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Povidone-iodine
Povidone-iodine
PVP 1
UNII85H0HZU99M, BETADINE
CAS number 25655-41-8, Molecular Formula, (C6-H9-N-O)x-.x-I2, Molecular Weight, 364.9431
1-ethenylpyrrolidin-2-one;molecular iodine Povidone-Iodine
CAS Registry Number: 25655-41-8
CAS Name: 1-Ethenyl-2-pyrrolidinone homopolymer compd with iodine
Additional Names: 1-vinyl-2-pyrrolidinone polymers, iodine complex; iodine-polyvinylpyrrolidone complex; polyvinylpyrrolidone-iodine complex; PVP-I
Trademarks: Betadine (Purdue Frederick); Betaisodona (Mundipharma); Braunol (Braun Melsungen); Braunosan H (Braun Melsungen); Disadine D.P. (Stuart); Efodine (Fougera); Inadine (J & J); Isodine (Blair); Proviodine (Rougier); Traumasept (Wolff)
Literature References: An iodophor, q.v., prepd by Beller, Hosmer, US2706701; Hosmer, US2826532; Siggia, US2900305 (1955, 1958, and 1959, all to GAF). Prepn, history and use: Shelanski, Shelanski, J. Int. Coll. Surg.25, 727 (1956).
Properties: Yellowish-brown, amorphous powder with slight characteristic odor. Aq solns have a pH near 2 and may be made more neutral (but less stable) by the addition of sodium bicarbonate. Sol in alc, water. Practically insol in chloroform, carbon tetrachloride, ether, solvent hexane, acetone. Solns do not give the familiar starch test when freshly prepared.
Therap-Cat: Anti-infective (topical).
Therap-Cat-Vet: Anti-infective (topical).
Keywords: Antiseptic/Disinfectant; Halogens/Halogen Containing Compounds.
- An iodinated polyvinyl polymer used as topical antiseptic in surgery and for skin and mucous membrane infections, also as aerosol. The iodine may be radiolabeled for research purposes.
Povidone-iodine is a stable chemical complex of polyvinylpyrrolidone (povidone, PVP) and elemental iodine. It contains from 9.0% to 12.0% available iodine, calculated on a dry basis. This unique complex was discovered in 1955 at the Industrial Toxicology Laboratories in Philadelphia by H. A. Shelanski and M. V. Shelanski. During in vitro testing to demonstrate anti-bacterial activity it was found that the complex was less toxic in mice than tincture of iodine. Human clinical trials showed the product to be superior to other iodine formulations. Povidone-iodine was immediately marketed, and has since become the universally preferred iodine antiseptic.
Povidone-iodine (PVP-I), also known as iodopovidone, is an antiseptic used for skin disinfection before and after surgery.[1][2] It may be used both to disinfect the hands of healthcare providers and the skin of the person they are caring for.[2] It may also be used for minor wounds.[2] It may be applied to the skin as a liquid or a powder.[2]
Side effects include skin irritation and sometimes swelling.[1] If used on large wounds, kidney problems, high blood sodium, and metabolic acidosis may occur.[1] It is not recommended in women who are less than 32 weeks pregnant or are taking lithium.[2] Frequent use is not recommended in people with thyroid problems.[2] Povidone-iodine is a chemical complex of povidone, hydrogen iodide, and elemental iodine.[3] It contains 10% Povidone, with total iodine species equaling 10,000 ppm or 1% total titratable iodine.[3] It works by releasing iodine which results in the death of a range of microorganisms.[1]
Povidone-iodine came into commercial use in 1955.[4] It is on the World Health Organization’s List of Essential Medicines.[5] Povidone-iodine is available over the counter.[6] It is sold under a number of brand names including Betadine.[2]
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Medical uses
Wound area covered in povidone-iodine. Gauze has also been applied.
Povidone-iodine is a broad spectrum antiseptic for topical application in the treatment and prevention of wound infection. It may be used in first aid for minor cuts, burns, abrasions and blisters. Povidone-iodine exhibits longer lasting antiseptic effects than tincture of iodine, due to its slow absorption via soft tissue, making it the choice for longer surgeries. Chlorhexidine provides superior results with equivalent adverse events.[7]
Consequently, PVP-I has found broad application in medicine as a surgical scrub; for pre- and post-operative skin cleansing; for the treatment and prevention of infections in wounds, ulcers, cuts and burns; for the treatment of infections in decubitus ulcers and stasis ulcers; in gynecology for vaginitis associated with candidal, trichomonal or mixed infections. For these purposes PVP-I has been formulated at concentrations of 7.5–10.0% in solution, spray, surgical scrub, ointment, and swab dosage forms; however, use of 10% povidone-iodine though recommended, is infrequently used, as it is poorly accepted by health care workers and is excessively slow to dry.[8][9]
Because of these critical indications, only sterile povidone-iodine should be used in most cases. Non-sterile product can be appropriate in limited circumstances in which people have intact, healthy skin that will not be compromised or cut. The non-sterile form of Povidone iodine has a long history of intrinsic contamination with Burkholderia cepacia (aka Pseudomonas cepacia), and other opportunistic pathogens. Its ability to harbor such microbes further underscores the importance of using sterile products in any clinical setting. Since these bacteria are resistant to povidone iodine, statements that bacteria do not develop resistance to PVP-I,[10] should be regarded with great caution: some bacteria are intrinsically resistant to a range of biocides including povidone-iodine.[11]
Antiseptic activity of PVP-I is because of free iodine (I2) and PVP-I only acts as carrier of I2 to the target cells. Most commonly used 10% PVP-I delivers about 1-3 ppm of I2 in a compound of more than 31,600 ppm of total iodine atoms. All the toxic and staining effects of PVP-I is due to the inactive iodine only.
Eyes
A buffered PVP-I solution of 2.5% concentration can be used for prevention of neonatal conjunctivitis, especially if it is caused by Neisseria gonorrhoeae, or Chlamydia trachomatis. It is currently unclear whether PVP-I is more effective in reducing the number of cases of conjunctivitis in neonates over other methods.[12] PVP-I appears to be very suitable for this purpose because, unlike other substances, it is also efficient against fungi and viruses (including HIV and Herpes simplex).[13]
Pleurodesis
It is used in pleurodesis (fusion of the pleura because of incessant pleural effusions). For this purpose, povidone-iodine is equally effective and safe as talc, and may be preferred because of easy availability and low cost.[14]
Alternatives
There is strong evidence that chlorhexidine and denatured alcohol used to clean skin prior to surgery is better than any formulation of povidone-iodine[7]
Contraindications
PVP-I is contraindicated in people with hyperthyroidism (overactive thyroid gland) and other diseases of the thyroid, after treatment with radioiodine, and in people with dermatitis herpetiformis[why?] (Duhring’s disease).[15]
Side effects
The sensitization rate to the product is 0.7%.[16]
Interactions
The iodine in PVP-I reacts with hydrogen peroxide, silver, taurolidine and proteins such as enzymes, rendering them (and itself) ineffective. It also reacts with many mercury compounds, giving the corrosive compound mercury iodide, as well as with many metals, making it unsuitable for disinfecting metal piercings.[15]
Iodine is absorbed into the body to various degrees, depending on application area and condition of the skin. As such, it interacts with diagnostic tests of the thyroid gland such as radioiodine diagnostics, as well as with various diagnostic agents used on the urine and stool, for example Guaiacum resin.[15]
Structure
Structure of povidone-iodine complex.
Povidone-iodine is a chemical complex of the polymer povidone (polyvinylpyrrolidone) and triiodide (I3−).[17]
It is soluble in cold and mild-warm water, ethyl alcohol, isopropyl alcohol, polyethylene glycol, and glycerol. Its stability in solution is much greater than that of tincture of iodine or Lugol’s solution.
Free iodine, slowly liberated from the povidone-iodine (PVP-I) complex in solution, kills cells through iodination of lipids and oxidation of cytoplasmic and membrane compounds. This agent exhibits a broad range of microbiocidal activity against bacteria, fungi, protozoa, and viruses. Slow release of iodine from the PVP-I complex in solution minimizes iodine toxicity towards mammalian cells.
PVP-I can be loaded into hydrogels, which can be based on carboxymethyl cellulose (CMC), poly(vinyl alcohol) (PVA), and gelatin, or on crosslinked polyacrylamide. These hydrogels can be used for wound dressing. The rate of release of the iodine in the PVP-I is heavily dependent on the hydrogel composition: it increases with more CMC/PVA and decreases with more gelatin.
History
PVP-I was discovered in 1955, at the Industrial Toxicology Laboratories in Philadelphia by H. A. Shelanski and M. V. Shelanski.[18] They carried out tests in vitro to demonstrate anti-bacterial activity, and found that the complex was less toxic in mice than tincture of iodine. Human clinical trials showed the product to be superior to other iodine formulations.[19]
Following the discovery of iodine by Bernard Courtois in 1811, it has been broadly used for the prevention and treatment of skin infections, as well as the treatment of wounds. Iodine has been recognized as an effective broad-spectrum bactericide, and is also effective against yeasts, molds, fungi, viruses, and protozoans. Drawbacks to its use in the form of aqueous solutions include irritation at the site of application, toxicity, and the staining of surrounding tissues. These deficiencies were overcome by the discovery and use of PVP-I, in which the iodine is carried in a complexed form and the concentration of free iodine is very low. The product thus serves as an iodophor.
Research
Schematic of povidone-iodine complex wrapping a single wall carbon nanotube (black).[20]
Povidone-iodine has found application in the field of nanomaterials. A wound-healing application has been developed which employs a mat of single wall carbon nanotubes (SWNTs) coated in a monolayer of povidone-iodine.[20]
Research has previously found that the polymer polyvinylpyrrolidone (PVP, povidone) can coil around individual carbon nanotubes to make them water-soluble.[21]
References
- ^ Jump up to:a b c d World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. pp. 321–323. hdl:10665/44053. ISBN 9789241547659.
- ^ Jump up to:a b c d e f g British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 840. ISBN 9780857111562.
- ^ Jump up to:a b Encyclopedia of polymer science and technology (3 ed.). John Wiley & Sons. 2013. p. 728. ISBN 9780470073698. Archived from the original on 2017-01-13.
- ^ Sneader W (2005). Drug Discovery: A History. John Wiley & Sons. p. 68. ISBN 9780470015520. Archived from the original on 2017-01-13.
- ^ World 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.
- ^ “Povidone/iodine solution: Indications, Side Effects, Warnings – Drugs.com”. http://www.drugs.com. Archived from the original on 13 January 2017. Retrieved 11 January 2017.
- ^ Jump up to:a b Wade RG, Burr NE, McCauley G, Bourke G, Efthimiou O (September 2020). “The Comparative Efficacy of Chlorhexidine Gluconate and Povidone-iodine Antiseptics for the Prevention of Infection in Clean Surgery: A Systematic Review and Network Meta-analysis”. Annals of Surgery. Publish Ahead of Print. doi:10.1097/SLA.0000000000004076. PMID 32773627.
- ^ Slater K, Cooke M, Fullerton F, Whitby M, Hay J, Lingard S, et al. (September 2020). “Peripheral intravenous catheter needleless connector decontamination study-Randomized controlled trial”. American Journal of Infection Control. 48 (9): 1013–1018. doi:10.1016/j.ajic.2019.11.030. PMID 31928890.
- ^ Slater K, Fullerton F, Cooke M, Snell S, Rickard CM (September 2018). “Needleless connector drying time-how long does it take?”. American Journal of Infection Control. 46 (9): 1080–1081. doi:10.1016/j.ajic.2018.05.007. PMID 29880433. S2CID 46968733.
- ^ Fleischer W, Reimer K (1997). “Povidone-iodine in antisepsis–state of the art”. Dermatology. 195 Suppl 2 (Suppl 2): 3–9. doi:10.1159/000246022. PMID 9403248.
- ^ Rose H, Baldwin A, Dowson CG, Mahenthiralingam E (March 2009). “Biocide susceptibility of the Burkholderia cepacia complex”. The Journal of Antimicrobial Chemotherapy. 63 (3): 502–10. doi:10.1093/jac/dkn540. PMC 2640157. PMID 19153076.
- ^ Martin I, Sawatzky P, Liu G, Mulvey MR (February 2015). “Neisseria gonorrhoeae in Canada: 2009-2013”. Canada Communicable Disease Report. 41 (2): 35–41. doi:10.1002/14651858.CD001862.pub3. PMC 6457593.
- ^ Najafi Bi R, Samani SM, Pishva N, Moheimani F (2003). “Formulation and Clinical Evaluation of Povidone-Iodine Ophthalmic Drop”. Iranian Journal of Pharmaceuticical Research. 2 (3): 157–160.
- ^ Agarwal R, Khan A, Aggarwal AN, Gupta D (March 2012). “Efficacy & safety of iodopovidone pleurodesis: a systematic review & meta-analysis”. The Indian Journal of Medical Research. 135: 297–304. PMC 3361864. PMID 22561614.
- ^ Jump up to:a b c Jasek W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 983–5. ISBN 978-3-85200-181-4.
- ^ Niedner R (1997). “Cytotoxicity and sensitization of povidone-iodine and other frequently used anti-infective agents”. Dermatology. 195 Suppl 2 (Suppl 2): 89–92. doi:10.1159/000246038. PMID 9403263.
- ^ Kutscher, Bernhard (2020). “Dermatologicals (D), 4. Antiseptics and Disinfectants (D08), Anti‐Acne Preparations (D10), and Other Dermatological Preparations (D11)”. Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. pp. 1–22. doi:10.1002/14356007.w08_w03.
- ^ U.S. Patent 2,739,922
- ^ Sneader W (2005). Drug Discovery: A History. New York: John Wiley & Sons. p. 68. ISBN 978-0-471-89979-2.
- ^ Jump up to:a b Simmons TJ, Lee SH, Park TJ, Hashim DP, Ajayan PM, Linhardt RJ (2009). “Antiseptic Single Wall Carbon Nanotube Bandages” (PDF). Carbon. 47 (6): 1561–1564. doi:10.1016/j.carbon.2009.02.005. Archived from the original (PDF) on 2010-06-21.
- ^ Simmons TJ, Hashim D, Vajtai R, Ajayan PM (August 2007). “Large area-aligned arrays from direct deposition of single-wall carbon nanotube inks”. Journal of the American Chemical Society. 129 (33): 10088–9. doi:10.1021/ja073745e. PMID 17663555.
Further reading
- Wong RH, Hung EC, Wong VW, Wan IY, Ng CS, Wan S, Underwood MJ (2009). “Povidone-iodine wound irrigation: A word of caution”. Surgical Practice. 13 (4): 123–4. doi:10.1111/j.1744-1633.2009.00461.x. S2CID 71797553.
- Wong RH, Wong VW, Hung EC, Lee PY, Ng CS, Wan IY, Underwood MJ (2011). “Topical application of povidone-iodine before wound closure is associated with significant increase in serum iodine level”. Surgical Practice. 19 (3): 79–82. doi:10.1111/j.1744-1633.2011.00547.x. S2CID 70528331.
- Wong RH, Ng CS, Underwood MJ (May 2012). “Iodine pleurodesis–a word of caution”. European Journal of Cardio-Thoracic Surgery. 41 (5): 1209. doi:10.1093/ejcts/ezr137. PMID 22219431.
External links
“Povidone-iodine”. Drug Information Portal. U.S. National Library of Medicine.
| Povidone-iodine applied to an abrasion using a cotton swab. | |
| Clinical data | |
|---|---|
| Trade names | Betadine, Wokadine, Pyodine, others |
| Other names | polyvidone iodine, iodopovidone |
| AHFS/Drugs.com | Consumer Drug Information |
| License data | US DailyMed: Povidone-iodine |
| Routes of administration | Topical |
| ATC code | D08AG02 (WHO)D09AA09 (WHO) (dressing)D11AC06 (WHO)G01AX11 (WHO)R02AA15 (WHO)S01AX18 (WHO)QG51AD01 (WHO) |
| Legal status | |
| Legal status | US: OTC / Rx-only |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 25655-41-8 |
| PubChem CID | 410087 |
| DrugBank | DB06812 |
| ChemSpider | none |
| UNII | 85H0HZU99M |
| KEGG | D00863C08043 |
| ChEBI | CHEBI:8347 |
| ChEMBL | ChEMBL1201724 |
| CompTox Dashboard (EPA) | DTXSID8035712 |
| ECHA InfoCard | 100.110.412 |
| Chemical and physical data | |
| Formula | (C6H9NO)n·xI |
| Molar mass | variable |
| (what is this?) (verify) |
///////////Povidone-iodine, PVP 1, BETADINE
C=CN1CCCC1=O.II
NEW DRUG APPROVALS
ONE TIME
$10.00
PILOCARPINE
PILOCARPINE
- Molecular FormulaC11H16N2O2
- Average mass208.257 Da
2(3H)-Furanone, 3-ethyldihydro-4-[(1-methyl-1H-imidazol-5-yl)methyl]-, (3S-cis)-
202-128-4[EINECS]92-13-7 CAS
54-71-7[RN]
(+)-pilocarpine
(3S,4R)-3-Ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]dihydro-2(3H)-furanone
Product Ingredients
| INGREDIENT | UNII | CAS | INCHI KEY |
|---|---|---|---|
| Pilocarpine hydrochloride | 0WW6D218XJ | 54-71-7 | RNAICSBVACLLGM-GNAZCLTHSA-N |
| Pilocarpine nitrate | M20T465H6J | 148-72-1 | PRZXEPJJHQYOGF-GNAZCLTHSA-N |
PilocarpineCAS Registry Number: 92-13-7
CAS Name: (3S-cis)-3-Ethyldihydro-4-[(1-methyl-1H-imidazol-5-yl)methyl]-2(3H)-furanone
Trademarks: Ocusert Pilo (Cusi)
Molecular Formula: C11H16N2O2, Molecular Weight: 208.26
Percent Composition: C 63.44%, H 7.74%, N 13.45%, O 15.36%
Literature References: Cholinergic principle from Pilocarpus jaborandi Holmes, Rutaceae. Isoln: Petit, Polanovski, Bull. Soc. Chim. [3] 17, 557, 702 (1897). Structure: Jowett, J. Chem. Soc.77, 473, 851 (1900); 83, 438 (1903). Stereoisomeric with isopilocarpine: Polonovski, Polonovski, Bull. Soc. Chim. [4] 31, 1314 (1922). Has the cis configuration; isopilocarpine is trans: Zav’yalov, Dokl. Akad. Nauk SSSR82, 257 (1952). Absolute configuration: Hill, Barcza, Tetrahedron22, 2889 (1966). Synthesis: Preobrashenski et al.,Ber.66, 1187 (1933); Samokhvalov, Med. Prom. SSSR11, no. 2, 10 (1957); DeGraw, Tetrahedron28, 967 (1972); Link, Bernauer, Helv. Chim. Acta55, 1053 (1972). Stereoselective synthesis: A. Noordam et al.,Rec. Trav. Chim.98, 467 (1979). Review: Langenbeck, Angew. Chem.60, 297 (1948); van Rossum et al.,Experientia16, 373 (1960). Toxicity studies: Beccari, Boll. Chim. Farm.106, 8 (1967). Comprehensive description: A. A. Al-Badr, H. Y. Aboul-Enein, Anal. Profiles Drug Subs.12, 385-432 (1983). Clinical trial in Sjögren’s syndrome: F. B. Vivino et al., Arch. Intern. Med.159, 174 (1999); in radiation-induced xerostomia: J.-C. Horiot et al.,Radiother. Oncol.55, 233 (2000).
Properties: Oil or crystals, mp 34°. bp5 260° (partial conversion to isopilocarpine). [a]D18 +106° (c = 2). pK1 (20°) 7.15; pK2 (20°) 12.57. Sol in water, alcohol, chloroform; sparingly sol in ether, benzene. Almost insol in petr ether.
Melting point: mp 34°
Boiling point: bp5 260° (partial conversion to isopilocarpine)
pKa: pK1 (20°) 7.15; pK2 (20°) 12.57
Optical Rotation: [a]D18 +106° (c = 2)
Derivative Type: Hydrochloride
CAS Registry Number: 54-71-7
Trademarks: Akarpine (Akorn); Almocarpine (Ayerst); Isopto Carpine (Alcon); Pilogel (Alcon); Pilopine HS (Alcon); Pilostat (Bausch & Lomb); Salagen (MGI)
Molecular Formula: C11H16N2O2.HCl, Molecular Weight: 244.72
Percent Composition: C 53.99%, H 7.00%, N 11.45%, O 13.08%, Cl 14.49%
Properties: Hygroscopic crystals from alcohol, mp 204-205°. [a]D18 +91° (c = 2). Freely sol in water, alcohol. Practically insol in ether, chloroform. Keep well closed and protected from light.
Melting point: mp 204-205°
Optical Rotation: [a]D18 +91° (c = 2)
Derivative Type: Nitrate
CAS Registry Number: 148-72-1
Trademarks: Chibro Pilocarpine (Chibret); Licarpin (Allergan); Pilo (Novopharma); Pilofrin (Allergan); Pilagan (Allergan)
Molecular Formula: C11H16N2O2.HNO3, Molecular Weight: 271.27
Percent Composition: C 48.70%, H 6.32%, N 15.49%, O 29.49%
Properties: mp 173.5-174.0° (dec). Poisonous! [a]D +77 to +83° (c = 10). One gram dissolves in 4 ml water, 75 ml alcohol. Insol in chloroform, ether. Incompat. Silver nitrate, mercury bichloride, iodides, gold salts, tannin, calomel, KMnO4, alkalies.
Melting point: mp 173.5-174.0° (dec)
Optical Rotation: [a]D +77 to +83° (c = 10)
Derivative Type: Isopilocarpine
Additional Names: b-Pilocarpine
Properties: Hygroscopic oily liquid or prisms. bp10 261°. [a]D18 +50° (c = 2). pK1 (18°) 7.17. Miscible with water and alcohol; very sol in chloroform; less sol in benzene, ether. Almost insol in petr ether.
Boiling point: bp10 261°
pKa: pK1 (18°) 7.17
Optical Rotation: [a]D18 +50° (c = 2)
Derivative Type: Isopilocarpine hydrochloride hemihydrate
Molecular Formula: C11H16N2O2.HCl.½H2O, Molecular Weight: 253.73
Percent Composition: C 52.07%, H 7.15%, N 11.04%, O 15.76%, Cl 13.97%
Properties: Scales from alcohol + ether, mp 127°; when anhydr, mp 161°. [a]D18 +39° (c = 5). Sol in 0.27 part water; 2.1 parts alcohol.
Melting point: mp 127°; mp 161°
Optical Rotation: [a]D18 +39° (c = 5)
Derivative Type: Isopilocarpine nitrate
Molecular Formula: C11H16N2O2.HNO3, Molecular Weight: 271.27Percent Composition: C 48.70%, H 6.32%, N 15.49%, O 29.49%
Properties: Prisms from water, scales from alcohol, mp 159°. [a]D18 +39° (c = 2). Sol in 8.4 parts water, in 350 parts abs alcohol.
Melting point: mp 159°
Optical Rotation: [a]D18 +39° (c = 2)
Therap-Cat: Antiglaucoma agent; miotic; sialogogue.
Therap-Cat-Vet: Parasympathomimetic; miotic; gastric secretory stimulant.
Keywords: Antiglaucoma; Miotic; Sialagogue.
Pilocarpine is a muscarinic cholinergic agonist used on the eye to treat elevated intraocular pressure, various types of glaucoma, and to induce miosis. Also available orally to treat symptoms of dry mouth associated with Sjogren’s syndrome and radiotherapy.
Pilocarpine is a medication used to reduce pressure inside the eye and treat dry mouth.[1][3] As eye drops it is used to manage angle closure glaucoma until surgery can be performed, ocular hypertension, primary open angle glaucoma, and to bring about constriction of the pupil following its dilation.[1][4][5] However, due to its side effects it is no longer typically used in the long term management.[6] Onset of effects with the drops is typically within an hour and lasts for up to a day.[1] By mouth it is used for dry mouth as a result of Sjögren syndrome or radiation therapy.[7]
Common side effects of the eye drops include irritation of the eye, increased tearing, headache, and blurry vision.[1] Other side effects include allergic reactions and retinal detachment.[1] Use is generally not recommended during pregnancy.[8] Pilocarpine is in the miotics family of medication.[9] It works by activating cholinergic receptors of the muscarinic type which cause the trabecular meshwork to open and the aqueous humor to drain from the eye.[1]
Pilocarpine was isolated in 1874 by Hardy and Gerrard and has been used to treat glaucoma for more than 100 years.[10][11][12] It is on the World Health Organization’s List of Essential Medicines.[13] It was originally made from the South American plant Pilocarpus.[10]
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////////////////////////////////////////
Pilocarpine hydrochloride, KSS-694, MGI-647, Pilobuc, Pilocar, Isopto carpine, Spersacarpin, Pilo, Isopto-pilocarpine, Pilocarpina lux, Pilogel, PilaSite(sustained release), Salagen, Pilopine HS
SYN
The alkylation of pilosine (I) with ethyl chloride (II) by means of LDA in THF gives trans-pilocarpine (III), which is isomerized with LDA in THF, yielding a mixture of cis- and trans-pilocarpine (IV). Finally, this mixture is resolved by crystallization with di-p-toluoyl tartaric acid.
SYN
Journal of Organic Chemistry, 58(1), 62-4; 1993
https://pubs.acs.org/doi/abs/10.1021/jo00053a016
SYN
Tetrahedron, 65(39), 8283-8296; 2009
SYN
Science of Synthesis, 20b, 987-1046; 2006
SYN
https://linkinghub.elsevier.com/retrieve/pii/S0040402008014002
SYN
https://www.mdpi.com/1420-3049/26/12/3676/htm
Schmidt, Theresa et alFrom Molecules, 26(12), 3676; 2021
Figure 1. Structure of natural occurring pilocarpine (+)-1 and its enantiomer (–)-1.
Scheme 1. Reactions and conditions: (a) hν, Bengal rosa, 8 h, 20 °C, 76% (of 3) and 5% (of 4); (b) CH2(OCH3)2, P4O10, DCM, 20 °C, 5 h, 98%; (c) CH2(OCH3)2, P4O10, DCM, 20 °C, 5 h, 99%; (d) THF, Na, 25 °C, 15 h, 72%; (e) CH2(OCH3)2, P4O10, DCM, 20 °C, 5 h, 77% (of 6) and 19% (of 7); (f) HBr, reflux, 2 d, 83%; (g) HBr, reflux, 4 d, 4%.
Scheme 2. Reactions and conditions: (a) SOCl2, reflux, 3 h, quant.; (b) Hex-OH, reflux, 16 h, 98%; (c) Rh/Al2O3, H2 (1 at), THF, 5 d, quant.; (d) Lipase PS, pH = 7.0, 2 d, 22 °C, 48% (of (±)-16) and 42% (of (–)-17); (e) PLE, pH = 7.0, 22 °C, 2 d, 96%; (f) N-methylmorpholine, iBu-chloroformate, N,O-dimethylhydroxylamine hydrochloride, 23 °C, 1 d, 84% (of (+)-18) and 85% of (–)-18); (g) LiAlH4, Et2O, 23 °C, 30 min, 95% (of (+)-19) and 95% of (–)-19; (h) CH3NH2, TosMic, DCM, benzene, NEt3, 7 d, 23 °C, 59% (of (+1)-1 and 60% of (–)-1; Hex stands for n-hexyl.
(+)-Pilocarpine [(+)-1]
Following the procedure given for the synthesis of its enantiomer, (+)-1 (1.92 g, 59%) was obtained as a colorless oil; Rf = 0.60 (SiO2, DCM/MeOH/aq NH4OH (25%), 95:4:1); [α]D = +115.7° (c 0.6, CHCl3), ee > 99% (by HPLC, Chiralcel OC, n-hexane/ethanol, 3:7, 0.3 mL/min, UV-detection λ = 215 nm; tR = (+)-1 47.1 min, tR = (–)-1 = 52.32 min); IR (film), 1H-NMR, 13C-NMR and MS (ESI, MeOH) were identical to the enantiomer (vide supra); analysis calcd. for C11H16N2O2 (208.26): C 63.44, H 7.74, N 13.45; found: C 63.31, H 7.98, N 13.32
PAPERBy Fuerstner, AloisFrom e-EROS Encyclopedia of Reagents for Organic Synthesis, 1-7; 2001
| Clinical data | |
|---|---|
| Trade names | Isopto Carpine, Salagen, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a608039 |
| Pregnancy category | AU: B3 |
| Routes of administration | Topical eye drops, by mouth |
| Drug class | Miotic (cholinergic)[1] |
| ATC code | N07AX01 (WHO) S01EB01 (WHO) |
| Legal status | |
| Legal status | AU: S4 (Prescription only)UK: POM (Prescription only)US: ℞-only |
| Pharmacokinetic data | |
| Elimination half-life | 0.76 hours (5 mg), 1.35 hours (10 mg)[2] |
| Excretion | urine |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 92-13-7 54-71-7 (hydrochloride) |
| PubChem CID | 5910 |
| IUPHAR/BPS | 305 |
| DrugBank | DB01085 |
| ChemSpider | 5699 |
| UNII | 01MI4Q9DI3 |
| KEGG | D00525 |
| ChEBI | CHEBI:8207 |
| ChEMBL | ChEMBL550 |
| CompTox Dashboard (EPA) | DTXSID1021162 |
| ECHA InfoCard | 100.001.936 |
| Chemical and physical data | |
| Formula | C11H16N2O2 |
| Molar mass | 208.261 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
| (verify) |
Medical uses
Pilocarpine stimulates the secretion of large amounts of saliva and sweat.[14] It is used to prevent or treat dry mouth, particularly in Sjögren syndrome, but also as a side effect of radiation therapy for head and neck cancer.[15]
It may be used to help differentiate Adie syndrome from other causes of unequal pupil size.[16][17][clarification needed]
It may be used to treat a form of dry eye called aqueous deficient dry eye (ADDE)[18]
Surgery
Pilocarpine is sometimes used immediately before certain types of corneal grafts and cataract surgery.[19][20] In ophthalmology, pilocarpine is also used to reduce symptomatic glare at night from lights when the patient has undergone implantation of phakic intraocular lenses; the use of pilocarpine would reduce the size of the pupils, partially relieving these symptoms.[dubious – discuss] The most common concentration for this use is pilocarpine 1%.[citation needed] Pilocarpine is shown to be just as effective as apraclonidine in preventing intraocular pressure spikes after laser trabeculoplasty.[21]
Presbyopia
In 2021, the US Food and Drug Administration approved pilocarpine hydrochloride as an eyedrop treatment for presbyopia, age-related difficulty with near-in vision. Marketed as vuity, the effect lasts for 7 to 10 hours.[22]
Other
Pilocarpine is used to stimulate sweat glands in a sweat test to measure the concentration of chloride and sodium that is excreted in sweat. It is used to diagnose cystic fibrosis.[23]
Adverse effects
Use of pilocarpine may result in a range of adverse effects, most of them related to its non-selective action as a muscarinic receptor agonist. Pilocarpine has been known to cause excessive salivation, sweating, bronchial mucus secretion, bronchospasm, bradycardia, vasodilation, and diarrhea. Eye drops can result in brow ache and chronic use in miosis.
Pharmacology
Pilocarpine is a drug that acts as a muscarinic receptor agonist. It acts on a subtype of muscarinic receptor (M3) found on the iris sphincter muscle, causing the muscle to contract – resulting in pupil constriction (miosis). Pilocarpine also acts on the ciliary muscle and causes it to contract. When the ciliary muscle contracts, it opens the trabecular meshwork through increased tension on the scleral spur. This action facilitates the rate that aqueous humor leaves the eye to decrease intraocular pressure. Paradoxically, when pilocarpine induces this ciliary muscle contraction (known as an accommodative spasm) it causes the eye’s lens to thicken and move forward within the eye. This movement causes the iris (which is located immediately in front of the lens) to also move forward, narrowing the Anterior chamber angle. Narrowing of the anterior chamber angle increases the risk of increased intraocular pressure.[24]
Society and culture
Preparation
Plants in the genus Pilocarpus are the only known sources of pilocarpine, and commercial production is derived entirely from the leaves of Pilocarpus microphyllus (Maranham Jaborandi). This genus grows only in South America, and Pilocarpus microphyllus is native to several states in northern Brazil.[25]
Pilocarpine is extracted from the powdered leaf material in a multi-step process. First the material is treated with ethanol acidified with hydrochloric acid, and the solvents removed under reduced pressure. The resultant aqueous residue is neutralized with ammonia and put aside until the resin has completely settled. It is then filtered and concentrated by sugar solution to a small volume, made alkaline with ammonia, and finally extracted with chloroform. The solvent is removed under reduced pressure.[verification needed]
Cost
Pilocarpine is one of the lowest cost medications for glaucoma.[26]
Trade names
Pilocarpine is available under several trade names such as: Diocarpine (Dioptic), Isopto Carpine (Alcon), Miocarpine (CIBA Vision), Ocusert Pilo-20 and -40 (Alza), Pilopine HS (Alcon), Salagen (MGI Pharma), Scheinpharm Pilocarpine (Schein Pharmaceutical), Timpilo (Merck Frosst) and Vuity (Abbvie).
Research
Pilocarpine is used to induce chronic epilepsy in rodents, commonly rats, as a means to study the disorder’s physiology and to examine different treatments.[27][28] Smaller doses may be used to induce salivation in order to collect samples of saliva, for instance, to obtain information about IgA antibodies.
Veterinary
Pilocarpine is given in moderate doses (about 2 mg) to induce emesis in cats that have ingested foreign plants, foods, or drugs. One feline trial determined it was effective, even though the usual choice of emetic is xylazine.
References
- ^ Jump up to:a b c d e f g “Pilocarpine”. The American Society of Health-System Pharmacists. Archived from the original on 28 December 2016. Retrieved 8 December 2016.
- ^ Gornitsky M, Shenouda G, Sultanem K, Katz H, Hier M, Black M, Velly AM (July 2004). “Double-blind randomized, placebo-controlled study of pilocarpine to salvage salivary gland function during radiotherapy of patients with head and neck cancer”. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 98 (1): 45–52. doi:10.1016/j.tripleo.2004.04.009. PMID 15243470.
- ^ Tarascon Pocket Pharmacopoeia 2019 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. 2018. p. 224. ISBN 9781284167542.
- ^ World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 439. hdl:10665/44053. ISBN 9789241547659.
- ^ “Glaucoma and ocular hypertension. NICE guideline 81”. National Institute for Health and Care Excellence. November 2017. Retrieved 19 September 2019.
Ocular hypertension… alternative options include carbonic anhydrase inhibitors such as brinzolamide or dorzolamide, a topical sympathomimetic such as apraclonidine or brimonidine tartrate, or a topical miotic such as pilocarpine, given either as monotherapy or as combination therapy.
- ^ Lusthaus J, Goldberg I (March 2019). “Current management of glaucoma” (PDF). The Medical Journal of Australia. 210 (4): 180–187. doi:10.5694/mja2.50020. PMID 30767238. S2CID 73438590.
Pilocarpine is no longer routinely used for long term IOP control due to a poor side effect profile
- ^ Hamilton R (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 415. ISBN 9781284057560.
- ^ “Pilocarpine ophthalmic Use During Pregnancy | Drugs.com”. http://www.drugs.com. Archived from the original on 28 December 2016. Retrieved 28 December 2016.
- ^ British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 769. ISBN 9780857111562.
- ^ Jump up to:a b Sneader W (2005). Drug Discovery: A History. John Wiley & Sons. p. 98. ISBN 978-0-471-89979-2. Archived from the original on 2016-12-29.
- ^ Rosin A (1991). “[Pilocarpine. A miotic of choice in the treatment of glaucoma has passed 110 years of use]”. Oftalmologia (in Romanian). 35 (1): 53–5. PMID 1811739.
- ^ Holmstedt, B; Wassén, SH; Schultes, RE (January 1979). “Jaborandi: an interdisciplinary appraisal”. Journal of Ethnopharmacology. 1 (1): 3–21. doi:10.1016/0378-8741(79)90014-x. PMID 397371.
- ^ World 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.
- ^ “Pilocarpine”. MedLinePlus. U.S. National Library of Medicine. Archived from the original on 2010-03-06.
- ^ Yang, WF; Liao, GQ; Hakim, SG; Ouyang, DQ; Ringash, J; Su, YX (1 March 2016). “Is Pilocarpine Effective in Preventing Radiation-Induced Xerostomia? A Systematic Review and Meta-analysis”. International Journal of Radiation Oncology, Biology, Physics. 94 (3): 503–11. doi:10.1016/j.ijrobp.2015.11.012. hdl:10722/229069. PMID 26867879.
- ^ Kanski JJ, Bowling B (2015-03-24). Kanski’s Clinical Ophthalmology E-Book: A Systematic Approach. Elsevier Health Sciences. p. 812. ISBN 9780702055744.
- ^ Bartlett JD, James SD (October 2013). “Drug Affect the Autonomous Nervous System”. Clinical Ocular Pharmacology. Elsevier. p. 118. ISBN 9781483193915.
- ^ Mannis, Mark J; Holland, Edward J (September 2016). “Chapter 33: Dry Eye”. Cornea E-Book. Elsevier Health Sciences. p. 388. ISBN 978-0-323-35758-6. OCLC 960165358.
- ^ Parker, Jack (2017). Descemet Membrane Endothelial Keratoplasty (DMEK): A Review (PDF) (Thesis). Leiden University.
- ^ Ahmed E, E A (2010). Comprehensive Manual of Ophthalmology. JP Medical Ltd. p. 345. ISBN 9789350251751.
- ^ Zhang L, Weizer JS, Musch DC (February 2017). “Perioperative medications for preventing temporarily increased intraocular pressure after laser trabeculoplasty”. The Cochrane Database of Systematic Reviews. 2 (2): CD010746. doi:10.1002/14651858.CD010746.pub2. PMC 5477062. PMID 28231380.
- ^ Bankhead, Charles (2021-11-01). “First Eye Drop Treatment for Presbyopia Wins FDA Approval”. http://www.medpagetoday.com. Retrieved 2021-11-02.
- ^ Prasad RK (2017-07-11). Chemistry and Synthesis of Medicinal Agents: (Expanding Knowledge of Drug Chemistry). BookRix. ISBN 9783743821415.
- ^ Shaarawy TM, Sherwood MB, Hitchings RA, Crowston JG (September 2014). “Lsser Peripheral Iridoplasty”. Glaucoma E-Book. Elsevier Health Sciences. p. 718. ISBN 9780702055416.
- ^ De Abreu IN, Sawaya AC, Eberlin MN, Mazzafera P (November–December 2005). “Production of Pilocarpine in Callus of Jaborandi (Pilocarpus microphyllus Stapf)”. In Vitro Cellular & Developmental Biology – Plant. Society for In Vitro Biology. 41 (6): 806–811. doi:10.1079/IVP2005711. JSTOR 4293939. S2CID 26058596.
- ^ Schwab, Larry (2007). Eye Care in Developing Nations. CRC Press. p. 110. ISBN 9781840765229.
- ^ Károly N (2018). Immunohistochemical investigations of the neuronal changes induced by chronic recurrent seizures in a pilocarpine rodent model of temporal lobe epilepsy (Thesis). University of Szeged. doi:10.14232/phd.9734.
- ^ Morimoto K, Fahnestock M, Racine RJ (May 2004). “Kindling and status epilepticus models of epilepsy: rewiring the brain”. Progress in Neurobiology. 73 (1): 1–60. doi:10.1016/j.pneurobio.2004.03.009. PMID 15193778. S2CID 36849482.
External links
- “Pilocarpine”. Drug Information Portal. U.S. National Library of Medicine.
CLIP
Firms Team Up To Sustain Natural Pilocarpine
Sustainable harvest is key to a new pharmaceutical chemicals venture
https://cen.acs.org/articles/93/i11/Firms-Team-Sustain-Natural-Pilocarpine.html
Last summer, Andrew Badrot bought a portfolio of plant-sourced pharmaceutical chemicals from Boehringer Ingelheim and acquired BI’s distribution rights for pilocarpine, a plant-derived glaucoma treatment.
For BI, the transactions were small ones. The German drugmaker had been exiting its private-label active pharmaceutical ingredients (API) business, scaling back to produce only the chemicals it uses to manufacture its own drugs.
But for Badrot the deals were potentially big. He leads the company that bought the businesses—Centroflora CMS, a joint venture between the Brazilian botanicals firm Centroflora and CMS Pharma, Badrot’s custom chemicals consultancy. Together, Centroflora and Centroflora CMS are committed to nurturing the natural source of pilocarpine, an alkaloid used medicinally for more than 100 years, and to expanding into other APIs neglected by larger firms.
Pilocarpine’s source, Pilocarpus microphyllus, better known as jaborandi, had been harvested vigorously in the wild by Merck KGaA, which in 1975 built a factory in Parnaíba in northern Brazil to extract pilocarpine. By the mid-1980s, however, jaborandi had been overharvested, and the government declared it a protected species. Merck began obtaining the leaves from a plantation in the northern Brazilian state of Maranhão.
Demand for the drug as a glaucoma treatment began to decline, and Merck eventually closed the plant. When the market for the drug revived with new indications as a dry-mouth remedy, the company saw an opportunity to sell the site and did so in 2002.
The buyer was Centroflora, which was founded in 1957 in São Paulo. The firm was interested in adding pilocarpine to its botanical extracts business, according to its chief executive, Peter Andersen, a native of Brazil whose coffee-trader father bought into Centroflora in 1983. Along with the purchase, Centroflora signed a deal for BI to distribute the drug.
The company wanted to revitalize natural harvesting of jaborandi and began working with the Brazilian government to promulgate sustainable practices in the field. Centroflora also worked closely with a German government agency, Deutsche Gesellschaft für Internationale Zusammenarbeit (GIZ), which promotes sustainable harvesting internationally and had been working in the north of Brazil for decades.
Centroflora’s distribution agreement with BI arose through connections at GIZ, according to Andersen. BI also had been Merck’s biggest customer for pilocarpine.
But ecological sustainability was only half of the problem, Andersen says. Centroflora also found itself dealing with middlemen who would collect the jaborandi from poor family farms in remote areas and pay them next to nothing. Establishing a direct supply channel was not easy.
“I can spend a few days telling you about that process,” he says. “Stories of difficult relationships and difficult moments. But in some cases we managed to hire some of the middlemen to work for us on a salary basis. They made less money, but they had a job.”
Today, farmers in Brazil are paid at least twice what they were paid by intermediaries, Andersen says.
Key to the process was a program Centroflora launched in 2004 called Partnerships for a Better World to train and certify growers, establish community associations to support growers, and maintain sustainable harvesting practices.
Centroflora is the leading supplier of pilocarpine. Its only competitor, Sourcetech, with a plant near São Paulo, accesses jaborandi from the plantation that supplied Merck, now owned by U.S.-based Quercegen.
Pilocarpine accounts for only about 5% of Centroflora’s $95 million in annual sales. The company produces a long list of botanical extracts, including nutritional supplements and herbal medicines such as acai, acerola, coffee powder, and powdered fruit.The company manufactures at four facilities in Brazil, including the former Merck plant, which is dedicated to pilocarpine. But Andersen sees the partnership with CMS as a route to increase phytochemical API manufacturing at that site.
“The facility has the capacity to produce 12 metric tons per year of alkaloids,” Andersen says. It currently makes less than three metric tons. “So there is a lot of space to produce more, and the idea is that we can do some of the APIs we got from Boehringer Ingelheim.”
Those include atropine, digoxin, homatropine, and dihydroergotamine mesylate. Centroflora CMS also obtained distribution rights to BI’s scopolamine N-butyl bromide. All are derived from botanicals harvested on farms around the world.
Badrot was vice president of strategy for Lonza’s exclusive synthesis division before starting CMS in 2010 to consult on manufacturing and mergers and acquisitions in the custom chemicals business. “But for me, the dream was to return to manufacturing APIs,” he says.
The phytochemicals portfolio, including some of the oldest APIs made by BI, for which CMS has done consulting work, seemed like an ideal reentry to manufacturing, according to Badrot. “They are niche products that maybe fly a bit under the radar,” he says. “They seemed to fit us well because we can give them some attention.”
Centroflora CMS’s first order of business, he says, is to establish manufacturing for the BI products, which BI will continue to make until then. Badrot says Centroflora is well suited to manufacture at least the digoxin and atropine, but decisions have not been finalized. The partners will likely use contract manufacturers for some of the products. And Badrot says Centroflora CMS seeks to replicate the kind of deal it has with BI.
“We are looking for other companies with APIs that represent 0–1% of sales, products that lack focus,” he says. “We would take them over.”
Badrot and Andersen say they are also interested in sharing the Partnerships for a Better World program with other companies involved in harvesting natural products. And Centroflora looks for other ways to support its supply chain. Last month, it was approved as a trading member of the Union for Ethical BioTrade, a nonprofit that promotes sustainable development and biodiversity. As a member, Centroflora commits to sustainable sourcing practices and will be required to undergo periodic audits.
Last year, Centroflora received government recognition for its efforts on both the environmental and social fronts. The National Confederation of Industry in Brazil named Centroflora’s jaborandi harvesting program one of the country’s 10 most sustainable business practices. And Banco do Brasil, the national bank, recognized the firm for its work to improve conditions for farmers in the northern forest region of the country.
As the joint venture starts to work with its new portfolio of phytochemicals, both Andersen and Badrot look back at the jaborandi success as the road forward, a template for fostering a plant-based API business that may inspire other companies.
For Andersen, Partnerships for a Better World is an essential foundation of trust for the ecological and socially responsible harvesting of botanicals in Brazil. “There were a lot of problems along the way,” he says. “But we are at peace with it today.”
////////////////PILOCARPINE, Pilocarpine hydrochloride, KSS-694, MGI-647, Pilobuc, Pilocar, Isopto carpine, Spersacarpin, Pilo, Isopto-pilocarpine, Pilocarpina lux, Pilogel, PilaSite(sustained release), Salagen, Pilopine HS
CC[C@H]1[C@@H](CC2=CN=CN2C)COC1=O
NEW DRUG APPROVALS
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loteprednol etabonate
loteprednol etabonate
- Molecular FormulaC24H31ClO7
- Average mass466.952 Da
cas 82034-46-6
chloromethyl (8S,9S,10R,11S,13S,14S,17R)-17-ethoxycarbonyloxy-11-hydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17-carboxylate(11b,17a)-17-[(Ethoxycarbonyl)oxy]-11-hydroxy-3-oxo-androsta-1,4-diene-17-carboxylic acid chloromethyl ester
(11b,17a)-17-[(Ethoxycarbonyl)oxy]-11-hydroxy-3-oxoandrosta-1,4-diene-17-carboxylic Acid Chloromethyl Ester
(8S,9S,10R,11S,13S,14S,17R)-17-[(éthoxycarbonyl)oxy]-11-hydroxy-10,13-diméthyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodécahydro-3H-cyclopenta[a]phénanthrène-17-carboxylate de chlorométhyle
129260-79-3[RN]
17a-Ethoxycarbonyloxy-D’-cortienic Acid Chloromethyl Ester
82034-46-6[RN]
Androsta-1,4-diene-17-carboxylic acid, 17-((ethoxycarbonyl)oxy)-11-hydroxy-3-oxo-, chloromethyl ester, (11β,17α)-
Androsta-1,4-diene-17-carboxylic acid, 17-[(ethoxycarbonyl)oxy]-11-hydroxy-3-oxo-, chloromethyl ester, (11β,17α)-
Loteprednol Etabonate
CAS Registry Number: 82034-46-6
CAS Name: (11b,17a)-17-[(Ethoxycarbonyl)oxy]-11-hydroxy-3-oxoandrosta-1,4-diene-17-carboxylic acid chloromethyl ester
Additional Names: chloromethyl 17a-ethoxycarbonyloxy-11b-hydroxyandrosta-1,4-diene-3-one-17b-carboxylate; 17a-ethoxycarbonyloxy-D¢-cortienic acid chloromethyl ester
Manufacturers’ Codes: CDDD-5604; HGP-1; P-5604
Trademarks: Alrex (Bausch & Lomb); Lotemax (Bausch & Lomb)
Molecular Formula: C24H31ClO7, Molecular Weight: 466.95
Percent Composition: C 61.73%, H 6.69%, Cl 7.59%, O 23.98%
Literature References: Ophthalmic corticosteroid. Prepn: N. S. Bodor, BE889563 (1981 to Otsuka); idem,US4996335 (1991). Physicochemical properties: M. Alberth et al.,J. Biopharm. Sci.2, 115 (1991). HPLC determn in plasma and urine: G. Hochhaus et al.,J. Pharm. Sci.81, 1210 (1992). NMR structural studies: S. Rachwal et al.,Steroids61, 524 (1996); idem et al., ibid. 63, 193 (1998). Metabolism and transdermal permeability: N. Bodor et al.,Pharm. Res.9, 1275 (1992). Evaluation of effect on intraocular pressure: J. D. Bartlett et al.,J. Ocul. Pharmacol.9, 157 (1993). Clinical trial in keratoconjunctivitis sicca: S. C. Pflugfelder et al.,Am. J. Ophthalmol.138, 444 (2004). Review of ophthalmic clinical studies: J. F. Howes, Pharmazie55, 178-183 (2000).
Properties: Crystals from THF + hexane, mp 220.5-223.5°. Soly at 25° (mg/ml): 0.0005 in water; 0.037 in 50% propylene glycol + water. Lipophilicity (log K): 3.04.
Melting point: mp 220.5-223.5°
Therap-Cat: Anti-inflammatory (topical).
Keywords: Glucocorticoid.
Research Code：HGP-1; CDDD-5604; P-5604Trade Name：Lotemax® / Alrex®MOA：CorticosteroidIndication：Acne rosacea; Superficial punctate keratitis; Postoperative inflammation and pain following ocular surgery; Iritis; Herpes zoster keratitis; Allergic conjunctivitis; CyclitisCompany：Bausch & Lomb (Originator)Sales：ATC Code：S01BA14
Loteprednol etabonate was approved by the U.S. Food and Drug Administration (FDA) on Mar 9, 1998. It was developed and marketed as Lotemax® by Bausch & Lomb.
Loteprednol etabonate is a corticosteroid used in ophthalmology. It is indicated for the treatment of steroid responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe such as allergic conjunctivitis, acne rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitides.
Lotemax® is available as drops for ophthalmic use, containing 0.5% of Loteprednol etabonate. The recommended dose is one to two drops into the conjunctival sac of the affected eyes four times daily.
Loteprednol (as the ester loteprednol etabonate) is a corticosteroid used to treat inflammations of the eye. It is marketed by Bausch and Lomb as Lotemax[1] and Loterex.
It was patented in 1980 and approved for medical use in 1998.[2]
Loteprednol Etabonate is the etabonate salt form of loteprednol, an ophthalmic analog of the corticosteroid prednisolone with anti-inflammatory activity. Loteprednol etabonate exerts its effect by interacting with specific intracellular receptors and subsequently binds to DNA to modify gene expression. This results in an induction of the synthesis of certain anti-inflammatory proteins while inhibiting the synthesis of certain inflammatory mediators. Loteprednol etabonate specifically induces phospholipase A2 inhibitory proteins (collectively called lipocortins), which inhibit the release of arachidonic acid, thereby inhibiting the biosynthesis of potent mediators of inflammation, such as prostaglandins and leukotrienes.
Loteprednol etabonate is an etabonate ester, an 11beta-hydroxy steroid, a steroid ester, an organochlorine compound, a steroid acid ester and a 3-oxo-Delta(1),Delta(4)-steroid. It has a role as an anti-inflammatory drug. It derives from a loteprednol.
Loteprednol Etabonate (LE) is a topical corticoid anti-inflammatory. It is used in ophthalmic solution for the treatment of steroid responsive inflammatory conditions of the eye such as allergic conjunctivitis, uveitis, acne rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, and selected infective conjunctivitides. As a nasal spray, it can be used for the treatment and management of seasonal allergic rhinitis. Most prescription LE products, however, tend to be indicated for the treatment of post-operative inflammation and pain following ocular surgery. A number of such new formulations that have been approved include Kala Pharmaceutical’s Inveltys – the first twice-daily (BID) ocular corticosteroid approved for this indication, designed specifically to enhance patient compliance and simplified dosing compared to all other similar ocular steroids that are dosed four times daily. Moreover, LE was purposefully engineered to be a ‘soft drug’, one that is designed to be active locally at the site of administration and then rapidly metabolized to inactive components after eliciting its actions at the desired location, thereby subsequently minimizing the chance for adverse effects.
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2012-09-28 | New dosage form | Lotemax | Postoperative inflammation and pain following ocular surgery | Gel | 0.5% | Bausch & Lomb | |
| 2011-04-15 | New dosage form | Lotemax | Postoperative inflammation and pain following ocular surgery | Ointment | 0.5% | Bausch & Lomb | |
| 1998-03-09 | First approval | Lotemax | Allergic conjunctivitis,Acne rosacea,Superficial punctate keratitis,Herpes zoster keratitis,Iritis,Cyclitis | Suspension/ Drops | 0.5% | Bausch & Lomb |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2014-11-26 | Marketing approval | 露达舒/Lotemax | Allergic conjunctivitis,Acne rosacea,Superficial punctate keratitis,Herpes zoster keratitis,Iritis,Cyclitis,Postoperative inflammation and pain following ocular surgery | Suspension | 滴眼剂，0.5%（2.5ml：12.5mg，5ml：25mg） | Bausch & Lomb | |
| 2011-11-05 | Marketing approval | 露达舒/Lotemax | Allergic conjunctivitis,Acne rosacea,Superficial punctate keratitis,Herpes zoster keratitis,Iritis,Cyclitis,Postoperative inflammation and pain following ocular surgery | Suspension | 滴眼剂，0.5%（2.5ml：12.5mg，5ml：25mg）; 滴眼剂，0.5%（10ml：50mg，15ml：75mg） | Bausch & Lomb |
Reference：1. US4710495A / US4996335A.Route 2
Reference：1. CN103183714A.
SYN
doi:10.1016/0960-0760(91)90120-T doi: 10.1016/j.steroids.2011.01.006
| Clinical data | |
|---|---|
| Trade names | Lotemax |
| Other names | 11β,17α,Dihydroxy-21-oxa-21-chloromethylpregna-1,4-diene-3,20-dione 17α-ethylcarbonate |
| AHFS/Drugs.com | Micromedex Detailed Consumer Information |
| Routes of administration | Eye drops |
| Drug class | Corticosteroid; glucocorticoid |
| ATC code | S01BA14 (WHO) |
| Legal status | |
| Legal status | US: ℞-only |
| Pharmacokinetic data | |
| Bioavailability | None |
| Protein binding | 95% |
| Metabolism | Ester hydrolysis |
| Metabolites | Δ1-cortienic acid and its etabonate |
| Onset of action | ≤2 hrs (allergic conjunctivitis) |
| Elimination half-life | 2.8 hrs |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 82034-46-6 |
| PubChem CID | 444025 |
| IUPHAR/BPS | 7085 |
| DrugBank | DB14596 |
| ChemSpider | 392049 |
| UNII | YEH1EZ96K6 |
| KEGG | D01689 |
| ChEBI | CHEBI:31784 |
| ChEMBL | ChEMBL1200865 |
| CompTox Dashboard (EPA) | DTXSID2046468 |
| ECHA InfoCard | 100.167.120 |
| Chemical and physical data | |
| Formula | C24H31ClO7 |
| Molar mass | 466.96 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| Melting point | 220.5 to 223.5 °C (428.9 to 434.3 °F) |
| Solubility in water | 0.0005 mg/mL (20 °C) |
| showSMILES | |
| showInChI | |
| (what is this?) (verify) |
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Medical uses
Applications for this drug include the reduction of inflammation after eye surgery,[1] seasonal allergic conjunctivitis, uveitis,[3] as well as chronic forms of keratitis (e.g. adenoviral and Thygeson’s keratitis), vernal keratoconjunctivitis, pingueculitis, and episcleritis.[citation needed]
Contraindications
As corticosteroids are immunosuppressive, loteprednol is contraindicated in patients with viral, fungal or mycobacterial infections of the eye.[1][3][4]
Adverse effects
The most common adverse effects in patients being treated with the gel formulation are anterior chamber inflammation (in 5% of people), eye pain (2%), and foreign body sensation (2%).[5]
Interactions
Because long term use (more than 10 days) can cause increased intraocular pressure, loteprednol may interfere with the treatment of glaucoma. Following ocular administration, the drug is very slowly absorbed into the blood, therefore the blood level is limited to an extremely small concentration, and interactions with drugs taken by mouth or through any route other than topical ophthalmic are very unlikely.[1]
Pharmacology
Mechanism of action
Main article: Glucocorticoid § Mechanism of action
Pharmacokinetics
Neither loteprednol etabonate nor its inactive metabolites Δ1–cortienic acid and Δ1-cortienic acid etabonate are detectable in the bloodstream, even after oral administration. A study with patients receiving loteprednol eye drops over 42 days showed no adrenal suppression, which would be a sign of the drug reaching the bloodstream to a clinically relevant extent.[1]
Steroid receptor affinity was 4.3 times that of dexamethasone in animal studies.[1]
Retrometabolic drug design
Loteprednol etabonate was developed using retrometabolic drug design. It is a so-called soft drug, meaning its structure was designed so that it is predictably metabolised to inactive substances. These metabolites, Δ1-cortienic acid and its etabonate, are derivatives of cortienic acid, itself an inactive metabolite of hydrocortisone.[1][4][6]
- Cortisol, a naturally occurring corticosteroid, known as hydrocortisone when used as a drug
- Δ1-Cortienic acid, inactive metabolite of loteprednol
- Cortienic acid, inactive metabolite of hydrocortisone
Chemistry
Loteprednol etabonate is an ester of loteprednol with etabonate (ethyl carbonate). The pure chemical compound has a melting point between 220.5 °C (428.9 °F) and 223.5 °C (434.3 °F). Its solubility in water is 1:2,000,000,[4] therefore it is formulated for ophthalmic use as either an ointment, a gel, or a suspension.[7]
Loteprednol is a corticosteroid. The ketone side chain of classical corticosteroids such as hydrocortisone is replaced by a cleavable ester, which accounts for the rapid inactivation.[8] (This is not the same as the etabonate ester.)
Loteprednol etabonate
Chemical synthesis
References
- ^ Jump up to:a b c d e f g Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
- ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 488. ISBN 9783527607495.
- ^ Jump up to:a b Loteprednol Professional Drug Facts.
- ^ Jump up to:a b c Dinnendahl V, Fricke U (2008). Arzneistoff-Profile (in German). 6 (22 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
- ^ “Highlights of Prescribing Information: Lotemax” (PDF). 2012.
- ^ Bodor N, Buchwald P (2002). “Design and development of a soft corticosteroid, loteprednol etabonate”. In Schleimer RP, O’Byrne PM, Szefler SJ, Brattsand R (eds.). Inhaled Steroids in Asthma. Optimizing Effects in the Airways. Lung Biology in Health and Disease. 163. Marcel Dekker, New York. pp. 541–564.
- ^ “Loteprednol (Professional Patient Advice)”. Retrieved October 4, 2018.
- ^ Pavesio CE, Decory HH (April 2008). “Treatment of ocular inflammatory conditions with loteprednol etabonate”. The British Journal of Ophthalmology. 92 (4): 455–9. doi:10.1136/bjo.2007.132621. PMID 18245274. S2CID 25873047.
- ^ Druzgala P, Hochhaus G, Bodor N (February 1991). “Soft drugs–10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate”. The Journal of Steroid Biochemistry and Molecular Biology. 38 (2): 149–54. doi:10.1016/0960-0760(91)90120-T. PMID 2004037. S2CID 27107845.
Further reading
- Stewart R, Horwitz B, Howes J, Novack GD, Hart K (November 1998). “Double-masked, placebo-controlled evaluation of loteprednol etabonate 0.5% for postoperative inflammation. Loteprednol Etabonate Post-operative Inflammation Study Group 1”. Journal of Cataract and Refractive Surgery. 24 (11): 1480–9. doi:10.1016/s0886-3350(98)80170-3. PMID 9818338. S2CID 24423725.
////////////loteprednol etabonate
CCOC(=O)OC1(CCC2C1(CC(C3C2CCC4=CC(=O)C=CC34C)O)C)C(=O)OCCl
NEW DRUG APPROVALS
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$10.00
AVIPTADIL
AVIPTADIL
- Molecular FormulaC147H237N43O43S
37221-79-7[RN]
6J2WVD66KR
L-Asparagine, L-histidyl-L-seryl-L-α-aspartyl-L-alanyl-L-valyl-L-phenylalanyl-L-threonyl-L-α-aspartyl-L-asparaginyl-L-tyrosyl-L-threonyl-L-arginyl-L-leucyl-L-arginyl-L-lysyl-L-glutaminyl-L-met hionyl-L-alanyl-L-valyl-L-lysyl-L-lysyl-L-tyrosyl-L-leucyl-L-asparaginyl-L-seryl-L-isoleucyl-L-leucyl-
Vasoactive intestinal octacosapeptide
Invicorp (aviptadil + phentolamine)
(2S)-4-amino-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]propanoyl]amino]-3-methylbutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-carboxypropanoyl]amino]-4-oxobutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxybutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylpentanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-5-oxopentanoyl]amino]-4-methylsulfanylbutanoyl]amino]propanoyl]amino]-3-methylbutanoyl]amino]hexanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-3-hydroxypropanoyl]amino]-3-methylpentanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoic acid
Aviptadil Acetate
CAS#: 40077-57-4 (free base)
Chemical Formula: C155H253N43O51S
Exact Mass:
Molecular Weight: 3567.039
H-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2 tetraacetic acid.
Aviptadil had been in phase II clinical trials for the treatment of pulmonary arterial hypertension and idiopathic pulmonary fibrosis. But these researches were discontinued in 2011.
In 2006, Orphan Drug Designations were granted in the E.U. for the treatment of pulmonary arterial hypertension, and sarcoidosis and acute lung injury in 2006, and 2008, respectively.
The compound was co-developed by Lung Rx (subsidiary of United Therapeutics) and Mondobiotech.
Aviptadil (INN) is an injectable synthetic formulation of human vasoactive intestinal peptide (VIP).[1] VIP was discovered in 1970, and has been used to treat various inflammatory conditions, such as acute respiratory distress syndrome (ARDS), asthma and chronic obstructive pulmonary disease (COPD).
| Clinical data | |
|---|---|
| Trade names | RLF-100 / Zyesamiô |
| AHFS/Drugs.com | International Drug Names |
| ATC code | none |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 40077-57-4 |
| PubChem CID | 16132300 |
| ChemSpider | 17288959 |
| UNII | A67JUW790C |
| KEGG | D12127 |
| ChEMBL | ChEMBL2106041 |
| CompTox Dashboard (EPA) | DTXSID7048584 |
| Chemical and physical data | |
| Formula | C147H237N43O43S |
| Molar mass | 3326.83 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
| (what is this?) (verify) |
Regulatory history
ARDS in COVID-19
Studies have found that aviptadil may be beneficial for severely ill patients with COVID-19 related ARDS.[2] ACTIV-3, a trial examining aviptadil acetate (Zyesami), is recruiting patients as of 2 July 2021.[3] A separate trial is examining inhaled aviptadil for patients with high risk for ARDS, is ongoing as of 21 May 2021.[4] A trial for intravenous aviptadil for the same indication concluded in February 2021.[5]
U.S.-Israeli NeuroRx Inc partnered with Relief Therapeutics to develop aviptadil in the United States. In June 2020, the U.S. Food and Drug Administration granted fast-track designation to aviptadil for treatment of respiratory distress in COVID-19.[6] In September 2020, NeuroRX submitted a request for an Emergency Use Authorization to the US FDA for its use in patients in intensive care.[7] May 2021: NRx Pharmaceuticals Announces Positive Results for ZYESAMI™ (Aviptadil-acetate) and Submits Emergency Use Authorization Application to USFDA to Treat Critical COVID-19 in Patients Suffering from Respiratory Failure.[8]
Jan, 2021: Zuventus healthcare Ltd seeks approval for Aviptadil from India’s drug controller for emergency use in COVID-19 treatment. Mumbai’s Zuventus healthcare Ltd. has got the nod to conduct Phase 3 clinical trials of Aviptadil injectable formulation. The SEC noted that Zuventus had presented revised Phase 3 clinical trial protocol before the committee, and after “detailed deliberation”, it recommended grant of permission of Phase 3 trials with the drug.[9] [10]
Aviptadil/phentolamine combination for Erectile Dysfunction (ED)
October 2000 UK (Invicorp): Aviptadil, an injectable formulation of vasoactive intestinal polypeptide (VIP) in combination with the adrenergic drug phentolamine is approved as an effective alternative therapy for erectile dysfunction (ED) patients. 1 dose intracavernosal injection contains 25 micrograms aviptadil and 2 mg of phentolamine mesilate for the treatment of erectile dysfunction. Aviptadil dose used for treatment of erectile dysfunction is far lesser as compared to dose used for the treatment of ARDS.[11][12]
Vasoactive intestinal peptide (VIP)
Vasoactive intestinal peptide (VIP) is a 28-residue amino acid peptide first characterized in 1970 that was initially isolated from porcine duodenum. A member of the secretin/glucagon hormone superfamily. VIP was initially discovered owing to its potent vasodilatory effects (as its name implies). VIP is widely distributed in the central and peripheral nervous system as well as in the digestive, respiratory, reproductive, and cardiovascular systems as a neurotransmitter and neuroendocrine releasing factor. These effects contribute to an extensive range of physiological and pathological processes related to development, growth, and the control of neuronal, epithelial, and endocrine cell function.[13]
VIP Receptors
VIP acts on two receptors – VPAC1 and VPAC2, which are class B of G-protein-coupled receptors (GPCRs).VPAC1 is mainly present in the lung and T-lymphocytes, whereas VPAC2 is mainly seen in the smooth muscle,mast cells and the basal parts of the lung mucosa.[14]
Expression of VIP
VIP is produced in the neurons in the central and peripheral nervous systems. VIP is mainly localized in the myenteric and submucosal neurons and nerve terminals in the GI tract. Endogenous VIP is released by numerous stimuli such as acetylcholine (ACh), ATP, serotonin (5-HT), substance P (SP), GLP-2 from at least two populations of VIP-positive nerves: cholinergic and non-cholinergic VIP-releasing nerves. In guinea pig small intestine, most VIP-positive nerves in the mucosa and submucosa are non-cholinergic secretomotor neurons and well colocalized with neuronal nitric oxide synthase (nNOS) in human colonic circular muscles. VIP is also expressed in immune cells, such as activated T cells and therefore present in lymphoid tissues including Peyer’s patches, the spleen, and lymph nodes, in addition to the VIP-ergic innervation in lymphoid tissues. Beside the neuronal source, VIP is also expressed and released from endocrine organs – Heart, Thyroid, Kidney and GI tracts.[15]
Localization of VIP
- VIP is highly localised in lungs (70%) and binds with alveolar type II (AT II) cells via VPAC1.[2] The biological (vasodilator) activity of vasoactive intestinal peptide (VIP) was discovered in the lungs before the peptide was isolated and chemical identity characterized from intestine. Although VIP levels are consideralbly high in the brain or gut:VIP is localized in key sites in the lung, has potent activities on its major functions, and appears to play an important role in pulmonary physiology and disease.[16]
- The principal localization of VIP-containing neurons in the tracheobronchial tree is in the smooth muscle layer, around submucosal mucous glands and in the walls of pulmonary and bronchial arteries. Immunoreactive VIP is also present in neuronal cell bodies forming microganglia that provide a source of intrinsic innervation of pulmonary structures.[16]
Vasoactive Intestinal Peptide (VIP) and SARS-CoV-2
VIP is highly localised in lungs and binds with alveolar type II (AT II) cells via VPAC1 receptor. AT II cells constitute only 5% of pulmonary epithelium. Angiotensin Converting Enzyme 2 (ACE 2) surface receptors arepresent in AT II cells. AT II cells produces surfactant and plays an important role in the maintenance of type 1epithelial cells. SARS-CoV-2 enters into AT II cells by binding to ACE 2 surface receptors with its spike protein. SARS CoV-2 attack mainly type II cells (not type I alveolar cells) and results in the death of alveolar type II (AT 11) cells which produces surfactant, resulting in[2]
- Profound defect in oxygenation
- Leading to hypoxia
Mechanism of action of Aviptadil
- Pulmonary alveolar type II Cells have a high concentration of ACE 2 receptors on their cell membrane
- Investigators have confirmed that the SARS-CoV family of viruses selectively attack pulmonary Alveolar Type II (ATII) cells because of their ACE2 receptors, in contrast to other pulmonary epithelial cells.
- SARS-CoV Viruses bind to ACE2 receptors in order to enter the cell. Viral replication and rupture liberates inflammatory cytokines and destroys surfactant production
- VIP binds uniquely to receptors on Alveolar Type II cells in the lung, the same cells that bind the SARS-CoV-2 virus via their ACE2 receptors
- VIP is heavily concentrated in the lung and binds specifically to VIP receptors on alveolar type II cells. VIP exerts a broad anti-cytokine effect on immune system cells
- VIP specifically upregulates surfactant production via upregulation of C-Fos protein and protects type II cells from cytokine
- Upregulating the production of surfactant, the loss of which is increasingly implicated in COVID-19 respiratory failure [17]
Aviptadil a synthetic form of VIP results in rapid clinical recovery in patients with SARS-CoV-2 infection.[2]
Effect of Aviptadil on Lungs in COVID-19
Preservation of Pulmonary Tissue
Preserving surfactant production in the lung and in protecting type 2 alveolar cells. Significantly delayed the onset of edematous lung injury, effective in preventing ischemia-reperfusion injury, Prevents NMDA-induced caspase-3 activation in the Lung.[18]
Inhibits alveolar epithelial cell Apoptosis
VIP is a proven inhibitor of activation-induced perforin, as well as of granzyme B and therefore actively contributes to the reduction of deleterious proinflammatory and cell death-inducing processes, particularly in the lungs. Aviptadil restores barrier function at the endothelial/alveolar interface and thereby protects the lung and other organs from failure.[18]
VIP Promotes synthesis of pulmonary surfactant
Studies have demonstrated that VIP binds on type II cells and increases the incorporation of methyl-choline into phosphatidylcholine – the major component of the pulmonary surfactants by enhancing the activity of the enzyme choline-phosphate cytidylyltransferase. VIP upregulates C-Fos protein expression in cultured type II alveolar cells, which is instrumental in promoting synthesis of pulmonary surfactant phospholipids (Li 2007) and induces surfactant protein A expression in ATII cells through activation of PKC/c-Fos pathway.[18]
VIP decreases Pulmonary Inflammation
Anti-cytokine effect- Inhibits IL-6,TNF-α production and inhibit NF-kB activation. Protects against HCl-induced pulmonary edema.[18]
Pharmacokinetic Properties
Half-life: Its plasma half-life of elimination is 1 to 2 minutes.[2] Metabolism/Distribution: After injection of 1 µg radioactively labelled Aviptadil as bolus to patients a very rapid tissue distribution was observed Within 30 min about 45% of the radioactivity was found in the lungs Over an observation period of 24 hrs only minimal activity was detected in the GI tract & almost no activity was found in the liver or spleen Radioactivity in the lungs decreased within four hours to 25% and within 24 hours to 10% Apparent volume of distribution: Aviptadil has a volume of distribution of 14 ml/kg.[2] Tissue Distribution:Aviptadil binds to its receptors in discrete locations within the gastrointestinal, respiratory, and genital tracts. Aviptadil is localized on respiratory epithelium, smooth muscles of the airways, blood vessels and alveolar walls. Elimination:After injection of radiolabelled Aviptadil radioactivity was almost completely eliminated by the kidneys, 35% within 4 hours, and 90% within 24 hours
Justification for Aviptadil use in the treatment of ARDS
COVID-19-related death is primarily caused by Acute Respiratory Distress Syndrome (ARDS). The trigger for ARDS is widely attributed to a cytokine storm in the lungs, in which the virus causes release of inflammatory cytokines. As a result, alveolae of the lungs fill with fluid and become impermeable to oxygen, even in the setting of mechanical ventilation. SARS-CoV-2 is known to cause respiratory failure, which is the hallmark of Acute COVID-19. Tragically, survival of patients with COVID-19 who progress to Acute Respiratory Distress is dismal. There is an urgent need for a treatment approach that goes right into the heart of the matter – the alveolar type 2 cells which are vulnerable entry points and hosts for the SARS-CoV-2 virus.[19]
Aviptadil-Evidence from Studies in ARDS
Phase III Study-Increased Recovery and Survival in Patients With COVID-19 Respiratory Failure Following Treatment with Aviptadil
A multicenter, randomized, placebo-controlled trial in 196 patients with PCR+ COVID-19 receiving intensive care at 10 U.S. hospitals – 6 tertiary care and 4 regional hospitals to determine whether intravenous aviptadil (synthetic VIP) is superior to placebo in achieving recovery from respiratory failure and survival at 60 days post treatment. Primary, prespecified endpoint was “alive and free from respiratory failure at day 60.” Across all patients and sites of care, patients treated with aviptadil were significantly more likely to be alive and free from respiratory failure at 60 days, compared to those treated with placebo (P=.02) and demonstrated improvement in survival alone (P<.001). Advantages in survival for aviptadil-treated patients were seen in both the subgroup classified as 2 on the National Institute of Allergy and Infectious Disease (NIAID) ordinal scale (58.6% vs. 0%; p=.001) and the NIAID=3 subgroup (83.1% vs. 62.8%; p=.03). Among patients who recovered successfully, those treated with Aviptadil had a median 10-day reduction in length of hospital stay compared to placebo patients (P=.025). Treatment with aviptadil demonstrates multi-dimensional efficacy in improving the likelihood of recovery from respiratory failure and survival to 60 days, and markedly reduced hospital stay in critically ill patients with respiratory failure caused by COVID-19.[20]
Case report: Rapid Clinical Recovery from Critical COVID-19 Pneumonia with Aviptadil
A 54 year old man with double lung transplant presented with headache, fever and productive cough. COVID-19 infection was confirmed by positive RT-PCR of nasopharyngeal swab. The patient required only supportive care for 3 days and was discharged home. Two weeks later he presented with worsening dyspnea, fever and severe hypoxemia requiring high flow O2 and ICU admission. Chest CT showed diffuse bilateral consolidations. He had markedly elevated inflammatory markers. He was treated with dexamethasone and tocilizumab without improvement. He was not a candidate for Remdesivir due to chronic kidney disease. Convalescent plasma was not available, Pro-BNP level was normal; echocardiogram showed preserved biventricular function. He received Aviptadil, a total of three doses, per an open label access under an emergency use approved by USFDA. Rapid improvement in oxygenation and radiologic findings were noticed. No adverse effects were recorded. Patient was transferred out of the ICU 24 hours following the third dose and discharged home on room air 15 days later. This case report of lung transplant recipient with critical COVID-19 pneumonia treated with Aviptadil demonstrates rapid clinical and radiologic improvement.This is consistent with that VIP protects ATII cells, ameliorating the inflammation and improving oxygenation in critical COVID-19 pneumonia.[21]
Posology and method of administration
Aviptadil intravenous infusion is administered by infusion pump in escalating doses for 3 successive days
- Day 1 : Aviptadil 0.166 mcg/kg/hr (equivalent to 1 vial of Aviptadil Injection)
- Day 2 : Aviptadil 0.332 mcg/kg/hr (equivalent to 2 vials of Aviptadil Injection)
- Day 3 : Aviptadil 0.498 mcg/kg/hr (equivalent to 3 vials of Aviptadil Injection)
Duration of infusion depends on the patient’s body weight
- Body weight < 60 kg – 14 hour infusions of Aviptadil at escalating doses on 3 successive days
- Body weight 60 – 90 kg – 12 hour infusions of Aviptadil at escalating doses on 3 successive days
- Body weight > 90 kg – 10 hour infusions of Aviptadil at escalating doses on 3 successive days
Undesirable Effects
Gastrointestinal Disorders – Diarrhea, Vascular disorders – Hypotension, cutaneous flushing, facial flushing & Infusion related reactions[20]
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References
- ^ Keijzers GB (April 2001). “Aviptadil (Senatek)”. Current Opinion in Investigational Drugs. 2 (4): 545–9. PMID 11566015. Archived from the original on 2010-09-02. Retrieved 2020-04-01.
- ^ Jump up to:a b c d e f Raveendran, A; Al Dhuhli, K.; Harish Kumar, G. (2021). “Role of Aviptadil in COVID-19”. BMH Medical Journal. 8 (2): 77-83.
- ^ National Institute of Allergy and Infectious Diseases (NIAID) (2021-06-25). “A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients With COVID-19”. International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), University of Copenhagen, Medical Research Council, Kirby Institute, Washington D.C. Veterans Affairs Medical Center, AIDS Clinical Trials Group.
- ^ Leuppi, Jörg (2021-05-20). “Inhaled Aviptadil for the Treatment of COVID-19 in Patients at High Risk for ARDS: A Randomized, Placebo Controlled, Multicenter Trial”. Clinicaltrials.gov.
- ^ NeuroRx, Inc. (2021-02-23). “ZYESAMI (Aviptadil) for the Treatment of Critical COVID-19 With Respiratory Failure”. Lavin Consulting, LLC.
- ^ “Critically ill COVID-19 patients make quick recovery with treatment RLF-100”. New York Post. 2 August 2020. Retrieved 3 August 2020.
- ^ NeuroRx. “NeuroRx submits request for Emergency Use Authorization for RLF-100™ (aviptadil) in the treatment of patients with Critical COVID-19 and Respiratory Failure who have exhausted approved therapy”. http://www.prnewswire.com. Retrieved 2020-09-24.
- ^ Pharmaceuticals, NRx. “NRx Pharmaceuticals Announces Positive Results for ZYESAMI™ (Aviptadil-acetate) and Submits Emergency Use Authorization Application to USFDA to Treat Critical COVID-19 in Patients Suffering from Respiratory Failure”. http://www.prnewswire.com.
- ^ Das, Sohini (2021-01-25). “Dr Reddy’s, Zuventus get nod to conduct Covid-19 trials on repurposed drugs”. Business Standard India.
- ^ SECmeeting, e COVID-19. “Recommendations of the SECmeeting to examine COVID-19 related proposals under accelerated approval process made in its 140thmeeting held on 18.01.2021 & 19.01.2021 at CDSCO, HQ New Delhi” (PDF). CDSCO. Retrieved 1 July 2021.
- ^ Keijzers, GB (April 2001). “Aviptadil (Senatek)”. Current Opinion in Investigational Drugs. 2 (4): 545–9. PMID 11566015.
- ^ Procivni, Aviptadil/phentolamine mesilate. “Scientific discussion” (PDF).
- ^ Iwasaki, M; Akiba, Y; Kaunitz, JD (2019). “Recent advances in vasoactive intestinal peptide physiology and pathophysiology: focus on the gastrointestinal system”. F1000Research. 8: 1629. doi:10.12688/f1000research.18039.1. PMC 6743256. PMID 31559013.
- ^ Mathioudakis, A; Chatzimavridou-Grigoriadou, V; Evangelopoulou, E; Mathioudakis, G (January 2013). “Vasoactive intestinal Peptide inhaled agonists: potential role in respiratory therapeutics”. Hippokratia. 17 (1): 12–6. PMC 3738270. PMID 23935337.
- ^ Iwasaki, M; Akiba, Y; Kaunitz, JD (2019). “Recent advances in vasoactive intestinal peptide physiology and pathophysiology: focus on the gastrointestinal system”. F1000Research. 8: 1629. doi:10.12688/f1000research.18039.1. PMC 6743256. PMID 31559013.
- ^ Jump up to:a b Said, Sami I. (June 1988). “Vasoactive Intestinal Peptide in the Lung”. Annals of the New York Academy of Sciences. 527 (1 Vasoactive In): 450–464. Bibcode:1988NYASA.527..450S. doi:10.1111/j.1749-6632.1988.tb26999.x. PMID 2898912. S2CID 26804295.
- ^ Javitt, Jonathan C (2020-07-25). “Vasoactive Intestinal Peptide treats Respiratory Failure in COVID-19 by rescuing the Alveolar Type II cell”. doi:10.22541/au.159569209.99474501. S2CID 221509046.
- ^ Jump up to:a b c d Javitt, Jonathan C (2020-05-13). “Perspective: The Potential Role of Vasoactive Intestinal Peptide in treating COVID-19”. doi:10.22541/au.158940764.42332418. S2CID 219771946.
- ^ “Relief Therapeutics and NeuroRx Announce Final Manufacturing Validation of RLF-100 for Phase 2b/3 Clinical Trial in Patients with COVID-19 Associated Acute Respiratory Distress Syndrome”. GlobeNewswire News Room. 2020-05-14.
- ^ Jump up to:a b Youssef, Jihad G.; Lee, Richard; Javitt, Jonathan; Lavin, Philip; Lenhardt, Rainer; Park, David J; Perez Fernandez, Javier; Morganroth, Melvin; Jayaweera, Dushyantha (2021). “Increased Recovery and Survival in Patients With COVID-19 Respiratory Failure Following Treatment with Aviptadil: Report #1 of the ZYESAMI COVID-19 Research Group”. SSRN 3830051.
- ^ Beshay, S.; Youssef, J.G.; Zahiruddin, F.; Al-Saadi, M.; Yau, S.; Goodarzi, A.; Huang, H.; Javitt, J. (April 2021). “Rapid Clinical Recovery from Critical COVID-19 Pneumonia with Vasoactive Intestinal Peptide Treatment”. The Journal of Heart and Lung Transplantation. 40 (4): S501. doi:10.1016/j.healun.2021.01.2036. PMC 7979412. S2CID 232282732.
//////////AVIPTADIL, RLF 100, DK 1000
CCC(C)C(C(=O)NC(CC(C)C)C(=O)NC(CC(=O)N)C(=O)O)NC(=O)C(CO)NC(=O)C(CC(=O)N)NC(=O)C(CC(C)C)NC(=O)C(CC1=CC=C(C=C1)O)NC(=O)C(CCCCN)NC(=O)C(CCCCN)NC(=O)C(C(C)C)NC(=O)C(C)NC(=O)C(CCSC)NC(=O)C(CCC(=O)N)NC(=O)C(CCCCN)NC(=O)C(CCCNC(=N)N)NC(=O)C(CC(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)C(C(C)O)NC(=O)C(CC2=CC=C(C=C2)O)NC(=O)C(CC(=O)N)NC(=O)C(CC(=O)O)NC(=O)C(C(C)O)NC(=O)C(CC3=CC=CC=C3)NC(=O)C(C(C)C)NC(=O)C(C)NC(=O)C(CC(=O)O)NC(=O)C(CO)NC(=O)C(CC4=CN=CN4)N
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Marbofloxacin
Marbofloxacin
- Molecular FormulaC17H19FN4O4
- Average mass362.356 Da
115550-35-1[RN]
2,3-Dihydro-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[3,2,1-ij][4,1,2]benzoxadiazine-6-carboxylic Acid
6807
7H-1,3,4-Oxadiazino[6,5,4-ij]quinoline-6-carboxylic acid, 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-
8X09WU898T
марбофлоксацин
ماربوفلوكساسين
马波沙星
Marbofloxacin is a carboxylic acid derivative third generation fluoroquinolone antibiotic. It is used in veterinary medicine under the trade names Marbocyl, Forcyl, Marbo vet and Zeniquin. A formulation of marbofloxacin combined with clotrimazole and dexamethasone is available under the name Aurizon (CAS number 115550-35-1).
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PATENT
CN 107383058,
https://patents.google.com/patent/CN107383058B/enMarbofloxacin (Marbofloxacin) is fluoroquinolone antibacterial agent for animals, the entitled fluoro- 3- methyl-1 0- of 9- of chemistry (4- methylpiperazine-1-yl) -7- oxo -2,3- dihydro -7H- pyridine [3,2,1-ij] [4,1,2] benzo oxadiazines -6- carboxylic acid, It is developed by Roche Holding Ag, and is further developed by French Vetoquinol (method national strength and prestige are grand) company earliest, in nineteen ninety-five in Europe Listing.Marbofloxacin is after Enrofloxacin (Enrofloxacin), Danofloxacin (Danofloxacin), sarafloxacin (Sarafloxacin) etc. another third generation carbostyril family antibacterial drugs after, the drug have extensive antibacterial activity simultaneously With very good dynamic characteristic, sterilizing power is strong, absorbs fastly, widely distributed in vivo, with other antimicrobials without crossing drug resistant Property, easy to use, adverse reaction is small.Pharmacokinetic is studies have shown that Marbofloxacin removes long half time in animal body, biology Availability, almost without residual in the blood of animal, excrement and tissue, is well suited for clinically to antibiosis for animals close to 100% The requirement of element, structural formula are as follows:
Structure is complicated for Marbofloxacin, not only contains methyl piperazine substituent group, but also aromatic moieties contain pyridine benzo evil two Piperazine skeleton has had many documents and patent report at present and has reviewed its synthetic method, such as patent US4801584, ZL94190968.9, EP2010/067828, CN101619068, CN102060860, CN102617595, document J.Org. Chem., 1992,57 (2), 744-766, ” chemical reagent ” 2007,29 (11), 701-703., ” Chinese Journal of Pharmaceuticals ” 2002,33 (1), 1358-1363 etc..Patent US4801584 reports fluoro- via the fluoro- 4,8- dihydroquinoline -3- carboxylic acid, ethyl ester of 6,7- bis- preparation 6,7- bis- The method of 8- hydroxyl -1- (methylamino) -4- oxo-Isosorbide-5-Nitrae-dihydroquinoline -3- carboxylic acid, ethyl ester, this method are related to using valuableness And commercialization is not easy amination reagent O- (2, the 4- dinitrophenyl) oxyammonia largely purchased in 1 upper amino, by multistep reaction After complete the preparation of fluoro- 8- hydroxyl -1- (the methylamino) -4- oxo-Isosorbide-5-Nitrae-dihydroquinoline -3- carboxylic acid, ethyl ester of 6,7- bis-, passed through after It crosses and paraformaldehyde, N methyl piperazine reacts the preparation for realizing Marbofloxacin.Correlated response formula is as follows:
The patent literature reports such as patent ZL94190968.9 are that raw material prepares Ma Bosha from 2,3,4,5 tetra fluoro benzoic acid The synthetic route of star, this method are not only related to the multisteps hazardous reactions such as carboxylic acyloxy chlorination, Grignard Reagent preparation reaction, synthesize road Wire length, and 3- (the N- methyl formyl hydrazono-) ethyl acrylate for being difficult to prepare is used, and yield is low, be not suitable for industrially putting Mass production, correlated response formula are as follows:
Patent CN101619068 is condensed using 2,3,4,5- phenyl tetrafluoride carbamoylalkyl esters and inferior amine salt, obtained N- bis- Methyl substituted enamine derivates react the enamine for preparing the substitution of N- methyl-N- acyl group under organic acid catalysis with N- methylhydrazide Derivative, then 6,7,8- tri- fluoro- 1- (methylamino) -4- oxo-Isosorbide-5-Nitrae-dihydroquinoline-are completed in cyclization and hydrolysis under alkaline condition The preparation of 3- carboxylic acid realizes Ma Bosha finally by with N methyl piperazine, dimethyl formal (or diethyl formal) reaction The preparation of star.The technique uses the dimethyl suflfate and the height hazardous reaction reagent such as sodium hydride or alkalide of severe toxicity, because And it is subject to certain restrictions in commercial process.Correlated response formula is as follows:
In conclusion there are various deficiencies, such as chemistry examinations in the synthetic route of existing synthesis Marbofloxacin The defects of agent is expensive, reaction route is too long, using the chemical reagent for being unfavorable for industrialized production, the present inventor are real after study It tests, invents a kind of new method for preparing Marbofloxacin.The preparation of embodiment 1:1,1,1- tri- chloro- 4- (4- methylpiperazine-1-yl) butyl- 3- alkene -2- ketone(E) -1,1,1- tri- chloro-4-methoxy butyl- 3- alkene -2- ketone (Formulas I, R=Me) (10.18g, 50mmol), 1- methyl The mixture of piperazine (6.0g, 60mmol) and mesitylene (50mL) is heated to reflux temperature and stirs 6 hours, and system is natural Be cooled to room temperature, remove organic solvent under high vacuum reduced pressure, residue (14.2g, crude product do not purify) without further purification, directly It connects for reacting in next step.Embodiment 2:(6,8- bis- fluoro- 7- (4- methylpiperazine-1-yl) -4- oxo -3- (2,2,2- trichloroacetyl) quinoline Quinoline -1 (4H)-yl) urethanes (Formula VII) preparationUnder nitrogen protection, the product (14.2g is not purified, is directly used) of embodiment 1 is dissolved in toluene (120mL), then body Triethylamine (72mL, 514mmol) is added in system, system is heated to reflux temperature.Under reflux temperature, slowly dripped into reaction system Add toluene (60mL) solution of 2,3,4,5- phenyl tetrafluoride formyl chloride (16g, 75.3mmol).Rear system reflux is added dropwise 30min, then system slow cooling is to 60 DEG C, heat filtering.Filtrate is transferred in 500ml reaction flask, and carbazic acid second is then added Ester (Formula V, R2=Et) (6.25g, 60mmol).System is reacted 12 hours at a temperature of 60-65 DEG C after addition.To reaction H is slowly added in system2O (150mL) quenching reaction, system are naturally cooling to room temperature.Filtering, obtains solid, and solid uses heptan Alkane/ethyl acetate system mashing processing, obtains solid (Formula VII, R2=Et) (21.2g).Embodiment 3:1- amino -6- fluoro- 8- hydroxyl -7- (4- methylpiperazine-1-yl) -4- oxo -1,4- dihydroquinoline -3- The preparation of carboxylic acid (Formula VIII)2 obtained solid of embodiment (21.2g) is placed in 200ml reaction flask, ethyl alcohol (50mL) is added into reaction system With water (50mL), system is heated to flowing back.The aqueous solution (30mL) of KOH (7.0g) is slowly added under counterflow condition to system, is dripped System maintains the reflux for state response 96 hours after adding.System is naturally cooling to room temperature, and H is added in system2O (100mL) and CH2Cl2(50ml) stands after stirring and separates organic phase, and water phase reuses CH2Cl2It is extracted twice (2 × 50mL).Water phase uses salt Sour regulation system is to acid (pH=3-4), and then water phase reuses CH2Cl2It is extracted twice (2 × 100mL), merges organic phase, subtract Pressure-off obtains solid (Formula VIII) (12.4g) after removing organic solvent.The preparation of embodiment 4:1,1,1- tri- chloro- 4- (4- methylpiperazine-1-yl) butyl- 3- alkene -2- ketoneSequentially added in reaction flask the chloro- 4- ethyoxyl butyl- 3- alkene -2- ketone (Formulas I, R=Et) of (E) -1,1,1- three (14.1g, 65mmol) and 1- methyl piperazine (7.0g, 70mmol).Then system is heated to 130-155 DEG C and is stirred to react 5 hours.System is cold But to room temperature, the complete raw material of a little unreacted of high vacuum removed under reduced pressure, residue (16.8g, crude product do not purify) is without pure Change, is directly used in and reacts in next step.Embodiment 5:(6,8- bis- fluoro- 7- (4- methylpiperazine-1-yl) -4- oxo -3- (2,2,2- trichloroacetyl) quinoline Quinoline -1 (4H)-yl) t-butyl carbamate (Formula VII, R2=tBu) preparationUnder nitrogen protection, the product (16.0g is not purified, is directly used) of embodiment 4 is dissolved in toluene (125mL), then N is added in system, N- diisopropylethylamine (104.5mL, 600mmol), system is heated to reflux temperature.Under reflux temperature, to Toluene (70mL) solution of 2,3,4,5- phenyl tetrafluoride formyl chloride (18.8g, 88mmol) is slowly added dropwise in reaction system.It is added dropwise Starting material Formula II is tracked to HPLC within system reflux 1 hour afterwards to disappear.Then system slow cooling is to 60 DEG C or so, hot mistake Filter.Filtrate is transferred in 500mL reaction flask, and tert-butyl carbazate (Formula V, R is then added2=tBu)(9.3g,70mmol).It is added After system reacted 48 hours at a temperature of 60-65 DEG C.H is slowly added into reaction system2O (150mL) quenching reaction, body System is naturally cooling to room temperature.Filtering obtains solid, and solid is handled using heptane/ethyl acetate system mashing, obtains solid (formula VII,R2=tBu) (19.3g) is directly used in next step without further purification.Embodiment 6:1- amino -6- fluoro- 8- hydroxyl -7- (4- methylpiperazine-1-yl) -4- oxo -1,4- dihydroquinoline -3- The preparation of carboxylic acid (Formula VIII)By 5 obtained solid of embodiment (19.0g) as in 200mL reaction flask, methanol (55mL) is added into reaction system With water (55mL), system is heated to flowing back.The aqueous solution (30mL) of CsOH (13.5g) is slowly added under counterflow condition to system, Rear system is added dropwise and maintains the reflux for state response 96 hours.System is naturally cooling to room temperature, and H is added in system2O (100mL) and CH2Cl2(50mL) stands after stirring and separates organic phase, and water phase reuses CH2Cl2It is extracted twice (2 × 50mL).Water phase uses salt Sour regulation system is to acid (pH=3-4), and then water phase reuses CH2Cl2It is extracted twice (2 × 100mL), merges organic phase, subtract Pressure-off obtains solid (Formula VIII) (8.8g) after removing organic solvent.Embodiment 7: the preparation of Marbofloxacin1- amino-6- fluoro- 8- hydroxyl-7- (4- methylpiperazine-1-yl) oxo-1-4- is sequentially added in 100mL reaction flask, 4- dihydroquinoline -3- carboxylic acid (Formula VIII, 6.0g), 85% formic acid (30mL) and 36.5% formalin (6.0mL). System is carefully slowly heated to 75 DEG C or so reactions 1 hour after addition.Then system is cooled to 10 DEG C hereinafter, being carefully added into 25% ammonium hydroxide (25mL), stir 0.5 hour.Then activated carbon (1g) is added into system, mistake after 1 hour is sufficiently stirred Filter, filtrate methylene chloride extract 2 times (2 × 100mL).Merge organic phase, anhydrous sodium sulfate dries, filters, organic phase high vacuum Removed under reduced pressure solvent obtains Marbofloxacin crude product (5.4g).H is added in the crude product2In O (50mL), first acid for adjusting pH value is slowly added dropwise To 3.2 (pH meter detections), 4 hours are stood, filtering, filtrate added drop-wise sodium bicarbonate aqueous solution adjusting pH value to 6.2 (pH meter detections), A large amount of solids are precipitated, and ice salt bath cooling system stirs 1 hour to 0 DEG C or so, filtering, obtain Marbofloxacin after product drying (4.72g)。
Patent
Publication numberPriority datePublication dateAssigneeTitleUS4801584A *1986-09-121989-01-31Hoffmann-La Roche Inc.Pyrido(3,2,1-IJ)-1,3,4 benzoxadiazine derivativesCN1116849A *1993-01-231996-02-14辉瑞大药厂Process for the manufacture of a tricyclic compoundCN102060860A *2011-01-072011-05-18安徽美诺华药物化学有限公司Preparation method of MarbofloxacinCN102617595A *2012-03-232012-08-01江西华士药业有限公司Preparation method of fluoroquinolone antibacterial medicament marbofloxacinCN102712598A *2009-11-192012-10-03新梅斯托克尔卡·托瓦纳·兹德拉维尔公司A process for a preparation of marbofloxacin and intermediate thereof
CN110283186A *2019-07-192019-09-27海门慧聚药业有限公司A kind of crystal form of Marbofloxacin and preparation method thereof
PATENT
CN 107522718
PATENT
CN 102617595,
PATENT
Indian Pat. Appl., 2009CH00164,
Example 2: Preparation of ethyl 6,8-difluoro-1-(N~methylfomnamido)-7-(4-methyl-1- piperazinyl)-4-oxo-4H-quinoline-3-carboxylate hydrochloride of Formula (Ilia)
STR IIIA
Water (400 ml) and the compound of Formula (IIa) (200 g) are charged into a round bottom flask at 28°C and concentrated HCI (124 ml) is added slowly at a temperature below 40°C, and the mass is heated to 95-1OO0C. 300 ml of water and ethanol are distilled under vacuum at 1004C. The mass is cooled to 25-30°C. Acetone (400 ml) Is added and the mass is cooled to 0-5°C. The mass is maintained at 0-58C for 30-60 minutes and the product is filtered. The product is washed with pre-chilled acetone (200 ml) and dried under vacuum at 70-75°C for 12-15 hours to obtain the title compound. Yield: 181.0 g (95%). Example 3: Preparation of marbofloxacin from the compound of Formula (Ilia) Ethylene glycol (100 ml) and potassium hydroxide (17.3 g) are stirred for 10- 15 minutes for dissolution. A compound of Formula (Ilia) (10 g) is added and the mass is heated to 120-130’C, and then maintained for 24 hours. The mass is cooled to 30°C and water (15 ml) is added. Hydrochloric acid (36%, 18 ml) is slowly added below 404C.rformic acid (6 ml) is slowly added below 40°C and the mass is stirred for 20-30 minutes. Formaldehyde (5 ml) is added and the mass is then heated to 70-75°C and maintained for 1-2 hours. The mass is slowly cooled to 15-20°C and stirred for 30-60 minutes. The obtained solid dihydroformate salt is filtered and the wet cake is washed with pre-chilled demineralized water (5 ml). The material is suction dried for 2-3 hours. Methanol (50 ml), demineralized water (15 ml), and the wet cake are charged into a round-bottom flask and stirred for 10-15 minutes.
Ammonia solution (25%, 7.5 ml) is added and stirred for 30-60 minutes at 25-35°C. The turbid solution is filtered and the wet cake is washed with methanol (5 ml) at 25- 35°C. The water and methanol are distilled at 60-70°C under vacuum until 20 ml remain. The mass is cooled to 0-5°C and maintained for 30-60 minutes. The solid is filtered at 0-5°C and the wet cake is washed with methanol (10 ml). The material is suction dried for 30-60 minutes and the product is dried at 60-70°C under vacuum for 18-20 hours. Yield: 6.51 g (70%). Example 4: preparation of marbofloxacin from a compound of Formula (Ilia) Ethylene glycol (150 ml) and potassium hydroxide (72.2 g) are stirred for 10- 15 minutes for dissolution. A compound of Formula (Ilia) (50 g) is added and the mass is heated to 115-1256C, and then is maintained for 10-12 hours at 115— 125°C. The mass is cooled to 25-35°C and water (150 ml) is added. Formic acid (98%, 100 m!) is slowly added below 45°C and the mass is stirred for 30-60 minutes. Formaldehyde (37-41%, 35 ml) is added to the mass, which is then heated to 70- 75°C and maintained for 1-2 hours. The mass is slowly cooled to 0-5°C and stirred for 1-2 hours. The obtained solid dihydroformate salt is filtered and the wet cake is washed with pre-chilled water (50 ml). The material is suction dried for 1 hour and washed with pre-chilled acetone (50 ml) and suction dried for 1 hour. Methanol (250 ml), water (100 ml), and the wet cake are charged into a round-bottom flask and stirred for 10-15 minutes. Ammonia solution (25%, 40 mi) is added and stirred for 30-60 minutes at 25-35°C. The turbid solution is filtered and the wet cake is washed with methanol (50 ml) at 25-35°C. The filtrate is distilled at 60-70°C under vacuum until 75-100 ml remain. The mass is cooled to 10-15’C and maintained for 30-60 minutes. The solid free base is filtered at 10-15°C and the wet cake is washed with chilled methanol (50 ml). The material is suction dried for 30-^60 minutes and the product is dried at 60-70°C under vacuum for 10-12 hours. Yield: 33.0 g (70.8%). Example 5: Preparation of marbofloxacin from a compound of Formula (Ilia) Water (350 ml) and potassium hydroxide (86.6 g) are stirred for 10 minutes. A compound of Formula (Ilia) (50 g) is added and the mass is heated to 100-104°C. The mass is maintained for 105-110 hours at 100-1040C, then is copied to 25-35°C and water (65 ml) is added. Hydrochloric acid (36%, 125 ml) is slowly added below 40°C and the mass is stirred for 30 minutes. Formaldehyde (37%, 19 ml) is added and the mass is heated to 70-756C. The mass is maintained for 1-2 hours at 70-75 0C and then is slowly cooled to 0-5°C and maintained for 30-60 minutes. The obtained solid hydrochloride salt is filtered and the bed is washed with pre-chilled water (25 ml) at 0-5°C. The material is suction dried. Ethanol (250 ml), water (75 ml), ammonia solution (25%, 38 ml) and the wet cake are charged into a round-bottom flask and stirred for 1-2 hours at 25-35° C. The turbid solution is filtered and the bed is washed with ethanol (50 ml). The filtrate is distilled at 65-70°C under vacuum until 100 ml remain. The mass is cooled to 0-5°C and maintained for 30-60 minutes. The solid free base is filtered and the wet cake is washed with pre-chilled ethanol (50 ml). The product is dried under vacuum at 60-70°C for 15-^20 hours. Yield: 23.3 g (50%).
Example 6: Preparation of marbofloxacin from a compound of Formula (IIa) Ethylene glycol (60 ml) and potassium hydroxide (28.05 g) are stirred for 10- 15 minutes for dissolution. A compound of Formula (IId) (20 g) is added. The mass is heated to 120-135°C and maintained for 4-6 hours. The mass is cooled to 30°C and water (60 ml) is added. Formic acid (98-100%, 40 ml) is slowly added below 40°C and stirred for 20-30 minutes. Formaldehyde (37-41%, 12 ml) is added to the mass, which is heated to 70-75°C and maintained for 1-2 hours. The mass is slowly cooled to O-S6C and stirred for 30-60 minutes. The obtained solid dihydroformate salt is filtered and the wet cake is washed with pre-chilled water (20 ml). The material is suction dried for 2-3 hours. Methanol (100 ml), water (30 ml), and the wet cake are charged into a round-bottom flask and stirred for 10-15 minutes. Ammonia solution (25%, 20 ml) is added and stirred for 30-60 minutes at 25-35°C. The turbid solution is filtered and the wet cake is washed with methanol (10 ml) at 25-35°C. The water and methanol are distilled at 60-70°C under vacuum until 40 ml remain. The mass is cooled to 0-5°C and maintained for 30-60 minutes. The solid free base is filtered at 0-5°C and the wet cake is washed with methanol (20 ml). The material is suction dried for 30-60 minutes and the product is dried at 60-70°C under vacuum for 18-20 hours. Yield: 12.6 g (71%)
Example 7: Purification of marbofloxacin To crude marbofloxacin (25 g) is added methanol (125 ml) and ammonia (18.75 ml). Half of the volume of the methanol and ammonia solution is removed by azeotropic distillation. The mass is slowly cooled and maintained for 1 hour. The product is filtered and washed with chilled methanol (25 ml). The product is suction dried for 30 minutes and dried under vacuum for 12 hours, to yield pure marbofloxacin of a purity 99.80%. XRD pattern, DSC thermogram, TGA1 and IR are substantially in accordance with Figs. 1, 2, 3, and 4, respectively. Yield: 22 g (88.0%),
PATENT
Indian Pat. Appl., 2009CH00163,
PATENT
WO 2011061292
PATENT
CN 102060860,
PATENT
CN 101619068,
PATENT
https://patents.google.com/patent/EP2332916A2/en
- Marbofloxacin is the common name for 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyridol(3,2,1-ij)(4,2,1)benzoxadiazin-6-carboxylic acid, of the formula :
- [0003]
Marbofloxacin is a potent antibiotic of the fluoroquinolone group. - [0004]
EP 259804 describes marbofloxacin as well as a synthesis for the preparation thereof by a multistep process which is unpractical for a large scale manufacture, since it requires high temperatures and reagents not suitable for large-scale production, resulting in low over-all yields. The process for the preparation is disclosed in the reaction scheme 1. - [0005]
EP 680482 discloses an alternative approach for the preparation of marbofloxacin, wherein hydroxy group is introduced into molecule by means of reaction of intermediate with alkali metal hydroxide in aqueous media. The starting material used is 2,3,4,5-tetrafluorobenzoic acid. Disadvantages of this process are relatively high excess of alkali metal hydroxide and lengthy procedure. The process for the synthesis according to this patent is shown in the reaction scheme 2. - [0006]
Research Disclosure No. 291, 1988, pages 548-551 discloses an alternative route of synthesis also starting from 2,3,4,5-tetrafluorobenzoic acid. Later steps of the process are shown in the reaction scheme 3. - [0007]
IT 1313683 relates to a process for preparation of marbofloxacin by a process via benzyl ether. Ether was debenzylated in aqueous solution by hydrogenating over 5% Pd/BaSO4 and the obtained product is cyclized using HCOOH/HCOH. - [0008]
In view of the prior art there still exists a need for an improved method for preparation of marbofloxacin and intermediates thereof suitable for a large-scale production.
Examples
- [0068]
A high resolution HPLC method is used to determine an amount and purity compounds of formula I, II and IV. The tests are carried out in X-Bridge C18, 150 x 4.6mm, 3.5µm column. The mobile phase is gradient of A) 5mM NH4COOCH3 pH=7.0 B) acetonitrile. Gradient: 0’=10%B, 10’=20%B, 25′-30’=90%B, 32’=10%B. - [0069]
The chromatograph is equipped with a UV detector set at 250 nm and 315nm, the flow rate is 1.0 ml per minute at 30°C.
Example 1a) 6,8-difluoro-1-(methylamino)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 6,8-difluoro-1-(methylamino)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid sodium salt
- [0070]
- [0071]
4.137g of Ethyl 6,8-difluoro-1-(N-methylformamido)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (10.14mmol) was put into 40mL of 10% H2SO4 and stirred at 100°C for 7 hours. Reaction mixture was cooled and crystals were formed. Mixture was cooled to 4°C and filtered with suction. Filter cake was washed with a mixture of H2O/EtOH/THF (1/1/5) and dried. 3.260g of 6,8-difluoro-1-(methylamino)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as yellow crystals were obtained (91%). - [0072]
In case the sodium salt is desired the product obtained in previous step was put into 5mL of EtOH and 10mL of CH2Cl2 and 1.20g of NaOH dissolved in 2mL of water was added. Solution was stirred at room temperature. for 1h, dried with Na2SO4 and evaporated. 2.90g of pure title product was isolated (yellow powder, 7.71mmol, 76%).
b) 6,8-difluoro-1-(methylamino)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- [0073]
- [0074]
400mg of Ethyl 6,8-difluoro-1-(N-methylformamido)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0, 979mmol) was put into 2mL of 10% H2SO4 and stirred at 100°C for 2 hours. Reaction mixture was cooled and crystals were formed. To this mixture 1,7mL of 25% aq. NH3 was slowly added. At first very dense suspension was formed that dissolves with further addition of ammonia solution. At the end clear solution formed with pH of 9. Ammonium sulphate was precipitated by the addition of 10mL of EtOH , filtered off and washed with 5mL of H2O/EtOH (1/2). Mother liquor was dried on the rotary evaporator and 10 mL of EtOH/H2O mixture (7/3) was added to precipitate residual inorganic salt, which was again filtered off. Remaining yellow solution was dried on a rotary evaporator to obtain 321mg of yellow powder (0.912 mmol, 93%).
Example 26-fluoro-8-hydroxy-1-(methylamino)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- [0075]
- [0076]
178 mg of 6,8-difluoro-1-(methylamino)-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid sodium salt (0.470mmol) was mixed with 360 mg of Me4NOH.5H2O (2.00 mmol) and stirred at 100°C for 4 hours. Ammonium salt melts and dark brown oil is formed during the reaction. Reaction mixture was cooled to room temperature and 0.10mL of HCOOH was added to neutralize hydroxide. 5mL of EtOH is added to precipitate the product, which was filtered with suction and filter cake was washed with 2mL of cold EtOH. 90mg of the product was obtained.
Example 39-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxylic acid formate salt
- [0077]
- [0078]
180 mg of 6,8-difluoro-1-(methylamino)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid sodium salt (0.481mmol) was mixed with 360 mg of Me4NOH.5H2O (2.00 mmol) and stirred at 100°C for 3 hours. Ammonium salt melts and dark brown oil is formed during the reaction. Reaction mixture was cooled to room temperature and 1 mL of HCOOH was added followed by addition of 0.4 mL of 37% aq. solution of HCHO and stirred at 70°C for additional hour. Reaction mixture was cooled to room temperature and 5mL of EtOH was added to precipitate the product, which was filtered with suction and filter cake was washed with 2mL of cold EtOH. 111 mg of grey powder was obtained.
Example 49-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxylic acid formate salt
- [0079]
- [0080]
1.14g of 6,8-difluoro-1-(methylamino)-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (3.00mmol) was mixed with 3.06g of Me4NOH.5H2O (16.96mmol) and stirred at 100°C for 5 hours. Ammonium salt melts and dark brown oil is formed during the reaction. Reaction mixture was cooled to room temperature and 1.44 mL of HCOOH (85% aq. sol) was added followed by addition of 0.5 mL of 37o aq. solution of HCHO and the flask was cooled on the water bath at 22°C. Another 1.44mL of 85% HCOOH was added and the reaction mixture was warmed to 70°C for 30min and after cooling 20mL of EtOH was added to the reaction mixture and left in a refrigerator for 16h. Precipitate was filtered under reduced pressure and washed with cold ethanol (10mL). After drying 1.23g of grayish powder was obtained (90%) .
Example 59-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxylic acid
- [0081]
- [0082]
1.145g of 6,8-difluoro-1-(methylamino)-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (3.01mmol) was mixed with 2.72g of Me4NOH.5H2O (15.00mmol) and stirred at 100°C for 8 hours. Ammonium salt melts and dark brown oil is formed during the reaction. Reaction mixture was cooled to room temperature and 3.0 mL of HCOOH was added followed by addition of 0.5 mL of 37% aq. solution of HCHO (6.0mmol) and the flask was cooled on the water bath at 22°C. Precipitate was immediately formed. The flask was warmed to 70°C, during which precipitate was dissolved. After stirring at 70°C for 30min (precipitate was formed again after 5min) reaction flask was cooled to room temperature and 20mL of EtOH was added to the reaction mixture and left in a refrigerator for 16h. Precipitate was filtered under reduced pressure and washed with cold ethanol (10mL). After drying 1.165g of grayish powder was obtained (85%), with a purity of 97.11% (HPLC). - [0083]
Crude reaction product was mixed with 0.9mL of 25% NH3 aqueous solution and crystallized in a mixture of 26mL of EtOH and 14mL H2O. 0.673g of powder was obtained (61%) with a purity of 98.75% (HPLC).
Example 69-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxylic acid
- [0084]
- [0085]
1.140g of 6,8-difluoro-1-(methylamino)-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (3.00mmol) was mixed with 2.72g of Me4NOH.5H2O (15.01mmol) and stirred at 100°C for 8 hours. Ammonium salt melts and dark brown oil is formed during the reaction. Reaction mixture was cooled to room temperature and 3.0 mL of HCOOH was added followed by addition of 0.5 mL of 37% aq. solution of HCHO (6.0mmol) and the flask was cooled on the water bath at 22°C. Precipitate was immediately formed. The flask was warmed to 70°C, during which precipitate was dissolved and stirred for 30 min (after stirring for at 70°C for 5min precipitate formed again). Reaction flask was cooled to room temperature and 20mL of H2O was added to the reaction mixture and left in a refrigerator for 16h. Precipitate was filtered under reduced pressure and washed with cold ethanol (10mL). After drying 1.022g of greyish powder was obtained (75%). with a purity of 97.11% (HPLC). - [0086]
Crude reaction product was mixed with 0.9mL of 25% NH3 aqueous solution and crystallised in a mixture of 20mL of EtOH and 6mL CHCl3. 0.771g of yellow powder was obtained (71%) with a purity of 99.50% as determined by HPLC.
Example 79-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxylic acid
- [0087]
- [0088]
1.142 g of 6,8-difluoro-1-(methylamino)-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (3.01mmol) was mixed with 3.26g of Me4NOH.5H2O (18.01mmol) and stirred at 100°C for 4 hours. Ammonium salt melts and dark brown oil is formed during the reaction. Reaction mixture was cooled to room temperature and 3.0 mL of HCOOH was added followed by addition of 0.5 mL of 37% aq. solution of HCHO (6.0mmol) and the flask was cooled on the water bath at 22°C. Precipitate was immediately formed. The flask was warmed to 70°C, during which precipitate was dissolved and stirred for 30 min (after stirring for at 70°C for 5min precipitate formed again). Reaction flask was cooled to room temperature and dried on the rotary evaporator. 20mL of H2O was added to the reaction mixture and cooled in a refrigerator. Precipitate was filtered under reduced pressure. After drying 1.147g of white powder was obtained (84%). - [0089]
Crude reaction product was mixed with 5mL of water and 2mL of 25% aqueous solution of NH3 and clear solution was obtained. To this solution, 7mL of EtOH was added and dried under reduced pressure. Product was crystallized in a mixture of 15mL of EtOH and 10mL CHCl3 to obtain 0.4321g of white powder (41%) with a purity of 98.63% as determined by HPLC
Example 89-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxylic acid
- [0090]
- [0091]
1.136 g of 6,8-difluoro-1-(methylamino)-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2.98mmol) was mixed with 2.73g of Me4NOH.5H2O (15.00mmol) and stirred at 100°C for 7 hours. Ammonium salt melts and dark brown oil is formed during the reaction. Reaction mixture was cooled to room temperature and 3.0 mL of HCOOH was added followed by addition of 0.5 mL of 37% aq. solution of HCHO (6.0mmol) and the flask was cooled on the water bath at 22°C. Precipitate was immediately formed. The flask was warmed to 70°C, during which precipitate was dissolved and stirred for 30 min (after stirring for at 70°C for 5min precipitate formed again). Reaction flask was cooled to room temperature and dried on the rotary evaporator. 20mL of H2O was added to the reaction mixture and cooled in a refrigerator. Precipitate was filtered under reduced pressure. After drying 1.039g of grey powder was obtained (77%). - [0092]
Crude reaction product was neutralized with 2mL of 25% aqueous solution of NH3 and clear solution was diluted with 15mL of EtOH and 9mL of H2O. Solution was partially dried under reduced pressure until the formation of precipitate. At this point mixture was cooled in a refrigerator and precipitate was isolated by filtration under reduced pressure to obtain 0.675g of powder (65%) with a purity of 98.84% as determined by HPLC.
Example 99-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxylic acid
- [0093]
- [0094]
1.140g of 6,8-difluoro-1-(methylamino)-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (3.01mmol) was mixed with 3.30g of Me4NOH.5H2O (18.20mmol) and stirred at 100°C for 4 hours. Ammonium salt melts and dark brown oil is formed during the reaction. Reaction mixture was cooled to room temperature and 3.0 mL of HCOOH was added followed by addition of 0.5 mL of 37% aq. solution of HCHO (6.0mmol) and the flask was cooled on the water bath at 22°C. Precipitate was immediately formed. The flask was warmed to 70°C, during which precipitate was dissolved and stirred for 30 min (after stirring for at 70°C for 5min precipitate formed again). Reaction flask was cooled to room temperature and dried on the rotary evaporator. 20mL of H2O was added to the reaction mixture and cooled in a refrigerator. Precipitate was filtered under reduced pressure to obtain 0.847g of solid, while mother liquid was diluted with EtOH and concentrated under reduced pressure until precipitate forms, which was filtered again to obtain additional 0.208g of solid. The yield of combined solid material is 1.055g, 77%. Crude reaction product (formate salt) was crystallized in H2O/EtOH (25mL/10mL) to obtain 0.722g (53%) of yellow powder. Formate salt was put in 20mL of EtOH/CH2Cl2 mixture (1/1) and 0.5mL of 25%aq. NH3 was added to obtain clear solution. Solution was dried with Na2SO4 and solvent evaporated under reduced pressure to obtain 0.580g of yellow powder (53%).
Example 109-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxylic acid
- [0095]
- [0096]
100 mL reactor with a rotary stirrer was charged with 10,16g of 6,8-difluoro-1-(methylamino)-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (28,83mmol) and 26,50g of Me4NOH˙5H2O (146,25mmol) that was previously mixed together. Temperature of the heating jacket was set to 100°C and stirring to 100s-1, while water was allowed to evaporate out of the reactor during the reaction. Reaction was stirred at specified temperature for 5 hours and homogenous dark brown oil was obtained. Temperature of reactor was cooled to 20°C, 30mL of HCOOH was added and stirred well so that all oil is transformed into brown suspension. 4,5mL of 37% aq. HCHO was added drop-wise and heated at 70°C for 30min. Reaction mixture was cooled to 20°C and 20mL of water added to precipitate the product in the form of formate complex. Suspension was cooled to 0°C and filtered under reduced pressure and washed the filter cake with additional 10mL of cold water to obtain 8,38g of white powder. Mother liquor was partially evaporated under reduced pressure and when solid started to precipitate it was filtered again to obtain additional 0.80g of powder. 50mL of EtOH was added into the mother liquor to precipitate the product and after filtration at reduced pressure further 0.80g of white powder was obtained. Product was collected and 9,98g of white powder was suspended in a mixture of 50mL of EtOH and 50mL of CH2Cl2. Into the suspension 25% aq. NH3 was added to neutralize the formate complex and after addition of 12mL of NH3 all product was dissolved and small amount of solid material is formed. 5g of anhydrous Na2SO4 was added to dry the organic solution and it was filtered off and solvent evaporated under reduced pressure. 8.99g of slightly yellow powder was obtained in 86% yield.
Example 11Crystallization from ethanol/toluene/water 2:1:1
- [0097]
8.4g of crude marbofloxacin was suspended in a mixture of 83 ml of ethanol, 41ml of toluene and 41 ml of water and heated to reflux. From the clear yellow solution formed 83 ml of solvent mixture was distilled off, whereby the temperature rose from 74 to about 79°C, and a yellow precipitate was formed. The suspension was cooled to 20° – 25°C, stirred for 1 hour, filtered, and the filter cake was washed with 3 portions of 6 ml of ethanol to yield after drying in vacuum dryer the product in more than 95% yield.
Example 12Crystallization of marbofloxacin starting from marbofloxacin formate
- [0098]
26g of marbofloxacin formate was suspended in a mixture of 65ml of ethanol and 27ml of water. Under stirring a solution of 25% ammonia in ethanol (20ml 25%NH3/10ml EtOH) is slowly (about 30 minutes) added by drops until the substance is dissolved and pH value of 7-9 is reached. The reaction was stirred for about 15 minutes and filtered. The filtrate was evaporated at 110°C until about 60ml of the solvent was distilled off and marbofloxacin started to precipitate. After distillation the suspension was cooled and stirred for 0.5 to 1 hour at 0-5°C, filtered, to yield after drying at 40°C/50mbar for 3 to 5 hours the product in 100%yield.
Example 13Crystallization from ethanol
- [0099]
1g of marbofloxacin was dissolved under heating to reflux in 160ml of ethanol, after filtration, the solution is cooled and the crystallized product is recovered in more than 90% yield.
Example 146,7,8-Trifluoro-1-methylamino-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid
- [0100]
- [0101]
10mmol of 6,7,8-Trifluoro-1-(N-methylformamido)-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid ethyl ester was put in the round bottomed flask. 20mL of 10% H2SO4 was added and stirred with the temperature of the sand bath of 100°C for the time periods specified in the following table. Reaction mixture was cooled down to 4°C, filtered and the cake washed with water and the conversion an yield were determined. - [0102]
The experiment was repeated but starting compound was mixed with 1.0mL of solvent (EtOH, AcOH or MeCN as specified in the following table) before adding the 10% H2SO4. - [0103]
The starting compound is insoluble in aqueous phase. By mixing the starting compound with a small amount of polar solvent (EtOH, MeCN, AcOH) a film is formed around the crystals which improves wetting of the crystals with the aqueous acid. Without addition of polar solvent prior to adding the aqueous acid solution wetting of the crystals is impaired and the reaction is slower.Exp.Reaction time (solvent)Conversion (yield)14.016h65%14.027h60%14.0324h100%14.0424h100% (94%)14.056h (0.1mL AcOH per mmol)91%14.066h (0.1mL EtOH per mmol)89%14.0721h (0.1mL MeCN per mmol)100% (97%)14.0821h (0.1mL MeCN per mmol)100% (96%)
Example 156,7,8-Trifluoro-1-methylamino-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid
- [0104]
3.30g of 6,7,8-Trifluoro-1-(N-methylformamido)-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid ethyl ester (10.054 mmol) was put into the round-bottomed flask equipped with the magnetic stirrer. 1mL of MeCN was added and stirred for a minute. 20mL of 10% H2SO4 was added and stirred. The flask was put into the sand bath (T = 100°C) and stirred for 21h. Suspension was cooled down to 4°C and filtered under suction. Yellow powder was washed twice with cold water and dried. 2.646g of yellow powder was obtained (9.721 mmol, 96.7%) and identified by NMR spectroscopy to be title compound.
Example 166,7,8-Trifluoro-1-methylamino-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid
- [0105]
6,7,8-Trifluoro-1-(N-methylformamido)-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid ethyl ester (6.868g, 20.92 mmol) was mixed with 1mL of EtOH (to decrease the hydrophobicity of the substrate). Next, 40mL of 10% aqueous H2SO4 solution was added and the mixture was stirred at the temperature of the bath of 100°C for 12h. A white suspension formed which was cooled to 0°C and filtered under reduced pressure. The white powder was washed with cold water and cold EtOH and dried. 5.135g of yellow powder was obtained and identified as title compound by 19F and 1H NMR spectroscopy. The yield of hydrolysis was 90%.
Example 176,8-Difluoro-1-(methylamino)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-quinoline-3-carboxylic acid
- [0106]
- [0107]
6,7,8-Trifluoro-1-methylamino-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid (272mg, 1.0mmol, obtained as described in Example 16, and 400 mg of N-methylpiperazine (4.0mmol) were mixed with 1mL of EtOH and stirred under reflux temperature (jacket temperature Tj=100°C). After two hours of reaction clear solution formed, afterwards the product precipitated and a very dense suspension was formed. Reaction was stopped after three hours of stirring at Tj=100°C. A sample was put directly to the NMR analysis and only two signals were observed indicating reaction was quantitative. Crude reaction product was diluted with EtOH and neutralized by addition of aqueous solution of NH3 until pH of 8 was reached. Suspension was cooled to 0°C and product isolated by filtration under reduced pressure, washed further with 10mL of cool EtOH and dried. 138mg (39%) of product was obtained.
Example 186,8-Difluoro-1-(methylamino)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-quinoline-3-carboxylic acid
- [0108]
6,7,8-Trifluoro-1-methylamino-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid (1.087g, 3.993mmol), 484mg of N-methylpiperazine (4.83mmol) and 484 mg of Et3N (4.78mmol) were mixed with 8mL of EtOH and stirred under reflux temperature (Tj=100°C). After 19h of reflux yellow solution and white precipitate are formed in the reaction flask. Solvent was evaporated under reduced pressure and put directly to the NMR analysis. Crude reaction product was mixed with 20mL of EtOH and suspension cooled in the refrigerator. The product (white precipitate) was isolated by filtration under reduced pressure, washed further with 10mL of cool EtOH and dried. 1.178g of white powder was obtained (3.375 mmol, 800).
Example 196,8-Difluoro-1-(methylamino)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-quinoline-3-carboxylic acid
- [0109]
In accordance with examples 17 and 18 additional experiments were carried out using different reaction conditions for the conversion of 6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid into 6,8-difluoro-1-(methylamino)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-quinoline-3-carboxylic acid. The experiments were performed according to the following general procedure: 1.0mm of starting compound was put in the round bottomed flask and N-methylpiperazine (NMP), base and solvent were added according to the following table. Reaction mixture was stirred at the corresponding temperature. Solvent was evaporated and crude reaction mixture analyzed directly by NMR (1H and 19F).
Example 206,8-Difluoro-1-(N-methylformamido)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-quinoline-3-carboxylic acid ethyl ester
- [0111]
- [0112]
Substitution: 6,7,8-Trifluoro-1-(N-methylformamido)-4-oxo-1,4-quinoline-3-carboxylic acid ethyl ester (1.0 mmol, 324mg) was mixed with 2 equivalents of N-methylpiperazine (220mg) and 400mg Et3N stirred for three hours at 100°C. Reaction mixture liquefied in 10 minutes and solidified again within 30 minutes of the reaction (that is the reason for higher amount of TEA). After 3 hours of stirring was reaction mixture cooled to room temperature and analyzed by NMR spectroscopy. - [0113]
Substitution: The above reaction was repeated but Et3N was replaced by 1 equivalent of DABCO. - [0114]
In both cases, substitution was quantitative and analysis of the crude reaction mixtures showed that there was some hydrolysis of the ethyl ester (EE) to the free carboxylic acid (CA) group resulting in a product mixture. The results are summarized in the following table. Ethyl ester is readily soluble in water.Exp.Reaction conditionsConversion (yield)20.012.5 NMP, 1 DABCO, 100°C, 3h100% (48% EE, 52% CA)20.022.5 NMP, 4 Et3N, 100°C, 3h100% (58% EE, 42% CA)
Example 216,8-Difluoro-1-(methylamino)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-quinoline-3-carboxylic acid (one-pot reaction)
- [0115]
- [0116]
6,7,8-Trifluoro-1-(N-methylformamido)-4-oxo-1,4-quinoline-3-carboxylic acid ethyl ester (1.0 mmol, 324mg) was mixed with 2 equivalents of N-methylpiperazine (200mg) and stirred for one hour at 100°C. Reaction mixture liquefied in 10 minutes and solidified again within 30 minutes of reaction. After one hour of reaction the reaction mixture was cooled to room temperature and 10% aqueous H2SO4 (5mL) was added and stirred again at 100°C for two hours. Yellow solution was cooled to 0°C so that product precipitated. It was isolated by filtration under reduced pressure. Pure 6,8-difluoro-1-(methylamino)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-quinoline-3-carboxylic acid in the form of sulfate salt was obtained (as determined by NMR) as slightly yellow powder (279mg, 58%).
Example 22Synthesis of 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3, 7-dihydro-2H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxylic acid (Marbofloxacin, MBX)
- [0117]
13.5 g of 6,8-Difluoro-1-(methylamino)-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride and ca. 63 g of tetramethylammonium hydroxide water solution 25 % were charged into a reactor and slowly heated to 100°C. When this temperature was reached, water was removed by distillation at reduced pressure (between 0.8 to 0.3 bar) in such a manner that ca. 25 to 32 ml of water were removed in 3 hours. The reaction mixture was stirred for another 3 hours and after completion of the conversion, the reaction mixture was cooled to 0 – 10 °C and ca. 40.5 ml of formic acid were slowly added with violent agitation. The temperature was maintained below 20°C, preferable between 0 – 10°C. Then ca. 6.1 ml of formaldehyde were slowly added. After addition the reaction mixture was heated to 70°C and maintained at this temperature for about 30 minutes. - [0118]
The reaction mixture was cooled to room temperature (20 – 30°C), ca. 27 ml of purified water were added and the mixture was stirred for 30 minutes. Then the reaction mixture was cooled to 0 – 5°C and stirred at this temperature for at least 2 hours. The product marbofloxacin formate (MBXBZ) was centrifuged and washed with 10 – 15 g of cooled (0 – 5°C) purified water. The product was spun dried and collected. - [0119]
Wet product MBXBZ was added to the mixture of 67 ml of ethanol, 67 ml of methylene chloride and 16.2 ml of ammonia solution (ca. 25 0). If phases did not separate, additional 63 ml of methylene chloride and 33 ml of purified water were added. The pH of the water phase was adjusted to be between 7 and 9.5, preferable between 7.5 and 8.5. The mixture was agitated for approximately 15 minutes to 1 hour and then the layers were separated and both phases were subjected to in process control (IPC) analysis. - [0120]
If IPC results showed that extraction was not complete, ca. 63 ml of methylene chloride were added to the water layer and the extraction was repeated until the IPC specification was met. - [0121]
The organic phases were combined and ca. 6.8 mg of sodium sulphate anhydrous and optionally 0.4 mg of activated charcoal were added. The mixture was mixed for at least 30 minutes and filtered, then organic solvent was distilled off to obtain crude marbofloxacin.
Purification of the crude Marbofloxacin
- [0122]
In an inert atmosphere 5 g of purified water, 12 g of ethanol 96 % and 4.3 g of toluene (ratio between the solvents was within the following ranges: ethanol : toluene : water : 1.8 – 2.8 : 1 : 1.1 – 1.2) were charged into a reactor and wet crude marbofloxacin (MBXCA) from the previous step was added under nitrogen. The mixture was slowly heated to reflux (70 – 80°C) until a clear solution was obtained. The solution was stirred for 0.5 hour under this temperature and then one half of the azeotrope solvent mixture (toluene : water : ethanol = 51 % : 6 % : 43 %) was evaporated. Then the remaining mixture was cooled slowly to 5°C (allowed interval is between 0 and 25 °C) with agitation (optionally 1 % mass of product of disodium-EDTA can be added). The mixture was mixed for 1 to 3 hours and the product was then isolated by centrifugation, washed with 13 g of ethanol, spun dry and collected. The product was dried at temperature 40 – 45°C, p < 100 mbar for 8 hour.
Example 23Purification of Marbofloxacin
- [0123]
Marbofloxacin was dissolved in 20 parts by weight of water by addition of acetic acid. Marbofloxacin was completely dissolved at pH of 5.3. Active charcoal was added and the mixture was stirred overnight. The mixture was then filtered using activated charcoal filter. The pH of the filtrate was adjusted to 7.2 by use of KOH, the obtained suspension was stirred for 1 hour at room temperature and then the precipitated product was recovered. Marbofloxacin with a purity of 99,9% (HPLC area) was obtained. - [0124]
HPLC analysis was performed on a pentafluorophenyl propyl (PFP) column (type Luna® PFP, 150 x 4.6mm, 3µm, Phenomenex, USA); detector: UV315 nm; flow rate: 0.8 ml/min; injection volume: 5 µl; mobile phase: A: 0.02M NaH2PO4xH2O+0,1% TEA, pH2.5; B: acetonitrile : methanol = 5:95 (v/v) ; gradient: 0’=10B, 25’=100B, 30’= 100B, 32’=10B. The HPLC chromatogram of marbofloxacin prior to purification is shown in Figure 1, the HPLC chromatogram after purification is shown in Figure 2. As evident from the chromatograms all products with retention time above 24min were successfully eliminated.
Mechanism of action
Its mechanism of action is not thoroughly understood, but it is believed to be similar to the other fluoroquinolones by impairing the bacterial DNA gyrase which results in rapid bactericidal activity.[1] The other proposed mechanisms include that it acts against nondividing bacteria and does not require protein and RNA synthesis, which block protein and RNA synthesis respectively.[2]
Activity
Marbofloxacin is a synthetic, broad spectrum bactericidal agent. The bactericidal activity of marbofloxacin is concentration dependent, with susceptible bacteria cell death occurring within 20–30 minutes of exposure. Like other fluoroquinolones, marbofloxacin has demonstrated a significant post-antibiotic effect for both gram– and + bacteria and is active in both stationary and growth phases of bacterial replication.[3]
It has good activity against many gram-negative bacilli and cocci, is effective against:
- Aeromonas
- Brucella
- Campylobacter
- Chlamydia trachomatis
- Enterobacter
- Escherichia coli
- Haemophilus
- Klebsiella spp
- Mycobacterium
- Mycoplasma
- Proteus
- Pseudomonas aeruginosa
- Salmonella
- Serratia
- Shigella
- Staphylococci (including penicillinase-producing and methicillin-resistant strains)
- Vibrio
- Yersinia
Application
Marbofloxacin can be used both orally and topically. It is particularly used for infections of the skin, respiratory system and mammary glands in dogs and cats, as well as with urinary tract infections. For dogs, a dose ranges from 2.75 – 5.5 mg/kg once a day. The duration of treatment is usually at least five days, longer if there is a concurrent fungal or yeast infection.[4] Maximum duration of treatment is 30 days.[3]
Contraindications and side effects
Marbofloxacin should usually be avoided in young animals because of potential cartilage abnormalities. In rare occasion, it can cause central nervous system (CNS) stimulation and should be used with caution in patients with seizure disorders.[3] Under certain conditions it can cause discomfort such as cramps, treatable with diazepam. Other adverse effects are usually limited to gastrointestinal tract (GI) distress (vomiting, anorexia, soft stools, diarrhoea) and decreased activity.[3]
References
- ^ Boothe, D.M. (2001) Antimicrobial drugs. In Small Animal ClinicalPharmacology and Therapeutics, pp. 150–173. W. B. Saunders Co., Philadelphia, PA.
- ^ Hunter RP, Koch DE, Coke RL, Carpenter JW, Isaza R. Identification and comparison of marbofloxacin metabolites from the plasma of ball pythons (Python regius) and blue and gold macaws (Ara ararauna). J Vet Pharmacol Ther. 2007 Jun;30(3):257-62.
- ^ Jump up to:a b c d Plumb DC (ed). Plumb’s Veterinary Handbook, 7th ed. Ames, IA: Wiley-Blackwell Publishing, 2011.
- ^ Rougier S, Borell D, Pheulpin S, Woehrlé F, Boisramé B (October 2005). “A comparative study of two antimicrobial/anti-inflammatory formulations in the treatment of canine otitis externa”. Veterinary Dermatology. 16 (5): 299–307. doi:10.1111/j.1365-3164.2005.00465.x. PMID 16238809. Archived from the original on 2013-01-05.
External links
| Clinical data | |
|---|---|
| Trade names | XeniQuin bolus & Injection (Opsonin Agrovet BD) |
| AHFS/Drugs.com | International Drug Names |
| Routes of administration | By mouth |
| ATCvet code | QJ01MA93 (WHO) |
| Legal status | |
| Legal status | Veterinary use only |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 115550-35-1 |
| ChemSpider | 54663 |
| UNII | 8X09WU898T |
| ChEMBL | ChEMBL478120 |
| CompTox Dashboard (EPA) | DTXSID4046600 |
| ECHA InfoCard | 100.168.181 |
| Chemical and physical data | |
| Formula | C17H19FN4O4 |
| Molar mass | 362.356 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
| (what is this?) (verify) |
///////////////Marbofloxacin, марбофлоксацин , ماربوفلوكساسين , 马波沙星 ,
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STAUROSPORINE
STAUROSPORINE
(+)-Staurosporine
- Molecular FormulaC28H26N4O3
- Average mass466.531 Da
(2S,3R,4R,6R)-3-Methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one
6,10-Epoxy-6H,16H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiazonin-16-one, 7,8,9,10,17,18-hexahydro-7-methoxy-6-methyl-8-(methylamino)-, (6S,7R,8R,10R)-
62996-74-1[RN]
AM-2282
Antibiotic 230
antibiotic am 2282
StaurosporineCAS Registry Number: 62996-74-1
CAS Name: (9S,10R,11R,13R)- 2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-11-(methylamino)-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3¢,2¢,1¢-lm]pyrrolo[3,4-j][1,7]benzodiazonin-1-one
Manufacturers’ Codes: AM-2282; CGP-39360
Molecular Formula: C28H26N4O3, Molecular Weight: 466.53
Percent Composition: C 72.09%, H 5.62%, N 12.01%, O 10.29%
Literature References: Protein kinase C inhibitor; alkaloid isolated from Streptomyces staurosporeus. Isoln: S. Omura et al., J. Antibiot.30, 275 (1977). Crystal and molecular structure: A. Furusaki et al., J. Chem. Soc. Chem. Commun.1978, 800; eidem,Bull. Chem. Soc. Jpn.55, 3681 (1982). Corrected stereochemistry: N. Funato et al., Tetrahedron Lett.35, 1251 (1994). Total synthesis: J. T. Link et al., J. Am. Chem. Soc.117, 552 (1995); idem et al., ibid.118, 2825 (1996). Biosynthetic studies: D. Meksuriyen, G. A. Cordell, J. Nat. Prod.51, 884, 893 (1988); S.-W. Yang et al., ibid.62 1551 (1999). HPLC determn in blood and pharmacokinetics in rats: L. R. Gurley et al., J. Chromatogr. B712, 211 (1998). Inhibition of protein kinase C: T. Tamaoki et al., Biochem. Biophys. Res. Commun.135, 397 (1986); of other protein kinases: U. T. Rüegg, G. M. Burgess, Trends Pharmacol. Sci.10, 218 (1989). Induction of apoptosis: E. Falcieri et al., Biochem. Biophys. Res. Commun.193, 19 (1993); R. Bertrand et al., Exp. Cell Res.211, 314 (1994); of tyrosine phosphorylation: D. Rasouly, P. Lazarovici, Eur. J. Pharmacol.269, 255 (1994).
Properties: Pale yellow needles from chloroform-methanol as the methanol solvate, mp 270° (dec) (Omura). Also reported as yellow crystals from methanol, mp 288-291° (Meksuriyen, Cordell). [a]D25 +35.0° (c = 1 in methanol); [a]D22 +56.1° (c = 0.14 in methanol). uv max (methanol): 241.0, 266.0, 292.5, 321.5, 335.0, 355.0, 372.5 nm (log e 4.25, 4.26, 4.53, 3.88, 3.96, 3.81, 3.85). Sol in DMSO, DMF. Slightly sol in chloroform, methanol.
Melting point: mp 270° (dec); mp 288-291° (Meksuriyen, Cordell)
Optical Rotation: [a]D25 +35.0° (c = 1 in methanol); [a]D22 +56.1° (c = 0.14 in methanol)
Absorption maximum: uv max (methanol): 241.0, 266.0, 292.5, 321.5, 335.0, 355.0, 372.5 nm (log e 4.25, 4.26, 4.53, 3.88, 3.96, 3.81, 3.85)
Derivative Type: Hydrochloride
Molecular Formula: C28H26N4O3.HCl, Molecular Weight: 502.99
Percent Composition: C 66.86%, H 5.41%, N 11.14%, O 9.54%, Cl 7.05%
Properties: LD50 in mice (mg/kg): 6.6 i.p. (Omura).
Toxicity data: LD50 in mice (mg/kg): 6.6 i.p. (Omura)
Use: Pharmacological tool to study signal transduction pathways, tyrosine phosphorylation and to induce apoptosis.
An indolocarbazole that is a potent protein kinase C inhibitor which enhances cAMP-mediated responses in human neuroblastoma cells. (Biochem Biophys Res Commun 1995;214(3):1114-20)
Staurosporine (antibiotic AM-2282 or STS) is a natural product originally isolated in 1977 from the bacterium Streptomyces staurosporeus.[1] It was the first of over 50 alkaloids to be isolated with this type of bis-indole chemical structure. The chemical structure of staurosporine was elucidated by X-ray analysis of a single crystal and the absolute stereochemical configuration by the same method in 1994.[2]
Staurosporine was discovered to have biological activities ranging from anti-fungal to anti-hypertensive.[3] The interest in these activities resulted in a large investigative effort in chemistry and biology and the discovery of the potential for anti-cancer treatment.
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Synthesis Reference
Chikara Murakata, Toshimitsu Takiguchi, Shigeo Katsumata, Akira Mihara, Keiichi Takahashi, Hiromitsu Saito, Shiro Akinaga, Masami Okabe, Yutaka Saito, “Process for producing staurosporine derivatives.” U.S. Patent US5344926, issued December, 1990.
SYN
CN 113122591
WO 2021127275
CN 110642872
WO 2020200945
CN 107603922
WO2006002422
PAPER
Journal of Antibiotics, 51(7), 679-682; 1998
PAPER
Journal of the American Chemical Society, 117(1), 552-3; 1995
PATENT
WO2006002422
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006002422
Preparation of Staurosporine Analogs
|00501 ] As will become apparent to a skilled artisan, many of the bridged epoxy diindolopyrrolo-hexahydrobenzodiazocines are commercially available as final compounds or modifiable intermediates. Staurosporine was originally isolated from the bacterium Streptomyces staurosporeus. (S.Omura et al. J.Antibiotics, 30, 275
1977).
[00502] Synthesis of 9, 12-epoxy staurosporine analogs:
NOTE: 2) 120°, 6) 120°,
Reactantsi 4, Reagents : 7, Catalysts. 2, Solvents 18,
Steps: 9, Stages: 11, Most stages in any one stept 2
[00503] Greater detail is provided in Tetrahedron Letters, 36(46), 8383-6,
1995.
[00504] Alternative synthesis of 9,12-epoxy staurosporine analogs:
NOTEt 1) stereoselective, 5) Raney nickel present,
Reactantsi 5, Reagentsi 6, Catalystsi 4, Solvents! 5,
Stepsi 7, stagest 9, Most stages in any one step: 2 [00505] Greater detail is provided in Organic Letters, 3(11), 1689-1692; 2001.
[00506]
[00507] Synthesis of 9, 13-epoxy staurosporine analogs:
NOTE: 1) STEREOSELECTIVE, 3) (92%/65%/95%/92%) , 4) 100% OVERALL (5.5:1,
ALPHA: BETA), 5) STEREOSELECTIVE, KEY STEP, 8) (97%/91%), 9) PHOTOCHEM.,
12) STEREOSELECTIVE KEY STEP, 14) (92%/81%/82%),
Reactants: 10, Reagents: 20, Catalysts: 5, Solvents: 9,
Steps: 17, Stages: 35, Most stages in any one step: 6
[00508] Whereas, a more thorough description of reagents, reaction conditions, and other pertinent syntheses are described Journal of the American Chemical Society, 117(1), 552-3; 1995. Additionally, syntheses on staurosporine and analogs thereof are described by S.J Danishefsky et al, J.Am.Chem.Soc, 118, 28251996 and J.L.Wood et al, J.Am.Chem.Soc, 118, 106561996.
Table 1 : Staurosporine Analogs
PATENT
https://patents.google.com/patent/WO2020200945A1/enEXAMPLES
.
A2 B2
Example 1Method for obtaining crude midostaurin B1 from crude staurosporine A1
A reactor was loaded with crude staurosporine A1 (1 mol) and DMF (7 L). The solution was cooled to 0°C and subsequently DIPEA (1.5 mol) was added. Benzoyl chloride (1.2 mol) was added while keeping the temperature within the range 0-5°C. After 30 minutes from the end of the addition, an aqueous 1 % ammonium chloride solution (15 L) was added while keeping the temperature within the range 0-5°C. After 1 hour from the end of the addition, the suspension was filtered and the panel was washed with plenty of water. The solid was dried for 6 hours at 40°C, obtaining crude midostaurin B1 with 95% yield. Example 2Method for obtaining purified midostaurin B2 from crude midostaurin B1 – reduction of 3-hydroxymidostaurin to midostaurin with triethylsilanei. TFA/TESii. NaHC03iii. Crystallizationin MeTHFiv. Crystallization
in EtOH/H20
B4 B2
A reactor was loaded with crude midostaurin B1 (1 mol) and DCM (10 L). The solution was cooled to 0°C and subsequently added with TES (1 mol) and TFA (0.50 L) in this order, while keeping the temperature within the range 0-5°C. At the end of the additions the solution was brought to 20°C. After 3 hours the solution was added with an aqueous 5% sodium bicarbonate solution (20 L). At the end of the development of gas the resulting two phases were separated and the aqueous phase was washed twice with DCM (10 L). The collected organic phases were concentrated at atmospheric pressure, added with 2-MeTHF (30 L) and two changes of solvent at atmospheric pressure were carried out. The solution was clarified by filtration at 75°C and the panel was washed with 2-MeTHF. The filtrate was transferred into another reactor and cooled at 0°C in 8 hours. After further 2 hours at 0°C the suspension was filtered and the panel was washed twice with 2-MeTHF. The solid was dried for 12 hours at 80°C and subsequently transferred into another reactor. Ethanol (7 L) was added and the mixture was heated at 75°C up to complete dissolution. Water (30 L) was added with a concurrent cooling to 20°C. The resulting suspension was filtered and the panel was washed with plenty of water. The solid was dried for 12 hours at 80°C, obtaining purified midostaurin B2 with 85% yield. Example 3Method for obtaining purified staurosporine A2 from crude staurosporine A1 – reduction of 3-hydroxystaurosporine to staurosporine with triethylsilane
A reactor was loaded with crude staurosporine A1 (1 mol) and DCM (10 L). The solution was cooled to 0°C and subsequently added with TES (1 mol) and TFA (0.50 L) in this order, while keeping the temperature within the range 0-5°C. After 1 hour from the end of the additions, the solution was added with MeOH (10 L) and, subsequently, with an aqueous 5% sodium bicarbonate solution (20 L). At the end of the development of gas the resulting two phases were separated and the aqueous phase was washed twice with DCM (10 L). The collected organic phases were concentrated at atmospheric pressure, added with 2-MeTHF (50 L) and two changes of solvent at atmospheric pressure were carried out. The warm solution was clarified by filtration at 75°C and the panel was washed with 2-MeTHF. The filtrate was transferred into another reactor and cooled at 0°C in 8 hours. After further 2 hours at 0°C the suspension was filtered and the panel was washed twice with 2-MeTHF. The solid was dried for 12 hours at 80°C, obtaining purified staurosporine A2 with 80% yield. Example 4Method for obtaining purified staurosporine A2 from crude staurosporine A1 – derivatization of 3-hydroxystaurosporine with trifluoroacetic acid and purification by crystallization
A reactor was loaded with crude staurosporine A1 (1 mol) and DCM (10 L). The mixture was cooled to 0°C and added with TFA (0.50 L), while keeping the temperature within the range 0-5°C. After 1 hour from the end of the addition, the solution was added with MeOH (10 L) and, subsequently, with an aqueous 5% sodium bicarbonate solution (20 L). At the end of the development of gas the resulting two phases were separated and the aqueous phase was washed twice with DCM (10 L). The collected organic phases were concentrated at atmospheric pressure, added with 2-MeTHF (50 L) and two changes of solvent at atmospheric pressure were carried out. The warm solution was clarified by filtration at 75°C and the panel was washed with 2-MeTHF. The filtrate was transferred into another reactor and cooled at 0°C in 8 hours. After further 2 hours at 0°C the suspension was filtered and the panel was washed twice with 2-MeTHF. The solid was dried for 12 hours at 80°C, obtaining purified staurosporine A2 with 80% yield. Example 5Method for obtaining purified midostaurin B2 from purified staurosporine A2 i. BzCI/DIPEAii. NH4CI/H2Oiii. Crystallizationin MeTHFiv. Crystallization
in EtOH/H20
A2 B2
A reactor was loaded with purified staurosporine A2 (1 mol) and DMF (7 L). The solution was cooled to 0°C and subsequently DIPEA (1.5 mol) was added. Benzoyl chloride (1.2 mol) was added while keeping the temperature within the range 0-5°C. After 30 minutes from the end of the addition, an aqueous 1 % ammonium chloride solution (15 L) was added while keeping the temperature within the range 0-5°C. After 1 hour from the end of the addition, the suspension was filtered and the panel was washed with plenty of water. The solid was dried for 6 hours at 40°C and subsequently transferred into another reactor. 2-MeTHF (30 L) was added and the suspension was heated under reflux up to complete dissolution. The solution was clarified by filtration at 75°C and the panel was washed with 2-MeTHF. The filtrate was transferred into another reactor and cooled at 0°C in 8 hours. After further 2 hours at 0°C the suspension was filtered and the panel was washed twice with 2-MeTHF. The solid was dried for 12 hours at 80°C and subsequently transferred into another reactor. Ethanol (7 L) was added and the mixture was heated at 75°C up to complete dissolution. Water (30 L) was added with a concurrent cooling to 20°C. The resulting suspension was filtered and the panel was washed with plenty of water. The solid was dried for 12 hours at 80°C, obtaining purified midostaurin B2 with 85% yield.
ClaimsHide Dependent
1) A process for the preparation of midostaurin with high purity, that is with a content of 3-hydroxymidostaurin impurities (III) and (IV) lower than 0.1%, comprising the treatment with strong organic or inorganic acids in a water-immiscible solvent and, optionally, also with reducing silanes.2) The process for the preparation of midostaurin according to claim 1 , comprising the treatment of crude midostaurin with a reducing silane in the presence of a strong organic or inorganic acid.3) The process for the preparation of midostaurin according to claim 1 , comprising the treatment of crude staurosporine with a strong organic or inorganic acid, optionally with the concomitant addition of a reducing silane.4) The process for the preparation of midostaurin according to claim 1 , 2 or 3, wherein the water-immiscible solvent is an aprotic polar water-immiscible solvent.5) The process for the preparation of midostaurin according to claim 4 wherein the water-immiscible solvent is dichloromethane, dichloroethane, methyl tetrahydrofuran or methylethylketone, preferably dichloromethane.6) The process for the preparation of midostaurin according to claim 1 , 2 or 3, wherein the strong acid is trifluoroacetic acid.7) The process for the preparation of midostaurin according to claim 1 , 2 or 3, wherein the reducing silane is triethylsilane.8) The process for the preparation of midostaturin according to anyone of the preceding claims, further comprising the benzoylation reaction of staurosporine to midostaurin characterized in that the benzoylation reaction is quenched with an aqueous solution having a slightly acid pH.9) The process for the preparation of midostaurin according to claim 8 wherein the aqueous solution having a slightly acid pH is an aqueous ammonium chloride solution.10) The process for the preparation of midostaurin according to anyone of the preceding claims, comprising the obtainment of purified midostaurin by crystallization from 2-MeTHF and its further isolation by:dissolving the crystallized midostaurin in a water-miscible polar solvent, adding waterisolating purified midostaurin as an amorphous solid obtained by filtering and drying, with a content of organic solvents < 50ppm. 11) The process for the preparation of purified midostaurin according to claim 10, wherein the polar s
Patent
Publication numberPriority datePublication dateAssigneeTitleJPS5247055B21973-12-041977-11-30US5093330A1987-06-151992-03-03Ciba-Geigy CorporationStaurosporine derivatives substituted at methylamino nitrogenEP0575955A11992-06-221993-12-29Kyowa Hakko Kogyo Co., Ltd.Process for producing staurosporine derivativesWO2006048296A12004-11-052006-05-11Novartis AgOrganic compoundsWO2011064355A12009-11-302011-06-03Novartis AgPolymorphous forms iii and iv of n-benzoyl staurosporineWO2018165071A12017-03-062018-09-13Teva Pharmaceutical Works Ltd.Solid state forms of midostaurin
Biological activities
The main biological activity of staurosporine is the inhibition of protein kinases through the prevention of ATP binding to the kinase. This is achieved through the stronger affinity of staurosporine to the ATP-binding site on the kinase. Staurosporine is a prototypical ATP-competitive kinase inhibitor in that it binds to many kinases with high affinity, though with little selectivity.[4] Structural analysis of kinase pockets demonstrated that main chain atoms which are conserved in their relative positions to staurosporine contributes to staurosporine promiscuity.[5] This lack of specificity has precluded its clinical use, but has made it a valuable research tool. In research, staurosporine is used to induce apoptosis. The mechanism of how it mediates this is not well understood. It has been found that one way in which staurosporine induces apoptosis is by activating caspase-3.[6] At lower concentration, depending on the cell type, staurosporine induces specific cell cycle effects arresting cells either in G1 or in G2 phase of the cell cycle.[7]
Chemistry family
Main article: Indolocarbazole
Staurosporine is an indolocarbazole. It belongs to the most frequently isolated group of indolocarbazoles: Indolo(2,3-a)carbazoles. Of these, Staurosporine falls within the most common subgroup, called Indolo(2,3-a)pyrrole(3,4-c)carbazoles. These fall into two classes – halogenated (chlorinated) and non-halogenated. Halogenated indolo(2,3-a)pyrrole(3,4-c)carbazoles have a fully oxidized C-7 carbon with only one indole nitrogen containing a β-glycosidic bond, while non-halogenated indolo(2,3-a)pyrrole(3,4-c)carbazoles have both indole nitrogens glycosylated, and a fully reduced C-7 carbon. Staurosporine is in the non-halogenated class.[8]
Staurosporine is the precursor of the novel protein kinase inhibitor midostaurin (PKC412).[9][10] Besides midostaurin, staurosporine is also used as a starting material in the commercial synthesis of K252c (also called staurosporine aglycone). In the natural biosynthetic pathway, K252c is a precursor of staurosporine.
pyrrole(3,4-c)carbazol.svg)
Structure of an Indolo[2,3-a]pyrrole[3,4-c]carbazol
Biosynthesis
The biosynthesis of staurosporine starts with the amino acid L-tryptophan in its zwitterionic form. Tryptophan is converted to an imine by enzyme StaO which is an L-amino acid oxidase (that may be FAD dependent). The imine is acted upon by StaD to form an uncharacterized intermediate proposed to be the dimerization product between 2 imine molecules. Chromopyrrolic acid is the molecule formed from this intermediate after the loss of VioE (used in the biosynthesis of violacein – a natural product formed from a branch point in this pathway that also diverges to form rebeccamycin. An aryl aryl coupling thought to be catalyzed by a cytochrome P450 enzyme to form an aromatic ring system occurs.[8]
This is followed by a nucleophilic attack between the indole nitrogens resulting in cyclization and then decarboxylation assisted by StaC exclusively forming staurosporine aglycone or K252c. Glucose is transformed to NTP-L-ristoamine by StaA/B/E/J/I/K which is then added on to the staurosporine aglycone at 1 indole N by StaG. The StaN enzyme reorients the sugar by attaching it to the 2nd indole nitrogen into an unfavored conformation to form intermediated O-demethyl-N-demethyl-staurosporine. Lastly, O-methylation of the 4’amine by StaMA and N-methylation of the 3′-hydroxy by StaMB leads to the formation of staurosporine.[8]
Research in clinical use
When encapsulated in liposome nanoparticle, staurosporine is shown to suppress tumors in vivo in a mouse model without the toxic side effects which have prohibited its use as an anti-cancer drug with high apoptotic activity. Researchers in UC San Diego Moores Cancer Center develop a platform technology of high drug-loading efficiency by manipulating the pH environment of the cells. When injected into the mouse glioblastoma model, staurosporine is found to accumulate primarily in the tumor via fluorescence confirmation, and the mice did not suffer weight loss compared to the control mice administered with the free compound, an indicator of reduced toxicity.[11][12]
References
- ^ Omura S, Iwai Y, Hirano A, Nakagawa A, Awaya J, Tsuchiya H, Takahashi Y, Masuma R (1977). “A new alkaloid AM-2282 of Streptomyces origin taxonomy, fermentation, isolation and preliminary characterization”. J. Antibiot. 30 (4): 275–282. doi:10.7164/antibiotics.30.275. PMID 863788.
- ^ Funato N, Takayanagi H, Konda Y, Toda Y, Harigaya Y, Omura S (1994). “Absolute configuration of staurosporine by X-ray analysis”. Tetrahedron Lett. 35 (8): 1251–1254. doi:10.1016/0040-4039(94)88036-0.
- ^ [1] Rüegg UT, Burgess GM. (1989) Staurosporine, K-252 and UCN-01: potent but nonspecific inhibitors of protein kinases. Trends in Pharmacological Science 10 (6): 218-220.
- ^ Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP (2008). “A quantitative analysis of kinase inhibitor selectivity”. Nat. Biotechnol. 26 (1): 127–132. doi:10.1038/nbt1358. PMID 18183025. S2CID 205273598.
- ^ Tanramluk D, Schreyer A, Pitt WR, Blundell TL (2009). “On the origins of enzyme inhibitor selectivity and promiscuity: a case study of protein kinase binding to staurosporine”. Chemical Biology & Drug Design. 74 (1): 16–24. doi:10.1111/j.1747-0285.2009.00832.x. PMC 2737611. PMID 19519740.
- ^ Chae HJ, Kang JS, Byun JO, Han KS, Kim DU, Oh SM, Kim HM, Chae SW, Kim HR (2000). “Molecular mechanism of staurosporine-induced apoptosis in osteoblasts”. Pharmacological Research. 42 (4): 373–381. doi:10.1006/phrs.2000.0700. PMID 10987998.
- ^ Bruno S, Ardelt B, Skierski JS, Traganos F, Darzynkiewicz Z (1992). “Different effects of staurosporine, an inhibitor of protein kinases, on the cell cycle and chromatin structure of normal and leukemic lymphocytes”. Cancer Res. 52 (2): 470–473. PMID 1728418.
- ^ Jump up to:a b c Ryan KS (2008). “Structural studies of rebeccamycin, staurosporine, and violacein biosynthetic enzymes” (PDF). Ph.D. Thesis. Massachusetts Institute of Technology. Archived from the original (PDF) on 2012-03-14.
- ^ Midostaurin product page, Fermentek
- ^ Wang, Y; Yin, OQ; Graf, P; Kisicki, JC; Schran, H (2008). “Dose- and Time-Dependent Pharmacokinetics of Midostaurin in Patients With Diabetes Mellitus”. J Clin Pharmacol. 48 (6): 763–775. doi:10.1177/0091270008318006. PMID 18508951. S2CID 26657407.
- ^ News Release (21 October 2013). “Study Identifies Safe Delivery System for Tricky Yet Highly Potent Anti-Cancer Compounds”. UC San Diego Health System. Retrieved 27 October 2013.
- ^ Mukthavaram, Rajesh; Jiang, Pengei; Saklecha, Rohit; Simbery, Dmitri; Bharati, Ila; Nomura, Natsuko; Chao, Ying; Pastorino, Sandra (2013). “High-efficiency liposomal encapsulation of a tyrosine kinase inhibitor leads to improved in vivo toxicity and tumor response profile”. International Journal of Nanomedicine. 8 (1): 3991–4006. doi:10.2147/IJN.S51949. PMC 3808212. PMID 24174874.
| Clinical data | |
|---|---|
| ATC code | none |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 62996-74-1 |
| PubChem CID | 44259 |
| IUPHAR/BPS | 346 |
| DrugBank | DB02010 |
| ChemSpider | 40272 |
| UNII | H88EPA0A3N |
| ChEBI | CHEBI:15738 |
| ChEMBL | ChEMBL162 |
| PDB ligand | STU (PDBe, RCSB PDB) |
| CompTox Dashboard (EPA) | DTXSID30911019 DTXSID6041131, DTXSID30911019 |
| ECHA InfoCard | 100.109.946 |
| Chemical and physical data | |
| Formula | C28H26N4O3 |
| Molar mass | 466.541 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
| (what is this?) (verify) |
///////////STAUROSPORINE, AM-2282, CGP-39360
[H][C@]1(C[C@@]2([H])O[C@](C)(N3C4=CC=CC=C4C4=C5CNC(=O)C5=C5C6=CC=CC=C6N2C5=C34)[C@]1([H])OC)NC
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Alpha lipoic acid
Alpha lipoic acid
(+)-Thioctic acid
- Molecular FormulaC8H14O2S2
- Average mass206.326 Da
5-[3-(1,2-Dithiolanyl)]pentanoic Acid
5-19-07-00237[Beilstein]
62-46-4[RN](+)-Thioctic acid, (+)-α-Lipoic acid, (3R)-1,2-Dithiolane-3-pentanoic acid
(R)-(+)-1,2-Dithiolane-3-pentanoic acid, (R)-(+)-lipoic acid, (R)-(+)-α-Lipoic acid
(R)-6,8-Dithiooctanoic acid, (R)-6,8-thioctic acid, (R)-α-Lipoic Acid, (R)-α-Lipoic Acid
1,2-Dithiolane-3-pentanoic acid, (3R)-
5-[(3R)-1,2-Dithiolan-3-yl]pentanoic acidd-Thioctic acid, (R)-(+)-alpha-Lipoic acid, (R)-(+)-Thioctic acid, Dexlipotam
Thioctic Acid
CAS Registry Number: 62-46-4
CAS Name: 1,2-Dithiolane-3-pentanoic acid
Additional Names: 1,2-dithiolane-3-valeric acid; 6,8-thioctic acid; a-lipoic acid; 5-(1,2-dithiolan-3-yl)valeric acid; 5-[3-(1,2-dithiolanyl)]pentanoic acid; d-[3-(1,2-dithiacyclopentyl)]pentanoic acid; protogen A; acetate replacing factor; pyruvate oxidation factor
Trademarks: Biletan (Gador); Thioctacid (Viatris); Thioctan (Katwijk); Tioctan (Fujisawa)
Molecular Formula: C8H14O2S2, Molecular Weight: 206.33
Percent Composition: C 46.57%, H 6.84%, O 15.51%, S 31.08%
Literature References: Growth factor for many bacteria and protozoa; prosthetic group, coenzyme, or substrate in plants, microorganisms, and animal tissues. Isoln of naturally occurring d-form: L. J. Reed et al.,Science114, 93 (1951); eidem,J. Am. Chem. Soc.75, 1267 (1953); Patterson et al.,ibid.76, 1823 (1954). Syntheses of dl-form: Bullock et al.,ibid.74, 1868, 3455 (1952); Hornberger et al.,ibid. 2382; Reed, US2980716 and US3049549 (1961, 1962 to Res. Corp.); Lewis, Raphael, J. Chem. Soc.1962, 4263; Ose et al.,US3223712 (1965 to Yamanouchi); J. Tsuji et al.,J. Org. Chem.43, 3606 (1978). Biosynthesis via linoleic acid: J. P. Carreau Methods Enzymol.62, 152-158 (1974). Enantioselective synthesis of d-form: P. C. Bulmanpage et al.,Chem. Commun.1986, 1408. Clinical study in treatment of Wilson’s disease: S. F. Gomes da Costa, Arzneim.-Forsch.20, 1210 (1970). Use in treatment of mushroom poisoning: R. Plotzker et al.,Am. J. Med. Sci.283, 79 (1982); J. P. Hanrahan, M. A. Gordon, J. Am. Med. Assoc.251, 1057 (1984). Reviews: Wagner, Folkers, Vitamins and Coenzymes (Interscience, New York, 1964) pp 244-263; Schmidt et al.,Angew. Chem. Int. Ed.4, 846 (1965); Schmidt et al.,Adv. Enzymol. Relat. Areas Mol. Biol.32, 423 (1969).
Derivative Type: Sodium salt
CAS Registry Number: 2319-84-8
Molecular Formula: C8H13NaO2S2, Molecular Weight: 228.31
Percent Composition: C 42.09%, H 5.74%, Na 10.07%, O 14.02%, S 28.09%
Properties: White powder, sol in water. pH of aq solns about 7.4.
Derivative Type:d-Form
CAS Registry Number: 1200-22-2
Properties: Crystals by vacuum sublimation (at 85-90° and 25 microns). mp 46-48° (microblock). [a]D23 +104° (c = 0.88 in benzene). uv max (methanol): 333 nm (e 150). pKa 5.4. Practically insol in water. Sol in fat solvents.Melting point: mp 46-48° (microblock)
pKa: pKa 5.4
Optical Rotation: [a]D23 +104° (c = 0.88 in benzene)
Absorption maximum: uv max (methanol): 333 nm (e 150)
Derivative Type:dl-Form
CAS Registry Number: 1077-28-7
Properties: Yellow needles from cyclohexane, mp 60-61°. bp 160-165°. uv spectrum: Calvin, Fed. Proc.13, 703 (1954). Practically insol in water. Sol in fat solvents. Forms a water-soluble sodium salt.
Melting point: mp 60-61°
Boiling point: bp 160-165°
Derivative Type:l-Form
CAS Registry Number: 1077-27-6
Properties: Crystals from cyclohexane, mp 45-47.5° (microblock). [a]D23 -113° (c = 1.88 in benzene). uv max (methanol): 330 nm (e 140).
Melting point: mp 45-47.5° (microblock)
Optical Rotation: [a]D23 -113° (c = 1.88 in benzene)
Absorption maximum: uv max (methanol): 330 nm (e 140)
Derivative Type: Ethylenediamine
Trademarks: Tioctidasi (ISI)
Therap-Cat: Treatment of liver disease; antidote to poisonous mushrooms (Amanita species).
Keywords: Hepatoprotectant.
Lipoic acid (LA), also known as α-lipoic acid, alpha-lipoic acid (ALA) and thioctic acid, is an organosulfur compound derived from caprylic acid (octanoic acid).[3] ALA is made in animals normally, and is essential for aerobic metabolism. It is also manufactured and is available as a dietary supplement in some countries where it is marketed as an antioxidant, and is available as a pharmaceutical drug in other countries.[3]
Physical and chemical properties
Lipoic acid (LA), also known as α-lipoic acid,[3][4] alpha-lipoic acid (ALA), and thioctic acid[5] is an organosulfur compound derived from octanoic acid.[3] LA contains two sulfur atoms (at C6 and C8) connected by a disulfide bond and is thus considered to be oxidized although either sulfur atom can exist in higher oxidation states.[3]
The carbon atom at C6 is chiral and the molecule exists as two enantiomers (R)-(+)-lipoic acid (RLA) and (S)-(-)-lipoic acid (SLA) and as a racemic mixture (R/S)-lipoic acid (R/S-LA).
LA appears physically as a yellow solid and structurally contains a terminal carboxylic acid and a terminal dithiolane ring.
For use in dietary supplement materials and compounding pharmacies, the USP has established an official monograph for R/S-LA.[6][7]
Biological function
“Lipoate” is the conjugate base of lipoic acid, and the most prevalent form of LA under physiological conditions.[3] Most endogenously produced RLA are not “free” because octanoic acid, the precursor to RLA, is bound to the enzyme complexes prior to enzymatic insertion of the sulfur atoms. As a cofactor, RLA is covalently attached by an amide bond to a terminal lysine residue of the enzyme’s lipoyl domains. One of the most studied roles of RLA is as a cofactor of the pyruvate dehydrogenase complex (PDC or PDHC), though it is a cofactor in other enzymatic systems as well (described below).[3]
Only the (R)-(+)-enantiomer (RLA) exists in nature and is essential for aerobic metabolism because RLA is an essential cofactor of many enzyme complexes.[3]
Biosynthesis and attachment
The precursor to lipoic acid, octanoic acid, is made via fatty acid biosynthesis in the form of octanoyl-acyl carrier protein.[3] In eukaryotes, a second fatty acid biosynthetic pathway in mitochondria is used for this purpose.[3] The octanoate is transferred as a thioester of acyl carrier protein from fatty acid biosynthesis to an amide of the lipoyl domain protein by an enzyme called an octanoyltransferase.[3] Two hydrogens of octanoate are replaced with sulfur groups via a radical SAM mechanism, by lipoyl synthase.[3] As a result, lipoic acid is synthesized attached to proteins and no free lipoic acid is produced. Lipoic acid can be removed whenever proteins are degraded and by action of the enzyme lipoamidase.[8] Free lipoate can be used by some organisms as an enzyme called lipoate protein ligase that attaches it covalently to the correct protein. The ligase activity of this enzyme requires ATP.[9]
Cellular transport
Along with sodium and the vitamins biotin (B7) and pantothenic acid (B5), lipoic acid enters cells through the SMVT (sodium-dependent multivitamin transporter). Each of the compounds transported by the SMVT is competitive with the others. For example research has shown that increasing intake of lipoic acid[10] or pantothenic acid[11] reduces the uptake of biotin and/or the activities of biotin-dependent enzymes.
Enzymatic activity
Lipoic acid is a cofactor for at least five enzyme systems.[3] Two of these are in the citric acid cycle through which many organisms turn nutrients into energy. Lipoylated enzymes have lipoic acid attached to them covalently. The lipoyl group transfers acyl groups in 2-oxoacid dehydrogenase complexes, and methylamine group in the glycine cleavage complex or glycine dehydrogenase.[3]
2-Oxoacid dehydrogenase transfer reactions occur by a similar mechanism in:
- the pyruvate dehydrogenase complex
- the α-ketoglutarate dehydrogenase or 2-oxoglutarate dehydrogenase complex
- the branched-chain oxoacid dehydrogenase (BCDH) complex
- the acetoin dehydrogenase complex.
The most-studied of these is the pyruvate dehydrogenase complex.[3] These complexes have three central subunits: E1-3, which are the decarboxylase, lipoyl transferase, and dihydrolipoamide dehydrogenase, respectively. These complexes have a central E2 core and the other subunits surround this core to form the complex. In the gap between these two subunits, the lipoyl domain ferries intermediates between the active sites.[3] The lipoyl domain itself is attached by a flexible linker to the E2 core and the number of lipoyl domains varies from one to three for a given organism. The number of domains has been experimentally varied and seems to have little effect on growth until over nine are added, although more than three decreased activity of the complex.[12]
Lipoic acid serves as co-factor to the acetoin dehydrogenase complex catalyzing the conversion of acetoin (3-hydroxy-2-butanone) to acetaldehyde and acetyl coenzyme A.[3]
The glycine cleavage system differs from the other complexes, and has a different nomenclature.[3] In this system, the H protein is a free lipoyl domain with additional helices, the L protein is a dihydrolipoamide dehydrogenase, the P protein is the decarboxylase, and the T protein transfers the methylamine from lipoate to tetrahydrofolate (THF) yielding methylene-THF and ammonia. Methylene-THF is then used by serine hydroxymethyltransferase to synthesize serine from glycine. This system is part of plant photorespiration.[13]
Biological sources and degradation
Lipoic acid is present in many foods in which it is bound to lysine in proteins,[3] but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract.[14] Naturally occurring lipoic acid is always covalently bound and not readily available from dietary sources.[3] In addition, the amount of lipoic acid present in dietary sources is low. For instance, the purification of lipoic acid to determine its structure used an estimated 10 tons of liver residue, which yielded 30 mg of lipoic acid.[15] As a result, all lipoic acid available as a supplement is chemically synthesized.
Baseline levels (prior to supplementation) of RLA and R-DHLA have not been detected in human plasma.[16] RLA has been detected at 12.3−43.1 ng/mL following acid hydrolysis, which releases protein-bound lipoic acid. Enzymatic hydrolysis of protein bound lipoic acid released 1.4−11.6 ng/mL and <1-38.2 ng/mL using subtilisin and alcalase, respectively.[17][18][19]
Digestive proteolytic enzymes cleave the R-lipoyllysine residue from the mitochondrial enzyme complexes derived from food but are unable to cleave the lipoic acid-L–lysine amide bond.[20] Both synthetic lipoamide and (R)-lipoyl-L-lysine are rapidly cleaved by serum lipoamidases, which release free (R)-lipoic acid and either L-lysine or ammonia.[3] Little is known about the degradation and utilization of aliphatic sulfides such as lipoic acid, except for cysteine.[3]
Lipoic acid is metabolized in a variety of ways when given as a dietary supplement in mammals.[3][21] Degradation to tetranorlipoic acid, oxidation of one or both of the sulfur atoms to the sulfoxide, and S-methylation of the sulfide were observed. Conjugation of unmodified lipoic acid to glycine was detected especially in mice.[21] Degradation of lipoic acid is similar in humans, although it is not clear if the sulfur atoms become significantly oxidized.[3][22] Apparently mammals are not capable of utilizing lipoic acid as a sulfur source.
Chemical synthesis
-Lipoic_acid_molecular_structure.png)
(R)-Lipoic acid (RLA, top) and (S)-lipoic acid (SLA, down). A 1:1 mixture (racemate) of (R)- and (S)-lipoic acid is called (RS)-lipoic acid or (±)-lipoic acid (R/S-LA).
SLA did not exist prior to chemical synthesis in 1952.[23][24] SLA is produced in equal amounts with RLA during achiral manufacturing processes. The racemic form was more widely used clinically in Europe and Japan in the 1950s to 1960s despite the early recognition that the various forms of LA are not bioequivalent.[25] The first synthetic procedures appeared for RLA and SLA in the mid-1950s.[26][27][28][29] Advances in chiral chemistry led to more efficient technologies for manufacturing the single enantiomers by both classical resolution and asymmetric synthesis and the demand for RLA also grew at this time. In the 21st century, R/S-LA, RLA and SLA with high chemical and/or optical purities are available in industrial quantities. At the current time, most of the world supply of R/S-LA and RLA is manufactured in China and smaller amounts in Italy, Germany, and Japan. RLA is produced by modifications of a process first described by Georg Lang in a Ph.D. thesis and later patented by DeGussa.[30][31] Although RLA is favored nutritionally due to its “vitamin-like” role in metabolism, both RLA and R/S-LA are widely available as dietary supplements. Both stereospecific and non-stereospecific reactions are known to occur in vivo and contribute to the mechanisms of action, but evidence to date indicates RLA may be the eutomer (the nutritionally and therapeutically preferred form).[32][33]
Pharmacology
Pharmacokinetics
A 2007 human pharmacokinetic study of sodium RLA demonstrated the maximum concentration in plasma and bioavailability are significantly greater than the free acid form, and rivals plasma levels achieved by intravenous administration of the free acid form.[34] Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved.[34]
The various forms of LA are not bioequivalent.[25][non-primary source needed] Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.[34]
The toxic dose of LA in cats is much lower than that in humans or dogs and produces hepatocellular toxicity.[35]
Pharmacodynamics
The mechanism and action of lipoic acid when supplied externally to an organism is controversial. Lipoic acid in a cell seems primarily to induce the oxidative stress response rather than directly scavenge free radicals. This effect is specific for RLA.[4] Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms.[36] LA is able to scavenge reactive oxygen and reactive nitrogen species in a biochemical assay due to long incubation times, but there is little evidence this occurs within a cell or that radical scavenging contributes to the primary mechanisms of action of LA.[4][37] The relatively good scavenging activity of LA toward hypochlorous acid (a bactericidal produced by neutrophils that may produce inflammation and tissue damage) is due to the strained conformation of the 5-membered dithiolane ring, which is lost upon reduction to DHLA. In cells, LA is reduced to dihydrolipoic acid, which is generally regarded as the more bioactive form of LA and the form responsible for most of the antioxidant effects and for lowering the redox activities of unbound iron and copper.[38] This theory has been challenged due to the high level of reactivity of the two free sulfhydryls, low intracellular concentrations of DHLA as well as the rapid methylation of one or both sulfhydryls, rapid side-chain oxidation to shorter metabolites and rapid efflux from the cell. Although both DHLA and LA have been found inside cells after administration, most intracellular DHLA probably exists as mixed disulfides with various cysteine residues from cytosolic and mitochondrial proteins.[32] Recent findings suggest therapeutic and anti-aging effects are due to modulation of signal transduction and gene transcription, which improve the antioxidant status of the cell. However, this likely occurs via pro-oxidant mechanisms, not by radical scavenging or reducing effects.[4][37][39]
All the disulfide forms of LA (R/S-LA, RLA and SLA) can be reduced to DHLA although both tissue specific and stereoselective (preference for one enantiomer over the other) reductions have been reported in model systems. At least two cytosolic enzymes, glutathione reductase (GR) and thioredoxin reductase (Trx1), and two mitochondrial enzymes, lipoamide dehydrogenase and thioredoxin reductase (Trx2), reduce LA. SLA is stereoselectively reduced by cytosolic GR whereas Trx1, Trx2 and lipoamide dehydrogenase stereoselectively reduce RLA. (R)-(+)-lipoic acid is enzymatically or chemically reduced to (R)-(-)-dihydrolipoic acid whereas (S)-(-)-lipoic acid is reduced to (S)-(+)-dihydrolipoic acid.[40][41][42][43][44][45][46] Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, thiol-disulfide exchange reactions.[47]
RLA may function in vivo like a B-vitamin and at higher doses like plant-derived nutrients, such as curcumin, sulforaphane, resveratrol, and other nutritional substances that induce phase II detoxification enzymes, thus acting as cytoprotective agents.[39][48] This stress response indirectly improves the antioxidant capacity of the cell.[4]
The (S)-enantiomer of LA was shown to be toxic when administered to thiamine-deficient rats.[49][50]
Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by competitive inhibition.[51][52][53][54][55]
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Uses
R/S-LA and RLA are widely available as over-the-counter nutritional supplements in the United States in the form of capsules, tablets, and aqueous liquids, and have been marketed as antioxidants.[3]
Although the body can synthesize LA, it can also be absorbed from the diet. Dietary supplementation in doses from 200–600 mg is likely to provide up to 1000 times the amount available from a regular diet. Gastrointestinal absorption is variable and decreases with the use of food. It is therefore recommended that dietary LA be taken 30–60 minutes before or at least 120 minutes after a meal. Maximum blood levels of LA are achieved 30–60 minutes after dietary supplementation, and it is thought to be largely metabolized in the liver.[56]
In Germany, LA is approved as a drug for the treatment of diabetic neuropathy since 1966 and is available as a non-prescription pharmaceutical.[57]
Clinical research
According to the American Cancer Society as of 2013, “there is no reliable scientific evidence at this time that lipoic acid prevents the development or spread of cancer”.[58] As of 2015, intravenously administered ALA is unapproved anywhere in the world except Germany for diabetic neuropathy, but has been proven reasonably safe and effective in four clinical trials; however another large trial over four years found no difference from placebo.[59] As of 2012, there was no good evidence alpha lipoic acid helps people with mitochondrial disorders.[60] A 2018 review recommended ALA as an anti-obesity supplement with low dosage (< 600 mg/day) for a short period of time (<10 weeks); however, it is too expensive to be practical as a complementary therapy for obesity.[61]
SYN
WO 0210151
DE 19709069; EP 0863125; US 6013833
A synthetic route based on the asymmetric reduction of oxo diesters has been reported. Meldrum’s acid (LII) was acylated by methyl adipoyl chloride (LI) in the presence of pyridine to produce the intermediate (LIII) which, upon alcoholysis with isobutanol, led to oxo diester (LIV). Enantioselective reduction of (LIV) by means of baker’s yeast furnished the (S)-hydroxy diester (LV). Alternatively, the analogous oxo diester (LVI) was prepared by acylation of methyl acetoacetate with methyl adipoyl chloride (LI), followed by deacetylation in the presence of ammonium hydroxide. Then, asymmetric chemical reduction of (LVI) by hydrogenation in the presence of the chiral catalyst Ru2Cl4[(S)-BINAP]2 provided the (S)-hydroxy diester (LVII). Regioselective reduction of either diester (LV) or (LVII) by means of NaBH4 in refluxing THF furnished dihydroxy ester (XLVIII). After conversion of (XLVIII) to the dimesylate (XLIX), displacement with potassium thioacetate afforded the bis(acetylthio) derivative (LVIII), which was further hydrolyzed with KOH to provide dihydrolipoic acid (LIX). In a related procedure, dihydrolipoic acid (LIX) was prepared by reaction of dimesylate (XLIX) with sodium disulfide, followed by reductive treatment with NaBH4 and NaOH. The title cyclic disulfide was then obtained by oxidation of the dithiol (LIX) using oxygen in the presence of FeCl3.
SYN
DE 10036516; WO 0210113
The key dihydroxy ester intermediate (XIII) was also obtained by asymmetric hydrogenation of hydroxy ketoester (XLIII) in the presence of (S)-BINAP-dichlororuthenium catalyst. The precursor hydroxy ketoester (XLIII) was prepared by two alternative procedures. In one method, the racemic dihydroxy ester (XLII) was selectively oxidized to (XLIII) by means of NaOCl. In another method, the unsaturated keto ester (XLIV) was epoxidized by means of sodium percarbonate, and the resultant epoxide (XLV) was then reduced to the hydroxy ketoester (XLIII) by catalytic hydrogenation over PtO2.
SYN
WO 0230919
Both enantiomers of racemic 8-chloro-6-hydroxyoctanoic acid (LX) were separated employing either (+)- or (-)-alpha-methylbenzylamine. Esterification of the (R)-(-)-enantiomer with HCl-MeOH provided the chloro hydroxy ester (LXI). Further chlorination of (LXI) with SOCl2 and pyridine proceeded with inversion of configuration at C-6 to furnish the (S)-dichloro derivative (LXII). The cyclic disulfide (L) was then prepared by treatment of chloride (LXII) with sulfur and sodium sulfide in boiling EtOH. Basic hydrolysis of the methyl ester group of (LXII) then afforded (R) alpha lipoic acid. The title compound was also obtained from the (S)-(+)-acid (LXIII). Reaction of hydroxy acid (LXIII) with methanesulfonyl chloride produced the chloro mesylate (LXIV), which was then cyclized to the target disulfide in the presence of sulfur and Na2S.
SYN
The reaction of the chiral dibenzoyloxy-dihydropyran (LXV) with H2SO4 and HgSO4 gives the unsaturated aldehyde (LXVI), which is condensed with the phosphorane (LXVII) to yield the hepatdienoic ester (LXVIII). The hydrogenation of (LXVIII) with H2 over Pd/C affords the heptanoic ester (LXIX), which is treated with Ts-Cl and pyridine to provide the tosyloxy derivative (LXX). The cyclization of (LXX) by means of K2CO3 gives the chiral epoxide (LXXI), which is condensed with vinylmagnesium bromide (LXXII) to yield 6(S)-hydroxy-8-nonenoic acid methyl ester (LXXIII). The oxidation of the terminal double bond of (LXXIII) with ozone affords the carbaldehyde (LXXIV), which is reduced with NaBH4 to provide 6(S),8-dihydroxyoctanoic acid methyl ester (XLVIII). The reaction of (XLVIII) with Ms-Cl and pyridine gives the dimesylate (XLIX), which is treated with Na2S2 to yield the lipoic acid methyl ester (L), which is hydrolyzed to the target acid with KOH in H2O.
SYN
DE 3629116; EP 0261336
Alkylation of the lithio-dianion of propargyl alcohol (XIII) with 6-bromo-1-hexene (XIV), followed by in situ reduction of the resultant disubstituted acetylene with lithium metal gave the allylic alcohol (XV). Asymmetric Sharpless epoxidation of (XV) using tert-butyl hydroperoxide in the presence of L-(+)-diisopropyl tartrate afforded the (S,S)-epoxy alcohol (XVI). This was reduced to the chiral diol (XVII) employing Red-Al?in THF. After formation of the bis-mesylate (XVIII), oxidative cleavage of the terminal double bond by means of NaIO4 in the presence of ruthenium catalyst furnished the carboxylic acid (XIX). The mesylate groups were finally displaced by sodium disulfide to produce the desired cyclic disulfide compound.
SYN
Both enantiomers of racemic 8-chloro-6-hydroxyoctanoic acid (LX) were separated employing either (+)- or (-)-alpha-methylbenzylamine. Esterification of the (R)-(-)-enantiomer with HCl-MeOH provided the chloro hydroxy ester (LXI). Further chlorination of (LXI) with SOCl2 and pyridine proceeded with inversion of configuration at C-6 to furnish the (S)-dichloro derivative (LXII). The cyclic disulfide (L) was then prepared by treatment of chloride (LXII) with sulfur and sodium sulfide in boiling EtOH. Basic hydrolysis of the methyl ester group of (LXII) then afforded (R) alpha lipoic acid. The title compound was also obtained from the (S)-(+)-acid (LXIII). Reaction of hydroxy acid (LXIII) with methanesulfonyl chloride produced the chloro mesylate (LXIV), which was then cyclized to the target disulfide in the presence of sulfur and Na2S.
| DE 19533881; EP 0763533; US 5731448 |
SYN
WO 9638437
A different strategy was based on the enantioselective oxidation of a cyclohexanone derivative by enzymic Baeyer-Villiger reaction. Keto ester (XXXVIII) was protected as the ethylene ketal (XXXIX) and subsequently reduced to alcohol (XL) using LiAlH4. Acetylation of alcohol (XL) to acetate (XLI), followed by acidic ketal hydrolysis afforded cyclohexanone (XLII) (9,10). The racemic ketone (XLII) was then subjected to oxidative cleavage by monooxigenase 2 obtained from Pseudomonas putida to furnish the (R)-lactone (XLIV) along with unreacted (S)-cyclohexanone (XLIII) (9-11). The use of cyclohexanone monooxigenase from Acinetobacter NCIMB 9871 has also been reported for this reaction (12). Methanolysis of lactone (XLIV) in the presence of NaOMe gave rise to the (R)-dihydroxy ester (XLV). Inversion of the configuration of (XLV) was accomplished by Mitsunobu coupling with p-nitrobenzoic acid (XLVI) to produce the (S)-p-nitrobenzoate ester (XLVII). Smooth hydrolysis of ester (XLVII) provided methyl (S)-6,8-dihydroxyoctanoate (XLVIII), which was processed through intermediates (XLIX) and (L), as for the isopropyl (X) (Scheme 29605101a) and ethyl (XXIX) (Scheme 29605103a) homologues, to afford the title compound.
SYN
| Tetrahedron Lett 2001,42(29),4891 |
The olefinic diester (XXXVIII) was subjected to OsO4-catalyzed asymmetric dihydroxylation using hydroquinidine 1,4-phthalazinediyl diether [(DHQD)2-PHAL] as chiral ligand to afford diol (XXXIX). This was converted to the cyclic sulfate (XL) by treatment with SOCl2, followed by RuCl3-catalyzed NaIO4 oxidation of the intermediate sulfite. Regioselective reduction of sulfate (XL) at the alpha position with NaBH4 in DMA led to the (3S)-alcohol (XLI). Further selective reduction of the ethyl ester group of (XLI) was achieved by treatment with NaBH4-Et3N in MeOH-DMF, yielding the target intermediate dihydroxy ester (XIII).
SYN
1,6-Hexanediol (I) was protected as the mono-tetrahydropyranyl ether (II), and the free hydroxyl group was subsequently oxidized to aldehyde (III) under Swern conditions. Reformatskii reaction of aldehyde (III) with the organozinc reagent generated from ethyl bromoacetate yielded the racemic hydroxy ester (IV). The requisite (S)-enantiomer (VI) was obtained via oxidation of (IV) to oxo ester (V) using pyridinium chlorochromate, and then asymmetric hydrogenation in the presence of (S)-(-)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl dichlororuthenium complex. Oxo ester (V) was also prepared by SnCl2-catalyzed insertion of ethyl diazoacetate into aldehyde (III). The chiral hydroxy ester (VI) was then reduced to diol (VII) by means of NaBH4-CuSO4. After conversion of (VII) to the corresponding dimesylate (VIII), removal of the tetrahydropyranyl protecting group under acidic conditions gave alcohol (IX). This was sequentially oxidized with PCC to aldehyde, and then with Ag2O to furnish the target dimesylate acid intermediate (X).
SYN
Tetrahedron Asymmetry 2000,11(4),879
The intermediate 6(S)-hydroxy-8-nonenoic acid methyl ester (III) has been obtained by enantioselective allylation of 6-oxohexanoic acid methyl ester (I) with allyltributylstannane (II) catalyzed by the chiral catalyst (R)-BINOL/Ti(O-iPr)4 in refluxing dichloromethane (other BINOL/metal catalysts have also been studied).
SYN
Tetrahedron Lett 1985,26(21),2535
Aldehyde (II), prepared by ozonolysis of cyclohexene (I), was ketalized with (S,S)-2,4-pentanediol (III) to afford dioxane (IV). Titanium chloride-mediated coupling of acetal (IV) with the ketene acetal (V) afforded diastereoselectively adduct (VI), which was subsequently hydrolyzed to carboxylic acid (VII) by means of trifluoroacetic acid. Removal of the pentanediol moiety to furnish the (R)-alcohol (IX) was accomplished via Jones oxidation of the secondary alcohol (VII) to ketone (VIII), followed by beta-elimination in the presence of piperidinium acetate. Reduction of the free carboxyl group by borane-tetrahydrofuran complex gave diol (X), which was further converted to dimesylate (XI). Disulfide displacement of the mesylate groups provided (+)-lipoic acid isopropyl ester (XII), which was finally hydrolyzed to the title acid using K2CO3 in MeOH/H2O.
SYN
Tetrahedron Lett 1987,28(44),5313
A short synthetic strategy utilized the cyclic thioketal (XXXIII), derived from d-menthone (XXXII) and 1,3-propanedithiol, as the chiral template. Stereospecific oxidation of dithiane (XXXIII) employing NaIO4 produced sulfoxide (XXXIV). The carbanion generated from sulfoxide (XXXIV) was stereoselectively alkylated by 5-bromopentanoic acid (XXXV) in the presence of TMEDA to furnish the trans alkylated compound (XXXVI). Finally, acidic hydrolysis of (XXXVI) formed the intermediate mercapto sulfinic acid (XXXVII) which spontaneously cyclized to the desired dithiolane derivative.
SYN
Tetrahedron Lett 1987,28(19),2183
Diisopropylidene mannitol (I) was first converted into the dibutyltin derivative (II), which was subsequently mono-benzylated to (III). Acetylation of (III) with acetic anhydride in pyridine gave (IV). After acidic hydrolysis of the isopropylidene ketals of (IV), the resultant tetraol (V) was converted into tetramesylate (VI). Reductive elimination in (VI) with Zn and NaI produced diene (VII). The acetate group of (VII) was then hydrolyzed to (VIII) using NaOMe. Intermediate (VIII) was reacted with triethyl orthoacetate in the presence of propionic acid to generate the allyl vinyl ether (IX), which underwent a Claisen rearrangement to the diene-ester (X). Selective hydroboration-oxidation of the terminal double bond of (X) yielded the primary alcohol (XI). Subsequent benzyl group hydrogenolysis in (XI) furnished the target intermediate diol (XII).
SYN
Esterification of diisopropylidene mannitol (I) with benzoyl chloride in pyridine afforded dibenzoate (II). Hydrolysis of the isopropylidene ketals of (II) with aqueous HOAc gave tetraol (III), which was further converted to tetramesylate (IV) on treatment with methanesulfonyl chloride and pyridine. Reductive elimination of the mesylate groups of (IV) using Zn dust and NaI yielded diene (V). The benzoate esters of (V) were then removed by treatment with sodium methoxide. The resultant divinylglycol (VI) was reacted with dibutyltin oxide to produce the tin derivative (VII), which was converted to the target intermediate, themono-benzyl ether (VIII), by treatment with benzyl bromide in hot DMF.
SYN
Tetrahedron Lett 1989,30(42),5705
Alkylation of the dianion of octyl acetoacetate (XIII) with 4-iodobutyronitrile (XIV) provided the cyano keto ester (XV). Enantiospecific reduction of (XV) utilizing baker’s yeast gave rise to the desired (S)-hydroxy ester (XVI) in high enantiomeric excess. Subsequent ester group reduction in (XVI) by means of LiBH4 provided diol (XVII). The target dihydroxy ester (XII) was then obtained by alcoholysis of nitrile (XVII) under acidic conditions.
SYN
J Chem Soc Chem Commun 1995,(15),1563
A different strategy was based on the enantioselective oxidation of a cyclohexanone derivative by enzymic Baeyer-Villiger reaction. Keto ester (XXXVIII) was protected as the ethylene ketal (XXXIX) and subsequently reduced to alcohol (XL) using LiAlH4. Acetylation of alcohol (XL) to acetate (XLI), followed by acidic ketal hydrolysis afforded cyclohexanone (XLII) (9,10). The racemic ketone (XLII) was then subjected to oxidative cleavage by monooxigenase 2 obtained from Pseudomonas putida to furnish the (R)-lactone (XLIV) along with unreacted (S)-cyclohexanone (XLIII) (9-11). The use of cyclohexanone monooxigenase from Acinetobacter NCIMB 9871 has also been reported for this reaction (12). Methanolysis of lactone (XLIV) in the presence of NaOMe gave rise to the (R)-dihydroxy ester (XLV). Inversion of the configuration of (XLV) was accomplished by Mitsunobu coupling with p-nitrobenzoic acid (XLVI) to produce the (S)-p-nitrobenzoate ester (XLVII). Smooth hydrolysis of ester (XLVII) provided methyl (S)-6,8-dihydroxyoctanoate (XLVIII), which was processed through intermediates (XLIX) and (L), as for the isopropyl (X) (Scheme 29605101a) and ethyl (XXIX) (Scheme 29605103a) homologues, to afford the title compound.
SYN
Synthesis (Stuttgart) 1996,(5),594
Racemic tetrahydro-2-furylmethanol (I) was converted to tosylate (II), which was further displaced by KCN to yield nitrile (III). Basic hydrolysis of nitrile (III), followed by Fischer esterification of the resultant carboxylic acid (IV) provided ethyl ester (V). Enzymatic resolution of racemic ester (V) by means of the lipase from Candida cylindracea generated a mixture of the (R)-acid (VI) and the unreacted (S)-ester (VII), which were separated by column chromatography. The desired (S) ester (VII) was then reduced to alcohol (VIII) with LiAlH4 in cold Et2O. Regioselective opening of the cyclic ether (VIII) with iodotrimethylsilane in acetone furnished the acetonide of 6-iodo-1,3-hexanediol (IX). Alkylation of benzyl methyl malonate (X) with iodide (IX) provided malonate (XI). Hydrogenolysis of the benzyl ester group of (XI), followed by thermal decarboxylation led to ester (XII). The target dihydroxy ester precursor (XIII) was then obtained by acid-catalyzed hydrolysis of the acetonide function.
SYN
Synthesis (Stuttgart) 1996,(11),1289
Addition of vinylmagnesium bromide to 2-nitrocyclohexanone (XIV) afforded the nitro alcohol (XV). Ring cleavage of (XVI) in the presence of anhydrous CuSO4 absorbed on silica gel gave the nitro ketone (XVI). Nitro group hydrolysis in (XVI) by successive treatment with NaOMe and H2SO4 in MeOH furnished oxo ester (XVII) as the main product. This was enantiospecifically reduced with baker’s yeast to yield the (S)-alcohol (XVIII). Selective methyl ether cleavage with tetrabutylammonium iodide and BF3 provided the dihydroxy ester precursor (XIII).
SYN
An alternative route to (+)-lipoic acid used ethyl 4,6-di-O-acetyl-2,3-dideoxy-alpha-D-erythro-hexopyranoside (XX), prepared from triacetyl-D-glucal, as the chiral starting point. Deacetylation of (XX) with sodium methoxide under Zemplen conditions gave diol (XXI) which, after conventional benzylation, led to the 4,6-di-O-benzyl derivative (XXII). Ring opening of the cyclic acetal (XXII) with propanediol in the presence of boron trifluoride afforded the dithiane derivative (XXIII). The free hydroxyl group of (XXIII) was converted into xanthate (XXIV) by reaction with NaH and CS2, followed by methyl iodide. Reductive cleavage of the xanthate group by means of Bu3SnH and AIBN provided (XXV). Hydrolysis of the thioacetal function with HgO and BF3 provided aldehyde (XXVI). Chain homologation was performed by Wittig reaction of aldehyde (XXVI) with phosphorane (XXVII) to afford the unsaturated ester (XXVIII). Simultaneous double bond hydrogenation and benzyl ether cleavage in the presence of Raney nickel led to dihydroxy ester (XXIX). This was converted to the corresponding dimesylate (XXX), which was further cyclized to disulfide (XXXI) using the in situ generated sodium disulfide as in the precedent Schemes. Finally, basic hydrolysis of the ethyl ester (XXXI) yielded the title carboxylic acid.
| Carbohydr Res 1986,148(1),51 |
SYN
Diisopropylidene mannitol (I) was first converted into the dibutyltin derivative (II), which was subsequently mono-benzylated to (III). Acetylation of (III) with acetic anhydride in pyridine gave (IV). After acidic hydrolysis of the isopropylidene ketals of (IV), the resultant tetraol (V) was converted into tetramesylate (VI). Reductive elimination in (VI) with Zn and NaI produced diene (VII). The acetate group of (VII) was then hydrolyzed to (VIII) using NaOMe. Intermediate (VIII) was reacted with triethyl orthoacetate in the presence of propionic acid to generate the allyl vinyl ether (IX), which underwent a Claisen rearrangement to the diene-ester (X). Selective hydroboration-oxidation of the terminal double bond of (X) yielded the primary alcohol (XI). Subsequent benzyl group hydrogenolysis in (XI) furnished the target intermediate diol (XII).
| J Carbohydr Chem 1990,9(2-3),307 |
SYN
J Chem Soc Chem Commun 1986,(18),1408
SYN
https://www.sciencedirect.com/science/article/abs/pii/S1381117713003342
References
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| Names | |
|---|---|
| IUPAC name(R)-5-(1,2-Dithiolan-3-yl)pentanoic acid | |
| Other namesα-Lipoic acid; Alpha lipoic acid; Thioctic acid; 6,8-Dithiooctanoic acid | |
| Identifiers | |
| CAS Number | 1077-28-7 (racemate) 1200-22-2 (R) |
| 3D model (JSmol) | Interactive image |
| ChEBI | CHEBI:30314 |
| ChEMBL | ChEMBL134342 |
| ChemSpider | 5886 |
| DrugBank | DB00166 |
| ECHA InfoCard | 100.012.793 |
| IUPHAR/BPS | 4822 |
| KEGG | C16241 |
| MeSH | Lipoic+acid |
| PubChem CID | 6112 |
| UNII | 73Y7P0K73Y (racemate) VLL71EBS9Z (R) |
| CompTox Dashboard (EPA) | DTXSID7025508 |
| showInChI | |
| showSMILES | |
| Properties | |
| Chemical formula | C8H14O2S2 |
| Molar mass | 206.32 g·mol−1 |
| Appearance | Yellow needle-like crystals |
| Melting point | 60–62 °C (140–144 °F; 333–335 K) |
| Solubility in water | Very Slightly Soluble(0.24 g/L)[1] |
| Solubility in ethanol 50 mg/mL | Soluble |
| Pharmacology | |
| ATC code | A16AX01 (WHO) |
| Pharmacokinetics: | |
| Bioavailability | 30% (oral)[2] |
| Related compounds | |
| Related compounds | Lipoamide Asparagusic acid |
| Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). | |
 verify (what is ?) | |
| Infobox references |
//////////Alpha lipoic acid, d-Thioctic acid, (R)-(+)-alpha-Lipoic acid, (R)-(+)-Thioctic acid, Dexlipotam,
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Acetaminosalol
Acetaminosalol
- Molecular FormulaC15H13NO4
- Average mass271.268 Da
- ацетаминосалол [Russian] [INN], أسيتامينوسالول [Arabic] [INN], 醋氨沙洛 [Chinese] [INN]
(1E)-N-{4-[(2-Hydroxybenzoyl)oxy]phenyl}ethanimidic acid118-57-0[RN]
204-261-3[EINECS]
CAS Registry Number: 118-57-0
CAS Name: 2-Hydroxybenzoic acid 4-(acetylamino)phenyl ester
Additional Names:p-acetamidophenyl salicylate; acetylaminophenyl salicylate; acetyl-p-aminosalol; p-acetylaminophenol salicylic acid ester; phenetsal
Trademarks: Salophen (Bayer); Phenosal
Molecular Formula: C15H13NO4
Molecular Weight: 271.27
Percent Composition: C 66.41%, H 4.83%, N 5.16%, O 23.59%
Literature References: Prepn: Brewster, J. Am. Chem. Soc.40, 1136 (1918).
Properties: Crystals from hot ethanol, mp 187°. Practically insol in petr ether, cold water, more sol in warm water. Sol in alcohol, ether, benzene. Incompatible with alkalies and alkaline solns which dissolve it with decompn. The alkaline soln gradually becomes blue when boiled, the blue color being discharged upon continued boiling and again produced upon cooling and exposure to air.
Melting point: mp 187°
Therap-Cat: Analgesic; antipyretic; anti-inflammatory.
Therap-Cat-Vet: Analgesic; antipyretic.
Keywords: Analgesic (Non-Narcotic); Anti-inflammatory (Nonsteroidal); Salicylic Acid Derivatives; Antipyretic.
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Acetaminosalol is an organic compound with the chemical formula C15H13NO4.
It is an esterification product of salicylic acid and paracetamol. It was marketed by Bayer under the brand name Salophen as an analgesic in the late 19th and early 20th centuries.
Action and uses
In a warm alkaline solution acetaminosalol is broken up into salicylic acid and paracetamol. It is decomposed in the intestines, even when given as an injection. It was used as a substitute for salicylic acid in acute rheumatism, and as an intestinal antiseptic. It was similarly effective and much safer than salol, another intestinal antiseptic commonly used at the time. The fact that it is tasteless renders it easy to administer.Advertisement for early 20th century Bayer products, including Salophen
SYNJournal of Organic Chemistry, 86(5), 4254-4261; 2021
| Names | |
|---|---|
| Preferred IUPAC name4-Acetamidophenyl 2-hydroxybenzoate | |
| Identifiers | |
| CAS Number | 118-57-0 |
| 3D model (JSmol) | Interactive imageInteractive image |
| ChEBI | CHEBI:250620 |
| ChEMBL | ChEMBL92590 |
| ChemSpider | 1907 |
| ECHA InfoCard | 100.003.875 |
| EC Number | 204-261-3 |
| MeSH | Salophen |
| PubChem CID | 1984 |
| UNII | O3J7H54KMD |
| CompTox Dashboard (EPA) | DTXSID7045865 |
| showInChI | |
| showSMILES | |
| Properties | |
| Chemical formula | C15H13NO4 |
| Molar mass | 271.272 g·mol−1 |
| Density | 1.327 g cm−3 |
| log P | 2.562 |
| Acidity (pKa) | 7.874 |
| Basicity (pKb) | 6.123 |
| Hazards | |
| Flash point | 241.9 °C (467.4 °F; 515.0 K) |
| Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). | |
| verify (what is ?) | |
| Infobox references |
///////////////Acetaminosalol, nalgesic , Anti-inflammatory, Salicylic Acid Derivatives, Antipyretic, ацетаминосалол , أسيتامينوسالول , 醋氨沙洛 ,
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Dichlorquinazine
CORRECT STR OF Dichlorquinazine
7-chloro-N-[1-[4-[2-[(7-chloroquinolin-4-yl)amino]propyl]piperazin-1-yl]propan-2-yl]quinolin-4-amine;methanesulfonic acid
- 1,4-Piperazinediethanamine, N,N’-bis(7-chloro-4-quinolinyl)-α,α’-dimethyl- (9CI)
- Quinoline, 4,4-[1,4-piperazinediylbis[(1-methylethylene)imino]]bis[7-chloro- (7CI)
- Quinoline, 4,4′-[1,4-piperazinediylbis[(1-methylethylene)imino]]bis[7-chloro- (8CI)
- N1,N4-Bis(7-chloro-4-quinolinyl)-α1,α4-dimethyl-1,4-piperazinediethanamine
- 1,4-Bis[2-(7-chloro-4-quinolylamino)propyl]piperazine
- Bis[(chloro-7”-quinolyl-4”)amino-2′-propyl]-1,4-piperazine
- Dichlorquinazine
- N,N’-Bis(7-chloro-4-quinolyl)-α,α’-dimethylpiperazine-1,4-diethylamine
- NSC 129790
- RP 12278
- WR 3863
WRONG STRUCTURE
WRONG STRUCTURE
Dichlorquinazine
- BRN 0867697
- Dichlorquinazine
- EINECS 234-130-6
- NSC 129790
- RP 12278
- UNII-HT3GAD2SCM
- WR 3863
cas 10547-40-7
C28H32Cl2N6, mw
| 523.5 |
7-chloro-N-[2-[4-[2-[(7-chloroquinolin-4-yl)amino]propan-2-yl]piperazin-1-yl]propan-2-yl]quinolin-4-amine
VARIANT
RN: 23256-65-7
Molecular Formula, C28-H32-Cl2-N6.C-H4-O3-S, Molecular Weight, 619.6144
- RP-12278 mesylate
- WR-3863 mesylate
- Quinoline, 4,4′-(1,4-piperazinediylbis((1-methylethylene)imino))bis(7-chloro-, tetramethanesulfonate bis((7-chloro-4”-quinolyl)-2′-aminopropyl)-1,4-piperazine methanesulfonate
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PATENTS
BE 626239
4-(Chloro or alkoxy)quinolines are treated with a 1,4-bis(aminoalkyl)piperazine to give the title compds. which can be used as antiinflammatory agents and as amebicides. Thus, a mixt. of 16.3 g. 4-chloroquinoline, 10 g. 1,4-bis(3-aminopropyl)piperazine, 55 g. PhOH, and 0.2 g. NH4Cl is heated 5 hrs. at 175°, poured into a mixt. of 500 ml. H2O and 100 ml. NaOH (d. 1.33), filtered, the ppt. is treated with a mixt. of 80 ml. H2O and 20 ml. NaOH, the mixt. filtered, and the ppt. washed with 500 ml. H2O and dried to give 15.9 g. 1,4-bis[3-(4-quinolyl)aminopropyl]piperazine, m. 210°(MeOH-H2O). Similarly prepd. are the following I: n, R, R1, R2, X, Y, m.p.; 2, H, H, H, MeO, H, 245° (HCONMe2); 2, H, H, H, H, SO2NMe2, 271° (HCONMe2); 2, H, H, H, H, CF3, 293° (HCONMe2); 3, Me, H, H, H, H, ∼100°; 3, Me, Ac, H, H, H, -(1); 3, Me, H, H, MeOH, 180° and 190°; 3, Me, Ac, H, MeO, H, -(2); 1, Me, H, Me, H, Cl, 264°; 2, H, H, H, Cl, H, 264° (BuOH); 1, Me, H, H, H, CF3, 240° (MeCOEt); 2, H, H, H, H, MeO, 200° (EtOH); 2, H, H, Me, H, MeO, 216° (EtOH); 3, Me, H, H, H, MeO, 218° (CH2Cl2); (1) bis(acid maleate) m. 155° (iso-PrOH), (2) bis(acid maleate) m. 155° The following II were also prepd.: n, R, R1, R2, m.p.; 1, Me, A(R = R1 = X = Y = H,Z =Cl), A(R = R1 = X = Z = H,Y = Cl), 208-10° (HCONMe2); 1, Me, A(R = R1 = X = Y= H, Z = Cl), A(R = R1 = X = Y = H,Z = MeO), 206-8° (HCONMe2); 1, Me, A(R1 = X = Y = H, R = 4-ClC6H4, Z = Cl), A(R = R1 = X = Y = H,Z = Cl, 230-2° (HCONMe2) The following III were prepd.: n, R, m, R1, R2, m.p.; 3, Me, 1, H, A(R = R1 = X = Y = H, Z= Cl), 190-1° and 213-15°; 2, H, 2, H, A(R = X = Y = H, R1 = Me, Z =Cl), 198° (PrOH); 3, Me, 2, H, A(R = R1 = X = Y = H,Z = Cl), 160-2°; 1, Me, 1, H, A(R = R1 = X = Y = H,Z = Cl), 178°; 1, Me, 1, Me, A(R1 = X = Z = H,R = Me, Y =AcNH), 330° (decompn.) (EtOH); 2, H, 2, H, A(R1 = X = Y = H,R = 4-ClC6H4,Z = Cl), 320-1° (HCONMe2); 2, H, 2, H, A(R = Y = Z = H, R1 = Me, X = Cl) 96° (iso-PrOH); 1, Me, 1, Me, A(R = R1 = X = Z = H, Y = Cl), 220° and 246-8°; 1, Me, 1, Me, A(R1 = X = Z = H, R = Me, Y = NH2), 305° (EtOH-H2O); 1, Me, 1, Me, A(R1 = X = Z = H, R = Me, Y = MeO, 244° (EtOH) Also prepd. were (m.p. given): 1,4-bis[2-(7-chloro-4-quinolylamino)propyl]hexahydro-1,4-diazepine, 169°; 1-[5-(7-chloro-4-quinolylamino)-2-pentyl]-4-[2-(7-chloro-4-quinolylamino)propyl] piperazine, 210-12°(HCONMe2); 1,4-bis[3-(7-chloro- 4-quinolylamino)propyl] hexahydro-1,4-diazepine, 186° (HCONMe2). The following were prepd. (m.p. and optical rotation given):L(+)-1,4-bis[2-(7-chloro-4-quinolylamino)propyl]piperazine, 250-1°, [α]23.5D 382° ± 1° (c 4, 50:50 MeOH-H2O); D(-)-1,4- bis[2-(7-chloro-4-quinolylamino)propyl] piperazine, 250-1°, [α]25D -382.5° ± 1° (c 4, 50:50 MeOH-H2O); DL-1,4-bis[2-(7-chloro-4-quinolylamino)propyl]piperazine (IV), 266-8°, -; meso-1,4-bis [2-(7-chloro-4-quinolylamino)propyl] piperazine (V), 270-1° (HCONMe2), -; equimol. mixt. of IV and V, 250-2°, -; 1,4-bis[2-(6-chloro-4-quinolylamino)propyl]piperazine-form A (VI-form A), 227° -; VI-form B, 110° and 245°, -. Also prepd. are the following intermediates of the general formula VII (R = H) (X, Y, Z, and m.p. given): OH, H, SO2NMe2, ∼288°; Cl, H,SO2NMe2, 170°; HO(CH2)3CHMeNH, H, H, 158° (EtOH); AcO(CH2)3CHMeNAc, H, H, -; HO(CH2)3CHMeNAc, H, H, -; MeSO3(CH2)3CHMeNAc, H, H, -; N-(5-piperazino-2-pentyl)acetamido, H, H, -; HO(CH2)3CHMeNH, MeO, H, -; AcO(CH2)3CHMeNAc, MeO, H, -; HO(CH2)3CHMeNAc, MeO, H, -; MeSO3(CH2)3CHMeNAc, MeO, H, -; N-(5-piperazino-2-pentyl)acetamido, MeO, H, -; Me(HOCH2)CH, H, Cl, 210°; Me(ClCH2)CH, H, Cl, 148-50°; Me(HOCH2)CH, Cl, H, 192°; Me(ClCH2)CH, Cl, H, 142°; Me(HOCH2)CH, H, MeO, 170°; Me(ClCH2)CH, H, MeO, 160°. Also prepd. were (m.p. given): VII (R = CO2Et, X = OH, Y = H, Z = SO2NMe2), ∼335°; VII (R = CO2H, X = OH, Y = H, Z = SO2HMe2), 310° (decompn.); 1,4-bis(2-oxopropyl)hexahydro-1,4-diazepine, -; 1,4-bis(2-oximinopropyl)hexahydro-1,4-diazepine, 180-1°; 1,4-bis(2-aminopropyl)hexahydro-1,4-diazepine, -; 1,4-bis(2-cyanoethyl)-hexahydro-1,4-diazepine, -. The following were prepd. (m.p. and optical rotation given): L(+)-4-(3-hydroxy-2-propylamino)-7-chloroquinoline, 223-4°, [α]24D 28.5° ± 2° (c 1, EtOH); L(+)-4-(3-chloro-2-propylamino)-7-chloroquinoline, 146-7°, [α]24D 103 ± 1° (c 2, EtOH); L(+)-4-(3-piperazino-2-propylamino)-7-chloroquinoline, 128-30°, [α]23D 139 ± 1° (c 2, EtOH); D(-)-4-(3-hydroxy-2-propylamino)-7-chloroquinoline, 223-4°, [α]25D – 31 ± 2° (c 1, EtOH); D(-)-4-(3-chloro-2-propylamino)-7-chloroquinoline, 147-8°, [α]24D -101 ± 1° (c 2, EtOH); D(-)-4-(3-piperazino-2-propylamino)-7-chloroquinoline, 131-2°, [α]23D -137 ± 1° (c 2, EtOH)
PATENT
FR CAM42 19631007.
Piperazines (I) are antiinflammatory and anthelmintic agents. A mixt. of 8.25 g. MeCH(NH2)CH2OH, 19.8 g. 4,6-dichloroquinoline, and 55 g. PhOH is heated to give 16.0 g. 6-chloro-4-[(3-hydroxy-2-propyl)-amino]quinoline (II), m. 192°. II (14.0 g.) is treated with a soln. of 10.6 g. SOCl2 in 40 ml. CHCl3 to give 12.5 g. 6-chloro-4-[(3-chloro-2-propyl)amino]quinoline (III), m. 142°. A mixt. of 13.2 g. 1-[2-(7-chloro-4-quinolylamino)propyl]piperazine, 11.0 g. III, 6.4 g. NaI, 2.3 g. anhyd. Et3N, and 200 ml. AcEt is refluxed 18 hrs., the solvent is distd. in vacuo, and the residue is taken up in 100 ml. MeOH. The mixt. is made alk. with 110 ml. NaOH (d. 1.33), poured into 1000 ml. H2O, and the ppt. that forms is filtered off, washed with H2O, and recrystd. in HCONMe2 to give 11.0 g. 1-[2-(7-chloro-4-quinolylamino)propyl]-4-[2-(6-chloro-4-quinolylamino)propyl]piperazine, m. 208-10°. Similarly prepd. are the following I (R, m, R1, n, R2, R3, R4, and m.p. given): H, 2, H, 2, H, MeO, H, 245°; H, 2, H, 2, H, H, SO2NMe2, 271°; H, 2, H, 2, H, H, CF3, 293°; Me, 3, Me, 3, H, MeO, H, 180° and 190°; Me, 3, H, 1, H, H, Cl, 190-1° and 213-15°; H, 2, H, 2, H, Cl, H, 264°; Me, 1, Me, 1, H, H, CF3, 240°; H, 2, H, 2, H, H, MeO, 200°; Me, 3, H, 2, H, H, Cl, 160-2°; Me, 1, H, 1, H, H, Cl, 178°; Me, 1, Me, 1, Me, AcNH, H, 330°; H, 2, H, 2, p-ClC6H4, H, Cl, 320-1°; Me, 1, Me, 1, H, Cl, H, 227° (form A); Me, 1, Me, 1, H, Cl, H, 110° and 245° (form B); H, 3, H, 3, H, H, Cl, 239-41°; Me, 1, Me, 1, Me, NH2, H, 305°; Me, 1, Me, 1, Me, MeO, H, 244°; Me, 3, Me, 3, Me, 3, H, H, MeO, 218°; H, 3, H, 3, H, H, Cl, 240-2°. Also prepd. are (m.p. given): 1,4-bis[2-(7-chloro-4-quinolylamino)propyl]hexahydrodiazepine, 169°; 2,5-dimethyl-1,4-bis[2-(7-chloro-4-quinolylamino)propyl)piperazine, 264°; 1-[5-(7-chloro-4-quinolylamino [-2-pentyl]-4-[2-(7-chloro -4-quinolylamino)propyl]piperazine, 210-12°; 2,5-dimethyl-1,4-bis[3-(7-methoxy-4-quinolylamino)propyl]piperazine, 216°; 1,4-bis[3-(3-methyl-7-chloro-4-quinolylamino)propyl] piperazine, 198°; 1,4-bis[3-(7-chloro-4-quinolylamino)propyl]hexahydrodiazepine, 186°; 1-[2(7-chloro-4-quinolylamino)propyl]-4-[2-(7-methoxy-4-quinolylamino)propyl]piperazine, 206-8°; 1,4-bis[3-(3-methyl-5-chloro-4- quinolylamino)propyl]piperazine, 96°; 1 – [2 -[2 -(p – chlorophenyl)- 7- chloro- 4- quinolylamino]propyl] -4 – [2 – (7 – chloro – 4-quinolylamino)propyl]piperazine, 230-2°; L(+) 1,4-bis[2-(7-chloro-4-quinolylamino)propyl]piperazine, 250-1°, [α]23.5D + 382° ± 1° (c 4, 50/50 MeOH-H2O); L(+)-7-chloro-4-(3-hydroxy-2-propylamino)quinoline, 223-4°, [α]24D 28.5° ± 2° (c 1, EtOH); L(+)-7-chloro-4-(3-chloro-2-propylamino)quinoline, 146-7°, [α]24D 103° + 1° (c 2, EtOH); L(+)-7-chloro-4-(3-piperazino-2-propylamino)quinoline 128-30°, [α]23D 139° ± 1° (c 2, EtOH); D(–)-1,4-bis[2-(7-chloro-4-quinolylamino)propyl]piperazine, 250-1°, [α]25D -382° ± 1° (c 4, 50:50 MeOH-H2O); meso- 1,4 – bis [2 – (7 – chloro – 4 – quinolylamino)propyl] piperazine, 270-1°.
Patent Information
BE 612207
| Publication Number | Title | Priority Date | Grant Date |
|---|---|---|---|
| US-2016045487-A1 | Compositions and methods for treating neuropathy | 2013-03-27 | |
| WO-2014160811-A1 | Compositions and methods for treating neuropathy | 2013-03-27 | |
| AU-2014234258-A1 | Piperaquine microcapsules and compositions containing them | 2013-03-22 | |
| AU-2014234258-B2 | Piperaquine microcapsules and compositions containing them | 2013-03-22 | 2019-02-14 |
| CA-2907628-A1 | Piperaquine microcapsules and compositions containing them | 2013-03-22 |
| Publication Number | Title | Priority Date | Grant Date |
|---|---|---|---|
| EP-2976069-A1 | Piperaquine microcapsules and compositions containing them | 2013-03-22 | |
| EP-2976069-B1 | Piperaquine microcapsules and compositions containing them | 2013-03-22 | 2020-05-06 |
| US-2014322296-A1 | Piperaquine microcapsules and compositions containing them | 2013-03-22 | |
| US-2016045447-A1 | Piperaquine microcapsules and compositions containing them | 2013-03-22 | |
| US-9668979-B2 | Piperaquine microcapsules and compositions containing them | 2013-03-22 | 2017-06-06 |
| Publication Number | Title | Priority Date | Grant Date |
|---|---|---|---|
| WO-2014147242-A1 | Piperaquine microcapsules and compositions containing them | 2013-03-22 | |
| AU-2009215107-A1 | Treatments for neuropathy | 2008-02-12 | |
| AU-2009215107-B2 | Treatments for neuropathy | 2008-02-12 | 2013-05-09 |
| AU-2013203934-A1 | Treatments for neuropathy | 2008-02-12 | |
| CA-2714676-A1 | Treatments for neuropathy | 2008-02-12 |
| Publication Number | Title | Priority Date | Grant Date |
|---|---|---|---|
| CA-2714676-C | Treatments for neuropathy | 2008-02-12 | 2015-04-14 |
| EP-2240177-A2 | Treatments for neuropathy | 2008-02-12 | |
| US-2009203735-A1 | Treatments for neuropathy | 2008-02-12 | |
| US-2011086878-A1 | Treatments for Neuropathy | 2008-02-12 | |
| US-2016058749-A1 | Treatments for neuropathy | 2008-02-12 |
////////////////Dichlorquinazine, BRN 0867697, Dichlorquinazine, EINECS 234-130-6, NSC 129790, RP 12278, UNII-HT3GAD2SCM, WR 3863
CC(C)(NC1=C2C=CC(=CC2=NC=C1)Cl)N3CCN(CC3)C(C)(C)NC4=C5C=CC(=CC5=NC=C4)Cl
WRONG
CC(CN1CCN(CC(C)Nc2ccnc3cc(Cl)ccc23)CC1)Nc4ccnc5cc(Cl)ccc45.CS(=O)(=O)O
AND
Clc1ccc2c(c1)nccc2NC(C)CN1CCN(CC(C)Nc2ccnc3cc(Cl)ccc32)CC1
CORRECT
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LERIGLITAZONE
LERIGLITAZONE
C19H20N2O4S,
| MW 372.4 |
Hydroxypioglitazone, CAS 146062-44-4
MIN 102, Hydroxy Pioglitazone (M-IV)лериглитазон [Russian] [INN]ليريغليتازون [Arabic] [INN]乐立格列酮 [Chinese] [INN]
5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione
Hydroxypioglitazone is a member of the class of thiazolidenediones that is the hydroxy derivative of pioglitazone. It has a role as a human xenobiotic metabolite. It is a member of thiazolidinediones, a member of pyridines and an aromatic ether. It derives from a pioglitazone.
- OriginatorIDIBELL
- DeveloperMinoryx Therapeutics
- ClassNeuroprotectants; Phenyl ethers; Pyridines; Small molecules; Thiazolidinediones
- Mechanism of ActionPeroxisome proliferator-activated receptor gamma agonists
- Orphan Drug StatusYes – Adrenoleucodystrophy; Friedreich’s ataxia
- Phase II/IIIAdrenoleucodystrophy
- Phase IIFriedreich’s ataxia
- PreclinicalCNS disorders
- 23 Sep 2020Leriglitazone receives Rare Pediatric Disease designation from the US FDA for X-linked adrenoleukodystrophy before September 2020
- 23 Sep 2020Minoryx Therapeutics licenses leriglitazone to Sperogenix Therapeutics in China, Hong Kong and Macau for X-linked adrenoleukodystrophy (X-ALD)
- 14 Sep 2020Minoryx Therapeutics completes the phase II FRAMES trial in Friedreich’s ataxia (In adolescents, In adults) in Spain, Germany, France and Belgium (PO) (NCT03917225)
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Leriglitazone (Hydroxypioglitazone), a metabolite of pioglitazone. Leriglitazone (Hydroxypioglitazone) PioOH is a PPARγ agonist, stabilizes the PPARγ activation function-2 (AF-2) co-activator binding surface and enhances co-activator binding, affording slightly better transcriptional efficacy. Leriglitazone (Hydroxypioglitazone) binds to the PPARγ C-terminal ligand-binding domain (LBD) with Ki of 1.2 μM，induces transcriptional efficacy of the PPARγ (LBD) with EC50 of 680 nM.
Leriglitazone is under investigation in clinical trial NCT03917225 (A Clinical Study to Evaluate the Effect of MIN-102 on the Progression of Friedreich’s Ataxia in Male and Female Patients).
Treatment of X-Linked Adrenoleukodystrophy
PATENT
WO 9218501
WO 9322445
PAPER
Chemical & Pharmaceutical Bulletin (1995), 43(12), 2168-72
https://www.jstage.jst.go.jp/article/cpb1958/43/12/43_12_2168/_article
The metabolites of (±)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2, 4-thiazolidinedione (1, pioglitazone), which is a representative insulin-sensitizing agent, were synthesized to confirm their structures and for studies of their pharmacological properties. Of the metabolites identified, a compound hydroxylated at the 2-position of the ethoxy chain (3) and compounds oxygenated at the ethyl side chain attached to the pyridine ring (4, 5) were found to be active, although the potency was slightly lower than that of the parent compound.
PAPER
Journal of Medicinal Chemistry (1996), 39(26), 5053-5063.
https://pubs.acs.org/doi/10.1021/jm9605694
Pioglitazone (5-(4-(2-(5-ethyl-2-pyridyl)ethoxy)benzyl)-2,4-thiazolidinedione, 2) is a prototypical antidiabetic thiazolidinedione that had been evaluated for possible clinical development. Metabolites 6−9 have been identified after dosing of rats and dogs. Ketone 10 has not yet been identified as a metabolite but has been added to the list as a putative metabolite by analogy to alcohol 6 and ketone 7. We have developed improved syntheses of pioglitazone (2) metabolites 6−9 and the putative metabolite ketone 10. These entities have been compared in the KKAy mouse model of human type-II diabetes to pioglitazone (2). Ketone 10 has proven to be the most potent of these thiazolidinediones in this in vivo assay. When 6−10 were compared in vitro in the 3T3-L1 cell line to 2, for their ability to augment insulin-stimulated lipogenesis, 10 was again the most potent compound with 6, 7, and 9 roughly equivalent to 2. These data suggest that metabolites 6, 7, and 9 are likely to contribute to the pharmacological activity of pioglitazone (2), as had been previously reported for ciglitazone (1).
PATENT
WO 2015150476
Compound 5-[4-[2-(5-(1 -hydroxyethyl)-2-pyridinyl)ethoxy]benzyl]-2,4-thiazolidinedione of formula (1 ) can be prepared according to Scheme 1 (see e.g. J.Med.Chem. 1996, 39(26),5053).
Scheme 1
Scheme 2
Yet another method to prepare mixtures (c) – comprising compound (2) and (4) – and (d) – comprising compounds (3) and (5) – (scheme 3), includes the resolution of the racemic mixture VIII using the already described methods (chiral HPLC separation, enzymatic resolution, chiral resolution, etc) followed by double bond reduction in each of the enantiomers Villa and Vlllb.
Scheme 4
Compounds of formula (2), (3), (4) and (5) may be obtained from mixtures (c) and (d) (Scheme 45) by chiral HPLC separation. Alternatively, the desired enantiomerically pure compounds can be prepared by chiral synthetic procedures known to those skilled in the art (for example: asymmetric hydrogenolysis of the corresponding single isomer of compound VI).
HPLC Method
Column: Symmetry Shield RP-18, 5 μηη (4.6 x 250 mm); wavelength: 210 nm; flow: 1 mL/min; run time: 28 min; mobile phase-gradient: (t/%B): 0/10, 8/10, 12/60, 16/80, 20/80, 24/10, 28/10 [A: Water (potassium dihydrogen o-phosphate (pH~3)), B: Acetonitrile]
A mixture of compounds (2) and (4) (mixture (c)) and a mixture of compounds (3) and (5) (mixture (d)) were prepared according to Scheme 7.
Example 6: Preparation of diastereomeric mixtures D-1 and D-2 of M-IV:
Scheme 1 :
Ent-1 (VIII) Ent-2 (VIII)
Step 3 Step 3
MIV D-1 MIV D-2
Step 1 : Synthesis of compound VIII: HCI (48 ml, 2N) was added to a solution of compound VI (10 g, 0.024 mol) in methanol (200 ml) and the mixture was heated to reflux. After 4 h of reflux, the reaction mixture was cooled to r.t. and concentrated under reduced pressure to afford a yellow solid. The solid was suspended in water (70 ml) and neutralized using a saturated NaHC03 solution. The resulting pale yellow precipitate was collected by filtration and vacuum dried to afford compound VIII (7.5 g; 84% yield).
ES-MS [M+1]+: 371.0.
Step 2: Chiral prep. HPLC
Compound VIII (1 .0 g) was dissolved in a mixture containing equal volumes of acetonitrile, methanol and dichloromethane; injected (150 μΙ injections) in chiral prep-HPLC column (Chiralpak-IA 250 x 20 mm, 5 micron) and separated [Mobile phase- n-Hexane/0.05% Et3N in EtOH (50:50); flow Rate: 18ml/min; run time: 60 min]. The fractions containing the enantiomers Villa and Vlllb were separately concentrated under reduced pressure to minimum volume and the respective residues were diluted with EtOAc (100 ml), followed by water (50 ml). The resultant organic phases were
dried over anhydrous Na2S04 and concentrated to afford compounds Villa and Vlllb as off-white solids. Enantiomers Villa and Vlllb were isolated but the absolute configuration of each enantiomer has not been determined.
Compound Ent-1 (VIII): 250 mg (Yield: 50%); tR (Chiral HPLC) = 14.8 min; ES-MS [M+1]+: 371 .0; 1H NMR (400 MHz, DMSO-d6): δ 12.5 (br S, 1 H), 8.47 (s, 1 H), 7.71 (s, 1 H), 7.67 (dd, J = 8.0, 2.0 Hz, 1 H), 7.53 (d , J = 9.2 Hz, 2H), 7.31 (d, J = 7.6 Hz, 1 H), 7.08 (d, J = 8.8 Hz, 2H), 5.25 (d, J = 4.0 Hz, 1 H), 4.74-4.76 (m, 1 H), 4.43 (dd, J = 6.8, 6.4 Hz, 2H), 3.18 (t, J = 6.4 Hz, 2H), 1.34 (d, J = 6.4 Hz, 3H).
Compound Ent-2 (VIII): 237 mg (Yield: 47%); tR (Chiral HPLC) = 16.7 min; ES-MS [M+1]+: 371 .0; 1H NMR (400 MHz, DMSO-d6): δ 12.5 (br S, 1 H), 8.47 (s, 1 H), 7.71 (s, 1 H), 7.67 (dd, J = 8.0, 2.0 Hz, 1 H), 7.53 (d , J = 8.8 Hz, 2H), 7.31 (d, J = 8.0 Hz, 1 H), 7.08 (d, J = 9.2 Hz, 2H), 5.23 (d, J = 3.6Hz, 1 H), 4.75 (m, 1 H), 4.43 (dd, J = 6.8, 6.4 Hz, 2H), 3.18 (dd, J = 6.8, 6.4 Hz, 2H), 1 .34 (d, J = 6.4 Hz, 3H).
Synthesis of diastereomeric mixtures of M-IV
Synthesis of D-1 MIV
Step 3: A solution of NaBH4 (77 mg, 2.02 mmol) in 0.1 N NaOH (2 ml) was added slowly to a stirred solution of compound Ent-1 (VIII) (250 mg, 0.675 mmol), dimethylglyoxime (32 mg, 0.27 mmol) and CoCI2.6H20 (16 mg, 0.067 mmol) in a mixture of water (10 ml), THF (10 ml) and 1 M NaOH (0.5ml) solution at 10 °C, and the reaction mixture was stirred at r.t. for 1 h. After color of the reaction medium faded, additional quantity of NaBH4 (26 mg, 0.675 mmol) and CoCI2.6H20 (16 mg, 0.067 mmol) were added and stirring was continued at r.t. [additional quantities of CoC|2 and NaBH4 were added at 12 h intervals till the starting material was consumed, as monitored by LCMS]. After 90-96 h, the reaction mixture was neutralized with AcOH (pH~7); diluted with water (10 ml) and extracted in EtOAc (3 χ 50 ml). The combined organic extract was dried over anhydrous Na2S04 and concentrated to afford crude compound which was purified by flash column chromatography (Si02; 4% methanol in CH2CI2) to afford diastereomeric mixture of MIV D-1 (125 mg) as off-white solid.
Synthesis of D-2 MIV
Step 3: A solution of NaBH4 (72 mg, 1 .921 mmol) in 0.1 N NaOH (2 ml) was added slowly to a stirred solution of compound Ent-2 (VIII) (237 mg, 0.64 mmol), dimethylglyoxime (30 mg, 0.256 mmol) and CoCI2.6H20 (15 mg, 0.064 mmol) in a mixture of water (10 ml), THF (10 ml), and 1 M NaOH (0.5ml) solution at 10 °C, and the
reaction mixture was stirred at r.t. for 1 h. After color of the reaction medium faded, additional quantity of NaBH4 (24 mg, 0.64 mmol) and CoCI2.6H20 (15 mg, 0.064 mmol) were added and stirring was continued at r.t. [additional quantities of CoCI2.6H20 and NaBH4 were added at 12 h intervals till the starting material was consumed, as monitored by LCMS]. After 96 h, the reaction mixture was neutralized with AcOH (pH~7); diluted with water (10 ml) and extracted in EtOAc (3 χ 50 ml). The combined organic extract was dried over anhydrous Na2S04 and concentrated to afford crude compound, which was purified by flash column chromatography (Si02; 4% methanol in CH2CI2) to afford diastereomeric mixture of MIV D-2 (100 mg) as off-white solid.
MIV D-1 : yield: 125 mg (50%); tR (Chiral HPLC) = 17.8, 14.7 min; ES-MS [M+1]+: 373.0, 1H NMR (400 MHz, DMSO-d6): δ 12.00 (br s, NH), 8.46 (d, J = 2.0 Hz, 1 H), 7.67 (dd, J = 8.0, 2.4 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.13 (d, J = 8.8Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.27 (d, J = 4.0 Hz, 1 H), 4.88-4.85 (m, 1 H), 4.76-4.74 (m, 1 H), 4.30 (t, J = 6.8 Hz, 2H), 3.30 (m, 1 H), 3.14 (dd, J = 6.8, 6.4 Hz, 2H), 3.08-3.02 (m, 1 H), 1 .34 (d, J = 6.4 Hz, 3H).
MIV D-2: yield: 100 mg (42%); tR (Chiral HPLC) = 19.4, 16.5 min; ES-MS [M+1]+: 373.0; 1H NMR (400 MHz, DMSO-d6): δ 12.01 (br s, -NH), (d, J = 2.0 Hz, 1 H), 7.67 (dd, J = 8.0, 2.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.13 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.27 (d, J = 4.0 Hz, 1 H), 4.88-4.85 (m, 1 H), 4.76-4.74 (m, 1 H), 4.30 (dd, J = 6.8, 6.4 Hz, 2H), 3.30 (m, 1 H), 3.14 (dd, J = 6.8, 6.4 Hz, 2H), 3.08-3.02 (m, 1 H), 1.34 (d, J = 6.8 Hz, 3H).
Diastereomeric mixtures D-1 and D-2 of MIV correspond to mixtures (c) and (d) described above, but the specific diastereomers present in each diastereomeric mixture have not been assigned.
Example 7: in vitro ADME and toxicological characterization
Protocol: The assays performed include cytochrome P450 inhibition with the different isoforms, microsomal and hepatocyte stability, neurotoxicity in neural cells and hERG safety assays using a patch clamp electrophysiology measurement (FDA Draft Guidance for Industry. Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labelling Recommendations 2012, The European Medicines Agency (EMA) Guideline on the Investigation of Drug Interactions Adopted in 2012, Schroeder K et al. 2003 J Biomol Screen 8 (1 ); 50-64, Barter ZE et al. 2007
Curr Drug Metab 8 (1 ); 33-45, LeCluyse EL and Alexandre E 2010 Methods Mol Biol 640; 57-82). The results indicate a safe and favourable ADME profile for the compounds of the invention.
Example 8: The brain plasma ratios of Pioglitazone, MIV, Mill and Mil following oral dosing of a single administration of Pioglitazone at 4.5 mg/kg in male C57BL/6 mice.
The brain-plasma ratio was calculated based on levels of Pioglitazone, MIV, Mill and Mllin plasma and brain quantified at C max (maximal concentration) following oral dosing of a single administration of Pioglitazone at 4.5 mg/kg in male C57BL/6 mice. The percentage brain plasma ratio was 9, 13, 7 and 1 %, respectively, for Pioglitazone, Mil and Mill as shown in the Figure 4. Thus, active metabolites Mill and Mil crossed the BBB at much lower extent than Pioglitazone as it was predicted based on the physicochemical properties of the compounds (see Tablel ). In contrast, unexpectedly metabolite MIV crossed the BBB in a higher percentage than the parent compound Piolgitazone
The calculations of the both indexes (ClogP and QPIogBB) for Pioglitazone and its metabolites Mil and Mill are shown in Table 1 . For both indexes the 2 metabolites are lower than for pioglitazone, suggesting for Mil, and Mill a less favored penetration and distribution within CNS.
TABLE 1
PATENT
WO 2018116281
https://patents.google.com/patent/WO2018116281A1/enPioglitazone is a “dirty” drug which is converted to many metabolites in vivo. The metabolic pathway of pioglitazone after oral administration has been studied in several animal species and in humans and the metabolites have been described in the literature (see e.g. Sohda et al, Chem. Pharm. Bull., 1995, 43(12), 2168-2172) and Maeshiba et al, Arzneim.-Forsch/Drug Res, 1997, 47 (I), 29-35). At least six metabolites have been identified, named M-I to M-VI. Amongst these metabolites, M-II, M-III and M-IV show some pharmacological activity but are less active than Pioglitazone in diabetic preclinical models.
[0005] 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4- thiazolidinedione has the following structure:
[0006] Tanis et al. (J. Med. Chem. 39(26 ):5053-5063 (1996)) describe the synthesis of 5-[[4-[2-[5-( 1 -hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione as follows:Scheme 1
[0007] Tanis et al. describe that the intermediate 14 was obtained in a 27% yield by reacting compound 13 in an aqueous 37% formaldehyde at 170°C for 6 hours. In this process, 5-[[4- [2-[5-( 1 -hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione (compound 6 in Scheme 1) was obtained in a 2.47% overall yield.[0008] WO 2015/150476 Al describes the use of 5-[[4-[2-[5-(l-hydroxyethyl)-2- pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione, and its pharmaceutically acceptable salts, in the treatment of central nervous system (CNS) disorders. WO 2015/150476 Al describes that 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4- thiazolidinedione was prepared according to the process of Tanis et al. (supra) where the intermediate corresponding to compound 14 of Tanis et al. was prepared similarly at 160°C for 5 hours providing a 17% yield. The overall yield of 5-[[4-[2-[5-(l-hydroxyethyl)-2- pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione was about 1.5%.[0009] Due to the low yield of the intermediate 2-[5-(l-methoxymethoxy-ethyl)pyridine-2- yl]ethanol, the process step for preparing this intermediate is critical for the overall yield of the product, 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4- thiazolidinedione. In addition, the prior art process to obtain compound 14 is difficult to scale because the reaction is carried out in a pressure vessel at a very high temperature and it is a very dirty reaction.[0010] Accordingly, the processes described in the art afford the product 5-[[4-[2-[5-(l- hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione only in a very low overall yield and, therefore, they are not suitable for large scale synthesis. In addition, the prior art process employs CH3OCH2CI, a known carcinogen, for protecting the hydroxyl group in the key intermediate. There is a need for an improved process for synthesizing 5- [[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione, and its pharmaceutically acceptable salts.Formula I illustrated by Scheme 2:Scheme 2 r
B
deprotectionoptional saltformation
I (HCI salt)[0255] In another embodiment, the disclosure provides a process for preparing the compound of Formula I illustrated by Scheme 3 : Scheme 3C
Br. e
step ‘< step b step c
step step g
[0256] In another embodiment in Scheme 3, step c, the order of mixing of the reagents can be as follows: 1. n-BuLi, 2. ethylene oxide, and 3. Cul. This order of mixing is described in Example 2.[0257] In the step a, 2,5-dibromopyridine (1) is reacted with i-PrMgCl in THF and then further with acetaldehyde to obtain compound 2. The reaction mixture is preferably filtered over Celite® after the reaction to remove most of the salts. In one embodiment, the addition of acetaldehyde is conducted at a temperature between -15°C and -10°C to control the exothermic reaction. [0258] In the step b, compound 2 is reacted with TBDMS-C1 in the presence of imidazole having DMF as a solvent. The crude product 3 is advantageously purified by a short plug filtration.[0259] In the step c, the hydroxyl protected compound 3 is reacted with ethylene oxide in the presence of n-BuLi and Cu(I)iodide while maintaining the reaction temperature, i.e., the reaction mixture temperature, below -20°C. In one embodiment, the reaction temperature is maintained below -55°C while adding n-BuLi and Cu(I)iodide into the reaction mixture. In another embodiment, the temperature of the reaction mixture is maintained below -55°C while adding n-BuLi, followed by ethylene oxide and then Cu(I)iodide into the reaction mixture. In another embodiment, the temperature of the reaction mixture is maintained below -55°C while adding n-BuLi into the reaction mixture, followed by ethylene oxide. In this embodiment, Cu(I)iodide is added then into the reaction mixture while the reaction mixture temperature is maintained below -20°C, and preferably below -55 °C. The reaction mixture is then allowed to slowly warm to room temperature after the addition of the reagents and stirred at room temperature, e.g., 20-25°C, overnight. This process is described in detail in Example 2. After the reaction, the complexed copper is advantageously removed by washing with 10% ammonia. The crude compound 4 can be purified by column chromatography to give >99% pure product with a yield of about 52%.[0260] The following examples are illustrative, but not limiting, of the methods of the present invention. Suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art in view of this disclosure are within the spirit and scope of the invention.ExamplesCOMPARATIVE EXAMPLE 1Synthesis of 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]- 2,4-thiazolidinedione (9a) according to the process described in WO 2015/150476 Al Scheme 4
8a 9a[0261] (a) Synthesis of l-(6-methyl-pyridin-3-yl)-ethanol (3a)[0262] LiHMDS (1.0 M in tetrahydrofuran, 463 ml, 0.463 mol) was added drop wise to a cooled solution of methyl 6-methylnicotinate (la) (20 g, 0.132 mol) and ethyl acetate (82 g, 0.927 mol) in dimethylformamide at -50°C; gradually raised the temperature to room temperature and stirred at the same temperature. After 1 h, the reaction mixture was cooled to 0°C; slowly diluted with 20% sulphuric acid and heated to reflux. After 4 h, the reaction mixture was cooled to room temperature, and further to 0°C and basified with potassium carbonate. The reaction medium was diluted with water and extracted in ethyl acetate (3×50 mL). Combined organic extract was dried over sodium sulphate and concentrated to afford crude l-(6-methylpyridin-3-yl)ethan-l-one (2a) (20.0 g) which was taken to the next step without any purification. ES-MS [M+l]+: 136.1.Sodium borohydride (2.3 g, 0.06 mol) was added in small portions over 30 min, to a solution of compound 2a (16.4 g, 0.121 mol) in ethanol (160 mL) at 0°C and the reaction mixture was stirred at same temperature. After 1 h, the reaction mixture was diluted with sodium bicarbonate solution (sat) (2×200 mL) and extracted with dichloromethane (2×500 mL). The combined organic extract was dried over anhydrous sodium sulphate and concentrated to afford a pale yellow oil, which was purified by flash column chromatography (5% methanol/dichloromethane) to afford compound 3a (17.0 g; 93% yield over 2 steps) as a pale yellow oil. ES-MS [M+l]+: 138.1. 1H NMR (400 MHz, CDC13): δ 8.35 (d, J = 2.0 Hz, 1H), 7.63 (dd, J = 8.0, 2.4 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 4.89 (q, J = 6.5 Hz, 1H), 3.30 (br s, 1H), 2.50 (s, 3H), 1.48 (d, J = 6.5 Hz, 3H).[0263] (b) Synthesis of 5-(l-methoxymethoxy-ethyl)-2-methyl-pyridine (4a):Compound 3a (15 g, 0.109 mol) was added, drop wise, to a cooled suspension of sodium hydride (6.56 g, 0.164 mol) in tetrahydrofurane (150 mL) and stirred at 0°C. After 30 min, chloromethyl methyl ether (13.2 g, 0.164 mol) was added drop wise while stirring and keeping the internal temperature around 0°C. After addition is over, the reaction mixture was stirred at the same temperature for 1 h. The reaction was quenched with ice cold water (80 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extract was dried over anhydrous sodium sulphate and concentrated to afford an orange color oil, which was purified by flash column chromatography (1% methanol/dichloromethane) to afford compound 4a (10.0 g; 51% yield) as a pale yellow oil. ES-MS [M+l]+: 182.2. 1H NMR (400 MHz, CDC13): δ 8.45 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.0, 2.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 4.75 (q, J = 6.4 Hz, 1H), 4.57 (ABq, 2H), 3.36 (s, 3H), 2.53 (s, 3H), 1.48 (d, J = 6.6 Hz, 3H).[0264] (c) Synthesis of 2-[5-(l-methoxymethoxy-ethyl)-pyridin-2-yl]-ethanol (5a):A mixture of compound 4a (7.0 g, 0.0386 mol) and 37% formaldehyde solution (5.8 g, 0.077 mol) was heated to 160°C in a sealed glass tube for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford a crude compound which was purified by flash column chromatography (1% methanol/dichloromethane) to afford compound 5 (1.2 g; 17% yield) as pale yellow oil. ES-MS [M+l]+: 212.1. 1H NMR (400 MHz, CDC13): δ 8.42 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.0, 2.4 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.72 (q, J = 6.6 Hz, 1H), 4.65 (t, J = 5.6 Hz, 1H), 4.52 (ABq, 2H), 3.73 (m, 2H), 3.24 (s, 3H), 2.86 (t, J = 7.2 Hz, 2H), 1.49 (d, J = 6.4 Hz, 3H).[0265] The total yield for compound 5a from compound la was 8% molar.[0266] (d) Synthesis of 4-{2-[5-(l-methoxymethoxy-ethyl)-pyridin-2-yl]-ethoxy}- benzaldehyde (6a): Methanesulphonylchloride (1.19 g, 0.01 mol) was added, drop wise, to a cooled suspension of compound 5a (1.7 g, 0.008 mol) and triethylamine (1.79 ml, 0.013 mol) in dichloromefhane (20 mL) at 0°C and stirred at same temperature for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic extract was dried over anhydrous sodium sulphate and concentrated to afford 2-(5-(l-(methoxymethoxy)ethyl)pyridin-2-yl)ethyl methanesulfonate (2.04 g; 88% yield) as a yellow oil, which was taken to next step without purification. ES-MS [M+l]+: 290.[0267] 2-(5-(l-(methoxymethoxy)ethyl)pyridin-2-yl)ethyl methanesulfonate was added (2.3 g, 0.008 mol) to a stirred suspension of 4-hydroxybenzaldehyde (1.65 g, 0.0137 mol) and potassium carbonate (1.86 g, 0.0137 mol) in mixture of toluene (25 mL) and ethanol (25 mL); stirred at 85°C for 5 h. After consumption of the starting materials, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extract was washed with water; dried over anhydrous sodium sulphate and concentrated to afford a crude dark yellow liquid. The crude was purified by flash column chromatography (1% methanol/dichloromethane) to afford compound 6a (1.5 g; 60% yield) as pale yellow liquid. ES-MS [M+l]+: 316.1.[0268] (e) Synthesis of 5-(4-{2-[5-(l-methoxymethoxy-ethyl)-pyridin-2-yl]-ethoxy}- benzylidene)-thiazolidine-2,4-dione (7a):Piperidine (80 mg, 0.95 mmol) was added to a solution of compound 6a (0.6 g, 1.9 mmol) and thiazolidine-2,4-dione (0.22 g, 1.9 mmol) in ethanol (15 mL) and the mixture was heated to reflux overnight. After 15 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford crude mixture, which was purified by flash column chromatography (2% methanol/dichloromethane) to afford compound 7 (500 mg; 64% yield) as a yellow solid. ES-MS [M+l]+: 415.1. 1H NMR (400 MHz, DMSO-d6): δ 12.25 (br s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 8.0, 2.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.8 Hz, 2H), 4.73 (m, 1H), 4.60-4.40 (m, 4H), 4.22 (t, J = 6.2 Hz, 1H), 3.24 (s, 3H), 3.20 (t, J = 6.8 Hz, 2H), 1.41 (d, J = 6.0 Hz, 3H).[0269] (f) Synthesis of 5-(4-{2-[5-(l-hydroxy-ethyl)-pyridin-2-yl]-ethoxy}-benzyl)- thiazolidine-2,4-dione (9a): [0270] A solution of sodium borohydride (115 mg, 3.017 mmol) in 0.2N sodium hydroxide(1.2 mL) was added slowly to a stirred solution of compound 7 (0.5 g, 1.207 mmol), dimethylglyoxime (42 mg, 0.36 mmol) and C0CI2.6H2O (23 mg, 0.096 mmol) in a mixture of water (6 mL): tetrahydrofurane (6 mL) and 1M sodium hydroxide (1 mL) solution at 10°C and after addition, the reaction mixture was stirred at room temperature. After 1 h, the reaction color lightened and additional quantities of sodium borohydride (46 mg, 1.207 mmol) and C0CI2.6H2O (22 mg, 0.096 mmol) were added and stirring was continued at room temperature. After 12 h, the reaction was neutralized with acetic acid (pH~7); diluted with water (10 mL) and extracted in ethyl acetate (3×50 mL). The combined organic extract was dried over anhydrous sodium sulphate and concentrated to afford crude compound 8a, 5-(4- (2-(5-(l-(methoxymethoxy)ethyl)pyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione, (0.4 g) as pale yellow semi solid, which was taken to next step without purification. ES-MS [M+l]+: 417.5.[0271] 2N HC1 (2 mL) was added to a solution of compound 8a (0.4 g, 0.96 mmol) in methanol (20 ml) and the mixture was heated to reflux. After 4 h, the reaction mixture was cooled to room temperature and then concentrated under reduced pressure to afford a residue which was dissolved in water and the solution was neutralized using sodium bicarbonate solution (sat). The resulting white precipitate was collected by filtration to afford compound 9a (250 mg; 56% yield over 2 steps) as an off-white solid. ES-MS [M+l]+: 373.4. 1H NMR (400 MHz, DMSO-de): δ 12.00 (br s, -NH), 8.46 (d, J = 2.0 Hz, 1H), 7.66 (dd, J = 8.0, 2.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.25 (d, J = 4.4 Hz, 1H), 4.86 (m, 1H), 4.75 (m, 1H), 4.30 (t, J = 6.8 Hz, 2H), 3.30 (m, 1H), 3.14 (t, J = 6.4 Hz, 2H), 3.04 (m, 1H), 1.34 (d, J = 6.4 Hz, 3H).[0272] The overall yield of compound 9a was 1.5% molar.EXAMPLE 2Synthesis of 2-(5-(l-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)ethan-l-ol[0273] The synthesis of 2-(5-(l-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)ethan-l-ol was conducted according to the Scheme 5 using the reagents and solvents listed in Table 1 below: Scheme 5TBDMS-CI OTBDMS 1 . n-BuLi, <-55°C OTBDMSImidazole
DMF
[0274] The 1H-NMR spectra were recorded with Agilent MercuryPlus 300 NMR spectrometer.[0275] LC-MS data were obtained on an Agilent 1290 series with UV detector and HP 6130MSD mass detector using as column Waters XB ridge BEH XP (2.1 x 50 mm; 2.5 μιτι) and as eluent Ammonium acetate (10 mM); Water/ Methanol/ Acetonitrile.[0276] (a) l-(6-bromopyridin-3-yl)ethan-l-ol (2)[0277] A 20 L vessel was placed under nitrogen atmosphere and charged with tetrahydrofuran (5.5 L) and 2,5-dibromopyridine (1) (2000 g, 8.44 mol, 1.0 eq) (OxChem Corporation). The mixture was cooled to -10°C and isopropyl magnesium chloride (20% in THF, 6.02 L, 11.82 mol, 1.4 eq) (Rockwood Lithium) was added slowly over 1 h, keeping the reaction temperature below 5°C. After addition, the cooling bath was removed and the temperature was kept below 30°C (some additional cooling was needed to achieve this) and the reaction mixture was stirred overnight. After 16 h, a sample was taken; quenched with saturated aqueous ammonium chloride and extracted with methyl tert-buty\ ether (TBME). The TBME was evaporated under vacuum. 1H-NMR in deuterated chloroform showed complete conversion.[0278] The reaction mixture was cooled to -15°C and a solution of acetaldehyde (472 g,10.72 mol, 1.27 eq) (Acros) in tetrahydrofuran (200 mL) was added dropwise, while keeping temperature below -10°C. After the addition was complete, the cooling bath was removed and the temperature was allowed to rise to maximum of 5-8°C. After 1.5 h, a sample was taken and the reaction was quenched with aqueous ammonium chloride as described above. 1H-NMR showed the reaction was complete.[0279] Two batches were combined for work up.[0280] The reaction mixture was quenched by pouring the mixture into a solution of aqueous ammonium chloride (1 kg in 5 L water) and stirred for 15 min, filtered over Celite and rinsed thoroughly with toluene. The filtrate was transferred to a separation funnel and the obtained two layers system was separated. The aqueous layer was extracted with toluene (2 L). The combined organic layers were dried over sodium sulfate and filtered. Evaporation of the filtrate to dryness under vacuum yielded 3.49 kg (99%) of the desired crude material. XH NMR (300 MHz, CDC13): δ 8.30 (d, J = 2.5 Hz, 1H), 7.59 (dd, J = 8.0, 2.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 4,91 (q, J = 6.5 Hz, 1H), 1.49 (d, J = 6.5 Hz, 3H).[0281] (b) 2-bromo-5-(l-((tert-butyldimethylsilyl)oxy)ethyl)pyridine (3)[0282] A 50 L reactor under nitrogen atmosphere was charged with compound 2 (10.0 kg, around 49.5 mol) and DMF (16 L). The mixture was cooled to 10°C and imidazole (6.74 kg, 99 mol, 2.0 eq) (Apollo Scientific Ltd.) was added portion wise within 30 min. The mixture was cooled to 0°C and TBDMS-Cl (7.46 kg, 49.5 mol, 1.0 eq) (Fluorochem) was added portion wise within 5 h, keeping the temperature below 3°C. The mixture reaction temperature was allowed to reach room temperature and stirred overnig ht. H NMR of a sample showed complete conversion.[0283] The reaction mixture was transferred to a 100 L extraction-vessel and the product was extracted with heptane (2×7.5 L, 10 L). The combined heptane-layers were washed with water (2×6 L, 3 L) to remove small amounts of DMF, dried over sodium sulfate and evaporated under vacuum to give crude compound 3 (15.5 kg, 49.0 mol) in a 99.0% yield. This crude product was purified by a short plug filtration, using 10 kg silica/heptane and eluted with heptane (approx. 50 L). The product-fractions were combined and evaporated under vacuum to give 12.0 kg of purified compound 3 (38 mol) as a brown oil in a 76.8% molar yield. (Average yield for 3 experiments was 78%). HPLC-MS: Rt= 2.6 min, M+l=316.1 and 318.1; 1H NMR (300 MHz, CDC13): δ 8.55 (d, J = 2.2 Hz, 1H), 7.54 (dd, J = 8.2, 2.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 4,86 (q, J = 6.5 Hz, 1H), 1.40 (d, J = 6.5 Hz, 3H), 0.88 (s, 9H), 0.02 (d, J = 26 Hz, 2x3H).[0284] (c) 2-(5-(l-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)ethan-l-ol (4)[0285] The ethylene oxide solution in diethylether was prepared in advance. Diethylether(1.2 L) in a 3 L three-necked flask was cooled at -65 °C and ethylene oxide (462.3 g, 10.5 mol, 1.06 eq) (Linde) was added and stirred at -70°C. Alternatively, the ethylene oxide solution can be made at about -20°C and then added gradually to the reaction mixture having a temperature at about -60°C. [0286] To a solution of 2-bromo-5-(l-((ieri-butyldimethylsilyl)oxy)ethyl)pyridine (3) (3.13 kg, 9.90 mol, 1.0 eq) in diethylether (7.5 L) cooled at -59°C, n-butyllithium (4 L, 10.0 mol, 2.5M in hexanes, 1.01 eq) (Aldrich Chemistry) was added while keeping temperature between -58°C and -62°C. After addition, the mixture was stirred for 1 h while keeping temperature between -60°C and -68°C. The upfront prepared ethylene oxide solution was added at once to the reaction mixture, while temperature was around -62°C. Subsequently, copper(I) iodide (962.3 g, 5.05 mol, 0.51 eq) (Acros Organics) was added in portions of 120 g, every 10 min, keeping the temperature between -61°C and -63°C. Stirring was continued for 1 h after addition keeping temperature between -61°C and -63°C. The cooling bath was removed and allowing the temperature to rise to about 15°C and further to 25 °C with a water bath overnight.[0287] Workup: The reaction-mixture was poured into a solution of 1 kg ammonium- chloride in 5 L water and stirred for 30 min, then the layers were separated. The organic layer was washed with aqueous ammonium hydroxide (10%, 2.5 L, 4x) to remove Cu-complex (blue color disappeared). The combined organic layers were dried over sodium sulfate and evaporated to give 3.12 kg (max. 9.90 mol) crude compound 4 as a brown oil. The crude compound was purified over 20 kg silica (heptane/EtOAc) by eluting with 80 L heptane/EtOAc, 20 L EtOAc, 25 L EtOAc/MeOH 95/5, 25 L EtOAc/MeOH 9/1 and 10 L EtOAc/MeOH 8/2, to give 1.47 kg of purified compound 4 (5.22 mol) as a brown oil (with tendency to solidify) in a 52.7% average molar yield (HPLC-purity of 99.5%). (Average yield over 12 experiments 52%). HPLC-MS: Rt= 2.3 min, M+l=282.1; 1H NMR (300 MHz, CDC13): δ 8.42 (d, J = 2.1 Hz, 1H), 7.61 (dd, J = 8.3, 2.1 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 4,88 (q, J = 7.0 Hz, 1H), 4.01 (t, J=6.0 Hz, 2 H), 3.00 (t, J=6.0 Hz, 2 H), 1.41 (d, J =7.0 Hz, 3H), 0.90 (s, 9H), 0.02 (d, J = 26 Hz, 2x3H).[0288] Another 2.5% of the product was isolated by re -purifying impure product fraction.The total yield of compound 4 from compound 1 was 39.6% molar.EXAMPLE 3Synthesis of 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]- 2,4-thiazolidinedione hydrochloride (9) 2. Sodium bisulfiteethanol/water mixture
3. Addition 10% aqueous sodium hydroxide solution
until pH 12
from step e dimethylglyoxime7step g step f
step h[0289] The 1H-NMR spectra were recorded with a 400 MHz Avance Bruker NMR spectrometer. LC-MS data were obtained on a Agilent Technologies 6130 Quadrapole LC/MS using as column Agilent XDB-C18 and as eluent 0.1% formic acid (aq) and 0.05% formic acid in acetonitrile.[0290] Steps d and e: Synthesis of 4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]ethyl]-2- pyridinyl] ethoxy] -benzaldehyde (6)[0291] To a well stirred solution of 5-[[[(l,l-dimethylethyl)dimethylsilyl]-oxy]ethyl]-2- pyridineethanol (4) (obtained as described in Example 2) (1.91 kg) in toluene (8.6 L) at 5°C were added sodium hydroxide (30% aqueous, 2.79 L) and tetrabutylammonium bromide (7.2 g). p-Toluenesulfonyl chloride (1.62 kg) was next added in portions during 5 min. After the addition, the reaction mixture was allowed to reach room temperature in 0.5 h and stirred at this temperature for 18 h. Water (7.3 L) was then added and the mixture was mixed well. Once the solids were dissolved, the layers were allowed to settle and the organic layer was separated. This organic phase was washed with water (5.7 L, 2x), followed by washing with a solution of sodium chloride (57 g) in water (5.7 L). The solvents were concentrated at reduced pressure to an amount of 2.5 kg of a brown oil (compound 5).[0292] To this well stirred brown oil were added subsequently ethanol (7.8 L), water (0.86L), 4-hydroxybenzaldehyde (0.88 kg) and potassium carbonate (1.17 kg) and then the mixture was heated at 75 °C for 18 h. Then, the solvent was evaporated while adding toluene (7.7 L) during 6 h and then the reaction mixture was allowed to cool. At 30°C, water (7.6 L) was added, stirred until all solids were dissolved and the mixture was cooled to room temperature. The layers were allowed to settle and separated. The organic layer was washed with water (7.6 L). The first aqueous extract was extracted with toluene (2.8 L) and this organic extract was used to also extract the aqueous washing. The organic extracts were combined and concentrated under vacuum to give 3.49 kg of a black oil (crude title compound 6).[0293] 1.73 kg of this black oil was dissolved in ethanol (0.74 L) and added to a well stirred solution of sodium bisulfite (1.36 kg) in a mixture of water (3.27 L) and ethanol (0.74 L). The container of the black oil was rinsed with ethanol (0.37 L) twice and these two rinses were also added to the bisulfite reaction mixture. After 75 min, heptane (5.3 L) was added, well mixed for 5 min, and the layers were allowed to settle and separated. To the organic layer was added a solution of sodium bisulfite (0.55 kg) in water (2.65 L), and ethanol (1.06 L). After stirring for 30 min, the layers were allowed to settle and separated. The two bisulfide aqueous extracts were combined and flasks rinsed with water (2.12 L). Next, toluene (4.5 L) and heptane (4.5 L) were added, the mixture was well stirred and the pH was adjusted to 12 using sodium hydroxide (10% aq) (temperature became 32°C). After stirring for an additional 5 min, the layers were allowed to settle and separated at 30°C. The aqueous layer was extracted with a mixture of toluene (1.5 L) and heptane (3.0 L). The layers were separated and the organic layers were combined. The combined organic layers were washed with water (5 L, 2x) and concentrated under vacuum to give the purified title compound 6. This procedure was repeated with another 1.73 kg of the black oil (crude title compound 6) to give in total 2.77 kg of 4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]ethyl]-2- pyridinyl]ethoxy]-benzaldehyde (6) as brown oil which contained 24% m/m of toluene according to 1H NMR (yield = 80%, calculated from compound 4 and corrected for residual toluene). [0294] 1H NMR (CDC13) δ: 0.00 (s, 3H), 0.09 (s, 3H), 0.91 (s, 9H), 1.44 (d, = 6 Hz, 3H),3.30 (t, = 7 Hz, 2H), 4.47 (t, = 7 Hz, 2H), 4.92 (q, = 6 Hz, 1H), 6.99 – 7.30 (m, 3H), 7.62- 7.67 (m, 1H), 7.80 – 7.85 (m, 2H), 8.5- 8.54 (m, 1H) and 9.88 (s, 1H).[0295] LC-MS; rt 7.5 min: ES: M+ 387, 386.[0296] Step f: Synthesis of (5Z)-5-[[4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methylene]-2,4-thiazolidinedione (7)[0297] A solution of 4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]- ethoxy]-benzaldehyde (6) (2.75 kg, containing 24% m/m of toluene) and piperidine (6.0 g) in methanol (3.16 L) was concentrated at 40°C under reduced pressure. The residue was dissolved in methanol (10.4 L) and 2,4-thiazolidinedione (759 g) and piperidine (230 g) were added. The mixture was heated at 47°C. After 25 h, the reaction mixture was allowed to cool to room temperature. The mixture was kept at pH 5-6 by adjusting it with acetic acid, if necessary. After a night at room temperature, water (1.56 L) was added and the suspension was stirred at room temperature for additional 2 h. The solids were isolated by filtration, washed with methanol (1 L, 2x) and dried under vacuum to give crude compound 7 (1.65 kg). The crude compound was mixed with methanol (10 L) and dichloromethane (8.6 L) and heated at 32°C until all solids dissolved. Then, the solvents were removed by distillation until the temperature of the mixture reached 34°C at a pressure of 333 mbar. Then, it was allowed to cool to room temperature overnight and stirred at 2°C for additional 2 h. The solids were isolated by filtration, washed with methanol (0.5 L, 2x) and dried under vacuum to give title compound 7 (1.50 kg) (yield = 61%).[0298] 1H NMR (CDCI3) δ 0.00 (s, 3H), 0.08 (s, 3H), 0.90 (s, 9H), 1.43 (d, = 6 Hz, 3H),3.32 (t, = 7 Hz, 2H), 4.48 (t, = 7 Hz, 2H), 4.92 (q, = 6 Hz, 1H), 6.95 – 7.00 (m, 2H), 7.24 – 7,28 (m, 1H), 7.38 – 7.42 (m, 2H), 7.67 (s, 1H), 7.69 – 7.73 (m, 1H) and 8.48 (d, = 3 Hz, 1H).[0299] LC-MS; rt 7.5 min: ES: M+ 487, 486, 485.[0300] Step g: Synthesis of 5-[[4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]ethyl]-2- pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione (8)[0301] To a stirred suspension of (5Z)-5-[[4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]- ethyl]-2-pyridinyl]ethoxy]phenyl]methylene]-2,4-thiazolidinedione (7) (10 g) in THF (10 mL) and sodium hydroxide (IN aq, 21 mL) was added of a solution of cobalt chloride (26 mg) and of dimethylglyoxime (930 mg) in THF (2.3 mL) and water (1.0 mL). Then the suspension was put under a nitrogen atmosphere by applying the sequence of vacuum and flushing with nitrogen (4x). Thereafter, the suspension was heated to 30°C. Then, a stock solution of sodium borohydride was prepared by dissolving sodium borohydride (2.7 g) in a mixture of water (15.8 mL) and a solution of sodium hydroxide (1 N aq, 3.5 mL), which was put under a nitrogen atmosphere by applying a sequence of vacuum and flushing with nitrogen (3x). This was added to the suspension of compound 7 at a rate of 4.5 mL/h. Simultaneously, nitrogen gas-saturated acetic acid was added to the suspension at a rate of 0.7 mL/h to maintain a pH of 10.0-10.5. After 1 h 30 min the rate of addition of the sodium borohydride solution and acetic acid were both reduced by half. Next, 3 h 45 min after start of addition, the addition of sodium borohydride and acetic acid were stopped. The mixture was allowed to cool down to room temperature and acetone (2.5 mL) was added over a period of 1 minute. After stirring the reaction mixture for 15 min acetic acid was added until the pH was 5.5-6.0 (about 3 mL required). Next, a mixture of ethyl acetate/toluene (1/3 v/v, 30 mL) was added, well mixed and layers were allowed to settle. The aqueous layer was separated and washed with ethyl acetate/toluene (1/3 v/v, 10 mL). Both organic extracts were pooled and water (40 mL) was added, well mixed and layers were allowed to settle. The pH of the aqueous layer was adjusted to 5.5-6 using saturated sodium hydrogen carbonate solution (aq) and again mixed with the organic layer. Layers were allowed to settle and the organic layer was separated and concentrated under vacuum to give 11.09 g of yellow oil (crude mixture containing title compound 8 and its borane complex). Several batches were combined for work up.33.1 g of the crude mixture containing title compound 8 and its borane complex (not corrected for residual solvents) was dissolved in toluene (30 mL) and filtered. The filtrate was submitted to column chromatography (silica gel, gradient of toluene to toluene/ethyl acetate 1/1) to give 30.0 g of mixture of 5-[[4-[2-[5-[[[(l,l- dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methyl]-2,4- thiazolidinedione (8) and its borane complex as a slightly yellow oil (yield = 100% from compound 4, not corrected for residual solvents). [0303] 1H NMR (CDC13) δ: -0.03 – 0.10 (m, 6H), 0.87 – 0.93 (m, 9H), 1.42 (d, / = 6 Hz, 3H),3.05-3.71 (m, 4H), 4.30 – 4.51 (m, 3H), 4.87 – 4.94 (m, 1H), 6.82 – 6.88 (m, 2H), 7.10-7.92 (m, 5H), 8.49 (d, / = 3 Hz, 0.6H) and 8.72 (brs, 0.4H).[0304] LC-MS; rt 6.8 min: ES: M+ 489, 488, 487, M“ 487, 486, 485; rt 8.1 min: ES M“ 501,500, 499, 498, 485.[0305] Step h: Synthesis of 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]- methyl]-2,4-thiazolidinedione hydrochloride (9)[0306] To a stirred solution of the mixture of (5-[[4-[2-[5-[[[(l,l-dimethylethyl)- dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione and its borane complex (8) (5.17 g) in methanol (25.2 mL) at 22°C was added hydrochloric acid (30%, 2.75 mL) in about 5 min to give a temperature rise to 28°C. This solution was heated to 40 °C. Three hours after addition, the 11 g of volatiles were removed under reduced pressure. Then, acetonitrile (40.3 mL) was added and the mixture was heated at reflux for 0.5 h. Next, the suspension was allowed to cool down to room temperature and stirred for 1 h at room temperature. Solids were isolated by filtration, washed with a mixture of acetonitrile/water (20/1 v/v, 10 mL) and with acetonitrile (10 mL) and dried under vacuum at 40 °C to give 4.00 g of white solids (crude 9) (yield = 77%, not corrected for residual solvents).[0307] Purification of 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4- thiazolidinedione hydrochloride (9):[0308] The crude mixture of 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]- methyl]-2,4-thiazolidinedione hydrochloride (3.95 g, crude 9) was dissolved in methanol/water (7/2 v/v, 80 mL) by heating it to 49°C. To this solution was added washed norit (obtained by heating a suspension of norit (6 g) in methanol/water (7/2 v/v, 90 mL) at 45°C for 1 h, then isolating the norit by filtration and washing it twice with methanol/water (7/2 v/v, 30 mL) and drying it under vacuum at 40°C). Equipment was rinsed with methanol/water (7/2 v/v, 18 mL). After 0.5 h of stirring at 46°C, the warm suspension was filtered to remove the norit and filter was washed twice with methanol/water (7/2 v/v, 18 mL). The filtrate was concentrated under vacuum at a bath temperature of 60°C to a mass of 11.8 g (1 v of compound and 2 v of water). To the suspension was added butanone (19.7 mL, 5 v) and the mixture was heated at a bath temperature of 95°C. Under distillation at a constant volume, butanone (95 mL) was added. Next, heating was stopped and the suspension was allowed to reach room temperature in about 0.5 h. Subsequently it was stirred for 0.75 h at room temperature. The solids were isolated by filtration, washed with a mixture of butanone/water (95/5 v/v, 18 mL) and butanone (18 mL) and dried under vacuum at 40°C to give 3.57 g of compound 9 as white solids (yield = 91%).[0309] 1H NMR (DMSO-de): δ 12.00 (br s, -NH), 8.71 (d, = 2.0 Hz, 1H), 8.45 (dd, = 8.3,1.7 Hz, 1H), 7.98 (d, = 8.3 Hz, 1H), 7.15 (d, = 8.7 Hz, 2H), 6.88 (d, = 8.7 Hz, 2H), 5.57 (s, OH), 4.95 (q, = 6.5 Hz, 1H), 4.86 (dd, = 8.9, 4.4 Hz, 1H), 4.40 (t, = 6.3 Hz, 2H), 3.49 (t, = 6.2 Hz, 2H), 3.29 (dd, = 14.2, 4.4 Hz, 1H), 3.06 (dd, = 14.2, 9.0 Hz, 1H), 1.41 (d, = 6.5 Hz, 3H).[0310] LC-MS; rt 3.5 min: ES: M+ 374, 373, M“ 372, 371.EXAMPLE 4Conditions tested in the preparation of compound 5 in the Step d[0311] The conditions described in Table 2 below were tested in the step d in the preparation of compound 5 from compound 4 providing a good yield of compound 5:Table 2Entry Reaction Conditions Amount of p-Ts-Cl / Eq1 Toluene/water/Bu4NBr/NaOH 1.052 1.083 1.074 1.07+0.035 1.076 Et3N / DCM 1.187 1.408 Pyridine / DCM 1.40 EXAMPLE 5Conditions tested in the preparation of compound 6 in the Step e[0312] The conditions described in Table 3 below were tested in the step e in the preparation of compound 6 from compound 5 providing a good yield of compound 6:Table 3
PATENT
Compound 1 is administered to the subject. The structure of 5-[[4-[2-[5-(l -hydroxy ethyljpyri din-2 – yl]ethoxy]phenyl]methyl]-l,3-thiazolidine-2,4-dione is:
[0047] The present disclosure encompasses the use of stereoisomers of 5-[[4-[2-[5-(l- hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-l,3-thiazolidine-2,4-dione. 5-[[4-[2-[5- (l-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-l,3-thiazolidine-2,4-dione has two asymmetric centers and thus four stereoisomers are possible as follows:
//////////LERIGLITAZONE, MIN 102 , лериглитазон , ليريغليتازون , 乐立格列酮 , Hydroxy Pioglitazone, M-IV, PHASE 2
CC(C1=CN=C(C=C1)CCOC2=CC=C(C=C2)CC3C(=O)NC(=O)S3)O
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