Fosclevudine alafenamide
EIDD-2173; also known as ATI-2173
Fosclevudine alafenamide
Phase 2
| Molecular Weight | 529.45 |
|---|---|
| Formula | C22H29FN3O9P |
| CAS No. | 1951476-79-1 |
Hepatitis B virus (HBV) is an infectious disease that targets the liver resulting in either an acute infection, with symptoms arising in 45 to 160 days, or a chronic infection, which 350 million people worldwide are affected by. Estimates indicate that 600,000 deaths occur each year as a result of consequences related to HBV infection. HBV possesses a 3.2- kb relaxed circular DNA (rcDNA) genome that is used to form covalently closed circular DNA (cccDNA) in a host cell. The cccDNA is then transcribed by RNA polymerase II, a host DNA-dependent RNA polymerase, to produce pregenomic RNA (pgRNA). The pgRNA is then used by the virally encoded reverse transcriptase to form rcDNA. The goals of current treatments for chronic HBV infections are to reduce HBV replication and reduce liver damage.
Current treatments for chronic HBV infections include pegylated alpha interferon and nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). NRTIs are converted to their corresponding 5 ‘-triphosphate, or diphosphate in the case of phosphonate containing NRTIs, and reduce viral replication by inhibiting the HBV encoded polymerase. Clevudine is an NRTI that is no longer being developed for the treatment of chronic HBV because of drug-related skeletal myopathy that was a result of mitochondrial dysfunction in patients.
Interestingly, clevudine triphosphate has been shown to be a competitive nonsubstrate inhibitor of the HBV encoded polymerase, and due to its long intracellular half-life, is able to suppress HBV replication for an extended period of time after drug withdrawal.
The discovery and synthesis of the (S,S) and (S,R) diastereomers of clevudine phosphoramidate has been previously reported. These studies were undertaken to address the myopathy concerns associated with clevudine. The phosphoramidate moiety was utilized to deliver clevudine, as its 5 ‘-monophosphate, to the liver reducing 1) systemic exposure to clevudine and 2) the possibility of skeletal myopathy. Both phosphoramidates showed anti-HBV activity similar to clevudine with the (S,S) diastereomer being slightly more potent.
SYN
See U.S. Patent No. 10,683,319.
PATENT
WO20 17223421
PATENT
EXAMPLE 11 :
[0374] Preparation of intermediate ATI-2173 from Compound-10.
[0375] Experimental Procedure
[0376] (H-l) Crude Compound-10 in THF (see Example 10) was divided into three aliquots and stirred with 2% HC1 aq. solution at pH 5-6, 4-5, and 3-4; for 16 h at 20-25 °C; the aliquots were combined and stirred at 15-20 °C for 72 h, with no degradation of ATI-2173 observed over the second time period;
[0377] (H-2) the pH of the mixture was adjusted to 7 with 7% NaHCCh;
[0378] (H-3) phase separation was carried out using 2-MeTHF, the organic phase was washed with NA2SO4 aqueous soltion, then concentrated to 1-3 V, and MTBE (5 V) was added; this operation was repeated twice;
[0379] (H-5) ATI-2173 was precipitated gradually upon addition of seed crystal and addition of n-heptane (5 V);
[0380] (H-6) the product was filtered; and
[0381] (H-7) the wetcake was dried, resulting in ATI-2173 in 99.73a% purity and
84.4% yield.
[0382] EXAMPLE 12:
[0383] Crystallization of ATI-2173
[0384] Initial studies examined the use of single or mixed solvent systems to crystalize the amorphous product, ATI-2173. Several solvent conditions were screened, including single solvent and mixed solvent systems, in order to determine the potential for obtaining a crystalline material from the amorphous material. None of the solvents tested worked and all conditions produced an oil product. The results are shown below in Tables 8 and 9.
[0385] Table 8: Single Solvent Systems
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////////// EIDD-2173, ATI-2173, EIDD 2173, ATI 2173, Hepatitis B virus, ANTI HBV, Fosclevudine alafenamide, PHASE 2
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Palovarotene
Palovarotene
CAS 410528-02-8
4-[(E)-2-[5,5,8,8-tetramethyl-3-(pyrazol-1-ylmethyl)-6,7-dihydronaphthalen-2-yl]ethenyl]benzoic acid
FDA 8/16/2023
To reduce the volume of new heterotopic ossification in adults and pediatric patients (aged 8 years and older for females and 10 years and older for males) with fibrodysplasia ossificans progressiva
- RG-667
- RO-3300074
Palovarotene, sold under the brand name Sohonos, is a medication used for the treatment of heterotopic ossification and fibrodysplasia ossificans progressiva.[4][5] It is a highly selective retinoic acid receptor gamma (RARγ) agonist.[6]
It was approved for medical use in Canada in June 2022,[4] and in the United States in August 2023.[5]
Medical uses
Palovarotene is indicated for the treatment of heterotopic ossification and fibrodysplasia ossificans progressiva.[4][5]
History
Palovarotene is a retinoic acid receptor gamma (RARγ) agonist licensed to Clementia Pharmaceuticals from Roche Pharmaceuticals. At Roche, palovarotene was evaluated in more than 800 individuals including healthy volunteers and patients with chronic obstructive pulmonary disease (COPD).[7] A one-year trial did not demonstrate a significant benefit on lung density in moderate-to-severe emphysema secondary to severe α(1)-antitrypsin deficiency.[8]
In 2011, animal studies demonstrated that RARγ agonists, including palovarotene, blocked new bone formation in both an injury-induced mouse model of heterotopic ossification (HO) and a genetically modified biological mouse model of fibrodysplasia ossificans progressiva containing a continuously active ACVR1/ALK2 receptor in a dose-dependent manner.[9][10] A 2016 study demonstrated that palovarotene also inhibited spontaneous heterotopic ossification, maintained limb mobility and functioning, and restored skeletal growth in fibrodysplasia ossificans progressiva mouse models.[11]
Society and culture
Legal status
Palovarotene is being developed by Ipsen Biopharmaceuticals and was granted priority review and orphan drug designations by the United States Food and Drug Administration (FDA) for the treatment of fibrodysplasia ossificans progressiva[12][13] and orphan medicinal product designation by the European Medicines Agency (EMA) in 2014.[14][15][16][17] Phase II clinical studies failed to show a significant change in heterotopic bone volume, the main outcome measure, but prompted further investigation in a phase III clinical trial.[18] In December 2022, the FDA declined to approve palovarotene for the fibrodysplasia ossificans progressive without additional clinical trial data.[19] In January 2023, the European Medicines Agency (EMA) recommended the refusal of the marketing authorization for palovarotene for the treatment of fibrodysplasia ossificans progressiva.[20]
Research
Phase II
Clementia submitted a new drug application for palovarotene for the treatment of fibrodysplasia ossificans progressiva after observing positive phase II results.[21]
Phase III
In December 2019, Ipsen issued a partial clinical hold for people under the age of 14, due to reports of early fusion of growth plates.[22] Ipsen acquired Clementia in 2019.[23]
SYN
J. Med. Chem. 2025, 68, 2147−2182
Palovarotene (Sohonos). Palovarotene (7) is a selective retinoic acid receptor γ (RARγ) agonist that was
developed for the treatment of fibrodysplasia ossificans progressiva (FOP), a very rare autosomal dominant disorder, impacting ∼1 in2million individuals worldwide. 54,55 This orally bioavailable agonist reduces the incidence of heterotopic ossification in patients with FOP and was developed by the
French biopharmaceutical company Ipsen. 56 The small Molecule agonist was originally developed by Roche for a different indication, and was later licensed to Clementia Pharmaceuticals, which was ultimately acquired by Ipsen.
AlthoughapprovedbytheUSFDAinAugust2023,palovarotene was first approved by Health Canada in January 2022 for patients with FOP inadults andchildren aged 10 years and older for males and aged 8 years and older for females. With respect to pharmacodynamics, the agonist binds to RARγ and thus inhibits bone morphogenetic protein and Smad 1/5/8 signaling.57 This signaling inhibition permits normal muscle tissue repair and ultimately reduces the incidence of heterotopic ossification. A robust kilogram-scale synthesis of palovarotene has been disclosed in a patent by Roche and is depicted in Scheme 11.58
Starting from 2,5-dimethyl-2,5-hexanediol (7.1), the two tertiary alcohols were chlorinated with concentrated hydro chloric acid in toluene. Without isolation, the resulting
(54) Wentworth, K. L.; Masharani, U.; Hsiao, E. C. Therapeutic
advances for blocking heterotopic ossification in fibrodysplasia
ossificans progressiva. Br. J. Clin. Pharmacol. 2019, 85, 1180−1187.
(55) Semler, O.; Rehberg, M.; Mehdiani, N.; Jackels, M.; Hoyer
Kuhn, H. Current and emerging therapeutic options for the
management of rare skeletal diseases. Paediatr. Drugs 2019, 21, 95−
106.
(56) Hoy, S. M. Palovarotene: first approval. Drugs 2022, 82, 711−
716.
(57) Pignolo, R. J.; Pacifici, M. Retinoid agonists in the targeting of
heterotopic ossification. Cells 2021, 10, 3245.
(58) Martin, M. Process for preparing retinoid compounds. US
20070232810, 2007.
.
SYN
Desjardins, C., Grogan, D. R., Packman, J. N., & Harnett, M. (2017). Methods for treating heterotopic ossification (WO2017210792A1). World Intellectual Property Organization. https://patents.google.com/patent/WO2017210792A1
Chemical Communications (Cambridge, United Kingdom) (2019), 55(38), 5420-5422
WO2014105446
US20070232810
Patent
https://patents.google.com/patent/WO2002028810A3/en
WO2002028810
XAMPLE 12: PREPARATION OF 4-r(E)-2-(5,5.8.8-TETRAMETHYL-3-PYRAZOL-l-YLMETHYL -5.6.7.8-TETRAHYDRO-NAPHTHALEN-2-YL VINYLl BENZOIC ACID (6)
A mixture of 2.0 g (4.5 mmol) of (E)- methyl-4-[2-(3-bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate and 0.65 g (9.5 mmol) of pyrazole in 15 mL of N-methyl pyrrolidine was heated at 100°. After 2 hours, the reaction mixture was cooled to room temperature, poured into brine and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was stirred with hexane and the product was filtered off, washed with hexane and dried to give 1.6 g (83%) of methyl-4-[2-(5,5,8,8-Tetramethyl-3-pyrazol-l-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate (M+ = 429).
A mixture of 27.6 g (64.4 mmol) of methyl-4-[2-(5,5,8,8-tetramethyl-3-pyrazol-l-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate and 97 mL (193 mmol) of 2 N sodium hydroxide in 300 mL of ethyl alcohol was heated at reflux. After 1 hour, the reaction mixture was cooled to room temperature and diluted with 900 mL of water. The reaction mixture was acidified with 2 N HCl and the product was isolated by filtration, washed with water and pentane and dried to give 25.9 g (97%) of 4-[(E)-2-(5,5,8,8-tetramethyl-3-pyrazol-l-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid (m.p. = 246.5-248 °C) 6.
Proceeding as described in the example above but substituting pyrazole with pyrrole, 4-methylpyrazole, 1,2,4-triazole, moφholine, 2-pyrrohdone, 3,5-dimethylpyrzole,
δ – valerolactone, 2-methyhmidazole and 4-methylimidzole gave 4-[(E)-2-(5,5,8,8-tetramethyl-3-pyrrol-l-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 7, 4-{(E)-2-[5,5,8,8-Tetramemyl-3-(4-methylpyrazol-l-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 20, 4-[(E)-2-(5,5,8,8-Tetxamethyl-3-[l,2,4]triazol-l-ylmethyl-5,6,7,8Jetrahydro-naphthalen-2-yl]vinyl}benzoic acid 39, 4-[(E)-2-(5,5,8,8-tetramethyl-3-moφhohn-4-ylmethyl- 5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 138, 4-[(E)-2-(5,5,8,8-tetramethyl-3- (2-oxo-pyrrohdin-l-yl-methyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 139, 4-{(E)-2-[5,5,8,8-Tetramet yl-3-(3,5-mmemylpyτazol-l-yhnethyl-5,6,7,8-tetrahydro-napn^ 2-yl)vinyl]benzoic acid 143, 4-[(E)-2-(5,5,8,8-tetramethyl-3-(2-oxo-piperidin-l-yl-methyl-5,6,7,8-tetrahydro-naρhthalen-2-yl)vinyl]benzoic acid 146 4-{(E)-2-[5,5,8,8-Tetramethyl-3-(2-methyhmidazol-l-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 149and 4-{(E)-2-[5,5,8,8-Tetramethyl-3-(4-methyhmidazol-l-ylmethyl-5,6,7,8-tettahydro-naphthalen-2-yl)vinyl]benzoic acid 150 respectively.
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///////////
| Clinical data | |
|---|---|
| Trade names | Sohonos |
| Other names | R-667, RG-667 |
| License data | US DailyMed: Palovarotene |
| Routes of administration | By mouth |
| Drug class | Retinoic acid receptor gamma agonist |
| ATC code | M09AX11 (WHO) |
| Legal status | |
| Legal status | CA: ℞-only[1][2][3][4]US: ℞-only[5] |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 410528-02-8 |
| PubChem CID | 10295295 |
| DrugBank | DB05467 |
| ChemSpider | 8470763 |
| UNII | 28K6I5M16G |
| KEGG | D09365 |
| ChEBI | CHEBI:188559 |
| Chemical and physical data | |
| Formula | C27H30N2O2 |
| Molar mass | 414.549 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
References[
- ^ “Notice: Multiple Additions to the Prescription Drug List (PDL) [2022-01-24]”. Health Canada. 24 January 2022. Archived from the original on 29 May 2022. Retrieved 28 May 2022.
- ^ “Summary Basis of Decision – Sohonos”. Health Canada. 23 October 2014. Archived from the original on 6 August 2022. Retrieved 6 August 2022.
- ^ “Sohonos product information”. Health Canada. 20 June 2022. Archived from the original on 29 January 2023. Retrieved 28 January 2023.
- ^ Jump up to:a b c d “Sohonos Product Information”. Health Canada. 22 October 2009. Archived from the original on 18 August 2023. Retrieved 17 August 2023.
- ^ Jump up to:a b c d “Archived copy” (PDF). Archived (PDF) from the original on 18 August 2023. Retrieved 18 August 2023.
- ^ “Health Canada Approves Ipsen’s Sohonos (palovarotene capsules) as the First Approved Treatment for Fibrodysplasia Ossificans Progressiva” (Press release). Ipsen. 24 January 2022. Retrieved 28 May 2022 – via Business Wire.
- ^ Hind M, Stinchcombe S (November 2009). “Palovarotene, a novel retinoic acid receptor gamma agonist for the treatment of emphysema”. Current Opinion in Investigational Drugs. 10 (11): 1243–50. PMID 19876792.
- ^ Stolk J, Stockley RA, Stoel BC, Cooper BG, Piitulainen E, Seersholm N, et al. (August 2012). “Randomised controlled trial for emphysema with a selective agonist of the γ-type retinoic acid receptor”. The European Respiratory Journal. 40 (2): 306–12. doi:10.1183/09031936.00161911. PMID 22282548.
- ^ Shimono K, Tung WE, Macolino C, Chi AH, Didizian JH, Mundy C, et al. (April 2011). “Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists”. Nature Medicine. 17 (4): 454–60. doi:10.1038/nm.2334. PMC 3073031. PMID 21460849.
- ^ Kaplan FS, Shore EM (April 2011). “Derailing heterotopic ossification and RARing to go”. Nature Medicine. 17 (4): 420–1. doi:10.1038/nm0411-420. PMC 4913781. PMID 21475232.
- ^ Chakkalakal SA, Uchibe K, Convente MR, Zhang D, Economides AN, Kaplan FS, et al. (September 2016). “Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1(R206H) Fibrodysplasia Ossificans Progressiva (FOP) Mutation”. Journal of Bone and Mineral Research. 31 (9): 1666–75. doi:10.1002/jbmr.2820. PMC 4992469. PMID 26896819.
- ^ “Ipsen announces FDA Priority Review for NDA in patients with FOP”. Ipsen (Press release). 24 August 2022. Retrieved 28 January 2023.
- ^ “Palovarotene Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). 1 January 2013. Archived from the original on 29 January 2023. Retrieved 28 January 2023.
- ^ “EU/3/14/1368”. European Medicines Agency (EMA). 17 September 2018. Archived from the original on 27 January 2023. Retrieved 28 January 2023.
- ^ “Public summary of opinion on orphan designation. Palovarotene for the treatment of fibrodysplasia ossificans progressiva” (PDF). European Medicines Agency (EMA). Archived (PDF) from the original on 22 April 2016. Retrieved 11 April 2016.
- ^ “Clementia Pharmaceuticals Receives Fast Track Designation for Palovarotene for Treatment of Fibrodysplasia Ossificans Progressiva (FOP)” (Press release). Clementia Pharmaceuticals. 1 December 2014. Retrieved 11 April 2016 – via PR Newswire.
- ^ “Clementia Pharmaceuticals Receives EMA Orphan Medicinal Product Designation for Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva” (Press release). Clementia Pharmaceuticals. 21 November 2014. Retrieved 11 April 2016 – via PR Newswire.
- ^ Pignolo RJ, Baujat G, Hsiao EC, Keen R, Wilson A, Packman J, et al. (October 2022). “Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, Placebo-Controlled, Double-Blind Phase 2 Trial”. Journal of Bone and Mineral Research. 37 (10): 1891–1902. doi:10.1002/jbmr.4655. PMC 9804935. PMID 35854638. S2CID 250697248.
- ^ “FDA Tells Ipsen It Won’t Approve Palovarotene for FOP”. Global Genes. 27 December 2022. Archived from the original on 29 January 2023. Retrieved 28 January 2023.
- ^ “Sohonos: Pending EC decision”. European Medicines Agency (EMA). 26 January 2023. Archived from the original on 27 January 2023. Retrieved 28 January 2023.
- ^ “Clementia Announces Plan to Submit a New Drug Application for Palovarotene for the Treatment of FOP Based on Positive Phase 2 Results”. 23 October 2018. Archived from the original on 15 December 2019. Retrieved 15 December 2019.
- ^ “Ipsen Initiates Partial Clinical Hold for Palovarotene IND120181 and IND135403 Studies”. Archived from the original on 15 December 2019. Retrieved 15 December 2019.
- ^ “Ipsen Completes Acquisition of Clementia Pharmaceuticals”. Archived from the original on 15 December 2019. Retrieved 15 December 2019.
External links
Clinical trial number NCT03312634 for “An Efficacy and Safety Study of Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva. (MOVE)” at ClinicalTrials.gov
/////////FDA 2023, APPROVALS 2023, Palovarotene, Sohonos, RG-667, RO-3300074
syn
syn
European Journal of Medicinal Chemistry 265 (2024) 116124
Palovarotene (Sohonos)
On February 17, 2022, the FDA granted approval to Palovarotene for the treatment of heterotopic ossification (HO) linked to fibrodysplasia ossificans progressiva (FOP) [64]. FOP, or myositis ossificans pro
gressiva (MOP), is an uncommon hereditary condition marked by atypical bone growth in regions beyond the usual skeletal structure. It is commonly accompanied by recurring episodes of discomfort and abrupt
swelling of soft tissues. This disorder causes restricted mobility and fusion of joints, leading to deformities, limited movement, and premature mortality [65]. Palovarotene is an orally available retinoic acid receptor γ (RARγ) agonist [66]. Palovarotene specifically attaches to RARγ and hinders the phosphorylation process of mothers against decapentaplegic homolog (SMAD)1/5/8. This action results in the suppression of the bone morphogenetic protein (BMP)/ALK2 downstream signaling pathway, leading to a decrease in ALK2/SMAD-dependent chondrogenesis and osteoblast differentiation. Consequently, the over all effect is a reduction in endochondral ossification [67].
The preparation of Palovarotene is shown in Scheme 18 [68].Starting with 2,5-dimethylhexane-2,5-diol (PALO-001), a nucleophilic substitution reaction with HCl, followed by AlClpromoted Friedel-Crafts alkylation with 1-bromo-2-methylbenzene (PALO-003), gave PALO-004. PALO-005 was obtained by substitution with CuCN.The cyano group of PALO-005 was reduced to aldehyde by diisobutylalumium hydride (DIBAL-H) to obtain PALO-006. PALO-006 was subjected to Wittig-Horner reaction with methyl 4-((dimethoxyphosphoryl)methyl)benzoate PALO-007 to obtain olefin PALO-008.
PALO-008 was brominated with N-bromosuccinimide (NBS) to obtain PALO-009. PALO-009 was nucleophilic substituted with 1H-pyrazole (PALO-010) to obtain PALO-011, which was hydrolyzed under alkaline conditions to obtain the final product Palovarotene.
[64] S.M. Hoy, Palovarotene: first approval, Drugs 82 (2022) 711–716.
[65] R.J. Pignolo, E.M. Shore, F.S. Kaplan, Fibrodysplasia ossificans progressiva:
diagnosis, management, and therapeutic horizons, Pediatr. Endocrinol. Rev. 2
(2013) 437–448.
[66] G.J. Pavey, A.T. Qureshi, A.M. Tomasino, C.L. Honnold, D.K. Bishop, S. Agarwal,
S. Loder, B. Levi, M. Pacifici, M. Iwamoto, B.K. Potter, T.A. Davis, J.A. Forsberg,
Targeted stimulation of retinoic acid receptor-γ mitigates the formation of
heterotopic ossification in an established blast-related traumatic injury model,
Bone 90 (2016) 159–167.
[67] H. Kitoh, Clinical aspects and current therapeutic approaches for FOP,
Biomedicines 8 (2020) 325.
[68] J.-M. Lapierre, D.M. Rotstein, E.B. Sjogren, Preparation of New Retinoids for the
Treatment of Emphysema, Cancer and Dermatological Disorders, 2002.
WO2002028810.
NEW DRUG APPROVALS
ONE TIME
$10.00
Zavegepant
Zavegepant
ザベジェパント;
- 1337918-83-8
- as HCl: 1414976-20-7
C36H46N8O3 BASE
638.8 g/mol BASE
- Vazegepant
- BMS-742413
- BHV-3500
FDA APPR 3/9/2023Zavzpret
N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-1-oxopropan-2-yl]-4-(2-oxo-1H-quinolin-3-yl)piperidine-1-carboxamide
ZAVZPRET is indicated for the acute treatment of migraine with or without aura in adults.
The recommended dose of ZAVZPRET is 10 mg given as a single spray in one nostril, as needed. The maximum dose that may be given in a 24-hour period is 10 mg (one spray). The safety of treating more than 8 migraines in a 30-day period has not been established, Nasal spray: 10 mg of zavegepant per device. Each unit-dose nasal spray device delivers a single spray containing 10 mg of zavegepant.
ZAVZPRET (zavegepant) nasal spray contains zavegepant hydrochloride, a calcitonin generelated peptide receptor antagonist. Zavegepant hydrochloride is described chemically as (R)-N- (3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl) piperazin-1-yl)-1-oxopropan-2-yl)- 4-(2-oxo-1,2-dihydroquinolin-3-yl) piperidine-1-carboxamide hydrochloride and its structural formula is:
Its molecular formula is C36H46N8O3․HCl, representing a molecular weight of 675. 28 g/mol. Zavegepant free base has a molecular weight of 638.82 g/mol. Zavegepant hydrochloride is a white to off-white powder, freely soluble in water, and has pKa values of 4.8 and 8.8. Each unit-dose ZAVZPRET device for nasal administration delivers 10 mg of zavegepant (equivalent to 10.6 mg of zavegepant hydrochloride) in a buffered aqueous solution containing dextrose, hydrochloric acid, sodium hydroxide, and succinic acid in water for injection. The solution has a pH of 5.3 to 6.7.
Active ingredients in ZAVZPRET: zavegepant Inactive ingredients in ZAVZPRET: dextrose, hydrochloric acid, sodium hydroxide, and succinic acid in water for injection.
Zavegepant, sold under the brand name Zavzpret, is a medication used for the treatment of migraine.[1] Zavegepant is a calcitonin gene-related peptide receptor antagonist.[1] It is sprayed into the nose.[1] It is sold by Pfizer.[1]
The most common adverse reactions include taste disorders, nausea, nasal discomfort, and vomiting.[1]
Zavegepant was approved for medical use in the United States in March 2023.[1][2][3]
Medical usesZavegepant is a Calcitonin Gene-related Peptide Receptor Antagonist. The mechanism of action of zavegepant is as a Calcitonin Gene-related Peptide Receptor Antagonist.
Zavegepant is indicated for the acute treatment of migraine with or without aura in adults.[1]
Zavegepant is an antagonist of the calcitonin gene-related peptide (CGRP) receptor currently in phase 3 trials in an intranasal formulation for the treatment of migraine. If FDA approved, it will join other previously-approved “-gepant” drugs [rimegepant] and [ubrogepant] as an additional treatment alternative for patients with migraine, particularly those for whom traditional triptan therapy has proven ineffective. On April 15th, 2020, a phase 2 clinical trial (NCT04346615: Safety and Efficacy Trial of Vazegepant Intranasal for Hospitalized Patients With COVID-19 Requiring Supplemental Oxygen) began to investigate the use of intranasally administered zavegepant to combat the acute respiratory distress syndrome (ARDS) sometimes seen in patients with COVID-19. Acute lung injury activates the release of CGRP, which plays a role in the development of ARDS – CGRP antagonists, then, may help to blunt the significant inflammation associated with COVID-19. The clinical trial is expected to complete in September 2020.
Zavegepant is a highly soluble small molecule calcitonin gene related peptide (CGRP) receptor antagonist, with potential analgesic and immunomodulating activities. Upon administration, zavegepant targets, binds to and inhibits the activity of CGRP receptors located on mast cells in the brain. This may inhibit neurogenic inflammation caused by trigeminal nerve release of CGRP. In addition, by blocking the CGRP receptors located in smooth muscle cells within vessel walls, zavegepant inhibits the pathologic dilation of intracranial arteries. Zavegepant, by blocking the CGRP receptors, also suppresses the transmission of pain by inhibiting the central relay of pain signals from the trigeminal nerve to the caudal trigeminal nucleus. Altogether, this may relieve migraine. As CGRP receptors induce the release of pro-inflammatory mediators, such as interleukin-6 (IL-6), from inflammatory cells, zavegepant may prevent an IL-6-mediated inflammatory response. Zavegepant may also inhibit the CGRP-mediated induction of eosinophil migration and the stimulation of beta-integrin-mediated T cell adhesion to fibronectin at the site of inflammation, and may abrogate the CGRP-mediated polarization of the T cell response towards the pro-inflammatory state characterized by Th17 and IL-17. This may improve lung inflammation and oxygenation, prevent edema, and further lung injury. CGRP, a 37 amino-acid peptide expressed in and released from a subset of polymodal primary sensory neurons of the trigeminal ganglion and nerve fibers projecting to the airways and by pulmonary neuroendocrine cells, plays an important role in pain transmission, inflammation, and neurogenic vasodilatation. It is released upon acute lung injury and upregulation of transient receptor potential (TRP) channels.
SYN’
Synthesis of a CGRP Receptor Inhibitor
Publication Date: 2013
Publication Name: Synfacts
Azepino-indazoles as calcitonin gene-related peptide (CGRP) receptor antagonists
- PMID: 33096162Publication Date: 2021-01-01Journal: Bioorganic & medicinal chemistry lettersDiscovery of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BMS-742413): a potent human CGRP antagonist with superior safety profile for the treatment of migraine through intranasal delivery
PMID: 23632269Publication Date: 2013-06-01Journal: Bioorganic & medicinal chemistry letters
////////
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Patent
https://patents.google.com/patent/US20120245356A1/en
Patent
WO 2022165291
https://patents.google.com/patent/WO2022165291A1/en
Migraine is a chronic and debilitating disorder characterized by recurrent attacks lasting four to 72 hours with multiple symptoms, including typically one-sided, pulsating headaches of moderate to severe pain intensity that are associated with nausea or vomiting, and/or sensitivity to sound (phonophobia) and sensitivity to light (photophobia). Migraines are often preceded by transient neurological warning symptoms, known as auras, which typically involve visual disturbances such as flashing lights, but may also involve numbness or tingling in parts of the body. Migraine is both widespread and disabling. The Migraine Research Foundation ranks migraine as the world’s third most prevalent illness, and the Global Burden of Disease Study 2015 rates migraine as the seventh highest specific cause of disability worldwide. According to the Migraine Research Foundation, in the United States, approximately 36 million individuals suffer from migraine attacks. While most sufferers experience migraine attacks once or twice per month, more than 4 million people have chronic migraine, defined as experiencing at least 15 headache days per month, of which at least eight are migraine, for more than three months. Others have episodic migraine, which is characterized by experiencing less than 15 migraine days per month. People with episodic migraine may progress to chronic migraine over time. Migraine attacks can last four hours or up to three days. More than 90% of individuals suffering from migraine attacks are unable to work or function normally during a migraine attack, with many experiencing comorbid conditions such as depression, anxiety and insomnia. Also, those suffering from migraine often have accompanying nausea and have an aversion to consuming food or liquids during an attack.
CGRP (calcitonin gene-related peptide) is a 37 amino acid neuropeptide, which belongs to a family of peptides that includes calcitonin, adrenomedullin and amylin. In humans, two forms of CGRP (a-CGRP and 0-CGRP) exist and have similar activities. They vary by three amino acids and exhibit differential distribution. At least two CGRP receptor subtypes may also account for differential activities. The CGRP receptor is located within pain-signaling pathways, intracranial arteries and mast cells and its activation is thought to play a causal role in migraine pathophysiology. For example, research and clinical studies have shown: serum levels of CGRP are elevated during migraine attacks, infusion of intravenous CGRP produces persistent pain in migraine sufferers and non-migraine sufferers, and treatment with anti-migraine drugs normalizes CGRP activity.
Currently, clinicians use a number of pharmacologic agents for the acute treatment of migraine. A study published by the American Headache Society in 2015 concluded that the medications deemed effective for the acute treatment of migraine fell into the following classes: triptans, ergotamine derivatives, non-steroidal anti-inflammatory drugs (“NSAIDs”), opioids and combination medications. The current standard of care for the acute treatment of migraine is prescription of triptans, which are serotonin 5-HT IB/ID receptor agonists. Triptans have been developed and approved for the acute treatment of migraine over the past two decades. The initial introduction of triptans represented a shift toward drugs more selectively targeting the suspected pathophysiology of migraine. While triptans account for almost 80% of anti-migraine therapies prescribed at office visits by healthcare providers, issues such as an incomplete effect or headache recurrence remain important clinical limitations. In fact, only about 30% of patients from clinical trials are pain free at two hours after taking triptans. In addition, triptans are contraindicated in patients with cardiovascular disease, cerebrovascular disease, or significant risk factors for either because of potential systemic and cerebrovascular vasoconstriction from the 5-HT IB -mediated effects. Also, according to a January 2017 study published in the journal Headache, an estimated 2.6 million migraine sufferers in the United States have a cardiovascular event, condition or procedure that limits the potential of triptans as a treatment option.
Accordingly, there remains a significant unmet medical need for a novel migraine-specific medication that provides enhanced patient benefits compared to existing therapies.
Possible CGRP involvement in migraine has been the basis for the development and clinical testing of a number of compounds, including for example, advanced clinical candidates rimegepant (BHV-3000) and zavegepant (BHV-3500), which are developed by Biohaven Pharmaceutical Holding Company Ltd., New Haven, CT.
Zavegepant (also known as vazegepant) is a third generation, high affinity, selective and structurally unique small molecule CGRP receptor antagonist having the following formula I:
I
Zavegepant is described, for example, in WO 03/104236 published December 18, 2003 and US 8,481,546 issued July 9, 2013, which are incorporated herein in their entireties by reference.
While zavegepant is a highly soluble molecule, its bioavailability characteristics may render it challenging to prepare the drug in an oral dosage form. Enhancing the bioavailability of zavegepant and other CGRP inhibitors by different administration routes would therefore be desirable.
Calcitonin gene-related peptide (CGRP) is widely distributed in nociceptive pathways in human peripheral and central nervous system and its receptors are also expressed in pain pathways. While CGRP is involved in migraine pathophysiology, its role in non-headache pain has not been quite clear. There remains a need for new medicines to treat various pain disorders in patients in need thereof.
Scheme 1
Scheme 3
Scheme 4
tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-l -carboxylate. Sodium hydride in mineral oil (60%, 7.92 g, 198.02 mmoles) was washed with hexanes then suspended in dimethylformamide (220 mL). The mixture was cooled to 0°C. Trimethyl phosphonoacetate (29.0 mL, 189.82 mmoles) was added dropwise to the stirred reaction mixture. After 20 min at 0°C, a solution of A-/c/7-butoxycarbonyl-4-pi peri done (30.41 g, 152.62 mmoles) in dimethylformamide (80 mL) was added to the mixture dropwise. The reaction was stirred at room temperature for 3 h and then diluted with diethyl ether (650 mL). The mixture was washed once with water and the aqueous layer was extracted once with diethyl ether. The combined organic layers were washed 4 times with water and the aqueous phase was discarded. The organic phase was washed with brine and dried over magnesium sulfate, filtered, and concentrated to dryness. The title compound was obtained as a white solid in 92% yield. 1 H- NMR (300 MHz, CDCh): 5 = 5.68 (s, 1 H), 3.66 (s, 3 H), 3.40-3.51 (m, 4 H), 2.90 (t, J= 5.49, 2 H), 2.25 (t, J= 5.49, 2 H), 1.44 (s, 9 H).
ed-butyl 4-(2-methoxy-2-oxoethyl)piperidine-l -carboxylate. A solution of tert-butyl 4- (2-methoxy-2-oxoethylidene)piperidine-l -carboxylate (35.71 g, 140 mmoles) in a mixture of 1 : 1 ethyl acetate/methanol (220 mL) was carefully treated with 50% wet 10% palladium on carbon (3.3 g). The reaction vessel was charged with 55 psi of hydrogen gas and the mixture was shaken on a Parr apparatus at room temperature for 16 h. The reaction mixture was then filtered to remove the catalyst and the filtrate concentrated in vacuo. The title compound was obtained as a clear colorless oil in 97% yield. ‘H-NMR (300 MHz, CDCh): 5 = 4.04 (d, J= 10.25, 2 H), 3.64 (s, 3 H), 2.68 (t, J= 12.44, 2 H), 2.21 (d, J= 6.95, 2 H), 1.98-1.77 (m, 1 H), 1.64 (d, J= 13.54, 2 H), 1.41 (s, 9 H), 1.25-0.99 (m, 2 H).
4-[2-Hydroxy-l-methoxycarbonyl-2-(2-nitro-phenyl)-ethyl]-piperidine-l-carboxylic acid tert-butyl ester. A A-diisopropylamine (4.40 mL, 31.3 mmoles) was dissolved in tetrahydrofuran (50 mL). The mixture was cooled to -78°C. Butyllithium (2.5 M in hexanes, 12.4 mL, 31 mmoles) was added dropwise to the stirred solution. After stirring at -78°C for 30 min, a solution of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-l -carboxylate (6.65 g, 25.8 mmoles) in tetrahydrofuran (15 mL) was added dropwise to the mixture. Stirring was continued at -78°C for 1 h. A solution of 2-nitrobenzaldehyde (3.90 g, 25.8 mmoles) in tetrahydrofuran (20 mL) was then added to the mixture dropwise, and then stirring was continued at -78°C for a further 2.5 h. The reaction was quenched with cold aqueous ammonium chloride and then diluted with water. The mixture was extracted twice with ethyl acetate and the aqueous phase was discarded. The material was dried (magnesium sulfate) filtered, and concentrated to dryness. Silica gel chromatography afforded the desired product in 94% yield as light yellow foam. MS m/e (M- C4H8+H)+= 353.1.
4-(4-Hydroxy-2-oxo-l , 2, 3, 4-tetrahydro-quinolin-3-yl)-piperidine-l -carboxylic acid tertbutyl ester. In a 3 neck flask fitted with a nitrogen inlet, thermometer, and a mechanical stirrer, 4-[2-hydroxy-l -methoxy carbonyl-2-(2-nitro-phenyl)-ethyl]-piperidine-l -carboxylic acid tertbutyl ester (9.93 g, 24.3 mmoles) was dissolved in acetic acid (1.75 moles, 100 mL). Iron powder (8.90 g, 159 mmoles) was added to the vessel with stirring. The stirred mixture was slowly heated to 80°C for 30 min and then cooled to room temperature. It was then diluted with ethyl acetate and filtered through a pad of celite. Solids were washed with 20% methanol/ethyl acetate, and then with methanol. The filtrate was concentrated and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate. The layers were separated. The resulting aqueous phase was extracted twice with ethyl acetate. The organic layers were combined. The mixture was washed twice with water and the aqueous phase was discarded. The material was dried (magnesium sulfate) filtered, and concentrated to dryness. Silica gel chromatography afforded the title compound as light yellow foam in 77% yield. MS m/e (M-H)’ = 345.1.
3-(Piperidin-4-yl)quinolin-2(lH) hydrochloride . A stirred solution of 4-(4-hydroxy-2- oxo-l,2,3,4-tetrahydro-quinolin-3-yl)-piperidine-l-carboxylic acid tert-butyl ester (5.60 g, 16.2 mmoles) in ethyl acetate (70 mL) was treated with HC1 in dioxane (4N, 40 mmoles, 10 mL). The mixture was stirred at room temperature for 45 min. More HC1 in dioxane (4N, 120 mmoles, 30 mL) was then added and stirring was continued at room temperature for 16 h. The resulting solid was collected by filtration and washed with ethyl acetate. It was then suspended in 5% water-isopropanol (100 mL) and the mixture was warmed to reflux and stirred for 20 min. The mixture was cooled to room temperature and stirred at room temperature for 16 h. The solid was collected by filtration, washed with isopropanol, and dried under high vacuum. The title compound was obtained as white solid in 75% yield. ‘H-NMR (DMSO-de) 5 11.85 (s, 1 H), 9.02 (bs, 1 H), 8.88 (bs, 1 H), 7.70 (t, J= 3.81 Hz, 2 H), 7.53 – 7.30 (d, J= 8.24 Hz, 1 H), 7.17 (t, J= 7.48 Hz, 2 H), 3.36 (d, J= 12.51 Hz, 2 H), 3.10 – 2.94 (m, 3 H), 2.01 (d, J= 13.43 Hz, 2 H), 1.87 – 1.73 (m, 2 H); MS m/e (M+H)+ = 229.0.
4-Iodo-2,6-dimethylbenzenamine hydrochloride . To a suspension of sodium bicarbonate (126 g, 1.5 moles) and 2,6-dimethylaniline (61.5 mL, 500 mmoles) in methanol (700 mL) was added iodine monochloride (1.0 M in dichloromethane, 550 mL, 550 mmoles) at room temperature over 1 h. After addition was complete, stirring was continued for 3 h. The reaction was filtered to remove excess sodium bicarbonate and the solvent removed in vacuo. The residue was re-dissolved in diethyl ether (1.5 L) and treated with hydrochloric acid (2M in ether, 375 mL, 750 mmoles). The resulting suspension was stored in the freezer (-15°C) overnight. The solid was filtered and washed with diethyl ether until it became colorless, to give 126.5 g (89%) as a grey-green powder. ‘H-NMR (DMSO-de) 5 2.33 (s, 6 H), 7.48 (s, 2 H), 9.05 (bs, 3 H); 13C-NMR (DMSO-de) 5 17.4, 91.5, 133.1, 131.2, 136.9.
Methyl 2 -(benzyloxy carbonyl) acrylate . To a flame dried three-neck round bottom flask, fitted with a mechanical stirrer, was added (S)-methyl 2-(benzyloxycarbonyl)-3- hydroxypropanoate (129 g, 509 mmoles), anhydrous dichloromethane (2 L), and methanesulfonyl chloride (49.3 mL, 636 mmoles). The mixture was cooled to -15°C, and treated with tri ethylamine (213 mL, 1527 mmoles), dropwise, to ensure the temperature of the reaction mixture did not exceed 0°C. The addition of the first equivalent of triethylamine was exothermic. After addition of tri ethylamine, the mixture was stirred at 0°C for 30 min. The cooling bath was removed and the mixture stirred at room temperature for 1.5 h. The reaction was quenched by addition of methanol (21 mL). The mixture was washed with 0.5% aqueous potassium bisulfate until the washings were pH 5, then saturated sodium bicarbonate, and brine, dried over sodium sulfate, and concentrated. Flash chromatography (silica gel, 1 :9 ethyl acetate/hexanes) gave I l l g (92%) as a viscous colorless oil, which crystallized upon standing. ’H-NMR (DMSO-de) 5 3.71 (s, 3 H), 5.10 (s, 2 H), 5.60 (s, 1 H), 5.76 (s, 1 H), 7.39-7.35 (m, 5 H), 8.96 (s, 1 H); 13C-NMR (DMSO-de) 5 52.3, 65.9, 127.8, 128.1, 128.3, 128.8, 133.3, 136.3, 153.5, 163.7.
(Z)-Methyl 3-(4-amino-3,5-dimethylphenyl)-2-(benzyloxycarbonyl) acrylate. A 2 L round bottom flask was charged 4-iodo-2,6-dimethylbenzenamine hydrochloride salt (55 g, 194 mmoles), methyl 2-(benzyloxycarbonyl)acrylate (59.2 g, 252 mmoles), tetrabutylammonium chloride (59.2 g, 213 mmoles), palladium (II) acetate (4.34 g, 19.4 mmoles), and tetrahydrofuran (1.2 L, degassed by a flow of nitrogen for 30 min). The mixture was stirred so that a suspension was formed and then degassed by a flow of nitrogen for 30 min. Triethylamine (110 mL, 789 mmoles) was added and the resulting mixture was heated at reflux for 3 h. After cooling to room temperature, the reaction mixture was filtered through a pad of celite, washed with tetrahydrofuran (2 x 100 mL), and concentrated. The residue was dissolved in di chloromethane, washed with water (3X) and brine (2X), dried over sodium sulfate, and concentrated. Flash chromatography (silica gel, using 1 :9 ethyl acetate/dichloromethane) gave a tan solid. The solid was recrystallized from warm methanol (210 mL) and water (100 mL). The mixture was held at room temperature overnight, then at 0°C for 2 h, and finally at -15°C for 2 h. The resulting solid was filtered, washed with ice cold 1 : 1 methanol/water, and dried under high vacuum overnight to give 44.7 g (65%) as a light tan solid which was a mixture of ZZE isomers (73 :27). ’H-NMR (DMSO-de) 5, 2.05 (s, 6 H), 3.61 (s, 0.8 H), 3.68 (s, 2.2 H), 5.00 (s, 0.54 H), 5.13 (s, 1.46 H), 5.24 (s, 2 H), 7.40-7.21 (m, 8 H), 8.51 (s, 0.27 H), 8.79 (s, 0.73 H); 13C-NMR (DMSO-de) 5 17.8, 51.7, 65.3, 119.4, 120.0, 120.3, 127.3, 127.7, 128.3, 130.9, 135.8, 137.2, 146.9, 154.7, 166.0.
(R)-Methyl 3-(4-amino-3,5-dimethylphenyl)-2-(benzyloxycarbonyl)propanoate. A flame- dried 2 L Parr hydrogenation bottle was charged with (Z)-methyl 3-(4-amino-3,5- dimethylphenyl)-2-(benzyloxycarbonyl)acrylate (84.5 g, 239 mmoles), di chloromethane (300 mL), and methanol (300 mL). The bottle was swirled so that a light brown suspension was formed. The mixture was degassed using a flow of nitrogen for 30 min. To this was quickly added (-)-l,2-bis((2A,5A)-2,5-diethylphospholano)-bezene(cyclooctadiene) rhodium (I) tetrafluoroborate ([(2A,5A)-Et-DuPhosRh]BF4) (2.11 g, 3.20 mmoles). The bottle was immediately attached to a Parr Hydrogenator. After 5 cycles of hydrogen (60 psi) and vacuum, the bottle was pressurized to 65 psi and the suspension was agitated at room temperature for 16 h. The reaction had become homogeneous. The reaction mixture was concentrated, and the resulting residue purified by flash chromatography (silica gel, 1 :9 ethyl acetate/dichloromethane) to give 82.9 g (98%). ‘H-NMR (DMSO-de) 5 2.04 (s, 6 H), 2.65 (dd, J= 13.4, 9.8 Hz, 1H), 2.82 (dd, J= 13.7, 5.2 Hz, 1 H), 3.62 (s, 3 H), 4.15-4.10 (m, 1H), 4.41 (s, 2 H), 5.00 (s, 2 H), 6.68 (s, 2 H), 7.37-7.28 (m, 5 H), 7.70 (d, J= 7.9 Hz, 1 H); 13C-NMR (DMSO-de) 5 17.7, 35.9, 51.7, 56.1, 65.3, 120.4, 124.0, 127.5, 127.7, 128.2, 128.3, 136.9, 142.6, 155.9, 172.5.
(R)-Methyl 2-(benzyloxycarbonyl)-3-(7-methyl-lH-indazol-5-yl)propanoate. (R)-Methyl 3-(4-amino-3,5-dimethylphenyl)-2-(benzyloxycarbonyl)propanoate (50.0 g, 140 mmoles) was weighed into a flame-dried 5 L three neck round bottom flask, followed by the addition of toluene (2.4 L) and glacial acetic acid (120 mL, 2.1 moles). The mixture was mechanically stirred to form a clear solution, and then potassium acetate (103 g, 1.05 moles) was added. To the resulting white suspension, z.w-amyl nitrite (20.7 mL, 154 mmoles) was added dropwise at room temperature, and the resulting mixture was stirred at room temperature for 16 h. Saturated sodium bicarbonate (I L) was added, followed by the careful addition of solid sodium bicarbonate to neutralize the acetic acid. The mixture was extracted with a mixture of di chloromethane (2 L) and brine (1.5 L). After separation, the aqueous layer was extracted with di chloromethane (500 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. Solvents were removed to afford a tan solid, which was washed with hexanes (2 L) and toluene (150 mL). The solid was recrystallized from hot acetone (260 mL) and hexanes (700 mL). The slightly cloudy mixture was allowed to cool to room temperature slowly, then to 0°C for 1.5 h, and finally to -15°C for 1.5 h. The resulting solid was filtered and washed with ice-cold acetone/hexanes (1 : 1, 200 mL) to afford 39.1 g (76% yield). Analytical HPLC showed >98% UV purity. The enantiomeric excess (ee) was determined to be 99.8% (conditions: Chiralpak AD column, 4.6 x 250 mm, 10 pm; A = ethanol, B = 0.05% diethylamine/heptane; 85%B @1.0 mL/min. for 55 min. The retention times for R was 44.6 min and for S was 28.8 min). ‘H-NMR (DMSO-de) 5 2.48 (s, 3 H), 2.93 (dd, J= 13.4, 10.7 Hz, 1H), 3.10 (dd, J= 13.7, 4.9 Hz, 1H), 3.63 (s, 3H), 4.32-4.27 (m, 1 H), 4.97 (s, 2 H), 7.03 (s, 1 H), 7.24-7.22 (m, 2 H), 7.29 -7.27 (m, 3 H), 7.41 (s, 1 H), 7.83 (d, J= 8.2 Hz, 1H), 7.99 (s, 1H), 13.1 (s, 1 H); 13C-NMR (DMSO-de) 5 16.7, 36.5, 51.8, 56.0, 65.3, 117.6, 119.6, 122.7, 127.2, 127.4, 127.6, 128.2, 129.3, 133.4, 136.8, 139.2, 155.9, 172.4. Mass spec.: 368.16 (MH)+.
(R)-Methyl 2-amino-3-(7-methyl-lH-indazol-5-yl)propanoate. A Parr hydrogenation bottle was charged with (R)-methyl 2-(benzyloxycarbonyl)-3-(7-methyl-lH-indazol-5- yl)propanoate (11.0 g, 29.9 mmoles) and methanol (75 mL). The suspension was purged with nitrogen and treated with palladium (10% on charcoal, 700 mg). The bottle was shaken under hydrogen (15 psi) overnight. The mixture was filtered through a pad of celite to remove the catalyst. Concentration of the eluent gave 7.7 g (quant.) as an oil which was used without further purification. XH-NMR (CD3OD) 5 2.54 (s, 3 H), 2.98 (dd, J= 13.5, 7.0 Hz, 1 H), 3.09 (dd, J= 13.5, 5.9 Hz, 1 H), 3.68 (s, 3 H), 3.75 (dd, J= 7.0, 6.2 Hz, 1 H), 7.01 (s, 1 H), 7.39 (s, 1 H), 7.98 (s, 1 H). Mass spec.: 232.34 (M-H)’.
(R)-methyl 3-(7-methyl-lH-indazol-5-yl)-2-(4-(2-oxo-l,2-dihydroquinolin-3- yl)piperidine-l-carboxamido)propanoate. To a solution of (R)-methyl 2-amino-3-(7-methyl-lH- indazol-5-yl)propanoate hydrochloride (7.26 g, 27.0 mmoles) in dimethylformamide (50 mL) at room temperature was added N, A’-disuccinimidyl carbonate (7.60 g, 29.7 mmoles) followed by triethylamine (11.29 mL, 81 mmoles). The resulting mixture was stirred for 30 min and treated with 3-(piperidin-4-yl)quinolin-2(lH)-one (6.77 g, 29.9 mmoles) in portions. The reaction was allowed to stir for 24 h. The mixture was concentrated, dissolved in ethyl acetate, and washed sequentially with water, brine, and 0.5 N HC1 (2X). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography (silica gel, 20: 1 ethyl acetate/methanol) to give 11.9 g (78%). 1 H-NMR (CD3OD) 5 13.0 (s, 1 H), 11.8 (s, 1 H), 7.98 (s, 1 H), 7.63 (d, J= 7.6 Hz, 1 H), 7.57 (s, 1 H), 7.45 – 7.41 (m, 2 H), 7.27 (d, J= 8.2Hz, 1 H), 7.16 (t, J= 7.9 Hz, 1 H), 7.03 (s, 1 H), 6.85 (d, J= 7.9 Hz, 1 H), 4.31 – 4.26 (m, 1 H), 4.10 – 4.08 (m, 2 H), 3.60 (s, 3 H), 3.07 – 3.01 (m, 2 H), 2.93 – 2.88 (m, 1 H), 2.77 – 2.67 (m, 2 H), 2.48 (s, 3 H), 1.78 – 1.72 (m, 2 H), 1.34 – 1.26 (m, 2 H). Mass spec.: 488.52 (MH)+.
(R)-3-(7-methyl-lH-indazol-5-yl)-2-(4-(2-oxo-l,2-dihydroquinolin-3-yl)piperidine-l- carboxamido)propanoic acid. A solution of (R)-methyl 3-(7-methyl-lH-indazol-5-yl)-2-(4-(2- oxo-1, 2-dihydroquinolin-3-yl)piperidine-l-carboxamido)propanoate_(5.50 g, 11.3 mmoles) in tetrahydrofuran (50 mL) and methanol (10 mL) was cooled to 0°C. To this was added a cold (0°C) solution of lithium hydroxide monohydrate (0.95 g, 22.6 mmoles) in water (20 mL), dropwise over 15 min. The reaction was stirred at room temperature for additional 3 h. The mixture was concentrated to remove the organic solvents. The resulting residue was dissolved in a minimum amount of water, cooled to 0°C, and treated with cold (0°C) IN HC1 until pH 2 was attained. The resulting solid was collected by filtration, washed with cold water and ether, and then dried overnight under high vacuum to give 5.0 g (94%) as a white solid. ’H-NMR (DMSO- d6) 5 13.05 (bs, 1 H), 11.77 (s, 1 H), 7.98 (s, 1 H), 7.62 (d, J= 8.0 Hz, 1 H), 7.55 (s, 1 H), 7.44 (d, J= 8.2Hz, 1 H), 7.42 (s, 1 H), 7.27 (d, J= 8.2 Hz, 1 H), 7.16 (t, J= 7.6 Hz, 1 H), 7.05 (s, 1 H), 6.65 (d, J= 7.9 Hz, 1 H), 4.27 – 4.22 (m, 1 H), 4.10 – 4.07 (m, 2 H), 3.12 – 3.07 (m, 1 H), 3.03 – 2.99 (m, 1 H), 2.93 – 2.88 (m, 1 H), 2.77 – 2.66 (m, 2 H), 2.47 (s, 3 H), 1.77 – 1.74 (m, 2 H), 1.34 – 1.27 (m, 2 H). Mass spec.: 474.30 (MH)+.
(R)-N-(3-(7-methyl-lH-indazol-5-yl)-l-(4-(l-methylpiperidin-4-yl)piperazin-l-yl)-l- oxopropan-2-yl)-4-(2-oxo-l,2-dihydroquinolin-3-yl)piperidine-l-carboxamide (I). A flask was charged with (R)-3-(7-methyl-lH-indazol-5-yl)-2-(4-(2-oxo-l,2-dihydroquinolin-3- yl)piperidine-l-carboxamido)propanoic acid (2.9 g, 6.11 mmoles), triethylamine (3.00 mL, 21.5 mmoles), l-(l-methylpiperidin-4-yl)piperazine (1.23 g, 6.72 mmoles), and dimethylformamide (10 mL). The resulting solution was treated with 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium tetrafluoroborate (2.26 g, 7.03 mmoles) in portions. The reaction was allowed to stir at room temperature overnight. The mixture was concentrated under vacuum to remove dimethylformamide. The crude product was dissolved in 7% methanol in di chloromethane and purified by flash chromatography using 7% methanol in di chloromethane containing 2% of aqueous ammonium hydroxide as eluent. The pure fractions were collected and solvent was removed under vacuum. The desired product was crystallized from hot acetone to give the compound having Formula I in 77% yield. Analytical HPLC showed 99.0 % UV purity at 230 nm. The enantiomeric excess (ee) was determined to be >99.9% (conditions: Chiralpak AD column, 4.6 x 250 mm, 10 pm; eluent: 70% (0.05% diethylamine)/heptane/30%ethanol; @1.0 mL/min. for 45 min. The retention times were 18.7 min for R and 28.1 min for S). ‘H-NMR (500 MHz, DMSO-de) 5 ppm 13.01 (s, 1 H), 11.76 (s, 1 H), 7.96 (s, 1 H), 7.62 (d, J= 7.10 Hz, 1 H), 7.60 (s, 1 H), 7.42 (m, 1 H), 7.36 (s, 1 H), 7.26 (d, J = 8.25 Hz, 1 H), 7.14 (m, 1 H), 7.00 (s, 1 H), 6.69 (d, J= 8.25 Hz, 1 H), 4.78 (q, J= 7.79 Hz, 1 H), 4.14 (d, J= 12.37 Hz, 2 H), 3.54 (dd, J= 9.16, 4.58 Hz, 1 H), 3.24 (m, 1 H), 3.11 (m, 1 H), 2.97 (m, 1 H), 2.89 (m, 2 H), 2.69 (m, 4 H), 2.32 (m, 1 H), 2.21 (m, 1 H), 2.07 (m, 4 H), 1.95 (t, J= 8.25 Hz, 1 H), 1.87 (m, J= 11.28, 11.28, 3.55, 3.44 Hz, 1 H), 1.76 (t, J= 12.03 Hz, 2 H), 1.68 (t, J= 11.11 Hz, 2 H), 1.53 (t, J= 8.25 Hz, 1 H), 1.32 (m, 4 H), 1.16 (m, 2 H); 13C-NMR (DMSO-de) 5 16.80, 27.30, 30.51, 30.51, 30.67, 35.50, 38.04, 41.74, 44.00, 44.16, 45.35, 45.78, 48.14, 48.39, 51.45, 54.76, 54.76, 60.61, 114.53, 117.79, 119.29, 119.34, 121.57, 122.78, 127.46, 127.79, 129.29, 129.79, 133.31, 133.72, 136.98, 137.41, 139.12, 156.50, 161.50, 170.42.
Accurate mass analysis: m/z 639.3770, [MH]+, A = -0.2 ppm. Optical rotation: -27.36° @ 589 nm, concentration = 4.71 mg/mL in methanol. DESCRIPTION AND DOSAGE FORM
The physical and chemical properties of zavegepant (BHV-3500) drug substance mono-hydrochloride salt form are provided in Table 1.
Table 1 Physical and Chemical Properties
Biohaven number BHV-3500
Molecular formula C36H47CIN8O3
Molecular weight 675.26 (HO salt); 638.82 (free base)
Appearance White to off-white powder
Melting point ~178°C pH-solubility profile 105 mg/mL at pH = 8.2 and > 300 mg/mL at lower pH pKa 4.8 and 8.8 logD 1.21
Patent
US2022401439Bioorg Med Chem Lett
. 2021 Jan 1;31:127624.
doi: 10.1016/j.bmcl.2020.127624. Epub 2020 Oct 21.
References
- ^ Jump up to:a b c d e f g h https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216386s000lbl.pdf
- ^ https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/216386Orig1s000ltr.pdf
- ^ “Pfizer’s Zavzpret (Zavegepant) Migraine Nasal Spray Receives FDA Approval” (Press release). 10 March 2023.
Further reading
- Croop R, Madonia J, Stock DA, Thiry A, Forshaw M, Murphy A, Coric V, Lipton RB (October 2022). “Zavegepant nasal spray for the acute treatment of migraine: A Phase 2/3 double-blind, randomized, placebo-controlled, dose-ranging trial”. Headache. 62 (9): 1153–1163. doi:10.1111/head.14389. PMC 9827820. PMID 36239038.
- Noor N, Angelette A, Lawson A, Patel A, Urits I, Viswanath O, et al. (2022). “A Comprehensive Review of Zavegepant as Abortive Treatment for Migraine”. Health Psychology Research. 10 (3): 35506. doi:10.52965/001c.35506. PMC 9239361. PMID 35774914.
- Scuteri D, Tarsitano A, Tonin P, Bagetta G, Corasaniti MT (November 2022). “Focus on zavegepant: the first intranasal third-generation gepant”. Pain Management. 12 (8): 879–885. doi:10.2217/pmt-2022-0054. PMID 36189708. S2CID 252681912.
External links
- Clinical trial number NCT04571060 for “Randomized Trial in Adult Subjects With Acute Migraines” at ClinicalTrials.gov
- Clinical trial number NCT03872453 for “Acute Treatment Trial in Adult Subjects With Migraines” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Zavzpret |
| Other names | BHV-3500 |
| License data | US DailyMed: Zavegepant |
| Routes of administration | Nasal |
| Drug class | Calcitonin gene-related peptide receptor antagonist |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1337918-83-8as HCl: 1414976-20-7 |
| PubChem CID | 53472683as HCl: 134819878 |
| DrugBank | DB15688 |
| ChemSpider | 30814207 |
| UNII | ODU3ZAZ94Jas HCl: 000QCM6HAL |
| KEGG | D11898as HCl: D11899 |
| ChEMBL | ChEMBL2397415as HCl: ChEMBL4650220 |
| Chemical and physical data | |
| Formula | C36H46N8O3 |
| Molar mass | 638.817 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
////////FDA 2023, APPROVALS 2023, Vazegepant, BMS-742413, BHV-3500, ザベジェパント , Zavegepant, ZAVZPRET, BMS
PFIZERCC1=CC(=CC2=C1NN=C2)CC(C(=O)N3CCN(CC3)C4CCN(CC4)C)NC(=O)N5CCC(CC5)C6=CC7=CC=CC=C7NC6=O
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MAVORIXAFOR
MAVORIXAFOR
AMD 070
N1-(1H-BENZIMIDAZOL-2-YLMETHYL)-N1-((S)-5,6,7,8-TETRAHYDROQUINOLIN-8-YL)-BUTANE-1,4-DIAMINE
fda approved 4/26/2024, To treat WHIM syndrome (warts, hypogammaglobulinemia, infections and myelokathexis), Xolremdi
Mavorixafor (AMD-070) is a potent, selective and orally available CXCR4 antagonist, with an IC50 value of 13 nM against CXCR4 125I-SDF binding, and also inhibits the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC50 of 1 and 9 nM, respectively.
| Molecular Weight | 349.47 |
|---|---|
| Appearance | Solid |
| Formula | C21H27N5 |
| CAS No. | 558447-26-0 |
| SMILES | NCCCCN(CC1=NC2=C(N1)C=CC=C2)[C@@H]3C4=C(CCC3)C=CC=N4 |
PHASE 2
Mavorixafor trihydrochloride
| Molecular Weight | 458.86 |
|---|---|
| Appearance | Solid |
| Formula | C21H30Cl3N5 |
| CAS No. | 2309699-17-8 |
| SMILES | [H]Cl.[H]Cl.[H]Cl.NCCCCN(CC1=NC2=CC=CC=C2N1)[C@@H]3C4=NC=CC=C4CCC3 |
AMD-070 is a small molecule drug candidate that belongs to a new investigational class of anti-HIV drugs known as entry (fusion) inhibitors. Approximately 76% of HIV-patients with measurable viral load are infected with a strain of virus that is resistant to one or more classes of antiretroviral agents, thus reducing treatment options. Unlike many existing HIV drugs that target the virus after it has infected a healthy cell, AMD-070 blocks the virus from entering a healthy cell, thus preventing the replication process. AMD-070 targets the CXCR4 receptor on HIV and prevents the virus from entering and infecting healthy cells. AMD-070 is specific for the CXCR4 receptor and does not interact with any other chemokine receptors in vitro. AMD-070 strongly inhibits viral infection by all CXCR4 using virus (including virus using CXCR4 alone and/or virus using CXCR4 and CCR5) in vitro. AMD-070 is orally bioavailable in animals, it has suitable PK and toxicity profile for oral dosing. AMD-070 shows additive or synergistic effects in vitro in combination with other known anti-HIV agents. AMD-070 is active against CXCR4 using HIV strains that are resistant to existing antiretroviral therapies in vitro, reveals potent anti-HIV activity against CXCR4-using laboratory strains and clinical isolates. MD-070 had been in phase II clinical trials by Genzyme for the treatment of HIV infection. However, this research has been discontinued. AMD-070 has been studied in Phase I/II clinical trials for the treatment of Renal cell carcinoma and Phase I clinical trials for the treatment of malignant melanoma and solid tumours.
PAPER
https://pubs.acs.org/doi/10.1021/acs.oprd.2c00076
Org. Process Res. Dev. 2022, 26, 6, 1831–1836
A novel and practical synthesis of mavorixafor (1) is reported. The novelty of this synthetic route is the use of 8-chloro-5,6,7,8-tetrahydroquinoline (9) and 1,4-diaminobutane as the materials, instead of 8-amino-5,6,7,8-tetrahydroquinoline (4) and N,N-diprotected aminobutyraldehyde (6a or 6b). The preparation of (S)-8-(4-aminobutylamino)-5,6,7,8-tetrahydroquinoline (13) by resolution with N-acetyl-l-leucine was first achieved. Then the one-pot synthesis of 1 from 13 involving protection, condensation, and subsequent hydrolysis was successfully developed. In addition, the final product with a satisfactory purity (>99.5%, detected by both achiral and chiral HPLC) was obtained by a simple operation (salification) without column chromatographic purification.
NEW PAT
Scheme I
Mavorixafor
EXEMPLIFICATION
Example 1: Synthesis of Sulfonate adduct F-2d:
Scheme V:
1) AcOH, NaCI, water 1) Na 2 S 2 O 5 , THF, water
2) n-Heptane, THF 2) THF/n-heptane, acetonitrile
Step 1C Step 1 D
Step 1A: Preparation of Dl
Charge diethyl-4-aminobutyl acetal (E) (1.00 wt, 1.00 eq) to vessel A. Charge acetonitrile (10.0 vol, 7.8 wt) and adjust temperature to 20°C. Heat the mixture to 40°C. Concentrate the reaction mixture to 6.0 vol under reduced pressure at 35 to 45°C.
[0098] Acetonitrile filler (5.0 vol, 3.9wt) at 35 to 45°C. Concentrate the reaction mixture to 6.0 vol under reduced pressure 35 to 45°C. This step is repeated once as described below.
[0099] Acetonitrile filler (5.0 vol, 3.9wt) at 35 to 45°C. Concentrate the reaction mixture to 6.0 vol under reduced pressure at 35 to 45°C. Cool to 20°C.
[00100] Charge di-tert-butyl dicarbonate (1.1 eq, 1.5 wt) to a drum, followed by acetonitrile (0.4 vol, 0.3 wt) and agitate until fully dissolved. Concentrate the reaction mixture to 6.0 vol under reduced pressure at 35 to 45°C.
[00101] Charge this di-tert-butyl dicarbonate solution in acetonitrile to vessel A maintaining 20°C. Charge acetonitrile (1.5 vol, 1.1 wt) to the solution as a line rinse and stir at 20°C for 30 to 60 min..
[00102] Charge 4-dimethylaminopyridine (0.076 wt, 0.10 eq) to the vessel A at 20°C. Heat the solution to 40°C. Concentrate the reaction mixture to 5.0 vol under reduced pressure. Charge acetonitrile (5.0 vol, 3.9 wt) to the solution. Concentrate the reaction mixture to 5.0 vol under reduced pressure.
[00103] Take the resulting solution of Dl into next reaction without isolation.
Step IB: Preparation of Cl
[00104] Charge acetonitrile (2.0 vol, 1.6 wt) at 35 to 45°C to vessel A containing solution of D-1 from Step 1A.
[00105] Charge di-tert-butyl dicarbonate (1.4 eq, 1.9 wt) to a drum, followed by acetonitrile (10.0 vol, 7.8 wt) and agitate until fully dissolved. Charge this di-tert-butyl dicarbonate solution to vessel A, 2 to 6 h while distilling under vacuum at 35 to 45°C maintaining the volume of the reaction at 7.0 vol. Load acetonitrile (3.0 vol, 2.4 wt) over 20 to 40 min. as a line rinse while distilling under vacuum at 35 to 45°C, maintaining the volume of the reaction at 7.0 vol.
[00106] Charge di-tert-butyl dicarbonate, (0.14 eq, 0.19 wt) to a drum, followed by acetonitrile (1.0 vol, 0.74 wt) and agitate until fully dissolved. Charge this di-tert-butyl dicarbonate solution to vessel A over 20 to 40 min.. Charge acetonitrile (0.3 vol, 0.24 wt) over 10 to 20 min as a line rinse while distilling under vacuum at 35 to 45°C, maintaining the volume of the reaction at 7.0 vol.
[00107] Concentrate the reaction mixture to 5.0 vol distilling under vacuum at 35 to 45°C.
[00108] Charge n-heptane, (7.5 vol, 5.1 wt) to the reaction mixture, and concentrate the reaction mixture to 5.0 vol under reduced pressure at 40°C. This step is repeated once as described below.
[00109] Charge n-heptane, (7.5 vol, 5.1 wt) to the reaction mixture, and concentrate the reaction mixture to 5.0 vol under reduced pressure at 40°C.
[00110] Charge decolorizing, activated charcoal (0.2 wt) to the solution and stir for 1 to 2 h at 40°C. Filter the reaction mixture at 40°C. Charge n-heptane, (2.0 vol, 1.4 wt) to the reactor vessel and stir for 5 to 15 min. at 20°C before charging to the filter as a line rinse. Combine the filtrate and wash, and as required adjust to 20°C.
[00111] Take the resulting solution of Cl into next reaction without isolation.
Step 1C: Preparation of Bl
[00112] Charge 15% v/v acetic acid (2.0 vol) caution gas evolution, to vessel A containing solution of Cl from Step IB, maintaining the temperature at 20°C and stir for 10 min. at 20°C. Allow the phases to separate for 15 min. at 20°C. Discharge the aqueous phase to waste, retaining the organic phase in vessel A. This step is repeated once as described below.
[00113] Charge 15% v/v acetic acid (2.0 vol) maintaining 20°C and stir for 10 min. at 20°C. Allow the phases to separate for 15 min. at 20°C. Discharge the aqueous phase to waste, retaining the organic phase in vessel A.
[00114] Adjust the reaction to 30°C. Charge 4% w/w sodium chloride solution (2.1 vol) to the vessel maintaining the temperature at 30°C. Charge glacial acetic acid (4.1 vol, 4.3 wt) to the vessel maintaining 30°C. Stir the reaction mixture for 2 h maintaining the temperature at 30°C.
[00115] Charge purified water, (6.0 vol) at 30°C. Stir the contents for 5 to 10 min. at 30°C, and separate the phases, retaining the upper organic phase in vessel A. Charge the lower aqueous phase to vessel B.
[00116] Charge purified water (4.0 vol) at 30°C and stir for 5 to 10 min. maintaining the temperature at 30°C. Separate the phases at 30°C, retaining the upper organic phase in vessel A. Charge the lower aqueous phase to vessel B.
[00117] Adjust the temperature to 30°C of vessel B containing combined aqueous phases. Charge n-heptane, (2.0 vol, 1.4 wt) to vessel B and stir for 5 to 10 min. maintaining the temperature at 30°C. Separate the phases at 30°C, over 15 min.. Charge the upper organic phase to vessel A and recharge the lower aqueous phase to vessel B. This step is repeated two additional times as described below.
[00118] Charge n-heptane, (2.0 vol, 1.4 wt) to vessel B and stir for 5 to 10 min. maintaining the temperature at 30°C. Separate the phases at 30°C, over 15 min.. Charge the upper organic phase to vessel A and recharge the lower aqueous phase to vessel B.
[00119] Charge n-heptane, (2.0 vol, 1.4 wt) to vessel B and stir for 5 to 10 min. maintaining the temperature at 30°C. Separate the phases at 30°C, over 15 min., discharge the lower aqueous phase to waste and charge the upper organic layer to vessel A.
[00120] Concentrate the combined organic phases in vessel A to 3.0 vol at 10 to 20°C under reduced pressure. Offload the solution to new HDPE drum(s) and line rinse with n-heptane (0.5
vol, 0.4 wt) at 20°C. Homogenize the drum and store as “Bl solution in n-heptane,” and take into next reaction without isolation.
Step ID: Preparation of F-2d
[00121] Calculate a new 1.00 wt based on the above assay.
[00122] Charge “Bl solution in n-heptane” from Step 1C (1.00 wt, 1.00 eq, corrected for w/w assay, ca. 3.0 vol), into an appropriate vessel. THF load (3.0 vol, 2.7 wt). Heat the reaction mixture to 40°C.
[00123] Charge purified water, (0.02 vol, 0.02 wt) followed by sodium metabisulphite, (0.125 eq, 0.08 wt) as a solid via the charge hole at 40°C. Stir the resulting mixture for 30 to 35 min. at 40°C. This step was repeated four additional times to add the reagent in five portions total, as detailed below.
[00124] Charge purified water, (0.02 vol, 0.02 wt) followed by sodium metabisulphite, (0.125 eq, 0.08 wt) as a solid via the charge hole at 40°C. Stir the resulting mixture for 30 to 35 min. at 40°C.
[00125] Charge purified water, (0.02 vol, 0.02 wt) followed by sodium metabisulphite, (0.125 eq, 0.08 wt) as a solid via the charge hole at 40°C. Stir the resulting mixture for 30 to 35 min. at 40°C.
[00126] Charge purified water, (0.02 vol, 0.02 wt) followed by sodium metabisulphite, (0.125 eq, 0.08 wt) as a solid via the charge hole at 40°C. Stir the resulting mixture for 30 to 35 min. at 40°C.
[00127] Charge purified water, (0.02 vol, 0.02 wt) followed by sodium metabisulphite, (0.125 eq, 0.08 wt) as a solid via the charge hole at 40°C. Stir the resulting mixture for 36 hours at 40°C.
[00128] Cool the reaction mixture to 20°C over 3 to 4 h at a target constant rate. Filter the reaction mixture at 20°C on a 1-2 pm cloth.
[00129] Wash the solid with a pre-mixed mixture of THF (0.5 vol, 0.5 wt) and n-heptane (0.5 vol, 0.3 wt) maintaining the temperature at 20°C. This step was repeated an additional three times, as detailed below.
[00130] Wash the solid with n-heptane, (2.0 vol, 1.4 wt) as a line rinse and apply to the filtercake at 20°C.
[00131] Wash the solid with n-heptane, (2.0 vol, 1.4 wt) as a line rinse and apply to the filtercake at 20°C.
[00132] Wash the solid with acetonitrile, (2.0 vol, 1.6 wt) as a line rinse and apply to the filtercake at 20°C.
[00133] Dry the solid at 38°C under a flow of nitrogen for 12 h.
[00134] Determine residual solvent content. Pass criteria acetonitrile <2.0% w/w, n-heptane <2.0% w/w and tetrahydrofuran <2.0% w/w.
[00135] Yield of compound F-2d: 52-69%.
[00136] ‘H NMR (400 MHz, d 6 -DMSO): 8 5.22 (s, 1H), 3.77 (s, 1H), 3.45 (t, 2H), 1.70 (m, 2H), 1.44 (m, 20H) ). 13 C NMR (400 MHz, d 6 -DMSO): 8 152.6, 83.2, 82.0, 46.5, 29.6, 28.1, 26.0. FTIR (wavenumber, cm’ 1 ) 3294, 1721, 1738, 1367, 1233, 1180, 1135, 1109, 1045.
Example 2: Synthesis of F-3a:
Scheme VI:
Step 2A: Preparation of Gl
[00137] Charge J, (1.00 wt, 1.00 eq) to vessel A. Charge purified water, (1.0 vol, 1.0 wt) to vessel A and as necessary adjust the temperature to 20°C. Charge concentrated hydrochloric acid, (4.0 eq, 3.0 vol, 3.6 wt) to vessel A maintaining the temperature at 20°C. Line rinse with purified water, (0.5 vol, 0.5 wt) maintaining the contents of vessel A at 15 to 25°C.
[00138] Charge chloroacetic acid, (1.3 wt, 1.5 eq) and purified water, (1.0 vol, 1.0 wt) to vessel B and as necessary, adjust the temperature to 20°C. Stir until fully dissolved, expected 10 to 20 min.
[00139] Charge the chloroacetic acid solution to vessel A maintaining the temperature of vessel A at 20°C. Line rinse vessel A with purified water, (0.5 vol, 0.5 wt) at 15 to 25°C and charge to vessel B at 20°C. Heat the reaction mixture to 80°C. Stir the reaction mixture at 80°C for 20 h.
[00140] Cool the reaction mixture to 10°C over 1.5 h. Load 47% w/w potassium phosphate solution (6.0 vol) over 60 min. targeting a constant rate maintaining 10°C. Adjust the pH of the reaction mixture by charging 47% w/w potassium phosphate solution to pH 7.0 maintaining the reaction temperature at 10°C. Expected charge is 2.0 to 3.5 vol 47% w/w potassium phosphate solution.
[00141] Stir the slurry for >30 min. maintaining 10°C and rechecking the pH, pass criterion pH 7.0. Filter the reaction mixture through 20 pm cloth at 10°C. Wash the filter-cake with purified water, (1.0 vol, 1.0 wt) at 10°C. This step is repeated additional three times as described below.
[00142] Slurry wash the filter-cake in the reactor vessel with purified water, (10.0 vol, 10.0 wt) for 45 min. to 90 min. at 10°C. Filter the mixture through 20 pm cloth at 10°C.
[00143] Slurry wash the filter-cake in the reactor vessel with purified water, (10.0 vol, 10.0 wt) for 45 min. to 90 min. at 10°C. Filter the mixture through 20 pm cloth at 10°C.
[00144] Slurry wash the filter-cake in the reactor vessel with purified water, (10.0 vol, 10.0 wt) for 45 min. to 90 min. at 10°C. Filter the mixture through 20 pm cloth at 10°C.
[00145] Wash the filter-cake with purified water, (1.0 vol, 1.0 wt) at 10°C. The filter-cake was washed with purified water additional five times as described below.
[00146] Wash the filter-cake with purified water, (1.0 vol, 1.0 wt) at 10°C.
[00147] Wash the filter-cake with acetonitrile, (2×1.3 vol, 2×1.0 wt) at 10°C.
[00148] Dry the filter-cake on the filter under vacuum and strong nitrogen flow through the filter cake at 20°C until the water content is <15.0% w/w by Karl-Fisher analysis.
[00149] Dry the filter-cake on the filter under vacuum and strong nitrogen flow through the filter cake at 30°C until the water content is <5.0% w/w by Karl-Fisher analysis.
[00150] Dry the filter-cake on the filter under vacuum and strong nitrogen flow through the filter cake at 50°C until the water content is <1.0% w/w by Karl-Fisher analysis.
[00151] Yield of compound Gl: about 75%.
Step 2B: Preparation of F-3a
Charge di-/c/7-butyl dicarbonate, (1.85 wt, 1.4 eq) to vessel A followed by N,N-dimethylformamide, (2.6 wt, 2.7 vol) and stir at 20°C for 20 min. until dissolution achieved. Add A,A-diisopropylethylamine, (0.08 wt, 0.11 vol, 0.1 eq) to contents of vessel A at 20°C. Heat the contents of vessel A to 40°C.
[00153] Charge Gl, (1.00 wt) to vessel B followed by YW-di methyl form am ide, (5.2 wt, 5.5 vol) and adjust to 14°C.
[00154] Charge the Gl/DMF solution from vessel B to vessel A over 5 h at 40°C, at an approximately constant rate. Line rinse with Y,Y-di methyl form am ide, (0.4 wt, 0.4 vol), maintaining vessel A at 40°C. Stir the resulting reaction mixture at 40°C for 16 h.
[00155] Charge decolorizing charcoal activated, (0.20 wt). Adjust the mixture to 40°C and stir at 40°C for 60 to 90 min..
[00156] Clarify (filter) the reaction mixture into vessel B at 40°C. Charge N,N-dimethylformamide, (0.9 wt, 1.0 vol) via vessel A and filter at 40°C. Charge purified water, (3.5 vol) to the combined filtrates, over 60 min., maintaining the temperature at 40°C. As required, cool the mixture to 35°C over 30 to 60 min..
[00157] Filler F-3a, (0.02 wt) as seed material at 35°C. Stir at 34°C for 1.5 h then check for crystallization. Cool slurry to 30°C over 40 min.
[00158] Filler F-3a, (0.02 wt) as seed material at 30°C. Stir at 30°C for 1.5 h then check for crystallization.
[00159] Cool slurry at 20°C over 3.5 h at a targeted constant rate. Stir at 20°C for 3 hours. Charge purified water, (1.0 vol), maintaining the temperature at 20°C over 60 min..
Stir at 20°C for 3 hours.
[00160] Cool slurry to 2°C over 2.5 h. Stir at 2°C for 2.5 hours. Filter through 20 pm cloth and pull dry until no further filtrate passes. Wash the solid with pre-mixed Y,Y-di methyl form am ide / purified water, (2.0 vol, 1:2 v:v) at 2°C. Wash the solid with purified water, (2 x 3.0 vol) at 2°C. Dry under vacuum at 28°C until KF <0.2% w/w, and Y,Y-di methyl form am ide <0.4% w/w.
[00161] Yield of compound F-3a: 62-70%.
Example 3: Synthesis of Mavorixafor:
Scheme VI:
nce
Step 3A: Preparation of imine Q-1
[00162] To vessel A charge purified water, (8.7 vol, 8.7 wt) followed by potassium phosphate, (5.52 eq, 5.3 wt) portion-wise and cool to 15°C. Charge tetrahydrofuran, (4.3 vol, 3.8 wt) and n-heptane, (2.2 vol, 1.5 wt) to vessel A and cool the biphasic mixture to 0°C. Charge Fl, (1.00 eq, 1.00 wt) to the vessel in 2 portions maintaining 0°C.
[00163] Charge F-2d, (1.10 eq, 1.95 wt) to the vessel in 4 portions maintaining 0°C, ensuring portions are spaced by 10 min.. Stir the resulting biphasic mixture for 1.5 h at 0°C. Allow the layers to separate for 45 min. at 0°C before separating the layers. Retain the upper organic phase within vessel A.
[00164] Take the resulting solution of Ql into next reaction without isolation.
Step 3B: Preparation of amine P-1
[00165] To vessel B, charge tetrahydrofuran, (6.0 vol, 5.3 wt) and adjust to 15°C. Charge zinc chloride, (1.5 eq, 0.92 wt) to vessel B in 4 portions, maintaining 10 to 30°C. Adjust the reaction mixture in vessel B to 15°C. Stir the mixture at 15°C for 1 hour. Charge sodium borohydride,(1.0 eq, 0.17 wt) to vessel B in 2 portions maintaining 15°C. Cool the reaction mixture in vessel B to 15°C. Stir the mixture for 1 hour maintaining 15°C. Cool the reaction mixture in vessel B to -5°C.
[00166] Cool the retained organic solution of Ql in vessel A, from Step 3A, to -5°C.
[00167] Charge the organic solution in vessel A into vessel B over 1 to 2 h maintaining -5°C. Charge tetrahydrofuran, (1.0 vol, 0.9 wt) to vessel A as a line rinse and adjust to -5°C. Transfer the contents of vessel A to vessel B maintaining -5°C.
[00168] Stir the resulting reaction mixture in vessel B for 1.5 h maintaining -5°C.
[00169] Charge purified water, (4.5 vol, 4.5 wt) and glacial acetic acid, (1.0 eq, 0.27 wt, 0.26 vol) to the cleaned vessel A and cool to 0°C. Charge the contents of vessel B to vessel A over 1 to 2 h maintaining 0°C. Charge tetrahydrofuran, (1.0 vol, 0.9 wt) to vessel B as a vessel rinse, cool to 0°C and transfer to vessel A maintaining 0°C.
[00170] Warm the resulting mixture in vessel A to 30°C. Stir the resulting mixture in vessel A at 30°C for 1 h. Allow the layers to settle for 15 min. at 30°C before separating the layers. Retain the upper organic phase.
[00171] Cool the retained organic phase to 15°C. Charge to the vessel 25% w/w ammonia solution (3.0 vol) at 10 to 30°C. Cool the reaction mixture to 20°C. Charge to the vessel 25% w/w ammonium chloride solution (3.0 vol) at 20°C and stir for 1 h. Separate the layers for 15 min. at 20°C, retain the upper organic phase. Wash the retained organic phase with 10% w/w sodium chloride solution (3.0 vol) at 20°C for 10 min.. Allow the layers to settle for 10 min. at 20°C before separating and retaining the upper organic phase within the vessel.
[00172] Charge tert-butyl methyl ether, (0.5 vol, 0.4 wt) to the organic phase. Cool the mixture to 5°C. Adjust the pH of the reaction mixture to pH 5 with hydrochloric acid aqueous solution (expected ca. 9.0 vol) over 1 h at a targeted constant rate at 5°C. Stir the mixture at 5°C for 45 min.. Measure the pH of the aqueous phase to confirm the value is pH 5.
[00173] Charge sodium chloride, (2.1 wt) to the reaction mixture at 5°C and stir the mixture until everything is dissolved. Adjust the temperature of the reaction mixture to 20°C. Separate the layers at 20°C and retain the organic phase within the vessel. Tetrahydrofuran charge, (1.5 vol, 1.3 wt) maintaining 20°C.
[00174] Charge to the vessel 24% w/w sodium chloride solution (7.5 vol) at 20°C and stir for 10 min.. Separate the layers at 20°C and retain the organic phase in the vessel. This step is repeated additional one more time as described below.
[00175] Charge to the vessel 24% w/w sodium chloride solution (7.5 vol) at 20°C and stir for 10 min.. Separate the layers at 20°C and retain the organic phase in the vessel.
[00176] Heat the retained organic phase to 35°C and concentrate the mixture to 6.0 vol under reduced pressure maintaining 35°C.
[00177] Tetrahydrofuran charge, (15.0 vol, 13.2 wt) maintaining 35°C. Concentrate the mixture to 6.0 vol under reduced pressure maintaining 35°C.
[00178] Tetrahydrofuran charge, (15.0 vol, 13.2 wt) maintaining 35°C. Concentrate the mixture to 11.0 vol under reduced pressure maintaining 35°C.
[00179] Cool the mixture to -5°C. Load tert-butyl methyl ether, (10.0 vol, 7.4 wt) over 1 h maintaining -5°C. Stir the mixture at -5°C for 1.5 hours. Filter the solid on 1 to 2 pm filter cloth at -5°C. Wash the solid with pre-mixed tetrahydrofuran, (1.9 vol, 1.7 wt) and tert-butyl methyl ether, (3.1 vol, 1.9 wt) at -5°C as a displacement wash.
[00180] Wash the solid with tert-butyl methyl ether, (5.0 vol, 3.7 wt) at -5°C.
[00181] Dry the solid on the filter under a flow of nitrogen at 23°C.
[00182] Yield of compound P-1: 76-87%.
Step 3C: Preparation of compound 0-1
[00183] Charge purified water, (2.0 vol, 2.0 wt) followed by potassium phosphate, (3.3 eq, 1.54 wt), carefully portion-wise, maintaining <15°C, to vessel A. Charge toluene, (4.5 vol, 3.9 wt) to the vessel maintaining <15°C. As necessary, adjust the temperature to 10°C.
[00184] Charge P-1, (1.00 eq, 1.00 wt) to the vessel in two portions maintaining 10°C. Stir the reaction mixture at 10°C for 15 min..
[00185] Load F-3a, (1.1 eq, 0.64 wt) in 4 equal portions ensuring portions are spaced by 10 min. at 10°C.
[00186] Tetrabutylammonium iodide (TBAI) filler (0.20 eq, 0.16 wt). Heat the reaction mixture to 40°C. Stir the reaction mixture at 40°C for 30 h.
[00187] Charge pre-mixed 2-mercaptoacetic acid, (0.40 eq, 0.08 wt, 0.06 vol), and toluene, (0.5 vol, 0.4 wt) over 20 min. to Vessel A at 40°C. Line rinse with toluene, (0.5 vol, 0.4 wt) at 40°C. Adjust the temperature of the reaction mixture to 50°C. Stir the mixture at 50°C for 2.5 hours.
[00188] Adjust the temperature of Vessel A to 20°C. Charge purified water, (3.0 vol, 3.0 wt) maintaining 20°C. Stir the reaction mixture at 20°C for 15 min. and transfer to a new, clean HDPE container. Line/vessel rinse with toluene, (0.5 vol, 0.4 wt) at 20°C. Clarify (filter) the reaction mixture via a 1 pm filter at 20°C into clean Vessel A. Wash the vessel and the filter with toluene, (0.5 vol, 0.4 wt) at 20°C. Allow the layers to separate for 15 min. at 20°C, retaining the upper organic layer (organic layer 1).
[00189] Wash the aqueous layer with toluene, (2.5 vol, 2.2 wt) at 20°C for 15 min.. Allow the layers to separate for 15 min. at 20°C. Retain the upper organic layer (organic layer 2).
[00190] Combine the organic layer 1 and organic layer 2 and adjust the temperature to 20°C. Wash the combined organic layers with 10% w/w sodium chloride solution (5.0 vol) at 20°C for 15 min.. Allow the layers to settle for 15 min. at 20°C. Retain the upper organic layer.
[00191] Take the resulting solution of Ol into next reaction without isolation.
Step 3D: Preparation of compound Kl
[00192] Charge n-butanol, (2.4 wt, 3.0 vol) to vessel B and adjust to 5°C. Charge concentrated sulfuric acid, (1.1 wt, 5.0 eq, 0.6 vol) slowly to Vessel B maintaining <15°C. Line rinse with toluene, (0.4 wt, 0.5 vol) maintaining <15°C. Adjust the temperature of Vessel B to 25°C.
[00193] Heat the n-butanol/ sulfuric acid solution in Vessel B to 55°C. Charge the organic layer from Vessel A (from Step 3C) to the butanol/ sulfuric acid solution in Vessel B over 60 to 90 min. maintaining 55°C. Charge toluene, (1.3 wt, 1.5 vol) to Vessel A as a line rinse and transfer to Vessel B maintaining 55°C. Stir the contents of Vessel B at 55°C for 1.5 h.
[00194] Stir the mixture in Vessel B for 4.5 h at 55°C. Cool the contents of Vessel B to 20°C over 10 h. Filter the slurry over 1-2 pm filter cloth under nitrogen at 20°C. Wash the filter cake with pre-mixed toluene, (3.5 wt, 4.0 vol) and n-butanol, (1.0 vol, 0.8 wt) at 20°C. Wash the filter cake with toluene, (4.3 wt, 5.0 vol) at 20°C. Dry the solid at 30°C under vacuum.
[00195] Correct the output weight for assay. Expected 50-55% w/w.
[00196] Yield of compound K1: 89-92%.
Step 3E: Preparation of Mavorixafor Drug Substance
[00197] Charge Kl, (1.00 eq, 1.00 wt, corrected for HPLC assay) in vessel A followed by nitrogen-purged purified water, (2.0 wt, 2.0 vol) and if necessary, adjust the temperature to 20°C. Charge nitrogen-purged toluene, (12.0 wt, 14.0 vol) to the solution maintaining 20°C. Charge nitrogen-purged n-butanol, (0.8 wt, 1.0 vol) to the solution maintaining 20°C. Heat the biphasic mixture to 30°C. Charge nitrogen-purged 3.0 M aqueous sodium hydroxide solution (6.2 eq, 5.9 vol) maintaining 30°C. Check the pH (expected 12 to 13). Adjust the pH of the aqueous layer to pH 10.0 with nitrogen-purged 0.3 M sulfuric acid solution (expected up to 2.5 vol) maintaining 30°C. Stir the mixture at 30°C for 45 min..
[00198] Measure the pH to confirm the value is pH 10.0.
[00199] Allow the layers to settle at 30°C for 30 min. and separate the layers retaining the organic phase in the vessel, and discharge the aqueous layer into a separate container (container C).
[00200] Charge pre-mixed toluene, (4.1 wt, 4.7 vol) and n-butanol, (0.24 wt, 0.3 vol) to a separate vessel; heat the contents to 30°C and charge the aqueous layer from container C. As required adjust the temperature to 30°C and stir for 5 to 10 min. at 30°C. Allow the phases to separate for 10 to 15 min. at 30°C. Discharge the aqueous phase to waste and combine the organic phase to the organic phase in vessel A.
[00201] Charge nitrogen-purged purified water, (2.0 wt, 2.0 vol) to the organic layer maintaining the temperature at 30°C and stir for 5 to 10 min. at 30°C. Allow the phases to separate for 10 to 15 min. at 30°C. Discharge the aqueous phase to waste retaining the organic phase in the vessel. Heat the retained organic solution to 40°C. Concentrate the resulting organic phase to 7.0 vol by vacuum distillation at 40°C.
[00202] Charge nitrogen -purged toluene, (13.0 wt, 15.0 vol) to the mixture and concentrate the solution 7.0 vol by vacuum distillation at 40°C. This step is repeated additional one time as described below.
[00203] Charge nitrogen -purged toluene, (13.0 wt, 15.0 vol) to the mixture and concentrate the solution 7.0 vol by vacuum distillation at 40°C.
[00204] Charge nitrogen-purged toluene, (7.0 wt, 8.0 vol) to the mixture at 40°C, heat to 55°C and clarify the hot reaction mixture under nitrogen via a 1 pm filter.
[00205] Charge clarified nitrogen-purged toluene, (1.7 wt, 2.0 vol) to the mixture as a line and vessel rinse at 40°C. Concentrate the solution to 7.0 vol by vacuum distillation at 40°C. At the end of the distillation the product is expected to have precipitated. Heat the mixture to 63°C.
[00206] Adjust the temperature to 60.5°C. This batch will be referred to as the main batch.
[00207] Load seed material, (0.02 wt) to a new clean container. Charge clarified nitrogen-purged toluene, (0.09 wt, 0.10 vol) to this seed material and gently shake.
[00208] Seed the main batch with the slurry maintaining the temperature at 60.5 ± 2°C. Stir the reaction at the 60.5± 2°C for 1 hour.
[00209] Cool to 40°C for 2.5 h. Stir the reaction at 40°C for 1 hour.
[00210] Cool to 30°C over 2 h.. Stir the reaction at 30°C for 1 h.
[00211] Cool to 25°C 50 min. Stir the reaction at 25°C over 2 hours.
[00212] Cool to 2°C over 4 h. Stir the mixture for 12 hours at 2°C.
[00213] Filter the mixture at 2°C over 1 to 2 pm cloth. Wash the filter cake with clarified nitrogen-purged toluene, (2.0 vol, 1.7 wt) at 2°C. Dry the filter cake under vacuum and a flow of nitrogen for 1.5 h.
[00214] Dry the solid at 40°C under vacuum and a flow of nitrogen until drying specification is achieved.
[00215] Yield of the final compound mavorixafor: 72%.
[00216] When toluene is used as the recrystallization solvent, optionally with a dissolution aid such butanol or methanol, for maxorixa for recrystallization, advantages were found compared to using dichloromethane and isopropyl acetate. We have found that these solvents do not react with the API, and accordingly we believe that this change has caused the significant reduction of impurities A (imine), B (N-formyl) and C (acetamide) that we have observed.
[00217] In some embodiments, the mavorixafor composition included 7000, 6000, 5000, 4500, 4450, 4000, 3500, 3000, 2500, 2000, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1400, 1400, 1400 gold 50 ppm of toluene or less. In some embodiments, the mavorixafor composition comprises a detectable amount of toluene. In some embodiments, the mavorixafor composition comprises from a detectable amount of toluene to 1350 ppm of toluene.
////////
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| Description | Mavorixafor (AMD-070) is a potent, selective and orally available CXCR4 antagonist, with an IC50 value of 13 nM against CXCR4 125I-SDF binding, and also inhibits the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC50 of 1 and 9 nM, respectively. |
|---|---|
| IC50 & Target[1] | 125I-SDF-CXCR413 nM (IC50)HIV-1 (NL4.3 strain)1 nM (IC50, in MT-4 cells)HIV-1 (NL4.3 strain)9 nM (IC50, in PBMCs)HIV-1 (NL4.3 strain)3 nM (IC90, in MT-4 cells)HIV-1 (NL4.3 strain)26 nM (IC90, in PBMCs) |
| In Vitro | Mavorixafor (AMD-070) is a potent and orally available CXCR4 antagonist, with an IC50 value of 13 nM against CXCR4 125I-SDF binding, and also inhibits the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC50 of 1 and 9 nM, respectively. Mavorixafor (AMD-070) shows no effect on other chemokine receptors (CCR1, CCR2b, CCR4, CCR5, CXCR1, and CXCR2)[1]. Mavorixafor (AMD-070) (6.6 µM) significantly suppresses the anchorage-dependent growth, the migration and matrigel invasion of the B88-SDF-1 cells[2].MCE has not independently confirmed the accuracy of these methods. They are for reference only. |
| In Vivo | Mavorixafor (AMD-070) (2 mg/kg, p.o.) significantly reduces the number of metastatic lung nodules in mice, and lowers the expression of human Alu DNA in mice, without body weight loss[2].MCE has not independently confirmed the accuracy of these methods. They are for reference only. |
| Clinical Trial | NCT NumberSponsorConditionStart DatePhaseNCT00089466National Institute of Allergy and Infectious Diseases (NIAID)|AIDS Clinical Trials GroupHIV InfectionsNovember 2004Phase 1|Phase 2NCT02667886X4 PharmaceuticalsClear Cell Renal Cell CarcinomaJanuary 2016Phase 1|Phase 2NCT02823405X4 PharmaceuticalsMelanomaSeptember 15, 2016Phase 1NCT00361101Genzyme, a Sanofi Company|SanofiHIV Infections|X4 Tropic VirusOctober 2005Phase 1NCT03005327X4 PharmaceuticalsWHIM SyndromeDecember 2016Phase 2NCT04274738X4 PharmaceuticalsWaldenstrom´s MacroglobulinemiaApril 30, 2020Phase 1NCT04154488X4 PharmaceuticalsNeutropeniaOctober 16, 2020Phase 1NCT03995108X4 PharmaceuticalsWHIM SyndromeOctober 17, 2019Phase 3NCT05103917Abbisko Therapeutics Co, LtdTriple Negative Breast CancerJuly 21, 2021Phase 1|Phase 2NCT00063804National Institute of Allergy and Infectious Diseases (NIAID)|AIDS Clinical Trials GroupHIV Infections Phase 1NCT02923531X4 PharmaceuticalsClear Cell Renal Cell CarcinomaDecember 7, 2016Phase 1|Phase 2NCT02680782X4 Pharmaceuticals|CovanceHealthyJanuary 12, 2016Phase 1 |
REF
- [1]. Skerlj RT, et al. Discovery of novel small molecule orally bioavailable C-X-C chemokine receptor 4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication. J Med Chem. 2010 Apr 22;53(8):3376-88. [Content Brief][2]. Chow LN, et al. Impact of a CXCL12/CXCR4 Antagonist in Bleomycin (BLM) Induced Pulmonary Fibrosis and Carbon Tetrachloride (CCl4) Induced Hepatic Fibrosis in Mice. PLoS One. 2016 Mar 21;11(3):e0151765. [Content Brief][3]. Uchida D, et al. Effect of a novel orally bioavailable CXCR4 inhibitor, AMD070, on the metastasis of oral cancer cells. Oncol Rep. 2018 Jul;40(1):303-308. [Content Brief]
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Amcenestrant (SAR 439859)
Amcenestrant (SAR 439859)
アムセネストラント
| Molecular Weight | 554.48 |
|---|---|
| Formula | C31H30Cl2FNO3 |
| CAS No. | 2114339-57-8 |
6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid
8-(2,4-dichlorophenyl)-9-(4-{[(3 S )-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro – 5H- Benzo[7]annulene-3-carboxylic acid
8-(2,4-Dichlorophenyl)-9-(4-{[(3 S )-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5 H -benzo [7]annulene-3-carboxylic acid
C31H30Cl2FNO3 : 554.48 [ 2114339-57-8 ] _ _ _ _ _ _
| Efficacy | Antineoplastic, Selective estrogen receptor downregulator |
|---|---|
| Comment | Selective estrogen receptor downregulator (SERD) Treatment of breast cancer |
SAR439859 (compound 43d) is an orally active, nonsteroidal and selective estrogen receptor degrader (SERD). SAR439859 is a potent ER antagonist and has ER degrading activity with an EC50 of 0.2 nM for ERα degradation. SAR439859 demonstrates robust antitumor efficacy and limited cross-resistance in ER+ breast cancer.
Amcenestrant is an orally available, nonsteroidal selective estrogen receptor degrader/downregulator (SERD), with potential antineoplastic activity. Upon oral administration, amcenestrant specifically targets and binds to the estrogen receptor (ER) and induces a conformational change that promotes ER degradation. This prevents ER-mediated signaling and inhibits both the growth and survival of ER-expressing cancer cells.
Amcenestrant is reported to be a selective estrogen receptor degrader (SERD) which has estrogen receptor antagonist properties and accelerates the proteasomal degradation of the estrogen receptor. Amcenestrant is under clinical investigation as an anticancer agent, in particular for treatment of breast cancer.
The compound and processes for preparation thereof are described in International Publication No. WO 2017/140669.
Crystalline forms are described in International Publication No. WO 2021/116074.
PAPER
Journal of Medicinal Chemistry (2020), 63(2), 512-52
https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01293
6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3- yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic Acid (43d).
To a solution of 6-(2,4-dichloro-phenyl)-5-[4-[1-(3-fluoropropyl)-pyrrolidin-3-yloxy]-phenyl]-8,9-dihydro-7H-benzocycloheptene-2-carboxylic acid methyl ester (42d) (80 mg, 140.72 μmol) in methanol (5 mL) was added 5 N NaOH (562.88 μL), the reaction mixture was heated to 60 °C for 5 h, and the solvent was removed under reduced pressure. The residue was taken up in water (10 mL), and aqueous HCl (5 M) was added to pH 7. The slurry was extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of dichloromethane, acetonitrile, and methanol (90/5/5 v/v/v) to give 60 mg (77%) of 6- (2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]- oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d). 1 H NMR (400 MHz, DMSO-d6): 1.68 (m, 1H), 1.79 (dm, J = 25.3 Hz, 2 H), 2.07 to 2.23 (m, 5H), 2.38 (m, 1H), 2.46 (t, J = 7.2 Hz, 2H), 2.52 (m, 1H), 2.62 (m, 1H), 2.55 to 2.89 (m, 3H), 4.47 (td, J = 6.2 and 47.6 Hz, 2H), 4.72 (m, 1H), 6.63 (d, J = 8.9 Hz, 2H), 6.71 (m, 3H), 7.18 (d, J = 8.4 Hz, 1H), 8.26 (dd, J = 2.0 and 8.4 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 12.3 (m, 1H). LCMS: 554 (M + H)+ .
PATENT
Amcenestrant can be prepared according to methods known from the literature, for example U.S. Patent No. 9,714,221.
Example 1: Preparation of amorphous Amcenestrant
[00164] Amcenestrant (20 mg, prepared according to U.S. Patent No. 9,714,221) was dissolved in ethyl acetate (0.2 mL) at room temperature (25°C). Solution was left in opened flask at RT for 16 days, until all the solvent evaporated. Obtained solid was analyzed by XRPD.
PATENT
U.S. Patent No. 9,714,221
https://patents.google.com/patent/US9714221B1/en
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017140669
Example 51. 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid
Methode B:
Step 1 : 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.
To a solution of methyl 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide (D5) (150 mg, 298.56 μιηοΙ), in dioxane (12 ml) and water (2 ml), was added 2,4-dichlorophenyl-boronic acid (62.67 mg, 328.41 μηηοΙ), Cs2C03 (204.48 mg, 626.97 μηιοΙ), and Pd(dppf)CI2 (14.63 mg, 17.91 μιηοΙ). The reaction mixture was heated at 90°C for 3 hours, and partitioned between AcOEt and water. The phases were separated and the organic phase washed with brine, dried over MgS04 and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) to give 80 mg (47%) of 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.
LC/MS (m/z, MH+): 568
Step 2 : 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid
To a solution of 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (80 mg, 140.72μιηο!) in MeOH (5 ml) was added a solution of NaOH (562.88 μΙ, 5 M) and the reaction mixture was heated at 60°C for 5 hours and the solvent removed under reduced pressure. The residue was taken up in water (10 ml) and aqueous HCI (5 M) added to pH
7. The slurry was extracted with DCM, dried over MgS04 and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (90/5/5; V/V/V) to give 60 mg (77%) of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid.
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019020559
Intermediate (c). Tert-butyl (3S)-3-[4-(4,4!5!5-tetramethyl-1 !3,2-dioxaborolan-2yl)phenoxy]pyrrolidine-1 -carboxylate
To a solution of commercially available 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (a) (82.7 g, 364.51 mmol) in THF (2 L) was added under argon (R)-1 -N-Boc-3-hydroxypyrrolidine (b) (84.43 g, 437.41 mmol) followed by Ν,Ν,Ν’,Ν’-tetramethylazodicarboxamide (99.1 g, 546.77 mmol). The clear reaction mixture turned orange and triphenylphosphine (143.41 g, 546.77 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours, meanwhile a precipitate of triphenylphosphine oxide formed (Ph3P=0). The reaction mixture was poured in water (1 .5 L) and extracted with ethyl acetate (AcOEt) (3×1 .5 L). Gathered organic phases were dried over magnesium sulfate (MgS04), filtered and concentrated under reduced pressure. The residue was taken up into diisopropylether (1 .5 L) and the solid formed (Ph3P=0) was filtered. The solvent was concentrated under reduced pressure and the residue purified by column chromatography eluting with a mixture of heptane with AcOEt (90/10; v/v) to give 145 g (100%) of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1 -carboxylate (c) as a colorless oil.
1H NMR (400 MHz, DMSO-d6, δ ppm): 1 .27 (s : 12H); 1 .39 (s : 9H); 2.05 (m : 1 H); 2.14 (m : 1 H); 3.37 (3H); 3.55 (m : 1 H); 5.05 (s : 1 H); 6.94 (d, J = 8.4 Hz : 2H); 7.61 (d, J = 8.4 Hz : 2H)
Intermediate (d). (3S)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine, hydrochloride
To a solution of (S)-tert-butyl 3-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1 -carboxylate (c) (80 g, 195.23 mmol) in MeOH (450 ml) was added slowly HCI 4N in dioxane (250 ml).
After 1 .5 hours, the reaction mixture was concentrated under reduced pressure and the residue was taken up into Et20 with stirring to give a solid which then was filtered and dried under vacuum to give 61.8 g (95%) of (3S)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine, hydrochloride (d) as a white powder.
1H NMR (400 MHz, DMSO-d6, δ ppm): 1.28 (s : 12H); 2.10 (m : 1 H); 2.21 (m : 1 H); 3.31 (3H); 3.48 (m : 1 H); 5.19 (m : 1 H); 6.97 (d, J = 8.4 Hz : 2H); 7.63 (d, J = 8.4 Hz : 2H); 9.48 (s : 1 H); 9.71 (s : 1 H).
LC/MS (m/z, MH+): 290
Intermediate (e). (3S)-1 -(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine
To a suspension of (S)-3-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine hydrochloride (d) (20 g, 61.42 mmol) in acetonitrile (100 ml), was added K2C03 (21 .22 g, 153.54 mmol) and 1 -iodo-3-fluoropropane (12.15 g, 61.42 mmol), under argon. The reaction
mixture was stirred at 40°C for 24 hours. After cooling to room temperature, the reaction mixture was filtered and washed with acetonitrile. The filtrate was concentrated under reduced pressure and the residue was taken up in DCM and the solid formed was filtered and washed with DCM. The filtrate was concentrated to give 21.5 g (100%) of (3S)-1 -(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) as a yellow foam.
1H NMR (400 MHz, DMSO-d6, δ ppm): 1.27 (s : 12H); 1 .77 (m : 2H); 1 .84 (m : 1 H); 2.27 (m : 1 H); 2.41 (m : 1 H); 2.49 (2H); 2.62 (dd, J = 2.6 and 10.4Hz : 1 H); 2.69 (m : 1 H); 2.83 (dd, J = 6.2 and 10.4Hz : 1 H); 4.47 (td, J = 6.2 and 47Hz : 2H) ; 4.99 (m : 1 H); 6.77 (d , J = 8.4 Hz : 2H); 7.58 (d, J = 8.4 Hz : 2H).
LC/MS (m/z, MH+): 350
Intermediate (B). 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate
To a solution of 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A) (1 .52 g, 8.63 mmol), in acetone (60 ml), was added K2C03 (1 .19 g, 8.63 mmol) and pivaloyl chloride (1.06 ml, 8.63 mmol). The reaction mixture was stirred at room temperature for 16 hours, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane in AcOEt (100/0 to 85/15, v/v) to give 1.55 g (69%) of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate (B) as a colorless oil.
1H NMR (400 MHz, DMSO-d6, δ ppm): 7.65 (d, 1 H); 7.10-7.04 (m, 2H); 2.95 (t, 2H); 2.68 (t, 2H); 1 .85-1 .65 (m, 4H).
LC/MS (m/z, MH+): 261
Intermediate (C). 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate
To a solution of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate (B) (15 g, 57.62 mmol) in DCM (500 ml) was added dropwise under argon pyridine (7.28 ml, 86.43 mmol) and trifluoromethanesulfonic anhydride (19.58 ml, 1 15.24 mmol). The reaction mixture was stirred at room temperature for 2 hours and ice (200 g) was added. The phases were separated, the aqueous phase was washed with DCM and the gathered organic phases were dried over MgS04, filtered and evaporated under reduced pressure to give 22 g (97%) of 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate (C) as a white solid.
LC/MS (m/z, MH-): 391
Intermediate (D). 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimeth lpropanoate
To a solution of 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (C) (22 g, 56.07 mmol) and (3S)-1 -(3-fluoropropyl)-3-[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) (20.56 g, 58.87 mmol) in dioxane (420 ml) and water (120 ml) was added under argon Pd(dppf)CI2 (2.75 g, 3.36 mmol) and Cs2C03 (36.57 g, 1 12.13 mmol). The reaction mixture was stirred for 1 hour at room temperature and was partitioned between water and DCM. The aqueous phase was washed with DCM and the gathered organic phases dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0 to 5%; V/V) to give 31 g (100 %) of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (D).
LC/MS (m/z, MH+): 466
Intermediate (E). 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol
To a solution under argon of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (D) (24.8 g, 53.26 mmol) in MeOH (300 ml), was added NaOH 5M (23 ml, 1 15.00 mmol). The reaction mixture was stirred for 2 hours at room temperature. pH was then adjusted to 7 by addition of 6N aqueous HCI solution. The MeOH was concentrated under reduced pressure, then DCM was added. The organic phase was dried over MgS04, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/ MeOH from 100/0 to 95/05 to give 18.8 g (93%) of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (E) as a beige solid.
LC/MS (m/z, MH+): 382
Intermediate (F). 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate
To a solution of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (E) (20.6 g, 54.00 mmol) in DCM (200 ml) and pyridine (6.55 ml, 81 .00 mmol), cooled to 5°C (ice bath), was added dropwise trifluoromethanesulfonic anhydride (18.93 ml, 108.00 mmol) under argon, and the reaction temperature was maintained <15°C. The ice bath was removed, and the brown suspension was stirred at room temperature for 2 hours. Ice (200 g) and DCM (200 ml) were added and the phases separated. The organic phase was dried over MgS04, and concentrated under reduced pressure. The residue was
purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 24.7 g (89.1 %) of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (F) as a brown oil.
LC/MS (m/z, MH+): 514
Intermediate (G). Methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate
To a solution of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (F) (10.1 g, 19.67 mmol) in DMF (66 ml) and MeOH (33 ml), were added Pd(dppf)CI2 (909 mg, 1.18 mmol) and diisopropylethylamine (7.21 ml). The black suspension was carbonylated in an autoclave at 70°C under 5 bars of CO for 5 hours. The reaction mixture was filtered, then the filtrate was partially concentrated under reduced pressure. The residue was partitioned between AcOEt and water. The organic phase was washed with water (2x 100 ml), dried over MgS04, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCIW MeOH from 100/0 to 95/05 to give 7.13 g (86%) of methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (G) as a brown gum.
LC/MS (m/z, MH+): 424
Intermediate (A1 ). 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yltrifluoromethanesulfonate
To a solution of commercially available 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A) (18.5 g, 105 mmol) in DCM (185 ml) and lutidine (13.35 ml, 1 13.505 mmol), cooled at 5°C under argon, was added dropwise trifluoromethanesulfonic anhydride (20.22 ml,
123.29 mmol) while keeping temperature between 10 and 20°C. The reaction mixture was stirred for 1 hour at 5°C then at room temperature for 1 hour.
Then, ice (200 g) was added and the slurry partitioned between water and DCM. The organic phase was washed with aqueous NaHC03 solution, dried over MgS04, filtered off and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane/AcOEt from 100 to 90/10 to give 28.2 g (87%) of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate (A1 ) as an orange oil. LC/MS (m/z, MH+): 309
Intermediate (B1 ). Methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate
To a solution of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate (A1 ) (5.03 g, 16.32 mmol) in DMF (24 ml) and MeOH (12 ml), were added Pd(dppf)CI2 (754 mg, 0.98 mmol) and diisopropylethylamine (6 ml). The black suspension was carbonylated in an autoclave at 70°C under 5 bars of CO for 2.5 hours. The reaction mixture was filtered, then the filtrate was partially concentrated under reduced pressure, and the residue, was partitioned between AcOEt and water. The organic phase was washed with water (2x 75 ml) and aqueous HCI 0.5 N, dried over MgS04 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane/AcOEt from 100/0 to 90/10 to give 3.4 g (95%) of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (B1 ) as a colorless oil.
LC/MS (m/z, MH+): 219
Intermediate (C1 ). Methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate
To a solution of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (B1 ) (18,19 g, 83,34 mmol) in DCM (500 ml) and anhydrous pyridine (1 1 ml, 130,56 mmol), cooled at 5°C under argon, was added dropwise trifluoromethanesulfonic anhydride (30 ml, 176,54 mmol). The reaction mixture, a thick suspension, was stirred at room temperature for 24 hours, then ice was added and partitioned between water and DCM. The organic phase was dried over MgS04, filtered off and concentrated under reduced pressure to give 29 g (100%) of methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (C1 ) as a yellow gum.
LC/MS (m/z, MH+): 351
Intermediate (G). Methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate
To a solution of methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (C1 ) (29 g, 82.9 mmol), (3S)-1 -(3-fluoropropyl)-3-[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) (28.9 g, 82.9 mmol), in dioxane (225 ml) were added Pd(dppf)CI2 under argon, complex with DCM (3.73 g, 4.57 mmol) and Cs2C03 1 .5 M aqueous solution (1 1 1.12 ml, 166.68 mmol). The reaction mixture was stirred at 60°C for 1 hour.
After cooling to room temperature, the reaction mixture was poured into a mixture of water (500 ml) and AcOEt (400ml). The organic phase was washed with brine, dried over MgS04, filtered on celite and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 23 g (65%) of methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (G) as a brown gum.
LC/MS (m/z, MH+): 424
Intermediate (H). Methyl 8-bromo-9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide
To a solution of methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro- 5H-benzo[7]annulene-3-carboxylate (G) (13.93 g, 32.89 mmol), in DCM (150 ml) was added under argon pyridinium tribromide (15.78 g, 44.41 mmol). The reaction mixture was stirred for 1 hour at room temperature. Water (200 ml) was added, organic phase was then dried over MgS04, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 16.4 g (85%) of methyl 8-bromo-9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro- 5H-benzo[7]annulene-3-carboxylate hydrobromide (H) as a yellow meringue.
LC/MS (m/z, MH+): 502
Intermediate (I). 6-(2,4-dichloro-phenyl)-5-{4-[1 -(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}- -dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.
To a solution of methyl 8-bromo-9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide (H) (150 mg, 298.56 μηηοΙ), in dioxane (12 ml) and water (2 ml), was added 2,4-dichlorophenyl-boronic acid (62.67 mg, 328.41 μηιοΙ), Cs2C03 (204.48 mg, 626.97 μπιοΙ), and Pd(dppf)CI2 (14.63 mg, 17.91 mol). The reaction mixture was heated at 90°C for 3 hours, and partitioned between AcOEt and water. The phases were separated and the organic phase washed with brine, dried over MgS04 and concentrated under reduced pressure. The residue was purified by column
chromatography eluting with a mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) to give 80 mg (47%) of 6-(2,4-dichloro-phenyl)-5-{4-[1 -(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (I).
LC/MS (m/z, MH+): 568
Compound (1 ). 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen -2-carboxylic acid
To a solution of 6-(2,4-dichloro-phenyl)-5-{4-[1 -(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (I) (80 mg, 140.72 μηηοΙ) in MeOH (5 ml) was added a solution of NaOH (562.88 μΙ, 5 M) and the reaction mixture was heated at 60°C for 5 hours and the solvent removed under reduced pressure. The residue was taken up in water (10 ml) and aqueous HCI (5 M) added to pH 7. The slurry was extracted with DCM, dried over MgS04 and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (90/5/5; V/V/V) to give 60 mg (77%) of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid. 1H NMR (400 MHz, DMSO-d6, δ ppm): 1 .68 (m, 1 H); 1 ,79 (dm, J=25.3 Hz, 2 H); 2.07 to 2.23 (m, 5 H); 2.38 (m, 1 H); 2.46 (t, J=7.2 Hz, 2 H); 2.52 (m, 1 H); 2.62 (m, 1 H); 2.55 to 2.89 (m, 3 H); 4.47 (td, J=6.2 and 47.6 Hz, 2 H); 4.72 (m, 1 H); 6.63 (d, J=8.9 Hz, 2 H); 6.71 (m, 3 H); 7.18 (d, J=8.4 Hz, 1 H); 8.26 (dd, J=2.0 and 8.4 Hz, 1 H); 7.58 (d, J=2,0 Hz, 1 H); 7.63 (d, J=8.4 Hz, 1 H); 7.79 (s, 1 H); 12.3 (m, 1 H)
LC/MS (m/z, MH+): 554
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