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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai)
, INDIA
36Yrs Exp. in the feld of Organic Chemistry,Working for AFRICURE PHARMA as ADVISOR earlier with GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google,
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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was
with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules
and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc
He has total of 32 International and Indian awards
Percent Composition: C 41.81%, H 4.56%, N 14.63%, O 27.85%, S 11.16%
Literature References: Prepn from 5-nitrofurfural and 4-amino-3-methyltetrahydro-1,4-thiazine 1,1-dioxide: Herlinger et al.,DE1170957 corresp to US3262930 (1964 and 1966 to Bayer). Series of articles on pharmacology and clinical findings: Arzneim.-Forsch.22, 1563-1642 (1972). Toxicity data: K. Hoffmann, ibid. 1590.
Properties: Orange-red crystals from dil acetic acid, mp 180-182°. LD50 in mice, rats (mg/kg): 3720, 4050 by gavage (Hoffmann).
Melting point: mp 180-182°
Toxicity data: LD50 in mice, rats (mg/kg): 3720, 4050 by gavage (Hoffmann)
Common side effects include abdominal pain, headache, nausea, and weight loss.[1] There are concerns from animal studies that it may increase the risk of cancer but these concerns have not be found in human trials.[5] Nifurtimox is not recommended in pregnancy or in those with significant kidney or liver problems.[5] It is a type of nitrofuran.[5]
Chagas disease, caused by a parasite known as Trypanosoma cruzi (T.cruzi), is a vector-transmitted disease affecting animals and humans in the Americas. It is commonly known as American Trypanosomiasis.11
The CDC estimates that approximately 8 million people in Central America, South America, and Mexico are infected with T. cruzi, without symptoms. If Chagas disease is left untreated, life-threatening sequelae may result.11
Nifurtimox, developed by Bayer, is a nitrofuran antiprotozoal drug used in the treatment of Chagas disease. On August 6 2020, accelerated FDA approval was granted for its use in pediatric patients in response to promising results from phase III clinical trials. Continued approval will be contingent upon confirmatory data.10 A convenient feature of Bayer’s formulation is the ability to divide the scored tablets manually without the need for pill-cutting devices.10
Medical uses
Nifurtimox has been used to treat Chagas disease, when it is given for 30 to 60 days.[7][8] However, long-term use of nifurtimox does increase chances of adverse events like gastrointestinal and neurological side effects.[8][9] Due to the low tolerance and completion rate of nifurtimox, benznidazole is now being more considered for those who have Chagas disease and require long-term treatment.[5][9]
In the United States nifurtimox is indicated in children and adolescents (birth to less than 18 years of age and weighing at least 2.5 kilograms (5.5 lb) for the treatment of Chagas disease (American Trypanosomiasis), caused by Trypanosoma cruzi.[2]
Nifurtimox has also been used to treat African trypanosomiasis (sleeping sickness), and is active in the second stage of the disease (central nervous system involvement). When nifurtimox is given on its own, about half of all patients will relapse,[10] but the combination of melarsoprol with nifurtimox appears to be efficacious.[11] Trials are awaited comparing melarsoprol/nifurtimox against melarsoprol alone for African sleeping sickness.[12]
Combination therapy with eflornithine and nifurtimox is safer and easier than treatment with eflornithine alone, and appears to be equally or more effective. It has been recommended as first-line treatment for second-stage African trypanosomiasis.[13]
Pregnancy and breastfeeding
Use of nifurtimox should be avoided in pregnant women due to limited use.[5][8][14] There is limited data shown that nifurtimox doses up to 15 mg/kg daily can cause adverse effects in breastfed infants.[15] Other authors do not consider breastfeeding a contraindication during nifurtimox use.[15]
Side effects
Side effects occur following chronic administration, particularly in elderly people. Major toxicities include immediate hypersensitivity such as anaphylaxis and delayed hypersensitivity reaction involving icterus and dermatitis. Central nervous system disturbances and peripheral neuropathy may also occur.[8]
Contraindications
Nifurtimox is contraindicated in people with severe liver or kidney disease, as well as people with a background of neurological or psychiatric disorders.[5][16][20]
Mechanism of action
Nifurtimox forms a nitro-anion radical metabolite that reacts with nucleic acids of the parasite causing significant breakdown of DNA.[8] Its mechanism is similar to that proposed for the antibacterial action of metronidazole. Nifurtimox undergoes reduction and creates oxygen radicals such as superoxide. These radicals are toxic to T. cruzi. Mammalian cells are protected by presence of catalase, glutathione, peroxidases, and superoxide dismutase. Accumulation of hydrogen peroxide to cytotoxic levels results in parasite death.[8]
Manufacturing and availability
A bottle of nifurtimox
Nifurtimox is sold under the brand name Lampit by Bayer.[3] It was previously known as Bayer 2502.
Nifurtimox is only licensed for use in Argentina and Germany,[citation needed] where it is sold as 120-mg tablets. It was approved for medical use in the United States in August 2020.[3]
Nifurtimox, 1,1-dioxide 4-[(5-nitrofuryliden)amino]-3-methylthiomorpholine (37.4.7), is made by the following scheme. Interaction of 2-mercaptoethanol with propylene oxide in the presence of potassiumhydroxide gives (2-hydroxyethyl)-(2-hydroxypropylsul-fide) (37.4.3), which undergoes intramolecular dehydration using potassium bisulfate to make 2-methyl-1,4-oxithiane (37.4.4). Oxidation of this using hydrogen peroxide gives 2-methyl-1,4-oxithian-4,4-dioxide (37.4.5), which when reacted with hydrazine transforms to 4-amino-3-methyltetrahydro-1,4-thiazin-1,1-dioxide (37.4.6). Reacting this with 5-nitrofurfurol gives the corresponding hydrazone—the desired nifurtimox [58,59].
58. H. Herlinger, K.H. Heinz, S. Petersen, M.Bock, Ger. Pat. 1.170.957 (1964).
59. H. Herlinger, K.H. Heinz, S. Petersen, M. Bock, U.S. Pat. 3.262.930 (1966)
^ Jump up to:abcWorld Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^Pepin J, Milord F, Mpia B, et al. (1989). “An open clinical trial of nifurtimox for arseno-resistant T. b. gambiense sleeping sickness in central Zaire”. Trans R Soc Trop Med Hyg. 83(4): 514–7. doi:10.1016/0035-9203(89)90270-8. PMID2694491.
^Castro, José A.; de Mecca, Maria Montalto; Bartel, Laura C. (2006-08-01). “Toxic side effects of drugs used to treat Chagas’ disease (American trypanosomiasis)”. Human & Experimental Toxicology. 25 (8): 471–479. doi:10.1191/0960327106het653oa. ISSN0960-3271. PMID16937919.
^“Chagas disease”. World Health Organization. Archived from the original on 2014-02-27. Retrieved 2016-11-08.
^Clinical trial number NCT00601003 for “Study of Nifurtimox to Treat Refractory or Relapsed Neuroblastoma or Medulloblastoma” at ClinicalTrials.gov. Retrieved on July 10, 2009.
External links
“Nifurtimox”. Drug Information Portal. U.S. National Library of Medicine.
Pre-transplant treatment to make patients with donor specific IgG eligible for kidney transplantation
Immunosuppressant, Immunoglobulin modulator (enzyme)
Imlifidase is under investigation in clinical trial NCT02854059 (IdeS in Asymptomatic Asymptomatic Antibody-Mediated Thrombotic Thrombocytopenic Purpura (TTP) Patients).
Imlifidase is a cysteine protease derived from the immunoglobulin G (IgG)‑degrading enzyme of Streptococcus pyogenes.[1] It cleaves the heavy chains of all human IgG subclasses (but no other immunoglobulins), eliminating Fc-dependent effector functions, including CDC and antibody-dependent cell-mediated cytotoxicity (ADCC).[1] Thus, imlifidase reduces the level of donor specific antibodies, enabling transplantation.[1]
The benefits with imlifidase are its ability to convert a positive crossmatch to a negative one in highly sensitized people to allow renal transplantation.[1] The most common side effects are infections and infusion related reactions.[1]
Per the CHMP recommendation, imlifidase will be indicated for desensitization treatment of highly sensitized adult kidney transplant people with positive crossmatch against an available deceased donor.[1] The use of imlifidase should be reserved for people unlikely to be transplanted under the available kidney allocation system including prioritization programmes for highly sensitized people.[1]
History
Imlifidase was granted orphan drug designations by the European Commission in January 2017, and November 2018,[3][4] and by the U.S. Food and Drug Administration (FDA) in both February and July 2018.[5][6]
In February 2019, Hansa Medical AB changed its name to Hansa Biopharma AB.[4]
Ge S, Chu M, Choi J, Louie S, Vo A, Jordan SC, et al. (October 2019). “Imlifidase Inhibits HLA Antibody-Mediated NK Cell Activation and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) In Vitro”. Transplantation. doi:10.1097/TP.0000000000003023. PMID31644495.
Pralsetinib, sold under the brand name Gavreto, is a medication for the treatment of metastatic RET fusion-positive non-small cell lung cancer (NSCLC).[1] Pralsetinib is a tyrosine kinase inhibitor. It is taken by mouth.[1]
The most common adverse reactions include increased aspartate aminotransferase (AST), decreased hemoglobin, decreased lymphocytes, decreased neutrophils, increased alanine aminotransferase (ALT), increased creatinine, increased alkaline phosphatase, fatigue, constipation, musculoskeletal pain, decreased calcium, hypertension, decreased sodium, decreased phosphate, and decreased platelets.[1]
Pralsetinib was approved for medical use in the United States in September 2020.[1][2][3][4]
Medical uses
Pralsetinib is indicated for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test.[1][4]
History
Efficacy was investigated in a multicenter, open-label, multi-cohort clinical trial (ARROW, NCT03037385) with 220 participants aged 26-87 whose tumors had RET alterations.[1][4] Identification of RET gene alterations was prospectively determined in local laboratories using either next generation sequencing, fluorescence in situ hybridization, or other tests.[1] The main efficacy outcome measures were overall response rate (ORR) and response duration determined by a blinded independent review committee using RECIST 1.1.[1] The trial was conducted at sites in the United States, Europe and Asia.[4]
Efficacy for RET fusion-positive NSCLC was evaluated in 87 participants previously treated with platinum chemotherapy.[1] The ORR was 57% (95% CI: 46%, 68%); 80% of responding participants had responses lasting 6 months or longer.[1] Efficacy was also evaluated in 27 participants who never received systemic treatment.[1] The ORR for these participants was 70% (95% CI: 50%, 86%); 58% of responding participants had responses lasting 6 months or longer.[1]
Step 7: Synthesis of (1R,4S)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-carboxamide (Compound 129) and (1S,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide (Compound 130)
[0194]
[0195]
The title compounds were prepared from methyl 1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxylate (192 mg, 0.53 mmol) using the same two-step procedure (hydrolysis and amide coupling) outlined in Synthetic Protocols 1 and 2, with PyBOP as the amide coupling reagent instead of HATU. The products were initially isolated as a mixture of diastereomers (190 mg), which was then dissolved in 6 mL methanol and purified by SFC (ChiralPak AD-H 21×250 mm, 40% MeOH containing 0.25% DEA in CO2, 2.5 mL injections, 70 mL/min). Peak 1 was concentrated to give (1R,4S)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide (29 mg, 10%) as a white solid. Peak 2 was concentrated to give (1s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-carboxamide (130 mg, 46%) as a white solid.
Example 6. Synthesis of Compound 149Step 1: Synthesis of Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate
[0196]
[0197]
Methyl 4-iodo-1-methoxycyclohexanecarboxylate (3.37 g, 11.3 mmol) was dissolved in dimethylacetamide (38 mL) in a pressure vessel under a stream of N2. Rieke Zinc (17.7 mL of a 50 mg/mL suspension in THF, 13.6 mmol) was added quickly via syringe, and the vessel was capped and stirred at ambient temperature for 15 minutes. The vessel was opened under a stream of N2 and 2,4-dichloro-6-methylpyrimidine (1.84 g, 11.3 mmol) was added followed by PdCl2dppf (826 mg, 1.13 mmol). The vessel was capped and heated to 80° C. for one hour, then cooled to room temperature. The reaction mixture was diluted with EtOAc, filtered through celite, and the filtrate was washed with H2O (3×), brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 50% EtOAc-hexanes) to give methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate (74 mg, 2.2%) as a colorless oil. MS (ES+) C14H19ClN2O3 requires: 298, found: 299 [M+H]+.
Step 2: Synthesis of tert-Butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate
[0198]
[0199]
Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate (70.5 mg, 0.236 mmol), tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (69.8 mg, 0.354 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (20.0 mg, 0.2 equiv.), Pd2(dba)3 (21.6 mg, 0.1 equiv.), and potassium acetate (70 mg, 0.71 mmol) were combined in a vial under nitrogen and 0.98 mL dioxane was added. The reaction mixture was heated to 115° C. for 2 h, then cooled to ambient temperature. The reaction mixture was diluted with EtOAc, filtered through celite, concentrated onto silica gel, and the resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-hexanes) to give tert-butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate (48 mg, 44%) as a yellow oil. MS (ES+) C23H33N5O5 requires: 459, found: 460 [M+H]+.
Step 3: Synthesis of 1-Methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid
[0200]
[0201]
Lithium hydroxide monohydrate (13 mg, 0.31 mmol) was added to a solution of tert-butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate (47.7 mg, 0.104 mmol) in THF/MeOH/H2O (17:1:1, 1.8 mL). The reaction mixture was heated to 60° C. and stirred for 16 h. The reaction mixture was then cooled to ambient temperature and concentrated to give crude 1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid (57 mg, crude) which was used in the subsequent amide coupling without any further purification. MS (ES+) C17H23N5O3 requires: 345, found: 346 [M+H]+.
Step 4: Synthesis of (1s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide (Compound 149)
[0202]
[0203]
The title compound was prepared from 1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid (57 mg, 0.104 mmol) using the same procedured (amide coupling) outlined in Synthetic Protocols 1 and 2, with PyBOP as the amide coupling reagent instead of HATU. The products were initially isolated as a mixture of diastereomers (36 mg), which was then dissolved in 6 mL methanol-DCM (1:1) and purified by SFC (ChiralPak IC-H 21×250 mm, 40% MeOH containing 0.25% DEA in CO2, 1.0 mL injections, 70 mL/min). Peak 1 was an undesired isomer, and Peak 2 was concentrated to give (1 s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide (13.4 mg, 24%) as a white solid.
Synthesis of IntermediatesExample 7. Synthesis of Ketone and Boronate IntermediatesA. Methyl 1-methoxy-4-oxocyclohexane-1-carboxylate
[0204]
[0205]
The title compound was prepared as described in WO 2014/130810 A1 page 86.
B. Ethyl 1-ethoxy-4-oxocyclohexane-1-carboxylate
[0206]
Step 1: Synthesis of ethyl 8-ethoxy-1,4-dioxaspiro[4.5]decane-8-carboxylate
[0207]
A solution of 1,4-dioxaspiro[4.5]decan-8-one (20.0 g, 128 mmol) in CHBr3 (3234 g, 1280 mmol) was cooled to 0° C. and potassium hydroxide (57.5 g, 1024 mmol) in EtOH (300 mL) was added dropwise over 2.5 hrs. After stirring the mixture for 23 h, the mixture was concentrated, and the residue was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude product, which was purified by flash column chromatography on silica gel (gradient elution, PE:EA=15:1 to 10:1) to obtain the title compound (18.0 g).
Step 2: Synthesis of ethyl 1-ethoxy-4-oxocyclohexane-1-carboxylate
[0208]
To a solution of ethyl 8-ethoxy-1,4-dioxaspiro[4.5]decane-8-carboxylate (10 g, 43 mmol) in 1,4-dioxane (250 mL) was added aqueous HCl (6 M, 92.5 mL), and the mixture was stirred for 23 h at ambient temperature. The mixture was then diluted with H2O and extracted with EtOAc.
[0209]
The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography on silica gel (PE:EA=15:1) to obtain the product (8.0 g). 1H NMR (400 MHz, DMSO) δ 4.20-4.13 (m, 2H), 3.43 (q, J=6.9 Hz, 1H), 2.48-2.39 (m, 1H), 2.24-2.12 (m, 2H), 2.10-2.01 (m, 1H), 1.22 (t, J=7.1 Hz, 2H), 1.17 (t, J=7.0 Hz, 2H).
C. Ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate
[0210]
Step 1: Synthesis of ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate
[0211]
A solution of methylmagnesium bromide (3M, 109.8 mL, 329.4 mmol) was added dropwise to a suspension of CuCN (14.75 g, 164.7 mmol) in diethyl ether (50 mL) at 0° C. The mixture was stirred for 30 min at 0° C. and then cooled to −78° C. The solution of ethyl 2-methyl-4-oxocyclohex-2-ene-1-carboxylate (10 g, 54.9 mmol) in diethyl ether (10 mL) was then added dropwise. The mixture was stirred between −40° C. to −20° C. for 2 h, then was warmed to ambient temperature for 16 h. The reaction mixture was carefully added to a saturated solution of ammonium chloride. The aqueous layer was extracted twice with diethyl ether, and the organic layers were combined. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (PE:EA=10:1) to give ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate (1.16 g).
Step 2: Synthesis of ethyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate
[0212]
Ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate (1.16 g, 5.85 mmol) and DIPEA (3.03 g, 23.4 mmol) were dissolved in dry toluene (2 mL) and heated at 45° C. for 10 minutes. Trifluoromethanesulfonic anhydride (6.61 g, 23.4 mmol) in DCM (20 mL) was added dropwise over 10 min and the mixture was heated at 45° C. for 2 h. The mixture was allowed to cool to room temperature, concentrated, diluted with water (60 mL) and extracted with DCM (2×40 mL). The organic layer was washed with saturated sodium bicarbonate solution (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-petroleum ether) to afford ethyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (1 g).
Step 3: Synthesis of ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate
[0213]
Ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (1 g, 3.03 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.15 g, 4.54 mmol), Pd(dppf)Cl2 (73.5 mg, 0.09 mmol) and potassium acetate (891 mg, 9.08 mmol) were suspended in 1,4-dioxane (20 mL). The reaction mixture was flushed with nitrogen, then heated to 100° C. for 2 h. The mixture was cooled to room temperature, filtered, and concentrated, and the resulting brown oil was purified by flash column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-petroleum ether) to afford ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (618 mg).
D. Ethyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate
[0214]
[0215]
Ethyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate was prepared using the same synthetic protocol as described above using ethyl 2-methyl-4-oxocyclohexane-1-carboxylate as the starting material.
E. Methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate
[0216]
Step 1: Synthesis of methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate
[0217]
A mixture of acrylaldehyde (120 g, 2.14 mol), methyl methacrylate (200 g, 2.00 mol) and hydroquinone (2.2 g, 20 mmol) were heated in a sealed steel vessel at 180° C. for one h. The mixture was then cooled to ambient temperature and concentrated. The residue was purified by silica gel column chromatography (gradient elution, petroleum ether:ethyl acetate=100:1 to 80:1) to give methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate (70 g, 22% yield) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3): δ 6.38 (d, J=6.4 Hz, 1H), 4.73-4.70 (m, 1H), 3.76 (s, 3H), 2.25-2.22 (m, 1H), 1.99-1.96 (m, 2H), 1.79-1.77 (m, 1H), 1.49 (s, 3H).
Step 2: Synthesis of methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate
[0218]
To a solution of methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate (20.0 g, 128 mmol) in anhydrous tetrahydrofuran (200 mL) was added borane (67 mL, 1 M in tetrahydrofuran) dropwise at −5° C. The reaction mixture was stirred at 0° C. for 3 hours. This reaction was monitored by TLC. The mixture was quenched by a solution of sodium acetate (10.5 g, 128 mmol) in water (15 mL). Then the mixture was treated with 30% hydrogen peroxide solution (23.6 g, 208.2 mmol) slowly at 0° C. and stirred at 30° C. for 3 h. The mixture was then partitioned between saturated sodium sulfite solution and tetrahydrofuran. The aqueous layer was further extracted with tetrahydrofuran (2×). The combined organic layers were washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (gradient elution, petroleum ether:ethyl acetate=10:1 to 1:1) to give crude methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate (18 g, crude) as a pale yellow oil, which used directly for next step.
Step 3: Synthesis of methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate
[0219]
To a solution of methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate (18.0 g, 103 mmol) in anhydrous dichloromethane (200 mL) was added PCC (45.0 g, 209 mmol) in portions. The reaction mixture was stirred at ambient temperature until TLC indicated the reaction was completed. Petroleum ether (500 mL) was then added and the mixture was filtered. The filter cake was washed with petroleum ether (100 mL), and the filtrate was concentrated under vacuum to give methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate (15 g, 84% yield) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3): δ 4.25 (d, J=17.6 Hz, 1H), 4.07 (d, J=17.6 Hz, 1H), 3.81 (s, 3H), 2.52-2.44 (m, 3H), 2.11-2.04 (m, 1H), 1.53 (s, 3H).
Example 8. Synthesis of Iodide IntermediatesA. Methyl 1-methoxy-4-iodocyclohexane-1-carboxylate
[0220]
Step 1: Synthesis of methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate
[0221]
Methyl 1-methoxy-4-oxocyclohexanecarboxylate (4.00 g, 21.5 mmol) was dissolved in methanol (100 mL) and the solution was cooled to 0° C. Sodium borohydride (2.03 g, 53.7 mmol) was added in portions over 20 min. The reaction mixture was stirred for 30 min, then was quenched by addition of aqueous saturated NH4Cl solution. The quenched reaction mixture was evaporated to remove the MeOH, then the aqueous suspension was extracted with DCM (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to yield a residue that was purified by flash-column chromatography on silica gel (gradient elution, 5% to 100% ethyl acetate-hexanes) to afford methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate (2.00 g, 49.5%) as a colorless oil. MS (ES+) C9H16O4 requires: 188, found: 211 [M+Na]+.
Step 2: Synthesis of methyl 1-methoxy-4-iodocyclohexane-1-carboxylate
[0222]
Methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate (2.00 g, 10.6 mmol) was dissolved in THF (20 mL) and imidazole (723 mg, 10.6 mmol) and triphenylphosphine (3.34 g, 12.8 mmol) were added. The mixture was cooled to 0° C., and then a solution of iodine (3.24 g, 12.8 mmol) in THF (10 mL) was added dropwise over 15 min. The reaction mixture was allowed to warm to ambient temperature and was then stirred for 2 days, after which it was poured over saturated sodium thiosulfate solution and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, concentrated, and the residue was triturated with hexane (40 mL, stir for 20 min). The mixture was filtered, and the filtrate was evaporated to provide a residue that was purified by flash-column chromatography on silica gel (gradient elution, 0 to 30% ethyl acetate-hexanes) to give the title compound (2.37 g, 75%) as a pale yellow oil. MS (ES+) C9H15IO3 requires: 298, found: 299 [M+H]+.
B. Ethyl 1-ethoxy-4-iodocyclohexane-1-carboxylate
[0223]
[0224]
The title compound was prepared as described above using ethyl 1-ethoxy-4-oxocyclohexane-1-carboxylate as a starting material. C11H19IO3 requires: 326, found: 327 [M+H]−.
Example 9. Synthesis of Amine IntermediatesA. (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine
[0225]
Step 1: Synthesis of 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one
[0226]
4-Fluoro-1H-pyrazole (4.73 g, 55 mmol) and potassium carbonate (17.27 g, 125 mmol) were combined and stirred in N,N-dimethylformamide (41.7 mL) for 10 minutes in an open sealed tube before addition of 2-bromo-5-acetylpyridine (10 g, 50 mmol). The reaction tube was sealed and stirred for 20 hours at 100° C. The reaction mixture was then cooled to room temperature and poured into water (˜700 mL). The mixture was sonicated and stirred for 20 minutes, after which a beige solid was isolated by filtration, washed with small amounts of water, and dried to yield 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one (9.81 g, 96% yield). MS: M+1=206.0.
Step 2: Synthesis of (R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide
[0227]
To a stirred room temperature solution of 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one (9.806 g, 47.8 mmol) in THF (96 mL) was added (R)-(+)-t-Butylsulfinamide (5.79 g, 47.8 mmol) followed by titanium (IV) ethoxide (21.8 g, 96 mmol). The solution was stirred at 75° C. on an oil bath for 15 hours. The reaction solution was cooled to room temperature and then to −78° C. (external temperature) before the next step. To the −78° C. solution was added dropwise over nearly 55 minutes L-Selectride (143 mL of 1N in THF, 143 mmol). During addition, some bubbling was observed. The reaction was then stirred after the addition was completed for 15 minutes at −78° C. before warming to room temperature. LC-MS of sample taken during removal from cold bath showed reaction was completed. The reaction was cooled to −50° C. and quenched slowly with methanol (˜10 mL), then poured into water (600 mL) and stirred. An off-white precipitate was removed by filtration, with ethyl acetate used for washes. The filtrate was diluted with ethyl acetate (800 mL), the layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated down. The crude was purified by silica gel chromatography to yield (R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (10.5 g, 99% purity, 70.3% yield) as a light yellow solid. MS: M+1=311.1.
Step 3: Synthesis of (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine
[0228]
A solution of (R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (10.53 g, 33.9 mmol)) in methanol (79 mmol) and 4N HCl/dioxane (85 mL, 339 mmol) was stirred for 2.5 hours, at which point LC-MS showed reaction was complete. The reaction solution was poured into diethyl ether (300 mL) and a sticky solid was formed. The mixture was treated with ethyl acetate (200 mL) and sonicated. The solvents were decanted, and the sticky solid was treated with more ethyl acetate (˜200 mL), sonicated and stirred. The bulk of the sticky solid was converted to a suspension. A light yellow solid was isolated by filtration, washed with smaller amounts of ethyl acetate, and dried to yield (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine (7.419 g, 78% yield). LC-MS confirmed desired product in high purity. MS: M+1=207.1.
“Pralsetinib”. Drug Information Portal. U.S. National Library of Medicine.
“Pralsetinib”. NCI Drug Dictionary. National Cancer Institute.
Clinical trial number NCT03037385 for “Phase 1/2 Study of the Highly-selective RET Inhibitor, Pralsetinib (BLU-667), in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors (ARROW)” at ClinicalTrials.gov
Roche is investing $775 million in cash and equity for access to Blueprint Medicines’ oncology drug candidate pralsetinib, which is under review by the US Food and Drug Administration.
Pralsetinib is a small-molecule inhibitor of RET alterations—rare genetic fusions or mutations that occur at low levels across lung, thyroid, and many other cancers.
The drug will go up against Eli Lilly and Company’s Retevmo, an RET inhibitor that received FDA approval in May for certain lung and thyroid cancers. Lilly acquired Retevmo in its $8 billion purchase of Loxo Oncology in 2019, a deal to obtain Loxo’s pipeline of small molecules for genetically defined tumors.
But SVB Leerink analyst Andrew Berens points out that Retevmo has side effects: it can cause an irregular heart rhythm called QT prolongation and hemorrhagic events. That leaves room for pralsetinib, which Roche will be better able to get in front of oncologists, Berens argues. In addition to a vast commercial network, Roche brings diagnostic tools to help identify cancer patients whose tumors feature RET alterations.
The FDA has a deadline of Nov. 23 to decide on approving the drug for lung cancer.
Roche’s move lowers the likelihood of a takeover of Blueprint, which had appeared on many investors’ short lists of acquisition targets. “We were surprised by the profuse language framing this deal as ensuring Blueprint’s independence,” Piper Sandler stock analyst Christopher J. Raymond told investors in a note.
//////////Pralsetinib, GAVRETO, 2020 APPROVALS, FDA 2020
The medication, developed by Cassiopea and Intrepid Therapeutics,[2] was approved by the US Food and Drug Administration (FDA) for acne in August 2020.[6][7]
Medical uses
Clascoterone is indicated for the topical treatment of acne vulgaris in females and males age 12 years and older.[1][8] It is applied to the affected skin area in a dose of 1 mg cream (or 10 mg clascoterone) twice per day, once in the morning and once in the evening.[1] The medication should not be used ophthalmically, orally, or vaginally.[1]
Available forms
Clascoterone is available in the form of a 1% (10 mg/g) cream for topical use.[1]
The incidences of local skin reactions with clascoterone were similar to placebo in two large phase 3 randomized controlled trials.[1][9] Suppression of the hypothalamic–pituitary–adrenal axis (HPA axis) may occur during clascoterone therapy in some individuals due to its cortexolonemetabolite.[1][8] HPA axis suppression as measured by the cosyntropin stimulation test was observed to occur in 3 of 42 (7%) of adolescents and adults using clascoterone for acne.[1][8] HPA axis function returned to normal within 4 weeks following discontinuation of clascoterone.[1][8]Hyperkalemia (elevated potassium levels) occurred in 5% of clascoterone-treated individuals and 4% of placebo-treated individuals.[1]
Steady-state levels of clascoterone occur within 5 days of twice daily administration.[1] At a dosage of 6 g clascoterone cream applied twice daily, maximal circulating levels of clascoterone were 4.5 ± 2.9 ng/mL, area-under-the-curve levels over the dosing interval were 37.1 ± 22.3 h*ng/mL, and average circulating levels of clascoterone were 3.1 ± 1.9 ng/mL.[1] In rodents, clascoterone has been found to possess strong local antiandrogenic activity, but negligible systemic antiandrogenic activity when administered via subcutaneous injection.[10] Along these lines, the medication is not progonadotropic in animals.[10]
Clascoterone is rapidly hydrolyzed into cortexolone (11-deoxycortisol) and this compound is a possible primary metabolite of clascoterone based on in-vitro studies in human liver cells.[1][8] During treatment with clascoterone, cortexolone levels were detectable and generally below or near the low limit of quantification (0.5 ng/mL).[1] Clascoterone may also produce other metabolites, including conjugates.[1]
The elimination of clascoterone has not been fully characterized in humans.[1]
Clascoterone, also known as cortexolone 17α-propionate or 11-deoxycortisol 17α-propionate, as well as 17α,21-dihydroxyprogesterone 17α-propionate or 17α,21-dihydroxypregn-4-en-3,20-dione 17α-propionate, is a syntheticpregnanesteroid and a derivative of progesterone and 11-deoxycortisol (cortexolone).[11] It is specifically the C17α propionateester of 11-deoxycortisol.[10]
C17α esters of 11-deoxycortisol were unexpectedly found to possess antiandrogenic activity.[10] Clascoterone, also known as cortexolone 17α-propionate, was selected for development based on its optimal drug profile.[10] The medication was approved by the US Food and Drug Administration (FDA) for the treatment of acne in August 2020.[6]
Two large phase 3randomized controlled trials evaluated the effectiveness of clascoterone for the treatment of acne over a period of 12 weeks.[1][8][9] Clascoterone decreased acne symptoms by about 8 to 18% more than placebo.[1][9] The defined treatment success endpoint was achieved in about 18 to 20% of individuals with clascoterone relative to about 7 to 9% of individuals with placebo.[1][8][9] The comparative effectiveness of clascoterone between males and females was not described.[1][9]
A small pilot randomized controlled trial in 2011, found that clascoterone cream decreased acne symptoms to a similar or significantly greater extent than tretinoin 0.05% cream.[8][13] No active comparator was used in the phase III clinical trials of clascoterone for acne.[8] Hence, it’s unclear how clascoterone compares to other therapies used in the treatment of acne.[8]
The FDA approved clascoterone based on evidence from two clinical trials (Trial 1/NCT02608450 and Trial 2/NCT02608476) of 1440 participants 9 to 58 years of age with acne vulgaris.[14] The trials were conducted at 99 sites in the United States, Poland, Romania, Bulgaria, Ukraine, Georgia, and Serbia.[14]
Participants applied clascoterone or vehicle (placebo) cream twice daily for 12 weeks.[14] Neither the participants nor the health care providers knew which treatment was being given until after the trial was completed.[14] The benefit of clascoterone in comparison to placebo was assessed after 12 weeks of treatment using the Investigator’s Global Assessment (IGA) score that measures the severity of disease (on a scale from 0 to 4) and a decrease in the number of acne lesions.[14]
Dissolving the compound 11-deoxycortisol (1.04g, 3.0mmol, 1eq.) in 10mL of anhydrous pyridine, dissolving dried DMTrCl (1.2-1.5eq) in 5mL of anhydrous dichloromethane, dropwise adding a dichloromethane solution of DMTrCl into the reactant solution at room temperature, and reacting for 4 hours at room temperature; the reaction was quenched with methanol and the solvent was evaporated to dryness with an oil pump to give intermediate I in 85% yield (the next reaction was carried out without work-up, the solvent environment and catalyst were similar to the reaction of this step).
MS + 303(DMTr protecting group fragment), 649[M + H] +
Melting point: 95-97 deg.C
Example 2:
preparation of intermediate II
Wherein R is DMTr
Under the protection of nitrogen, dissolving the intermediate product I (1eq.) in 5mL of anhydrous dichloromethane, adding DMAP (0.1eq.) into the solution, dropwise adding triethylamine (1.2eq.) and propionic anhydride or propionyl chloride (1.2eq. ), reacting at 40 ℃ for 12 hours after dropwise adding, and evaporating the solvent to obtain an intermediate product II.
Or under the protection of nitrogen, dissolving the intermediate product I (1eq.) in 5mL of anhydrous pyridine, adding DMAP (0.1eq.) into the solution, dropwise adding triethylamine (1.2eq.) and propionic anhydride or propionyl chloride (1.2eq .), reacting at 80 ℃ for 4 hours after dropwise adding, and evaporating the solvent to obtain an intermediate product II. (the reaction in the step can be directly carried out for the next step of removing DMTr protecting group to obtain the reaction after solvent evaporation without strict purification post-treatment)
MS + :303(DMTr protecting group fragment), 727[ M + Na [)] + ,768[M+Na+CH 3 CN] + .
Example 3:
preparation of target Compound 1 (21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3, 20-dione)
Dissolving the concentrated intermediate product II in an ethyl acetate solution, slowly dropwise adding 0.5M hydrochloric acid solution or 2% trifluoroacetic acid-ethyl acetate solution at 0 ℃, reacting for 5 minutes at 0 ℃, removing DMTr protective groups, adding 5% sodium bicarbonate aqueous solution at 0 ℃, stirring, neutralizing acid in a reaction system, washing an ethyl acetate organic layer twice by using 5% sodium bicarbonate aqueous solution, removing acid and other water-soluble impurities in the ethyl acetate organic layer, drying the ethyl acetate organic layer by anhydrous sodium sulfate, evaporating to remove part of ethyl acetate solvent, adding petroleum ether into the remaining small amount of ethyl acetate solution, and recrystallizing in a system with 10 times of solvent amount of ethyl acetate-petroleum ether (5:1) to obtain a target product with high purity of 90%. The total yield from 11-deoxycortisol is up to 70%. The final product was free of isomerized by-products by HPLC and was not found by LCMS.
Alcoho lysis with CCL of cortexolone 17α, 21-dipropionate
Add butanol (0.4g, 5.45 mmoles) and CCL (17.4g, 3.86 U/mg, FLUKA) to a solution of cortexolone- 17α,21-dipropionate (0.5g, 1.09 mmoles) in toluene (50ml). Maintain the mixture under stirring, at 30 0C, following the progress of the reaction in TLC (Toluene/ethyl acetate 6/4) until the initial material is dissolved (24h). Remove the enzyme by means of filtration using a Celite layer. Recover the cortexolone 17α-propionate (0.437, 99%) after evaporation under low pressure. Through crystallisation, from diisopropyl ether you obtain a product with a purity >99% in HPLC.
(s, 3H, CH3– 18). P.f. 135-136 0C (acetone/hexane).
Example 5
Alcoho lysis with CALB of cortexolone- 17α, 21-dipropionate
Dissolve cortexolone, 17α, 2-dipropionate (0.5g, 1 .09 mmoles) in acetonitrile
(40ml), add CALB (2.3g, 2.5 U/mg Fluka) and octanol (0.875ml). Leave the mixture under stirring, at 30 0C, for 76 hrs. Remove the enzyme by means of filtration using a paper filter. Once the solvents evaporate, recover a solid
(0.4758) which upon analysis 1H-NMR shall appear made up of cortexolone- 17α- propionate at 91%.
Example 6
Crystallisation
Add the solvent (t-butylmethylether or diisopropylether) to the sample according to the ratios indicated in Table 3. Heat the mixture to the boiling temperature of the solvent, under stirring, until the sample dissolves completely. Cool to room temperature and leave it at this temperature, under stirring, for 6 hours. Filter using a buchner funnel and maintain the solid obtained, under low pressure, at a room temperature for 15 hours and then, at 400C, for 5 hours.
Example 7
Precipitation Disslove the sample in the suitable solvent (dichloromethane, acetone, ethyl acetate or ethanol) according to the ratios indicated in table 3 and then add the solvent, hexane or water, according to the ratios indicated in table 3, maintaining the mixture, under stirring, at room temperature. Recover the precipitate by filtration using a buchner funnel and desiccate as in example 6. Example 8.
Obtaining a pharmaceutical form containing the medication in a defined crystalline form.
Prepare a fluid cream containing 2 % cetylic alcohol, 16% glyceryl monostearate, 10% vaseline oil, 13 % propylene glycol, 10% poly ethylengly col with low polymerization 1.5% polysorbate 80 and 47.5 % purified water. Add 1 g of cortexolone 17α-propionate of crystalline form III to 100 g of this cream and subject the mixture to homogenisation by means of a turbine agitator until you obtain homogeneity. You obtain a cream containing a fraction of an active ingredient dissolved in the formulation vehicle and a non-dissolved fraction of an active ingredient, present as a crystal of crystalline form III. This preparation is suitable for use as a formulation vehicle for skin penetration tests on Franz cells, where a coefficient of penetration in the range of 0.04 to 0.03 cm/h is observed on the preparation. Example 9.
Obtaining the pharmaceutical form containing the medication in solvate form IV for replacing the solvent during the galenic formulation procedure Dissolve lOOg of cortexolone 17α-propionate of crystalline form III in 2500 g of propylene glycol under stirring at room temperature. Separately prepare, by using a turbo emulsifϊer raising the temperature up to about 700C, an emulsion with 250 g of Cetylic alcohol, 1500 g of glyceryl monostearate, 1000 g of liquid paraffin, 5 g of mixed tocopherols, 100 g of polysorbate 80 and 4650 g of water. After cooling the emulsion up to about 300C, add – under stirring and under negative pressure – the cortexolone 17α-propionate solution in propylene glycol. Maintain the emulsioned cream under stirring until you obtain homogeneity, making sure the temperature remains low by means the circulation of a coolant. The cream contains a dispersed crystalline fraction, made up of an active ingredient in solvate crystalline form IV, formed due to the precipitation of the active ingredient itself from the glycolic solution which contained it when the latter was added to the predominantly aqueous formulation. The DRX spectra of the crystalline form present in the cream are indicated in Fig. 30.
Several 17α-monoesters of cortexolone and its Δ9-derivative are endowed with antiandrogenic activity. Their synthesis can be accomplished by means of a lipase-catalyzed chemoselective alcoholysis of the corresponding 17α,21-diesters.
Cortexolone derivatives in which the hydroxyl group at position C-17α is esterified with short chain aliphatic or aromatic acids and the derivatives of the corresponding 9,11-dehydro derivative, are known to have an antiandrogenic effect.
[0002]
EP 1421099 describes cortexolone 17α-propionate and 9,11-dehydro-cortexolone-17-α-butanoate regarding a high antiandrogenic biological activity demonstrated both “in vitro” and “in vivo” on the animal.
[0003]
US3530038 discloses the preparation of a crystalline form of cortexolone-17α-propionate having a melting point of 126-129 °C and an IR spectrum with bands at (cm-1): 3500, 1732, 1713, 1655 and 1617.
[0004]
A method for obtaining the above mentioned derivatives is described by Gardi et al. (Gazz. Chim. It. 63, 43 1,1963) and in the United States patent US3152154 providing for the transformation of cortexolone, or transformation of 9,11-dehydrocortexolone, in the intermediate orthoester using orthoesters available in the market as a mixture of aprotic solvents such as cyclohexane and DMF, in presence of acid catalysis (ex. PTSA.H20). The intermediate orthoester thus obtained can be used as is or upon purification by suspension in a solvent capable of solubilising impurities, preferably in alcohols. The subsequent hydrolysis in a hydroalcoholic solution, buffered to pH 4-5 preferably in acetate buffer, provides the desired monoester.
[0005]
Such synthesis is indicated in the diagram 1 below
[0006]
However, the monoesters thus obtained were, in the reaction conditions, unstable and, consequently hard to manipulate and isolate (R. Gardi et al Tetrahedron Letters, 448, 1961). The instability is above all due to the secondary reaction of migration of the esterifying acyl group from position 17 to position 21.
[0007]
It is thus known that in order to obtain the above mentioned monoesters with a chemical purity in such a manner to be able to proceed to the biological tests, it is necessary to use, at the end of the synthesis, a purification process which is generally performed by means of column chromatography.
[0008]
Furthermore, US3152154 describes how the hydrolysis of the diester in a basic environment is not convenient due to the formation of a mixture of 17α,21-diol, of 17- and 21 -monoesters, alongside the initial non-reacted product.
[0009]
Now, it has been surprisingly discovered that an alcoholysis reaction using a lipase from Candida as a biocatalyst can be usefully applied during the preparation of 17α monoesters of cortexolone, or its 9,11-dehydroderivatives.
[0010]
As a matter of fact, it has been discovered that such enzymatic alcoholysis of the 17,21-diester of the cortexolone, or of its derivative 9,11-dehydro, selectively occurs in position 21 moving to the corresponding monoester in position 17, as shown in diagram 2 below:
[0011]
The chemoselectivity of the special enzymatic reaction in alcoholysis conditions, according to the present invention, opens new perspectives for preparation, at industrial level with higher yields, of 17α-monoesters with respect to the methods already indicated in literature.
[0012]
The diesters serving as a substrate for the reaction of the invention can be prepared according to the prior art, for example following the one described in B.Turner, (Journal of American Chemical Society, 75, 3489, 1953) which provides for the esterification of corticosteroids with a linear carboxylic acid in presence of its anhydride and PTSA monohydrate.
EXAMPLES
Example 1
Alcoholysis with CCL of cortexolone 17α, 21-dipropionate
[0055]
Add butanol (0.4g, 5.45 mmoles) and CCL (17.4g, 3.86 U/mg, FLUKA) to a solution of cortexolone-17α,21-dipropionate (0.5g, 1.09 mmoles) in toluene (50ml). Maintain the mixture under stirring, at 30 °C, following the progress of the reaction in TLC (Toluene/ethyl acetate 6/4) until the initial material is dissolved (24h). Remove the enzyme by means of filtration using a Celite layer. Recover the cortexolone 17α-propionate (0.437, 99%) after evaporation under low pressure. Through crystallisation, from diisopropyl ether you obtain a product with a purity >99% in HPLC.
Alcoholysis with CALB of cartexolone-17α, 21-dipropionate
[0061]
Dissolve cortexolone, 17α, 2-dipropionate (0.5g, 1.09 mmoles) in acetonitrile (40ml), add CALB (2.3g, 2.5 U/mg Fluka) and octanol (0.875ml). Leave the mixture under stirring, at 30 °C, for 76 hrs. Remove the enzyme by means of filtration using a paper filter. Once the solvents evaporate, recover a solid (0.4758) which upon analysis 1H-NMR shall appear made up of cortexolone-17α-propionate at 91%.
Example 6
Crystallisation
[0062]
Add the solvent (t-butylmethylether or diisopropylether) to the sample according to the ratios indicated in Table 3. Heat the mixture to the boiling temperature of the solvent, under stirring, until the sample dissolves completely. Cool to room temperature and leave it at this temperature, under stirring, for 6 hours. Filter using a buchner funnel and maintain the solid obtained, under low pressure, at a room temperature for 15 hours and then, at 40°C, for 5 hours.
Example 7 (comparative)
Precipitation
[0063]
Disslove the sample in the suitable solvent (dichloromethane, acetone, ethyl acetate or ethanol) according to the ratios indicated in table 3 and then add the solvent, hexane or water, according to the ratios indicated in table 3, maintaining the mixture, under stirring, at room temperature. Recover the precipitate by filtration using a buchner funnel and desiccate as in example 6.
Example 8.
Obtaining a pharmaceutical form containing the medication in a defined crystalline form.
[0064]
Prepare a fluid cream containing 2 % cetylic alcohol, 16% glyceryl monostearate, 10% vaseline oil, 13 % propylene glycol, 10% polyethylenglycol with low polymerization 1.5% polysorbate 80 and 47.5 % purified water. Add 1 g of cortexolone 17α-propionate of crystalline form III to 100 g of this cream and subject the mixture to homogenisation by means of a turbine agitator until you obtain homogeneity. You obtain a cream containing a fraction of an active ingredient dissolved in the formulation vehicle and a non-dissolved fraction of an active ingredient, present as a crystal of crystalline form III. This preparation is suitable for use as a formulation vehicle for skin penetration tests on Franz cells, where a coefficient of penetration in the range of 0.04 to 0.03 cm/h is observed on the preparation.
^ Jump up to:abRosette C, Rosette N, Mazzetti A, Moro L, Gerloni M (February 2019). “Cortexolone 17α-Propionate (Clascoterone) is an Androgen Receptor Antagonist in Dermal Papilla Cells In Vitro”. J Drugs Dermatol. 18 (2): 197–201. PMID30811143.
^ Jump up to:abcRosette C, Agan FJ, Mazzetti A, Moro L, Gerloni M (May 2019). “Cortexolone 17α-propionate (Clascoterone) Is a Novel Androgen Receptor Antagonist that Inhibits Production of Lipids and Inflammatory Cytokines from Sebocytes In Vitro”. J Drugs Dermatol. 18 (5): 412–418. PMID31141847.
^Celasco G, Moroa L, Bozzella R, Ferraboschi P, Bartorelli L, Di Marco R, Quattrocchi C, Nicoletti F (2005). “Pharmacological profile of 9,11-dehydrocortexolone 17alpha-butyrate (CB-03-04), a new androgen antagonist with antigonadotropic activity”. Arzneimittelforschung. 55 (10): 581–7. doi:10.1055/s-0031-1296908. PMID16294504.
^Trifu V, Tiplica GS, Naumescu E, Zalupca L, Moro L, Celasco G (2011). “Cortexolone 17α-propionate 1% cream, a new potent antiandrogen for topical treatment of acne vulgaris. A pilot randomized, double-blind comparative study vs. placebo and tretinoin 0·05% cream”. Br. J. Dermatol. 165 (1): 177–83. doi:10.1111/j.1365-2133.2011.10332.x. PMID21428978. S2CID38404925.
^World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82”. WHO Drug Information. 33 (3): 106. hdl:10665/330879.
^Der Sarkissian SA, Sun HY, Sebaratnam DF (August 2020). “Cortexolone 17 α-proprionate for hidradenitis suppurativa”. Dermatol Ther: e14142. doi:10.1111/dth.14142. PMID32761708.
External links
“Clascoterone”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02608450 for “A Study to Evaluate the Safety and Efficacy of CB-03-01 Cream, 1% in Subjects With Facial Acne Vulgaris (25)” at ClinicalTrials.gov
Clinical trial number NCT02608476 for “A Study to Evaluate the Safety and Efficacy of CB-03-01 Cream, 1% in Subjects With Facial Acne Vulgaris (26)” at ClinicalTrials.gov
Somapacitan, also known as NNC0195-0092,3 is a growth hormone analog indicated to treat adults with growth hormone deficiency.2,6 This human growth hormone analog differs by the creation of an albumin binding site, and prolonging the effect so that it requires weekly dosing rather than daily.5
Somapacitan was granted FDA approval on 28 August 2020.7
The most common side effects include: back pain, joint paint, indigestion, a sleep disorder, dizziness, tonsillitis, swelling in the arms or lower legs, vomiting, adrenal insufficiency, hypertension, increase in blood creatine phosphokinase (a type of enzyme), weight increase, and anemia.[2]
It was approved for medical use in the United States in August 2020.[2][3][4]
Somapacitan (Sogroya) is the first human growth hormone (hGH) therapy that adults only take once a week by injection under the skin; other FDA-approved hGH formulations for adults with growth hormone deficiency must be administered daily.[2]
Medical uses
Somapacitan is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency.[2]
Contraindications
Somapacitan should not be used in people with active malignancy, any stage of diabetic eye disease in which high blood sugar levels cause damage to blood vessels in the retina, acute critical illness, or those with acute respiratory failure, because of the increased risk of mortality with use of pharmacologic doses of somapacitan in critically ill individuals without growth hormone deficiency.[2]
History
Somapacitan was evaluated in a randomized, double-blind, placebo-controlled trial in 300 particpants with growth hormone deficiency who had never received growth hormone treatment or had stopped treatment with other growth hormone formulations at least three months before the study.[2] Particpants were randomly assigned to receive injections of weekly somapacitan, weekly placebo (inactive treatment), or daily somatropin, an FDA-approved growth hormone.[2] The effectiveness of somapacitan was determined by the percentage change of truncal fat, the fat that is accumulated in the trunk or central area of the body that is regulated by growth hormone and can be associated with serious medical issues.[2]
At the end of the 34-week treatment period, truncal fat decreased by 1.06%, on average, among particpants taking weekly somapacitan while it increased among particpants taking the placebo by 0.47%.[2] In the daily somatropin group, truncal fat decreased by 2.23%.[2] Particpants in the weekly somapacitan and daily somatropin groups had similar improvements in other clinical endpoints.[2]
It was approved for medical use in the United States in August 2020.[2][4] The U.S. Food and Drug Administration (FDA) granted the approval of Sogroya to Novo Nordisk, Inc.[2][4]
A Trial Investigating the Safety, Tolerability, Availability and Distribution in the Body of Once-weekly Long-acting Growth Hormone (Somapacitan) Compared to Once Daily Norditropin NordiFlex® in Adults With Growth Hormone Deficiency
A Trial Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a Single Dose of Long-acting Growth Hormone (Somapacitan) Compared to Daily Dosing of Norditropin® SimpleXx® in Children With Growth Hormone Deficiency
Investigating Efficacy and Safety of Once-weekly NNC0195-0092 (Somapacitan) Treatment Compared to Daily Growth Hormone Treatment (Norditropin® FlexPro®) in Growth Hormone Treatment naïve Pre-pubertal Children With Growth Hormone Deficiency
A Trial to Evaluate the Safety of Once Weekly Dosing of Somapacitan (NNC0195-0092) and Daily Norditropin® FlexPro® for 52 Weeks in Previously Human Growth Hormone Treated Japanese Adults With Growth Hormone Deficiency
Investigation of Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Multiple Doses of Somapacitan in Subjects With Mild and Moderate Degrees of Hepatic Impairment Compared to Subjects With Normal Hepatic Function.
A Trial to Compare the Safety of Once Weekly Dosing of Somapacitan With Daily Norditropin® FlexPro® for 26 Weeks in Previously Human Growth Hormone Treated Adults With Growth Hormone Deficiency
Trial to Compare the Efficacy and Safety of NNC0195-0092 (Somapacitan) With Placebo and Norditropin® FlexPro® (Somatropin) in Adults With Growth Hormone Deficiency.
Investigation of Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Multiple Doses of Somapacitan in Subjects With Various Degrees of Impaired Renal Function Compared to Subjects With Normal Renal Function
A dose-finding trial evaluating the effect and safety of once-weekly treatment of somapacitan compared to daily Norditropin® in children with short stature born small for gestational age with no catch-up growth by 2 years of age or older
A randomised, multinational, active-controlled,(open-labelled), dose finding, (double-blinded), parallel group trial investigating efficacy and safety of once-weekly NNC0195-0092 treatment compared to daily growth hormone treatment (Norditropin® FlexPro®) in growth hormone treatment naïve pre-pubertal children with growth hormone deficiency
A multicentre, multinational, randomised, open-labelled, parallel-group, active-controlled trial to compare the safety of once weekly dosing of NNC0195-0092 with daily Norditropin® FlexPro® for 26 weeks in previously human growth hormone treated adults with growth hormone deficiency
A multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) and active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of NNC0195-0092 with once weekly dosing of placebo and daily Norditropin® FlexPro® in adults with growth hormone deficiency for 35 weeks, followed by a 53-week open-label extension period
A randomised, open-labelled, active-controlled, multinational, dose-escalation trial investigating safety, tolerability, pharmacokinetics and pharmacodynamics of a single dose of long-acting growth hormone (NNC0195-0092) compared to daily dosing of Norditropin® SimpleXx® in children with growth hormone deficiency
Phase 1
Ongoing, Completed
2013-12-09
///////////Somapacitan, PEPTIDE.2020 APPROVALS, FDA 2020, ソマパシタン, NN8640
ClassAcetamides; Butyric acids; Hepatoprotectants; Small molecules; Sulfones; Thiazepines
Mechanism of Action Sodium-bile acid cotransporter inhibitors
Orphan Drug Status Yes – Primary biliary cirrhosis; Biliary atresia; Intrahepatic cholestasis; Alagille syndrome
New Molecular Entity Yes
Phase III Biliary atresia; Intrahepatic cholestasis
Phase II Alagille syndrome; Cholestasis; Primary biliary cirrhosis
No development reported Non-alcoholic steatohepatitis
22 Jul 2020 Albireo initiates an expanded-access programme for Intrahepatic cholestasis in USA, Canada, Australia and Europe
14 Jul 2020 Phase-III clinical trials in Biliary atresia (In infants, In neonates) in Belgium (PO) after July 2020 (EudraCT2019-003807-37)
14 Jul 2020 Phase-III clinical trials in Biliary atresia (In infants, In neonates) in Germany, France, United Kingdom, Hungary (PO) (EudraCT2019-003807-37)
UPDATE Bylvay, FDA APPROVED2021/7/20 AND EMA 2021/7/16
A-4250 (odevixibat) is a selective inhibitor of the ileal bile acid transporter (IBAT) that acts locally in the gut. Ileum absorbs glyco-and taurine-conjugated forms of the bile salts. IBAT is the first step in absorption at the brush-border membrane. A-4250 works by decreasing the re-absorption of bile acids from the small intestine to the liver, whichreduces the toxic levels of bile acids during the progression of the disease. It exhibits therapeutic intervention by checking the transport of bile acids. Studies show that A-4250 has the potential to decrease the damage in the liver cells and the development of fibrosis/cirrhosis of the liver known to occur in progressive familial intrahepatic cholestasis. A-4250 is a designated orphan drug in the USA for October 2012. A-4250 is a designated orphan drug in the EU for October 2016. A-4250 was awarded PRIME status for PFIC by EMA in October 2016. A-4250 is in phase II clinical trials by Albireo for the treatment of primary biliary cirrhosis (PBC) and cholestatic pruritus. In an open label Phase 2 study in children with cholestatic liver disease and pruritus, odevixibat showed reductions in serum bile acids and pruritus in most patients and exhibited a favorable overall tolerability profile.
Odevixibat is a highly potent, non-systemic ileal bile acid transport inhibitor (IBATi) that has has minimal systemic exposure and acts locally in the small intestine. Albireo is developing odevixibat to treat rare pediatric cholestatic liver diseases, including progressive familial intrahepatic cholestasis, biliary atresia and Alagille syndrome.
With normal function, approximately 95 percent of bile acids released from the liver into the bile ducts to aid in liver function are recirculated to the liver via the IBAT in a process called enterohepatic circulation. In people with cholestatic liver diseases, the bile flow is interrupted, resulting in elevated levels of toxic bile acids accumulating in the liver and serum. Accordingly, a product capable of inhibiting the IBAT could lead to a reduction in bile acids returning to the liver and may represent a promising approach for treating cholestatic liver diseases.
The randomized, double-blind, placebo-controlled, global multicenter PEDFIC 1 Phase 3 clinical trial of odevixibat in 62 patients, ages 6 months to 15.9 years, with PFIC type 1 or type 2 met its two primary endpoints demonstrating that odevixibat reduced serum bile acids (sBAs) (p=0.003) and improved pruritus (p=0.004), and was well tolerated with a low single digit diarrhea rate. These topline data substantiate the potential for odevixibat to be first drug for PFIC patients. The Company intends to complete regulatory filings in the EU and U.S. no later than early 2021, in anticipation of regulatory approval, issuance of a rare pediatric disease priority review voucher and launch in the second half of 2021.
Odevixibat is being evaluated in the ongoing PEDFIC 2 open-label trial (NCT03659916) designed to assess long-term safety and durability of response in a cohort of patients rolled over from PEDFIC 1 and a second cohort of PFIC patients who are not eligible for PEDFIC 1.
Odevixibat is also currently being evaluated in a second Phase 3 clinical trial, BOLD (NCT04336722), in patients with biliary atresia. BOLD, the largest prospective intervention trial ever conducted in biliary atresia, is a double-blind, randomized, placebo-controlled trial which will enroll approximately 200 patients at up to 75 sites globally to evaluate the efficacy and safety of odevixibat in children with biliary atresia who have undergone a Kasai procedure before age three months. The company also anticipates initiating a pivotal trial of odevixibat for Alagille syndrome by the end of 2020.
The odevixibat PFIC program, or elements of it, have received fast track, rare pediatric disease and orphan drug designations in the United States. In addition, the FDA has granted orphan drug designation to odevixibat for the treatment of Alagille syndrome, biliary atresia and primary biliary cholangitis. The EMA has granted odevixibat orphan designation, as well as access to the PRIority MEdicines (PRIME) scheme for the treatment of PFIC. Its Paediatric Committee has agreed to Albireo’s odevixibat Pediatric Investigation Plan for PFIC. EMA has also granted orphan designation to odevixibat for the treatment of biliary atresia, Alagille syndrome and primary biliary cholangitis.
A solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Example 18; 0.075 g, 0.114 mmol), butanoic acid, 2-amino-, 1,1-dimethylethyl ester, hydrochloride, (2S)-(0.031 g, 0.160 mmol) and Ν-methylmorpholine (0.050 ml, 0.457 mmol) in DMF (4 ml) was stirred at RT for 10 min, after which TBTU (0.048 g, 0.149 mmol) was added. After 1h, the conversion to the ester was complete. M/z: 797.4. The solution was diluted with toluene and then concentrated. The residue was dissolved in a mixture of DCM (5 ml) and TFA (2 ml) and the mixture was stirred for 7h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20-60% MeCΝ in 0.1M ammonium acetate buffer as eluent. The title compound was obtained in 0.056 g (66 %) as a white solid. ΝMR (400 MHz, DMSO-d6): 0.70 (3H, t), 0.70-0.80 (6H, m), 0.85-1.75 (14H, m), 2.10 (3H, s), 3.80 (2H, brs), 4.00-4.15 (1H, m), 4.65 (1H, d(AB)), 4.70 (1H, d(AB)), 5.50 (1H, d), 6.60 (1H, s), 6.65-7.40 (11H, m), 8.35 (1H, d), 8.50 (1H, d) 9.40 (1H, brs).
The compound l,l-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(A/-{(R)-a-[A/-((S)-l-carboxypropyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-l,2,5-benzothiadiazepine (odevixibat; also known as A4250) is disclosed in WO 03/022286. The structure of odevixibat is shown below.
As an inhibitor of the ileal bile acid transporter (IBAT) mechanism, odevixibat inhibits the natural reabsorption of bile acids from the ileum into the hepatic portal circulation. Bile acids that are not reabsorbed from the ileum are instead excreted into the faeces. The overall removal of bile acids from the enterohepatic circulation leads to a decrease in the level of bile acids in serum and the liver. Odevixibat, or a pharmaceutically acceptable salt thereof, is therefore useful in the treatment or prevention of diseases such as dyslipidemia, constipation, diabetes and liver diseases, and especially liver diseases that are associated with elevated bile acid levels.
According to the experimental section of WO 03/022286, the last step in the preparation of odevixibat involves the hydrolysis of a tert-butyl ester under acidic conditions. The crude compound was obtained by evaporation of the solvent under reduced pressure followed by purification of the residue by preparative HPLC (Example 29). No crystalline material was identified.
Amorphous materials may contain high levels of residual solvents, which is highly undesirable for materials that should be used as pharmaceuticals. Also, because of their lower chemical and physical stability, as compared with crystalline material, amorphous materials may display faster
decomposition and may spontaneously form crystals with a variable degree of crystallinity. This may result in unreproducible solubility rates and difficulties in storing and handling the material. In pharmaceutical preparations, the active pharmaceutical ingredient (API) is for that reason preferably used in a highly crystalline state. Thus, there is a need for crystal modifications of odevixibat having improved properties with respect to stability, bulk handling and solubility. In particular, it is an object of the present invention to provide a stable crystal modification of odevixibat that does not contain high levels of residual solvents, that has improved chemical stability and can be obtained in high levels of crystallinity.
Example 1
Preparation of crystal modification 1
Absolute alcohol (100.42 kg) and crude odevixibat (18.16 kg) were charged to a 250-L GLR with stirring under nitrogen atmosphere. Purified water (12.71 kg) was added and the reaction mass was stirred under nitrogen atmosphere at 25 ± 5 °C for 15 minutes. Stirring was continued at 25 ± 5 °C for 3 to 60 minutes, until a clear solution had formed. The solution was filtered through a 5.0 m SS cartridge filter, followed by a 0.2 m PP cartridge filter and then transferred to a clean reactor.
Purified water (63.56 kg) was added slowly over a period of 2 to 3 hours at 25 ± 5 °C, and the solution was seeded with crystal modification 1 of odevixibat. The solution was stirred at 25 ± 5 °C for 12 hours. During this time, the solution turned turbid. The precipitated solids were filtered through centrifuge and the material was spin dried for 30 minutes. The material was thereafter vacuum dried in a Nutsche filter for 12 hours. The material was then dried in a vacuum tray drier at 25 ± 5 °C under vacuum (550 mm Hg) for 10 hours and then at 30 ± 5 °C under vacuum (550 mm Hg) for 16 hours. The material was isolated as an off-white crystalline solid. The isolated crystalline material was milled and stored in LDPE bags.
An overhydrated sample was analyzed with XRPD and the diffractogram is shown in Figure 2.
Another sample was dried at 50 °C in vacuum and thereafter analysed with XRPD. The diffractogram of the dried sample is shown in Figure 1.
The diffractograms for the drying of the sample are shown in Figures 3 and 4 for 2Q ranges 5 – 13 ° and 18 – 25 °, respectively (overhydrated sample at the bottom and dry sample at the top).
A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Odevixibat (A4250) in Children with Biliary Atresia Who Have Undergone a Kasai Hepatoportoenterostomy (BOLD)
An Open-label Extension Study to Evaluate Long-term Efficacy and Safety of A4250 in Children with Progressive Familial Intrahepatic Cholestasis Types 1 and 2 (PEDFIC 2)
A Double-Blind, Randomized, Placebo-Controlled, Phase 3 Study to Demonstrate Efficacy and Safety of A4250 in Children with Progressive Familial Intrahepatic Cholestasis Types 1 and 2 (PEDFIC 1)
Copper Cu 64 dotatate, sold under the brand name Detectnet, is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positiveneuroendocrine tumors (NETs) in adults.[1]
Common side effects include nausea, vomiting and flushing.[2]
It was approved for medical use in the United States in September 2020.[1][2]
History
The U.S. Food and Drug Administration (FDA) approved copper Cu 64 dotatate based on data from two trials that evaluated 175 adults.[3]
Trial 1 evaluated adults, some of whom had known or suspected NETs and some of whom were healthy volunteers.[3] The trial was conducted at one site in the United States (Houston, TX).[3] Both groups received copper Cu 64 dotatate and underwent PET scan imaging.[3] Trial 2 data came from the literature-reported trial of 112 adults, all of whom had history of NETs and underwent PET scan imaging with copper Cu 64 dotatate.[3] The trial was conducted at one site in Denmark.[3] In both trials, copper Cu 64 dotatate images were compared to either biopsy results or other images taken by different techniques to detect the sites of a tumor.[3] The images were read as either positive or negative for presence of NETs by three independent image readers who did not know participant clinical information.[3]
Known imaging techniques with tremendous importance in medical diagnostics are positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), single photon computed tomography (SPECT) and ultrasound (US). Although today’s imaging technologies are well developed they rely mostly on non-specific, macroscopic, physical, physiological, or metabolic changes that differentiate pathological from normal tissue.
[0003]
Targeting molecular imaging (MI) has the potential to reach a new dimension in medical diagnostics. The term “targeting” is related to the selective and highly specific binding of a natural or synthetic ligand (binder) to a molecule of interest (molecular target) in vitro or in vivo.
[0004]
MI is a rapidly emerging biomedical research discipline that may be defined as the visual representation, characterization and quantification of biological processes at the cellular and sub-cellular levels within intact living organisms. It is a novel multidisciplinary field, in which the images produced reflect cellular and molecular pathways and in vivo mechanism of disease present within the context of physiologically authentic environments rather than identify molecular events responsible for disease.
[0005]
Several different contrast-enhancing agents are known today and their unspecific or non-targeting forms are already in clinical routine. Some examples listed below are reported in literature.
[0006]
For example, Gd-complexes could be used as contrast agents for MRI according to “Contrast Agents I” by W. Krause (Springer Verlag 2002, page one and following pages). Furthermore, superparamagnetic particles are another example of contrast-enhancing units, which could also be used as contrast agents for MRI (Textbook of Contrast Media, Superparamagnetic Oxides, Dawson, Cosgrove and Grainger Isis Medical Media Ltd, 1999, page 373 and following pages). As described in Contrast Agent II by W. Krause (Springer Verlag 2002, page 73 and following pages), gas-filled microbubbles could be used in a similar way as contrast agents for ultrasound. Moreover “Contrast Agents II” by W. Krause (Springer Verlag, 2002, page 151 and following pages) reports the use of iodinated liposomes or fatty acids as contrast agents for X-Ray imaging.
[0007]
Contrast-enhancing agents that can be used in functional imaging are mainly developed for PET and SPECT.
[0008]
The application of radiolabelled bioactive peptides for diagnostic imaging is gaining importance in nuclear medicine. Biologically active molecules which selectively interact with specific cell types are useful for the delivery of radioactivity to target tissues. For example, radiolabelled peptides have significant potential for the delivery of radionuclides to tumours, infarcts, and infected tissues for diagnostic imaging and radiotherapy.
[0009]
DOTA (1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10tetraazacyclododecane) and its derivatives constitute an important class of chelators for biomedical applications as they accommodate very stably a variety of di- and trivalent metal ions. An emerging area is the use of chelator conjugated bioactive peptides for labeling with radiometals in different fields of diagnostic and therapeutic nuclear oncology.
[0010]
There have been several reports in recent years on targeted radiotherapy with radiolabeled somatostatin analogs.
[0011]
US2007/0025910A1 discloses radiolabled somatostatin analogs primarily based on the ligand DOTA-TOC. The radionucleotide can be (64)Copper and the somatostatin analog may be octreotide, lanreotide, depreotide, vapreotide or derivatives thereof. The compounds of US2007/0025910A1 are useful in radionucleotide therapy of tumours.
[0012]
US2007/0025910A1 does not disclose (64)Cu-DOTA-TATE. DOTA-TATE and DOTA-TOC differ clearly in affinity for the 5 known somatostatin receptors (SST1-SST2). Accordingly, the DOTA-TATE has a 10-fold higher affinity for the SST2 receptor, the receptor expressed to the highest degree on neuroendocrine tumors. Also the relative affinity for the other receptor subtypes are different. Furthermore, since 177Lu-DOTATATE is used for radionuclide therapy, only 64Cu-DOTATATE and not 64Cu-DOTATOC can be used to predict effect of such treatment by a prior PET scan.
[0013]
There exists a need for further peptide-based compounds having utility for diagnostic imaging techniques, such as PET.
EXAMPLE
[0033]
Preparation of “Cu-Dotatate-DOTA-TATE
[0034]
64Cu was produced using a GE PETtrace cyclotron equipped with a beamline. The 64Cu was produced via the 64Ni (p,n) 64Cu reaction using a solid target system consisting of a water cooled target mounted on the beamline. The target consisted of 64Ni metal (enriched to >99%) electroplated on a silver disc backing. For this specific type of production a proton beam with the energy of 16 MeV and a beam current of 20 uA was used. After irradiation the target was transferred to the laboratory for further chemical processing in which the 64Cu was isolated using ion exchange chromatography. Final evaporation from aq. HCl yielded 2-6 GBq of 64Cu as 64CuCl2 (specific activity 300-3000 TBq/mmol; RNP >99%). The labeling of 64Cu to DOTA-TATE was performed by adding a sterile solution of DOTA-TATE (0.3 mg) and Gentisic acid (25 mg) in aq Sodium acetate (1 ml; 0.4M, pH 5.0) to a dry vial containing 64CuCl2 (˜1 GBq). Gentisic acid was added as a scavenger to reduce the effect of radiolysis. The mixture was left at ambient temperature for 10 minutes and then diluted with sterile water (1 ml). Finally, the mixture was passed through a 0.22 μm sterile filter (Millex GP, Millipore). Radiochemical purity was determined by RP-HPLC and the amount of unlabeled 64Cu2+ was determined by thin-layer chromatography. All chemicals were purchased from Sigma-Aldrich unless specified otherwise. DOTA-Tyr3-Octreotate (DOTA-TATE) was purchased from Bachem (Torrance, Calif.). Nickel-64 was purchased in +99% purity from Campro Scientific Gmbh. All solutions were made using Ultra pure water (<0.07 μSimens/cm). Reversed-phase high pressure liquid chromatography was performed on a Waters Alliance 2795 Separations module equipped with at Waters 2489 UV/Visible detector and a Caroll Ramsey model 105 S-1 radioactivity detector—RP-HPLC column was Luna C18, HST, 50×2 mm, 2.5 μm, Phenomenex. The mobile phase was 5% aq. acetonitrile (0.1% TFA) and 95% aq. acetonitrile (0.1% TFA).
[0035]
Thin layer chromatography was performed with a Raytest MiniGita Star TLC-scanner equipped with a Beta-detector. The eluent was 50% aq methanol and the TLC-plate was a Silica60 on Al foil (Fluka). Ion exchange chromatography was performed on a Dowex 1×8 resin (Chloride-form, 200-400 mesh).
The FDA has approved copper Cu 64 dotatate injection (Detectnet) for the localization of somatostatin receptor–positive neuroendocrine tumors (NETs), according to an announcement from RadioMedix Inc. and Curium Pharma.1
The positron emission tomography (PET) diagnostic agent is anticipated to launch immediately, according to Curium. Doses will be accessible through several nuclear pharmacies or through the nuclear medicine company.
“Detectnet brings an exciting advancement in the diagnosis of NETs for healthcare providers, patients, and their caregivers,” Ebrahim Delpassand MD, CEO of RadioMedix, stated in a press release. “The phase 3 results demonstrate the clinical sensitivity and specificity of Detectnet which will provide a great aid to clinicians in developing an accurate treatment approach for their [patients with] NETs.”
Copper Cu 64 dotatate adheres to somatostatin receptors with highest affinity for subtype 2 receptors (SSTR2). Specifically, the agent binds to somatostatin receptor–expressing cells, including malignant neuroendocrine cells; these cells overexpress SSTR2. The agent is a positron-producing radionuclide that possesses an emission yield that permits PET imaging.
“Perhaps most exciting is that the 12.7-hour half-life allows Detectnet to be produced centrally and shipped to sites throughout the United States,” added Delpassand. “This will help alleviate shortages or delays that have been experienced with other somatostatin analogue PET agents.”
Two single-center, open-label studies confirmed the efficacy of the diagnostic agent, according to Curium.2 In Study 1, investigators conducted a prospective analysis of 63 patients, which included 42 patients with known or suspected NETs according to histology, conventional imaging, or clinical evaluations, and 21 healthy volunteers. The majority of the participants, or 88% (n = 37) had a history of NETs at the time that they underwent imaging. Just under half of patients (44%; n = 28) were men and the majority were white (86%). Moreover, patients had a mean age of 54 years.
Images produced by the PET agent were interpreted to be either positive or negative for NET via 3 independent readers who had been blinded to the clinical data and other imaging information. Moreover, the results from the diagnostic agent were compared with a composite reference standard that was comprised of 1 oncologist’s blinded evaluation of patient diagnosis based on available histopathology results, reports of conventional imaging that had been done within 8 weeks before the PET imaging, as well as clinical and laboratory findings, which involved chromogranin A and serotonin levels.
Additionally, the percentage of patients who tested positive for disease via composite reference as well as through PET imaging was used to quantify positive percent agreement. Conversely, the percentage of participants who did not have disease per composite reference and who were determined to be negative for disease per PET imaging was used to quantify negative percent agreement.
Results showed that the percent reader agreement for positive detection in 62 scans was 91% (95% CI, 75-98) and negative detection was 97% (95% CI, 80-99). For reader 2, these percentages were 91% (95% CI, 75-98) and 80% (95% CI, 61-92), respectively, for 63 scans. Lastly, the percent reader agreement for reader 3 in 63 scans was 91% (95% CI, 75-98) positive and 90% (95% CI, 72-97) negative.
Study 2 was a retrospective analysis in which investigators examined published findings collected from 112 patients; 63 patients were male, while 43 were female. The mean age of patients included in the analysis was 62 years. All patients had a known history of NETs. Results demonstrated similar performance with the PET imaging agent.
In both safety and efficacy trials, a total of 71 patients were given a single dose of the diagnostic agent; the majority of these patients had known or suspected NETs and 21 were healthy volunteers. Adverse reactions such as nausea, vomiting, and flushing were reported at a rate of less than 2%. In all clinical experience that has been published, a total of 126 patients with a known history of NETs were given a single dose of the PET diagnostic agent. A total of 4 patients experienced nausea immediately after administration.
“Curium is excited to bring the first commercially available Cu 64 diagnostic agent to the US market,” Dan Brague, CEO of Curium, North America, added in the release. “Our unique production capabilities and distribution network allow us to deliver to any nuclear pharmacy, hospital, or imaging center its full dosing requirements first thing in the morning, to provide scheduling flexibility to the institution and its patients. We look forward to joining with healthcare providers and our nuclear pharmacy partners to bring this highly efficacious agent to the market.”
References
1. RadioMedix and Curium announce FDA approval of Detectnet (copper Cu 64 dotatate injection) in the US. News release. RadioMedix Inc and Curium. September 8, 2020. Accessed September 9, 2020. https://bit.ly/3m6iC0q.
2. Detectnet. Prescribing information. Curium Pharma; 2020. Accessed September 9, 2020. https://bit.ly/32eZxS3.
///////////////Copper Cu 64 dotatate, 銅(Cu64)ドータテート , FDA 2020, 2020 APPROVALS, Diagnostic, neuroendocrine tumors, Radioactive agent,
Cilofexor is under investigation in clinical trial NCT02943447 (Safety, Tolerability, and Efficacy of Cilofexor in Adults With Primary Biliary Cholangitis Without Cirrhosis).
Cilofexor (GS-9674) is a potent, selective and orally active nonsteroidal FXR agonist with an EC50 of 43 nM. Cilofexor has anti-inflammatory and antifibrotic effects. Cilofexor has the potential for primary sclerosing cholangitis (PSC) and nonalcoholic steatohepatitis (NASH) research.
Gilead , following a drug acquisition from Phenex , is developing cilofexor tromethamine (formerly GS-9674), the lead from a program of farnesoid X receptor (FXR; bile acid receptor) agonists, for the potential oral treatment of non-alcoholic steatohepatitis (NASH), primary biliary cholangitis/cirrhosis (PBC) and primary sclerosing cholangitis. In March 2019, a phase III trial was initiated for PSC; at that time, the trial was expected to complete in August 2022.
PATENT
Product case WO2013007387 , expiry EU in 2032 and in the US in 2034.
Novel crystalline forms of cilofexor as FXR agonists useful for treating nonalcoholic steatohepatitis. Gilead , following a drug acquisition from Phenex , is developing cilofexor tromethamine (formerly GS-9674), the lead from a program of farnesoid X receptor (FXR; bile acid receptor) agonists, for the potential oral treatment of non-alcoholic steatohepatitis (NASH), primary biliary cholangitis/cirrhosis (PBC) and primary sclerosing cholangitis. In March 2019, a phase III trial was initiated for PSC; at that time, the trial was expected to complete in August 2022. Family members of the cilofexor product case WO2013007387 , expire in the EU in 2032 and in the US in 2034.
solid forms of compounds that bind to the NR1H4 receptor (FXR) and act as agonists or modulators of FXR. The disclosure further relates to the use of the solid forms of such compounds for the treatment and/or prophylaxis of diseases and/or conditions through binding of said nuclear receptor by said compounds.
[0004] Compounds that bind to the NR1H4 receptor (FXR) can act as agonists or modulators of FXR. FXR agonists are useful for the treatment and/or prophylaxis of diseases and conditions through binding of the NR1H4 receptor. One such FXR agonist is the compound of Formula I:
I.
[0005] Although numerous FXR agonists are known, what is desired in the art are physically stable forms of the compound of Formula I, or pharmaceutically acceptable salt thereof, with desired properties such as good physical and chemical stability, good aqueous solubility and good bioavailability. For example, pharmaceutical compositions are desired that address
challenges of stability, variable pharmacodynamics responses, drug-drug interactions, pH effect, food effects, and oral bioavailability.
[0006] Accordingly, there is a need for stable forms of the compound of Formula I with suitable chemical and physical stability for the formulation, therapeutic use, manufacturing, and storage of the compound.
[0007] Moreover, it is desirable to develop a solid form of Formula I that may be useful in the synthesis of Formula I. A solid form, such as a crystalline form of a compound of Formula I may be an intermediate to the synthesis of Formula F A solid form may have properties such as bioavailability, stability, purity, and/or manufacturability at certain conditions that may be suitable for medical or pharmaceutical uses.
Description
Cilofexor (GS-9674) is a potent, selective and orally active nonsteroidal FXR agonist with an EC50 of 43 nM. Cilofexor has anti-inflammatory and antifibrotic effects. Cilofexor has the potential for primary sclerosing cholangitis (PSC) and nonalcoholic steatohepatitis (NASH) research[1][2].
Cilofexor (GS-9674; 30 mg/kg; oral gavage; once daily; for 10 weeks; male Wistar rats) treatment significantly increases Fgf15 expression in the ileum and decreased Cyp7a1 in the liver in nonalcoholic steatohepatitis (NASH) rats. Liver fibrosis and hepatic collagen expression are significantly reduced. Cilofexor also significantly reduces hepatic stellate cell (HSC) activation and significantly decreases portal pressure, without affecting systemic hemodynamics[3].
Animal Model:
Male Wistar rats received a choline-deficient high fat diet (CDHFD)[3]
Dosage:
30 mg/kg
Administration:
Oral gavage; once daily; for 10 weeks
Result:
Significantly increased Fgf15 expression in the ileum and decreased Cyp7a1 in the liver. Liver fibrosis and hepatic collagen expression were significantly reduced.
Safety and Efficacy of Selonsertib, Firsocostat, Cilofexor, and Combinations in Participants With Bridging Fibrosis or Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH)
Study in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-9674, and the Effect of Food on GS-9674 Pharmacokinetics and Pharmacodynamics
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of Cilofexor in Non-Cirrhotic Subjects with Primary Sclerosing Cholangitis
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects with Nonalcoholic Steatohepatitis (NASH)
A Phase 2, Randomized, Double-Blind, Placebo Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects with Primary Biliary Cholangitis Without Cirrhosis
A Phase 2, Randomized, Double-Blind, Placebo Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects with Primary Sclerosing Cholangitis Without Cirrhosis
Kyorin Pharmaceutical under license from Sanwa Kagaku Kenkyusho , is developing SK-1404 ([14C]-SK-1404, presumed to be lazuvapagon), for the iv treatment of nocturia, and as an oral formulation, as KRPN-118
Process for preparing benzazepine derivatives, particularly lazuvapagon a V2 receptor agonist, and their intermediates, useful for treating diabetes insipidus, hemophilia and overactive bladder.
[Fifth Step] to [Sixth Step]
[Chemical Formula 33] [In the formula, R 1 and R 2 have the same meanings as those in the first step, and * represents an asymmetric center. ]
[0074]
In the fifth step and the sixth step, the reaction can be performed according to a conventional method.
In the fifth step, compound (IX) is treated with a base (eg, sodium hydroxide, potassium hydroxide, etc.) in a suitable solvent (eg, alcohol solvent such as methanol, ethanol, etc., water), usually at room temperature to an organic solvent. A carboxylic acid compound of the compound (X) can be obtained by reacting at a temperature of the boiling point of the solvent for 30 minutes to 1 day. Next, in the sixth step, the obtained carboxylic acid compound is subjected to amidation with L-alaninol to obtain the compound (V). For the amidation, a method using a condensing agent, a method of reacting L-alaninol with a mixed acid anhydride or acid chloride of carboxylic acid, and the like can be used. In the method using a condensing agent, for example, the carboxylic acid compound and L-alaninol are condensed in a suitable organic solvent (chloroform, dimethylformamide, etc.) in the presence of a base (eg, diisopropylethylamine, triethylamine, etc.) (for example, 1 , 3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), etc.) alone or in combination with 1-hydroxybenztriazole (HOBt). (V) can be obtained. Further, in the method using a mixed acid anhydride, for example, a carboxylic acid derivative in an appropriate organic solvent (eg, dichloromethane, toluene, etc.) in the presence of a base (eg, pyridine, triethylamine, etc.), an acid chloride (eg, pivaloyl chloride, Tosyl chloride, etc.) or an acid derivative (eg, ethyl chloroformate, isobutyl chloroformate, etc.), and the resulting mixed acid anhydride is reacted with L-alaninol usually at 0° C. to room temperature to give compound (V). Can be obtained. Further, in the method of passing through an acid chloride, for example, an acid chloride is obtained by using a chlorinating agent (eg, thionyl chloride, oxalyl chloride, etc.) in a suitable organic solvent (eg, toluene, xylene, etc.) Acid chloride in the presence of a base (eg sodium carbonate, triethylamine etc.) in a suitable organic solvent (eg ethyl acetate, toluene etc.) with L-alaninol,
[0075]
Compound (V) can also exist as a solvate. The solvate of compound (V) can be obtained by a conventional method for producing a solvate. Specifically, it can be obtained by mixing the compound (V) with a solvent while heating if necessary, and then cooling and crystallizing the mixture while stirring or standing. It is desirable that the cooling be carried out while adjusting the cooling rate if necessary in consideration of the influence on the quality of crystal, grain size and the like. For example, cooling at a cooling rate of 20 to 1° C./hour is preferable, and cooling at a cooling rate of 10 to 3° C./hour is more preferable. As the organic solvent used in these methods, alcohol solvents such as methanol, ethanol, propanol, isopropanol, normal propanol, and tertiary butanol are preferable. The amount of the organic solvent used is preferably 3 to 20 times by weight, more preferably 5 to 10 times by weight, of the compound (V).
The present inventors have investigated the method described in Patent Document 1 by using N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H). -Pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide chiral compound was prepared and analyzed. As a result, the compound was amorphous (amorphous). Solid). Amorphous is known to be a thermodynamically non-equilibrium metastable state and generally has high solubility and dissolution rate, but is low in stability and is often unfavorable in terms of drug development. Therefore, an object of the present invention is to increase the applicability as a drug substance to (S)-N-[(S)-1-hydroxypropan-2-yl]-4 represented by the formula (I). -Methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide It is to provide an alcohol solvate or a crystal thereof.
[Chemical 1]
[Reference Example 1] Compound (I) (amorphous)
Compound (I) was produced by the following method.
[Chemical 5]
[0046]
(First Step)
1-(2-Methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b] Azepine-4-carboxylic acid ethyl ester was treated with methyl bromide in the presence of (R,R)-3,5-bistrifluoromethylphenyl-NAS bromide, cesium carbonate and cesium fluoride in a mixed solvent of benzene bromide and water. By carrying out methylation using (R)-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4 ,5-Tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester was obtained.
[0047]
(Second Step)
(R)-4-Methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5- Reduction of the ketone portion of tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester with a borane-ammonia complex prepared from sodium borohydride and ammonium sulfate in a toluene solvent gave (4R)-5. -Hydroxy-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine- 4-Carboxylic acid ethyl ester was obtained.
[0048]
(Third Step)
(4R)-5-hydroxy-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5- By chlorinating the hydroxyl group of tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester with phosphorus oxychloride in the presence of pyridine in a toluene solvent, (4S)-5-chloro-4-methyl-1 -(2-Methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester was obtained. It was
[0049]
(Step 4)
(4S)-5-chloro-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5- By stirring tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester in a methanol solvent in the presence of 10% palladium-carbon under slightly pressurized conditions of hydrogen gas, (S)-4-methyl- 1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester Obtained.
[0050]
(Fifth Step)
(S)-4-Methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H- Benzo[b]azepine-4-carboxylic acid ethyl ester is hydrolyzed with 30% sodium hydroxide in a solvent of water and methanol to give (S)-4-methyl-1-(2-methyl-4-( 3-Methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid was obtained.
[0051]
(Sixth Step)
(S)-4-Methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H- Benzo[b]azepine-4-carboxylic acid was converted to an acid chloride form using thionyl chloride in a toluene solvent. This acid chloride and L-alaninol are reacted in a mixed solvent of ethyl acetate and water in the presence of sodium carbonate to give (S)-N-((S)-1-hydroxypropan-2-yl)-4-methyl. -1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide (compound ( I)) was obtained.
[0052]
FIG. 7 shows the powder X-ray diffraction spectrum of the compound (I) obtained in the first to sixth steps. No clear peak was observed in the X-ray diffraction pattern, and the compound (I) of Reference Example 1 was found to be amorphous.
[0053]
[Example 1] Isopropanol solvate
of compound (I) To 5.0 g of amorphous compound (I) of Reference Example 1, 65 mL of isopropanol was added, and the mixture was stirred at room temperature for 30 minutes. After the precipitated suspension was dissolved by heating, it was allowed to cool to room temperature and stirred overnight at 5°C. The suspension was filtered, washed with chilled isopropanol and dried at 40° C. overnight to give 4.9 g of a white solid.
[0054]
When the obtained compound was analyzed by a thermogravimetric apparatus, the content of isopropanol was 8.2% with respect to the compound (I), and the molar ratio was 0.7 times the amount with respect to the compound (I). It was
[0055]
The powder X-ray diffraction spectrum and the infrared absorption spectrum of the compound obtained in Example 1 are shown in FIG. 1 and FIG. 2, respectively. The characteristic peaks shown in Table 1 were shown as the diffraction angle (2θ) or as the interplanar spacing d. The obtained compound was crystalline.
[0056]
[table 1]
FIG. 2 shows an infrared absorption spectrum of the compound obtained in Example 1.
Supernus Pharmaceuticals , under license from Afecta Pharmaceuticals , is developing molindone hydrochloride (SPN-810; SPN-801M; AFX-2201; presumed to be Zalvari), as a capsule formulation, for the potential oral treatment of conduct disorder in patients with attention deficit hyperactivity disorder. In 3Q15, the company initiated two phase III trials (CHIME 1 and CHIME 2) for compulsive aggression in ADHD. In November 2019, the trial was expected to complete in June 2020.
Molindone, sold under the brand name Moban, is an antipsychotic which is used in the United States in the treatment of schizophrenia.[1][2] It works by blocking the effects of dopamine in the brain, leading to diminished symptoms of psychosis. It is rapidly absorbed when taken orally.
Molindone was discontinued by its original supplier, Endo Pharmaceuticals, on January 13, 2010.[5]
An indole derivative effective in schizophrenia and other psychoses and possibly useful in the treatment of the aggressive type of undersocialized conduct disorder. Molindone has much lower affinity for D2 receptors than most antipsychotic agents and has a relatively low affinity for D1 receptors. It has only low to moderate affinity for cholinergic and alpha-adrenergic receptors. Some electrophysiologic data from animals indicate that molindone has certain characteristics that resemble those of clozapine. (From AMA Drug Evaluations Annual, 1994, p283)
Availability and Marketing in the USA
After having been produced and subsequently discontinued by Core Pharma in 2015-2017, Molindone is available again from Epic Pharma effective December, 2018.[6]
Adverse effects
The side effect profile of molindone is similar to that of other typical antipsychotics. Unlike most antipsychotics, however, molindone use is associated with weight loss.[4][7]
Chemistry
Synthesis
Molindone synthesis: SCHOEN KARL, J PACHTER IRWIN; BE 670798 (1965 to Endo Lab).
Condensation of oximinoketone 2 (from nitrosation of 3-pentanone), with cyclohexane-1,3-dione (1) in the presence of zinc and acetic acid leads directly to the partly reduced indole derivative 6. The transformation may be rationalized by assuming as the first step, reduction of 2 to the corresponding α-aminoketone. Conjugate addition of the amine to 1 followed by elimination of hydroxide (as water) would give ene-aminoketone 3. This enamine may be assumed to be in tautomeric equilibrium with imine 4. Aldol condensation of the side chain carbonyl group with the doubly activated ring methylene group would then result in cyclization to pyrrole 5; simple tautomeric transformation would then give the observed product. Mannich reaction of 6 with formaldehyde and morpholine gives the tranquilizer molindone (7).
US-20200262788
Process for preparing molindone and its intermediates useful for treating schizophrenia..
Molindone is chemically known as 4H-Indol-4-one, 3-ethyl-1,5,6,7-tetrahydro-2-methyl-5-(4-morpholinylmethyl) and represented by formula I. Molindone is indicated for management of schizophrenia and is under clinical trial for alternate therapies.
The compound molindone, process for its preparation and its pharmaceutically acceptable salts are disclosed in U.S. Pat. No. 3,491,093. Another application WO 2014042688 discloses methods of producing molindone. Since there are very limited methods for preparation of molindone reported in literature there exist a need for alternate process for preparation of molindone. The present invention provides novel process for preparation of Molindone (I) and its salts.
EXAMPLES
Example 1: Preparation of methyl 2-chloro-2-ethyl-3-oxobutanoate
A mixture of methyl acetoacetate (100 g), potassium tertiary butoxide (101.5 g) and tetrahydrofuran (400 ml) was stirred and a solution of ethyliodide (141 g) in tetrahydrofuran (200 ml) was added to it. The reaction mixture was stirred at 60° C. for about 15 hours. Water (250 ml) was added to the reaction mixture at 25° C. followed by addition of dichloromethane (500 ml). The organic layer was separated and concentrated. To the concentrate was added dichloromethane (1000 ml) and sulfuryl chloride (93.7 g) and the solution was stirred for about 18 hours at 25-30° C. Water (500 ml) was added to the reaction mixture. The organic layer was separated and concentrated to give the title compound.
Example 2: Preparation of 3-chloropentan-2-one
A mixture of methyl 2-chloro-2-ethyl-3-oxobutanoate (98.8 g) and water (240 ml) was treated with sulfuric acid (260 g) and stirred for 90 minutes at 75-80° C. The reaction mixture was poured into water (500 ml) and dichloromethane (500 ml). The organic layer was separated and concentrated. The concentrate was subjected to fractional distillation and pure compound was collected.
Example 3: Preparation of 3-chloropentan-2-one
A mixture of petane-2-one (15 g), acetic acid (60 ml) and N-chlorosuccinimide (24.4 g) was stirred for about 18 hours at 80-85° C. The reaction mixture was cooled and dichloromethane (100 ml) was added to it. The mixture was treated with sodium bicarbonate solution. The organic layer was separated and concentrated to give the title compound (2).
Example 4: Preparation of 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4)
A mixture of 3-bromopentan-2-one (17 g), cyclohexane-1,3-dione (11.5 g), triethyl amine (15.6 g) and acetonitrile (100 ml)) was stirred for about 2 hours at 55-60° C. The reaction mixture was concentrated and ethyl acetate (170 ml) and water (85 ml) was added. The organic layer separated and concentrated. The residue was subjected to column chromatography (ethylacetate: cyclohexane). The title compound was obtained. 1H NMR (500 MHz, CDCl 3), δ 5.14 (S 1H), δ 4.37 (d 1H), δ 2.50-2.55 (m 2H) δ 2.35-2.38 (m 2H), δ 2.16 (s 3H), δ 2.00-2.05 (m 2H) δ 1.88-1.90 (m 2H), δ 1.00-1.02 (m 3H); 13C NMR (500 MHz, CDCl 3), 206.04, 199.34, 176.63, 103.70, 77.12, 36.62, 28.88, 25.44, 21.00, 16.55, 9.41 ppm; Dept135 NMR (500 MHz, CDCl 3): 103.70, 83.78, 36.62, 28.87, 28.65, 25.45, 24.69, 21.00, 9.41 ppm; Mass: [M+1]=197.
Example 5: Preparation of 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5)
A mixture of 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (10 g), acetic acid (40 ml) and ammonium acetate (19.6 g) was stirred for about 3 hours at 95-100° C. The reaction mixture was cooled and concentrated. To the residue a mixture of ethyl acetate (60 ml) and water (50 ml) was added. The organic layer separated and concentrated to give the title compound.
Example 6: Preparation of 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5)
A mixture of cyclohexane-1,3-dione (3 g), dimethyl sulfoxide (15 ml), triethyl amine (2.7 g) and 3-chloropentan-2-one (3.2 g) was stirred for about 24 hours at 40-45° C. Aqueous ammonia (15 ml) was added to the mixture and stirred for about 10 hours at 25-30° C. A mixture of water (60 ml) and ethyl acetate (30 ml) was added to it. The organic layer separated and concentrated. The residue was subjected to column chromatography (ethyl acetate/n-hexane). The title compound was obtained.
Example 7: Preparation of Molindone Hydrochloride
A mixture of 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5 g), morpholine (4.42 g), paraformaldehyde (1.52 g) and ethanol (70 ml) was stirred for about 24 hours at 75-80° C. The reaction mixture was concentrated and water (50 ml) was added to the residue. The mixture was treated with concentrated hydrochloric acid followed by aqueous ammonia in presence of ethyl acetate. The organic layer was separated and concentrated to obtain molindone as a residue. Isopropanol hydrochloride was added to the residue and stirred for 30 minutes at 25-30° C. The solution was concentrated and ethyl acetate (15 ml) was added. The solid was filtered, washed with ethyl acetate and dried to obtain molindone hydrochloride.
^Aparasu RR, Jano E, Johnson ML, Chen H (October 2008). “Hospitalization risk associated with typical and atypical antipsychotic use in community-dwelling elderly patients”. Am J Geriatr Pharmacother. 6 (4): 198–204. doi:10.1016/j.amjopharm.2008.10.003. PMID19028375.
Doxecitine CAS951-77-9 MF C9H13N3O4 11/3/2025, FDA 2025, To treat thymidine kinase 2 deficiency in patients who start to show symptoms when they are 12 years…
Alizulatide vixocianine CAS 2924859-51-6 MF C115H145N17O25S, 2,197.55 L-Serine, N-[6-[2-[7-[1,3-dihydro-1,1-dimethyl-3-(4-sulfobutyl)-2H-benz[e]indol-2-ylidene]-1,3,5-heptatrien-1-yl]-1,1-dimethyl-1H-benz[e]indolio]-1-oxohexyl]-L-α-glutamyl-L-α-glutamyl-L-α-aspartyl-3-cyclohexyl-L-alanyl-L-phenylalanyl-D-seryl-D-arginyl-L-tyrosyl-L-leucyl-L-tryptophyl-, inner salt 4-[2-[7-[3-[6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2R)-5-carbamimidamido-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxy-2-hydroxyethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-6-oxohexyl]-1,1-dimethylbenzo[e]indol-3-ium-2-yl]hepta-2,4,6-trienylidene]-1,1-dimethylbenzo[e]indol-3-yl]butane-1-sulfonate diagnostic imaging agent, 8M3Q8XZ6MJ Alizulatide vixocianine is a polypeptide that can be discovered…
Limnetrelvir CAS 2923500-04-1 MF C27H23F4N5O4 MW 557.50 N-[(3R)-1-[4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl]pyrrolidin-3-yl]-8-fluoro-2-oxo-1H-quinoline-4-carboxamide N-{(3R)-1-[4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl]pyrrolidin-3-yl}-8-fluoro-2-oxo1,2-dihydroquinoline-4-carboxamideantiviral, ABBV-903, ABBV 903, 4TPS988XGG Limnetrelvir (ABBV-903) is a MPro inhibitor. Limnetrelvir could be used in antiviral research. SYN https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=4D458E543A941751578F87216FA39801.wapp1nA?docId=WO2024081351&_cid=P10-MJQJMM-46773-1#detailMainForm:MyTabViewId:PCTDESCRIPTION Example…
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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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